Challenging the current approaches to multiple myeloma- and other cancer-related bone diseases: from bisphosphonates to targeted therapy.

PubMed

Kleber, Martina; Udi, Josefina; Metzke, Barbara; Terpos, Evangelos; Roodmann, G David; Morgan, Gareth; Dispenzieri, Angela; Einsele, Hermann; Wäsch, Ralph; Engelhardt, Monika

2012-06-01

An international myeloma meeting entitled "Challenging the current approaches to multiple myeloma- and other cancer-related bone diseases: from bisphosphonates to targeted therapy" was held in Freiburg, Germany in July 2011 to discuss novel insights into and approaches to myeloma bone disease and other bone-seeking tumors. This review briefly summarizes the most prominent data of the meeting and current literature on our understanding of bone disease, the role of imaging techniques, operative interventions and systemic bone-seeking treatment, all of which should further improve our future therapeutic choices.

Bone tumor location in dogs given skeletal irradiation by {sup 239}Pu or {sup 226}Ra

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lloyd, R.D.; Taylor, G.N.; Miller, S.C.

1997-10-01

Statistical analyses have indicated that there was a significant difference between dogs injected with bone volume-seeking {sup 226} Ra as compared to those given bone surface-seeking {sup 239}Pu with respect to location within the skeleton of 334 radiation-induced primary bone malignancies. Corresponding differences also were event when dogs given bone volume-seeking {sup 90}Sr or bone surface-seeking {sup 241}Am, {sup 228}Th {sup 248,252}Cf, or {sup 224}Ra (which decays mostly on bone surfaces because of its short, 3.6 d half time) were included along with the {sup 226}Ra or {sup 239}Pu, respectively (562 total tumors). Further analysis suggested that higher values ofmore » percent red marrow (M) and bone turnover rate (R) are correlated with increased probability. of tumor appearance at a particular location within the skeleton for the surface seekers. Proportionately higher values of M and R are associated with skeletal sites containing mostly trabecular bone as compared to those with mostly compact (cortical) bone. Coefficients of determination (r{sup 2}) for the relationship between percent of total tumors vs the combination of percent red marrow and turnover rate (= MR) was about 0.7 for the surface seekers but only about 0.1 for the volume seekers. This indicates that the neoplastic effects of surface seekers, but not volume seekers, are associated with the presence of trabecular bone at the various sites of radio nuclide deposition within the skeleton. 10 refs., 3 tabs.« less

Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guerra Liberal, Francisco D. C., E-mail: meb12020@fe.up.pt, E-mail: adriana-tavares@msn.com; Tavares, Adriana Alexandre S., E-mail: meb12020@fe.up.pt, E-mail: adriana-tavares@msn.com; Tavares, João Manuel R. S., E-mail: tavares@fe.up.pt

Purpose: Throughout the years, the palliative treatment of bone metastases using bone seeking radiotracers has been part of the therapeutic resources used in oncology, but the choice of which bone seeking agent to use is not consensual across sites and limited data are available comparing the characteristics of each radioisotope. Computational simulation is a simple and practical method to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aims to evaluate and compare 11 different radioisotopes currently in use or under research for the palliative treatment of bonemore » metastases using computational methods. Methods: Computational models were used to estimate the percentage of deoxyribonucleic acid (DNA) damage (fast Monte Carlo damage algorithm), the probability of correct DNA repair (Monte Carlo excision repair algorithm), and the radiation-induced cellular effects (virtual cell radiobiology algorithm) post-irradiation with selected particles emitted by phosphorus-32 ({sup 32}P), strontium-89 ({sup 89}Sr), yttrium-90 ({sup 90}Y ), tin-117 ({sup 117m}Sn), samarium-153 ({sup 153}Sm), holmium-166 ({sup 166}Ho), thulium-170 ({sup 170}Tm), lutetium-177 ({sup 177}Lu), rhenium-186 ({sup 186}Re), rhenium-188 ({sup 188}Re), and radium-223 ({sup 223}Ra). Results: {sup 223}Ra alpha particles, {sup 177}Lu beta minus particles, and {sup 170}Tm beta minus particles induced the highest cell death of all investigated particles and radioisotopes. The cell survival fraction measured post-irradiation with beta minus particles emitted by {sup 89}Sr and {sup 153}Sm, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice, was higher than {sup 177}Lu beta minus particles and {sup 223}Ra alpha particles. Conclusions: {sup 223}Ra and {sup 177}Lu hold the highest potential for palliative treatment of bone metastases of all radioisotopes compared in this study. Data reported here may prompt future in vitro and in vivo experiments comparing different radionuclides for palliative treatment of bone metastases, raise the need for the careful rethinking of the current widespread clinical use of {sup 89}Sr and {sup 153}Sm, and perhaps strengthen the use of {sup 223}Ra and {sup 177}Lu in the palliative treatment of bone metastases.« less

Pharmacological management of osteogenesis

PubMed Central

Nardone, Valeria; D'Asta, Federica; Brandi, Maria Luisa

2014-01-01

Osteogenesis and bone remodeling are complex biological processes that are essential for the formation of new bone tissue and its correct functioning. When the balance between bone resorption and formation is disrupted, bone diseases and disorders such as Paget's disease, fibrous dysplasia, osteoporosis and fragility fractures may result. Recent advances in bone cell biology have revealed new specific targets for the treatment of bone loss that are based on the inhibition of bone resorption by osteoclasts or the stimulation of bone formation by osteoblasts. Bisphosphonates, antiresorptive agents that reduce bone resorption, are usually recommended as first-line therapy in women with postmenopausal osteoporosis. Numerous studies have shown that bisphosphonates are able to significantly reduce the risk of femoral and vertebral fractures. Other antiresorptive agents indicated for the treatment of osteoporosis include selective estrogen receptor modulators, such as raloxifene. Denosumab, a human monoclonal antibody, is another antiresorptive agent that has been approved in Europe and the USA. This agent blocks the RANK/RANKL/OPG system, which is responsible for osteoclastic activation, thus reducing bone resorption. Other approved agents include bone anabolic agents, such as teriparatide, a recombinant parathyroid hormone that improves bone microarchitecture and strength, and strontium ranelate, considered to be a dual-action drug that acts by both osteoclastic inhibition and osteoblastic stimulation. Currently, anti-catabolic drugs that act through the Wnt-β catenin signaling pathway, serving as Dickkopf-related protein 1 inhibitors and sclerostin antagonists, are also in development. This concise review provides an overview of the drugs most commonly used for the control of osteogenesis in bone diseases. PMID:24964310

Cardiotonic agent milrinone stimulates resorption in rodent bone organ culture.

PubMed Central

Krieger, N S; Stappenbeck, T S; Stern, P H

1987-01-01

The cardiotonic agent amrinone inhibits bone resorption in vitro. Milrinone, an amrinone analog, is a more potent cardiotonic agent with lower toxicity. In contrast to amrinone, milrinone stimulated resorption in cultures of neonatal mouse calvaria and fetal rat limb bones. Threshold doses were 0.1 microM in calvaria and 0.1 mM in limb bones; maximal stimulation occurred in calvaria at 0.1 mM. Maximal responses to milrinone and parathyroid hormone were comparable. Milrinone concentrations below 0.1 mM did not affect calvarial cyclic AMP. 0.5 microM indomethacin inhibited milrinone effects in calvaria but usually not in limb bones. 3 nM calcitonin inhibited milrinone-stimulated resorption and there was no escape from this inhibition. Structural homology between milrinone and thyroxine has been reported. We find similarities between milrinone and thyroxine actions on bone, because prostaglandin production was crucial for the effects of both agents in calvaria but not in limb bones, and neither agent exhibited escape from calcitonin inhibition. PMID:3027124

Pharmacotherapy of bone metastases in breast cancer patients.

PubMed

Petrut, Bianca; Simmons, Christine; Broom, Reuben; Trinkaus, Mateya; Clemons, Mark

2008-04-01

A diagnosis of bone metastases is often a devastating occurrence in breast cancer patients. Bone metastases are associated with increased morbidity as reflected through pain, reduced quality of life and skeletal-related events. This paper reviews the role of different pharmacotherapeutic agents in the treatment of bone metastases from breast cancer. Randomised controlled trials of osteoclast-inhibiting agents, that is the bisphosphonates, have shown significant patient benefit. The aims of bisphosphonates are to prevent and delay skeletal-related events, reduce bone pain and improve quality of life. However, there are some limitations with bisphosphonate treatment. Biochemical markers of bone turnover seem to be a promising tool in guiding bisphosphonate treatment and future research directions. Hopefully, patient management will be further improved as new agents become available such as denosumab, osteoprotegerin analogues and anti-angiogenic agents.

A new adhesive technique for internal fixation in midfacial surgery

PubMed Central

Endres, Kira; Marx, Rudolf; Tinschert, Joachim; Wirtz, Dieter Christian; Stoll, Christian; Riediger, Dieter; Smeets, Ralf

2008-01-01

Background The current surgical therapy of midfacial fractures involves internal fixation in which bone fragments are fixed in their anatomical positions with osteosynthesis plates and corresponding screws until bone healing is complete. This often causes new fractures to fragile bones while drilling pilot holes or trying to insert screws. The adhesive fixation of osteosynthesis plates using PMMA bone cement could offer a viable alternative for fixing the plates without screws. In order to achieve the adhesive bonding of bone cement to cortical bone in the viscerocranium, an amphiphilic bone bonding agent was created, analogous to the dentin bonding agents currently on the market. Methods The adhesive bonding strengths were measured using tension tests. For this, metal plates with 2.0 mm diameter screw holes were cemented with PMMA bone cement to cortical bovine bone samples from the femur diaphysis. The bone was conditioned with an amphiphilic bone bonding agent prior to cementing. The samples were stored for 1 to 42 days at 37 degrees C, either moist or completely submerged in an isotonic NaCl-solution, and then subjected to the tension tests. Results Without the bone bonding agent, the bonding strength was close to zero (0.2 MPa). Primary stability with bone bonding agent is considered to be at ca. 8 MPa. Moist storage over 42 days resulted in decreased adhesion forces of ca. 6 MPa. Wet storage resulted in relatively constant bonding strengths of ca. 8 MPa. Conclusion A new amphiphilic bone bonding agent was developed, which builds an optimizied interlayer between the hydrophilic bone surface and the hydrophobic PMMA bone cement and thus leads to adhesive bonding between them. Our in vitro investigations demonstrated the adhesive bonding of PMMA bone cement to cortical bone, which was also stable against hydrolysis. The newly developed adhesive fixing technique could be applied clinically when the fixation of osteosynthesis plates with screws is impossible. With the detected adhesion forces of ca. 6 to 8 MPa, it is assumed that the adhesive fixation system is able to secure bone fragments from the non-load bearing midfacial regions in their orthotopic positions until fracture consolidation is complete. PMID:18489785

Anabolic agents and bone quality.

PubMed

Sibai, Tarek; Morgan, Elise F; Einhorn, Thomas A

2011-08-01

The definition of bone quality is evolving particularly from the perspective of anabolic agents that can enhance not only bone mineral density but also bone microarchitecture, composition, morphology, amount of microdamage, and remodeling dynamics. This review summarizes the molecular pathways and physiologic effects of current and potential anabolic drugs. From a MEDLINE search (1996-2010), articles were identified by the search terms "bone quality" (1851 articles), "anabolic agent" (5044 articles), "PTH or parathyroid hormone" (32,229 articles), "strontium" or "strontium ranelate" (283 articles), "prostaglandin" (77,539 articles), and "statin" or "statins" (14,233 articles). The search strategy included combining each with the phrase "bone quality." Another more limited search aimed at finding more novel potential agents. Parathyroid hormone is the only US Food and Drug Administration-approved bone anabolic agent in the United States and has been the most extensively studied in in vitro animal and human trials. Strontium ranelate is approved in Europe but has not undergone Food and Drug Administration trials in the United States. All the studies on prostaglandin agonists have used in vivo animal models and there are no human trials examining prostaglandin agonist effects. The advantages of statins include the long-established advantages and safety profile, but they are limited by their bioavailability in bone. Other potential pathways include proline-rich tyrosine kinase 2 (PYK2) and sclerostin (SOST) inhibition, among others. The ongoing research to enhance the anabolic potential of current agents, identify new agents, and develop better delivery systems will greatly enhance the management of bone quality-related injuries and diseases in the future.

Seeking: Accurate Measurement Techniques for Deep-Bone Density and Structure

NASA Technical Reports Server (NTRS)

Sibonga, Jean

2009-01-01

We are seeking a clinically-useful technology with enough sensitivity to assess the microstructure of "spongy" bone that is found in the marrow cavities of whole bones. However, this technology must be for skeletal sites surrounded by layers of soft tissues, such as the spine and the hip. Soft tissue interferes with conventional imaging and using a more accessible area -- for example, the wrist or the ankle of limbs-- as a proxy for the less accessible skeletal regions, will not be accurate. A non-radioactive technology is strongly preferred.

The biological effects of tocotrienol on bone: a review on evidence from rodent models.

PubMed

Chin, Kok-Yong; Ima-Nirwana, Soelaiman

2015-01-01

Osteoporosis causes significant health care and economic burden to society, leading to a relentless search for effective preventive agents. Tocotrienol, a member of the vitamin E family, has demonstrated promising potential as an osteoporosis-preventing agent. This review summarizes evidence on the effects of tocotrienol on bone in animal models. Techniques used to examine the effects of tocotrienol on bone in animals included bone histomorphometry, X-ray microtomography, dual-energy X-ray absorptiometry, bone turnover markers, bone calcium content, and biomechanical strength. Tocotrienol was shown to improve osteoblast number, bone formation, mineral deposition, and bone microarchitecture in osteopenic rats. It also decreased osteoclast number and bone erosion in the rats. Tocotrienol supplementation resulted in an improvement in bone mineral density, although biomechanical strength was not significantly altered in the rats. The beneficial effects of tocotrienol on bone can be attributed to its role as an antioxidant, anti-inflammatory agent, suppressor of the mevalonate pathway, and modulator of genes favorable to bone formation.

The biological effects of tocotrienol on bone: a review on evidence from rodent models

PubMed Central

Chin, Kok-Yong; Ima-Nirwana, Soelaiman

2015-01-01

Osteoporosis causes significant health care and economic burden to society, leading to a relentless search for effective preventive agents. Tocotrienol, a member of the vitamin E family, has demonstrated promising potential as an osteoporosis-preventing agent. This review summarizes evidence on the effects of tocotrienol on bone in animal models. Techniques used to examine the effects of tocotrienol on bone in animals included bone histomorphometry, X-ray microtomography, dual-energy X-ray absorptiometry, bone turnover markers, bone calcium content, and biomechanical strength. Tocotrienol was shown to improve osteoblast number, bone formation, mineral deposition, and bone microarchitecture in osteopenic rats. It also decreased osteoclast number and bone erosion in the rats. Tocotrienol supplementation resulted in an improvement in bone mineral density, although biomechanical strength was not significantly altered in the rats. The beneficial effects of tocotrienol on bone can be attributed to its role as an antioxidant, anti-inflammatory agent, suppressor of the mevalonate pathway, and modulator of genes favorable to bone formation. PMID:25897211

[Regional blood flow and bone uptake of methylene-diphosphonate-technetium-99m].

PubMed

Vattimo, A; Martini, G; Pisani, M

1983-05-30

Sudeck's atrophy of the foot is an acute, patchy osteoporosis that, on bone scan, shows an increase in both bone blood flow and local bone uptake of bone-seeking radionuclides. The purpose of this study was to evaluate the relationship between bone uptake of 99mTc-MDP and local bone blood flow. In some patients with Sudeck's atrophy of one foot we measured local bone blood flow and bone uptake of 99mTc-MDP. External counting of radioactivity, with a count-rate of 1 second was performed for 60 minutes after i.v. injection of a known dose of 99mTc-MDP in some patients with Sudeck's atrophy of the foot. The regions of interest (ROI) were selected on the basis of a bone scan performed 24 hours earlier. We assumed that the data recorded during the first seconds (7-10) reflect local blood flow and the data at 60 minutes reflect the bone uptake. The ratio between the local blood flow in the involved and healthy foot was higher than the local bone uptake ratio. The ratio between bone uptake and local bone blood flow was higher in the normal foot than in the affected one. These results suggest that the bone avidity for bone-seeking radionuclides is lower in Sudeck's atrophy than in normal bone.

Invited review of a workshop: anabolic hormones in bone: basic research and therapeutic potential.

PubMed

Margolis, R N; Canalis, E; Partridge, N C

1996-03-01

Age-, postmenopause-, and disease-related conditions that result in low bone mass represent important public health issues. Maintenance of bone mass is a balance between bone resorption and formation and is influenced by diet, body composition, activity level, and the interactions between and among a large number of hormones, growth factors, and cytokines. Recent research has emphasized establishing a more complete understanding of the hormonal regulation of bone and developing anabolic agents with therapeutic potential for the treatment of low bone mass. The NIDDK at the NIH recently sponsored a Workshop, entitled Anabolic Hormones in Bone: Basic Research and Therapeutic Potential, that attempted to define the current state of the art knowledge of hormones, growth factors, and cytokines that affect bone mass, with particular emphasis on those that could potentially have a role as anabolic agents in bone. This review presents a condensed proceedings of that workshop along with a summary of the optimal requisites for the development of anabolic agents with therapeutic potential in bone.

Biocompatible, Biodegradable, and Enzymatic-Cleavable MRI Contrast Agents for Early Detection of Bone Metastatic Breast cancer

DTIC Science & Technology

2013-04-01

metastasis from breast cancer. The proposed imaging agent is consist of bone targeting moiety of Asp8 and MRI imaging moiety of DOTA (Gd) with a cathepsin K...the Gd chelator of DOTA . Asp8 has a high affinity for bone mineral and has been used as bone-targeting moiety in molecular therapeutics.(1-6) The use...findings in literature.(4, 7, 17) To obtain imaging agents for MRI studies, the above mentioned peptides were allowed to react with DOTA -NHS

EFFECT OF CHELATING AGENTS ON UPTAKE OF Ca$sup 45$ AND Sr$sup 85$ BY DEFATTED BONE IN VITRO

DOE Office of Scientific and Technical Information (OSTI.GOV)

Samachson, J.; Lederer, H.

The presence of chelating agents in buffered solutions affected the relative uptake of Ca/sup 45/ and Sr/sup 85/ by defatted bone powder. Strong chelating agents, like ethylenediaminetetraacetic acid and cyclohexanediaminetetraacetic acid, decreased the ratio of Ca/sup 45//Sr/sup 85/ uptake considerably in presence of Ca, Ca plus Sr, or Sr carrier. Citrate and adenosinetriphosphate had similar but weaker effects. No effect was shown by glucose, lactate, gluconate, bicarbonate, bicarbonate plus phosphate, glutamate, aspartate, borate, glycerophosphate, lysine or glutathione. Those compeunds which showed no effect had stability constants for Ca of less than 3. Strong chelating agents also decreased the relative amountmore » of Sr/sup 85/ removed from defatted bone powder by exchange. Results indicate that natural chelating agents may be partly responsible for the low Ca/sup 45//Sr/sup 85/ uptake ratio by bone from serum compared with uptake from synthetic inorganic solutions and emphasize the difficulty of removing be partly responsible for the low Ca/sup 45//Sr/sup 85/ uptske ratio by bone from serum compared with uptake from synthetic inorganic solutions and emphasize the difficulty of removing Sr/sup 35/ from bone with chelating agents now available. (auth)« less

Detection of breast cancer microcalcification using (99m)Tc-MDP SPECT or Osteosense 750EX FMT imaging.

PubMed

Felix, Dayo D; Gore, John C; Yankeelov, Thomas E; Peterson, Todd E; Barnes, Stephanie; Whisenant, Jennifer; Weis, Jared; Shoukouhi, Sepideh; Virostko, John; Nickels, Michael; McIntyre, J Oliver; Sanders, Melinda; Abramson, Vandana; Tantawy, Mohammed N

2015-03-01

In previous work, we demonstrated the presence of hydroxyapetite (type II microcalcification), HAP, in triple negative MDA-MB-231 breast cancer cells. We used (18)F-NaF to detect these types of cancers in mouse models as the free fluorine, (18)F(-), binds to HAP similar to bone uptake. In this work, we investigate other bone targeting agents and techniques including (99m)Tc-MDP SPECT and Osteosense 750EX FMT imaging as alternatives for breast cancer diagnosis via targeting HAP within the tumor microenvironment. Thirteen mice were injected subcutaneously in the right flank with 10(6) MDA-MB-231 cells. When the tumor size reached ~0.6 cm(3), mice (n=9) were injected with ~37 MBq of (99m)Tc-MDP intravenously and then imaged one hour later in a NanoSPECT/CT or injected intravenously with 4 nmol/g of Osetosense 750EX and imaged 24 hours later in an FMT (n=4). The imaging probe concentration in the tumor was compared to that of muscle. Following SPECT imaging, the tumors were harvested, sectioned into 10 μm slices, and underwent autoradiography or von Kossa staining to correlate (99m)Tc-MDP binding with HAP distribution within the tumor. The SPECT images were normalized to the injected dose and regions-of-interest (ROIs) were drawn around bone, tumor, and muscle to obtain the radiotracer concentration in these regions in units of percent injected dose per unit volume. ROIs were drawn around bone and tumor in the FMT images as no FMT signal was observed in normal muscle. Uptake of (99m)Tc-MDP was observed in the bone and tumor with little or no uptake in the muscle with concentrations of 11.34±1.46 (mean±SD), 2.22±0.95, and 0.05±0.04%ID/cc, respectively. Uptake of Osteosense 750EX was also observed in the bone and tumor with concentrations of 0.35±0.07 (mean±SD) and 0.04±0.01picomoles, respectively. No FMT signal was observed in the normal muscle. There was no significant difference in the bone-to-tumor ratio between the two modalities (5.1±2.3 for SPECT and 8.8±2.2 for FMT) indicating that there is little difference in tumor uptake between these two agents. This study provides evidence of the accessibility of HAP within the breast tumor microenvironment as an in vivo imaging target for bone-seeking agents. SPECT imaging using (99m)Tc-MDP can be rapidly translated to the clinic. FMT imaging using Osteosense 750EX is not currently approved for clinical use and is limited to animal research. Copyright © 2014 Elsevier Inc. All rights reserved.

Metastatic Bone Pain Palliation using (177)Lu-Ethylenediaminetetramethylene Phosphonic Acid.

PubMed

Alavi, Mehrosadat; Omidvari, Shapour; Mehdizadeh, Alireza; Jalilian, Amir R; Bahrami-Samani, Ali

2015-01-01

(177)Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP) is presently suggested as an excellent bone seeking radionuclide for developing metastatic bone pain (MBP) palliation agent owing to its suitable nuclear decay characteristics. To find the exact dosage and its efficiency, this clinical study was performed on the human being, using (177)Lu-EDTMP for MBP palliation. (177)Lu-EDTMP was prepared by Iran, atomic energy organization. Thirty consecutive patients with determined tumors, incontrollable MBP, and positive bone scan at 4 weeks before the beginning of the study participated in this study in the nuclear medicine ward. (177)Lu-EDTMP in the form of sterile slow IV injection was administered with a dose of 29.6 MBq/kg. Short form of brief pain inventory questionnaire was used to evaluate the efficiency of the intervention. Questionnaires were filled out by an expert nuclear physician every 2 weeks while the cell blood count was also checked every 2 weeks up to 12 weeks for evaluation of bone marrow suppression and hematological toxicity. Furthermore, whole body scan was done at days 1, 3, and 7. Twenty-five patients showed a significant pain relief since 2 weeks after the injection, and continued until the end of the follow up period (12 weeks). There were no significant early complications such as bone marrow suppression, hematological toxicity, and no systemic adverse effects. No complication was observed in renal function. Twenty one patients showed flare phenomenon that was started after the 12.2 ± 1.78 h lasting for 38.4 ± 23.08. Sixteen patients (53%) were completely treated; nine patients (30%) showed a partial response, and five patients (17%) had no response to treatment. Total response to treatment was achieved in 25 patients (83%). At the end of the evaluation, no bone marrow suppression or hematologic toxicity was observed. (177)Lu-EDTMP has shown suitable physical and biological properties with good results in long term bone pain relief for patients with bone metastasis.

Metastatic Bone Pain Palliation using 177Lu-Ethylenediaminetetramethylene Phosphonic Acid

PubMed Central

Alavi, Mehrosadat; Omidvari, Shapour; Mehdizadeh, Alireza; Jalilian, Amir R.; Bahrami-Samani, Ali

2015-01-01

177Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP) is presently suggested as an excellent bone seeking radionuclide for developing metastatic bone pain (MBP) palliation agent owing to its suitable nuclear decay characteristics. To find the exact dosage and its efficiency, this clinical study was performed on the human being, using 177Lu-EDTMP for MBP palliation. 177Lu-EDTMP was prepared by Iran, atomic energy organization. Thirty consecutive patients with determined tumors, incontrollable MBP, and positive bone scan at 4 weeks before the beginning of the study participated in this study in the nuclear medicine ward. 177Lu-EDTMP in the form of sterile slow IV injection was administered with a dose of 29.6 MBq/kg. Short form of brief pain inventory questionnaire was used to evaluate the efficiency of the intervention. Questionnaires were filled out by an expert nuclear physician every 2 weeks while the cell blood count was also checked every 2 weeks up to 12 weeks for evaluation of bone marrow suppression and hematological toxicity. Furthermore, whole body scan was done at days 1, 3, and 7. Twenty-five patients showed a significant pain relief since 2 weeks after the injection, and continued until the end of the follow up period (12 weeks). There were no significant early complications such as bone marrow suppression, hematological toxicity, and no systemic adverse effects. No complication was observed in renal function. Twenty one patients showed flare phenomenon that was started after the 12.2 ± 1.78 h lasting for 38.4 ± 23.08. Sixteen patients (53%) were completely treated; nine patients (30%) showed a partial response, and five patients (17%) had no response to treatment. Total response to treatment was achieved in 25 patients (83%). At the end of the evaluation, no bone marrow suppression or hematologic toxicity was observed. 177Lu-EDTMP has shown suitable physical and biological properties with good results in long term bone pain relief for patients with bone metastasis. PMID:26097421

Recent biological trends in management of fracture non-union

PubMed Central

Emara, Khaled M; Diab, Ramy Ahmed; Emara, Ahmed Khaled

2015-01-01

Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. Currently, there is a plethora of different strategies to augment the impaired or “insufficient” bone-regeneration process, including the “gold standard” autologous bone graft, free fibula vascularised graft, allograft implantation, and use of growth factors, osteoconductive scaffolds, osteoprogenitor cells and distraction osteogenesis. Improved “local” strategies in terms of tissue engineering and gene therapy, or even “systemic” enhancement of bone repair, are under intense investigation, in an effort to overcome the limitations of the current methods, to produce bone-graft substitutes with biomechanical properties that are as identical to normal bone as possible, to accelerate the overall regeneration process, or even to address systemic conditions, such as skeletal disorders and osteoporosis. An improved understanding of the molecular and cellular events that occur during bone repair and remodeling has led to the development of biologic agents that can augment the biological microenvironment and enhance bone repair. Orthobiologics, including stem cells, osteoinductive growth factors, osteoconductive matrices, and anabolic agents, are available clinically for accelerating fracture repair and treatment of compromised bone repair situations like delayed unions and nonunions. A lack of standardized outcome measures for comparison of biologic agents in clinical fracture repair trials, frequent off-label use, and a limited understanding of the biological activity of these agents at the bone repair site have limited their efficacy in clinical applications. PMID:26396938

Biocompatible, Biodegradable, and Enzymatic-Cleavable MRI Contrast Agents for Early Detection of Bone Metastatic Breast Cancer

DTIC Science & Technology

2012-04-01

detection of bone metastasis from breast cancer. The proposed imaging agent is consist of bone targeting moiety of Asp8 and MRI imaging moiety of DOTA ...peptide onto DOTA followed by Gd complexation was performed to achieve the proposed imaging agent. Non-targeting and CTSK-insensitive controls were...synthesis (SPPS) strategy, and purified by preparative HPLC. The chemical structures of peptides were shown below. Peptides reacted with DOTA -NHS

Uranium in bone: metabolic and autoradiographic studies in the rat.

PubMed

Priest, N D; Howells, G R; Green, D; Haines, J W

1982-03-01

The distribution and retention of intravenously injected hexavalent uranium-233 in the skeleton of the female rat has been investigated using a variety of autoradiographic and radiochemical techniques. These showed that approximately one third of the injected uranium is deposited in the skeleton where it is retained with an initial biological half-time of approximately 40 days. The studies also showed that: 1 Uranium is initially deposited onto all types of bone surface, but preferentially onto those that are accreting. 2 Uranium is deposited in the calcifying zones of skeletal cartilage. 3 Bone accretion results in the burial of surface deposits of uranium. 4 Bone resorption causes the removal of uranium from surfaces. 5 Resorbed uranium is not retained by osteoclasts and macrophages in the bone marrow. 6 Uranium removed from bone surfaces enters the bloodstream where most is either redeposited in bone or excreted via the kidneys. 7 The recycling of resorbed uranium within the skeleton tends to produce a uniform level of uranium contamination throughout mineralized bone. These results are taken to indicate that uranium deposition in bone shares characteristics in common with both the 'volume-seeking radionuclides' typified by the alkaline earth elements and with the 'bone surface-seeking radionuclides' typified by plutonium.

Skeletal scintigraphy and quantitative tracer studies in metabolic bone disease

NASA Astrophysics Data System (ADS)

Fogelman, Ignac

Bone scan imaging with the current bone seeking radiopharmaceuticals, the technetium-99m labelled diphosphonates, has dramatically improved our ability to evaluate skeletal pathology. In this thesis, chapter 1 presents a review of the history of bone scanning, summarises present concepts as to the mechanism of uptake of bone seeking agents and briefly illustrates the role of bone scanning in clinical practice. In chapter 2 the applications of bone scan imaging and quantitative tracer techniques derived from the bone scan in the detection of metabolic bone disease are discussed. Since skeletal uptake of Tc-99m diphosphonate depends upon skeletal metabolism one might expect that the bone scan would be of considerable value in the assessment of metabolic bone disease. However in these disorders the whole skeleton is often diffusely involved by the metabolic process and simple visual inspection of the scan image may not reveal the uniformly increased uptake of tracer. Certain patterns of bone scan abnormality have, however, been reported in patients with primary hyperparathyroidism and renal osteo-dystrophy; the present studies extend these observations and introduce the concept of "metabolic features" which are often recognisable in conditions with generalised increased bone turnover. As an aid to systematic recognition of these features on a given bone scan image a semi-quantitative scoring system, the metabolic index, was introduced. The metabolic index allowed differentiation between various groups of patients with metabolic disorders and a control population. In addition, in a bone scan study of patients with acromegaly, it was found that the metabolic index correlated well with disease activity as measured by serum growth hormone levels. The metabolic index was, however, found to be a relatively insensitive means of identifying disease in individual patients. Patients with increased bone turnover will have an absolute increase in skeletal uptake of tracer. As a means of quantitating this uptake the use of bone to soft-tissue ratios derived from the bone scan image by computer was critically evaluated. The technique was shown to be observer dependent and again found to be of limited value due to the large overlap of patient results with those from control subjects. In chapter 3 the use of bone scan imaging in metabolic bone disease has been compared with radiology. Despite the difficulties mentioned above the metabolic index was employed, and the bone scan found to be the more sensitive investigation in primary hyperparathyroidism, renal osteodystrophy and osteomalacia. In osteoporosis, however, the bone scan was often unable to identify disease and radiology remains the investigation of choice. In a further study comparing bone scanning and radiology in Paget's disease, the bone scan was found to be clearly the more sensitive investigation. As a result of the work described in chapter 2 it became apparent that a sensitive means of quantitating absolute bone uptake of tracer could be of diagnostic value. In chapter 4 a promising new quantitative technique is described in which the 24-hour whole-body retention of Tc-99m diphosphonate (WBR) is measured using a shadow-shield whole-body monitor. At 24 hours after injection, diphosphonate has reached a stable equilibrium in bone reflecting skeletal metabolic activity, while tracer in the soft-tissues of the body has been largely excreted via the urinary tract. It was found that this technique provided a sensitive means of detecting patients with primary hyperparathyroidism, osteomalacia, renal osteodystrophy and Paget's disease and that in these conditions all the results from individual patients lay outside the control range. In further studies the WBR technique was shown to be highly reproducible and not subject to any significant technical errors.

A Model for Assessing the Clinical and Economic Benefits of Bone-forming Agents for Reducing Fractures in Postmenopausal Women at High, Near-term Risk of Osteoporotic Fracture.

PubMed

O'Hanlon, Claire E; Parthan, Anju; Kruse, Morgan; Cartier, Shannon; Stollenwerk, Bjorn; Jiang, Yawen; Caloyeras, John P; Crittenden, Daria B; Barron, Richard

2017-07-01

The goal of this study was to assess and compare the potential clinical and economic value of emerging bone-forming agents using the only currently available agent, teriparatide, as a reference case in patients at high, near-term (imminent, 1- to 2-year) risk of osteoporotic fractures, extending to a lifetime horizon with sequenced antiresorptive agents for maintenance treatment. Analyses were performed by using a Markov cohort model accounting for time-specific fracture protection effects of bone-forming agents followed by antiresorptive treatment with denosumab. The alternative bone-forming agent profiles were defined by using assumptions regarding the onset and total magnitude of protection against fractures with teriparatide. The model cohort comprised 70-year-old female patients with T scores below -2.5 and a previous vertebral fracture. Outcomes included clinical fractures, direct costs, and quality-adjusted life years. The simulated treatment strategies were compared by calculating their incremental "value" (net monetary benefit). Improvements in the onset and magnitude of fracture protection (vs the teriparatide reference case) produced a net monetary benefit of $17,000,000 per 10,000 treated patients during the (1.5-year) bone-forming agent treatment period and $80,000,000 over a lifetime horizon that included 3.5 years of maintenance treatment with denosumab. Incorporating time-specific fracture effects in the Markov cohort model allowed for estimation of a range of cost savings, quality-adjusted life years gained, and clinical fractures avoided at different levels of fracture protection onset and magnitude. Results provide a first estimate of the potential "value" new bone-forming agents (romosozumab and abaloparatide) may confer relative to teriparatide. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Cancer-targeted therapies and radiopharmaceuticals

PubMed Central

Rachner, Tilman D; Jakob, Franz; Hofbauer, Lorenz C

2015-01-01

The treatment of bone metastases remains a clinical challenge. Although a number of well-established agents, namely bisphosphonates and denosumab, are available to reduce the occurrence of skeletal-related events, additional cancer-targeted therapies are required to improve patients' prognosis and quality of life. This review focuses on novel targets and agents that are under clinical evaluation for the treatment of malignant bone diseases such as activin A, src and endothelin-1 inhibition or agents that are clinically approved and may positively influence bone, such as the mTOR inhibitor everolimus. In addition, the potential of alpharadin, a novel radiopharmaceutical approved for the treatment of prostatic bone disease, is discussed. PMID:26131359

Novel therapies in benign and malignant bone diseases.

PubMed

Rachner, Tilman D; Hadji, Peyman; Hofbauer, Lorenz C

2012-06-01

With an ageing population and improving cancer therapies, the two most common benign and malignant bone diseases, osteoporosis and bone metastases, will continue to affect an increasing number of patients. Our expanding knowledge of the molecular processes underlying these conditions has resulted in novel bone targets that are currently being explored in clinical trials. Clearly, the approval of denosumab, a monoclonal antibody directed against RANKL, has just marked the beginning of a new era for bone therapy with several additional new therapies lining up for clinical approval in the coming years. Potential agents targeting the osteoclast include cathepsin K, currently in phase 3 trials, and src inhibitors. Amongst anabolic agents, inhibitors of the Wnt-inhibitor sclerostin and dickkopf-1 are promising in clinical trials. Here, we will provide a comprehensive overview of the most promising agents currently explored for the treatment of bone diseases. Copyright © 2012 Elsevier Inc. All rights reserved.

The botanical molecule p-hydroxycinnamic acid as a new osteogenic agent: insight into the treatment of cancer bone metastases.

PubMed

Yamaguchi, Masayoshi

2016-10-01

Bone homeostasis is maintained through a balance between osteoblastic bone formation and osteoclastic bone resorption. Bone loss with aging is induced by decreasing in osteoblastic bone formation and increasing in osteoclastic bone resorption, thereby leading to osteoporosis. Osteoporosis with its accompanying decrease in bone mass is widely recognized as a major public heath problem. Pharmacologic and nutritional factors may play a role in the prevention and treatment of bone loss with aging. p-Hydroxycinnamic acid (HCA), which stimulates bone mineralization in mouse bone tissues in vitro, has been found to be present in the leafstalk of wasabi (Wasabi japonica MATSUM) among various food and plants. Other phenolic acids including cinnamic acid, ferulic acid, caffeic acid and 3,4-dimethoxycinnamic acid did not have osteogenic effects. HCA was demonstrated to stimulate osteoblastic bone formation and suppresses osteoclastic bone resorption in vitro by antagonizing activation of the nuclear factor kappa B. Oral administration of HCA was found to exhibit restorative effects on bone loss induced by ovariectomy and diabetic states, supporting a role in the treatment of osteoporosis. Moreover, HCA was demonstrated to prevent the suppressed osteoblastic mineralization and the enhanced osteoclastogenesis in mouse bone marrow cells cocultured with bone metastatic MDA-MB-231 human breast cancer cells in vitro. The botanical molecule HCA, as a new osteogenic agent, is suggested to play a role in the treatment of cancer bone metastases. This review will discuss an advanced recent finding that HCA may be a useful agent to treat bone metabolic disorder.

A systematic review of dosing frequency with bone-targeted agents for patients with bone metastases from breast cancer

PubMed Central

Hutton, Brian; Addison, Christina L.; Campbell, Kaitryn; Fergusson, Dean; Mazarello, Sasha; Clemons, Mark

2013-01-01

Background Bone-targeted agents are usually administered to breast cancer patients with bone metastases every 3–4 weeks. Less frequent (‘de-escalated’) treatment may provide similar benefits with improved safety and reduced cost. Methods To systematically review randomised trials comparing de-escalated treatment with bone-targeted agents (i.e. every 12–16 weeks) to standard treatment (i.e. every 3–4 weeks), a formal systematic review of the literature was performed. Two individuals independently screened citations and full text articles. Random effects meta-analyses of clinically important outcomes were planned provided homogeneous studies were identified. Results Five relevant studies (n=1287 patients) were identified. Sample size ranged from 38 to 425. Information on outcomes including occurrence of SREs, bone pain, urinary N-telopeptide concentrations, serum C-telopeptide concentrations, pain medication use and safety outcomes was not consistently available. Two trials were non-inferiority studies, two dose-response evaluations and one was a pilot study. Bone-targeted agents use varied between studies, as did duration of prior therapy. Patient populations were considered heterogeneous in several ways, and thus no meta-analyses were performed. Observations from the included studies suggest there is potential that 3 month de-escalated treatment may provide similar benefits compared to 3–4 weekly treatment and that lower doses of zoledronic acid and denosumab might be equally effective. Conclusions Studies comparing standard and de-escalated treatment with bone-targeted agents in breast cancer are rare. The benefits of standard treatment compared to de-escalated therapy on important clinical outcomes remain unclear. Future pragmatic studies must be conducted to determine the merits of this approach. PMID:26909282

[Establishment of a novel chinese human lung adenocarcinoma cell line CPA-Yang3 and its real bone metastasis clone CPA-Yang3BM in immunodeficient mice].

PubMed

Yang, Shunfang; Shi, Meiping; Cao, Jie; Su, Jianzhong; Zhao, Lanxiang; Lei, Bei; Chang, Cheng; Lu, Jianying; Ye, Jianding; Xie, Wenhui

2011-02-01

The recurrence and metastasis of lung cancer is a tough problem worldwide. The aim of this study is to establish a novel Chinese lung adenocarcinoma cell line and its real bone-seeking clone sub-line for exploring the molecular mechanism of lung cancer metastasis. The cells came from the pleural effusion of a sixty-five years old female patient with lung adenocarcinoma and supraclavicular lymph node metastases. The gene expression was detected by real-time quantitative PCR. Intracardiac injection of the cells into nude mice was performed and in vivo imaging was obtained by bone scintigraphy and conventional radiography. Bone metastases were determined on bone scintigraphy and then the lesions were resected under deep anesthesia for bone metastasis cancer cell culture. The process was repeated for four cycles to obtain a real bone-seeking clone. The tumorigenesis rate started at 4th passage in immunodeficient mice via subcutaneously and as well as later passages. Approximately 1×10⁶ cancer cells were injected into left cardiac ventricle of immunodeficient mice resulted bone metastasis sites were successfully revealed by bone scintigraphy and pathological diagnosis, the mandible (100%), scapula (33%), humerus (50%), vertebral column (50%), femur (66.7%) and accompanied invasion with other organs, the adrenal gland (17%), pulmonary (33%), liver (50%), submaxillary gland (33%) in the mice after inoculation two-three weeks. The chromosome karyotype analysis of the cells was subdiploid. Quantitative real-time PCR was used to examined and compared with SPC-A-1 lung adenocarcinoma, ESM1, VEGF-C, IL-6, IL-8, AR, SVIL, FN1 genes were overexpress. The novel cell was named CPA-Yang3. The femur metastasis cell was repeated in vivo-in vitro-in vivo with three cycles and harvested a real bone metastasis clone. It was named CPA-Yang3BM. Tne characteristics of novel strain CPAYang3 is a highly metastasis cell line of Chinese lung adenocarcinoma and CPA-Yang3BM is a real bone-seeking clone.

Maintaining Restored Bone with Bisphoshonate in the Ovariectomized Rat Skeleton: Dynamic Histomorphometry of Changes in Bone Mass

NASA Technical Reports Server (NTRS)

Jee, W. S. S.; Tang, L.; Ke, H. Z.; Setterberg, R. B.; Kimmel, D. B.

1993-01-01

This experiment contains the crucial data for the Lose, Restore and Maintain (LRM) concept, a practical approach for reversing existing osteoporosis. The LRM concept uses ovariectomy (ox) to lose bone, an anabolic agent to restore bone mass and then switches to an anti-resorptive agent to maintain bone mass. We ox'd or sham-ox'd rats for 150 days (Loss Phase), treated them with 6 mg PGE2/kg/d for 75 days to restore lost cancellous bone mass (Restore Phase) and then stopped PGE2 treatment and began treatment with 1 or 5 micro-g/kg Risedronate, a bisphosphonate twice a week for 60 days (Maintain Phase). During the Loss Phase, cancellous bone volumes of the proximal tibial metaphysis (PTM) in the ox'd rat fell to 19% of initial controls. During the Restore Phase, the PTM bone volume in ox'd rats doubled. However, when PGE2 treatment was stopped, the PGE2-induced cancellous bone disappeared. In contrast, 5 micro-g of Risedronate inhibited the bone loss and maintained it at the PGE2 treatment level. The key dynamic histomorphometry value for the restore (R) and maintenance (M) phases was the ratio of bone formation to resorption rates. The ratio was elevated to 5.8 in the R phase and depressed to 0.4 for no and 1 micro-g Risedronate treated M phase and to a ratio of near unity of 1.1 for the 5 micro-g Risedronate treatment. These findings indicate that we were successful in maintaining the new PTM bone induced by PGE2 after discontinuing PGE2 by administering enough Risedronate, a resorption inhibitor. We concluded that the LRM concept is correct and such an approach should be considered when employing anabolic agents or growth factors in the treatment of osteoporosis. Continued use of an anabolic agent may not be appropriate because of cost, potential adverse side effects and a loss of efficacy.

Maintaining Restored Bone with Bisphosphonate in the Ovariectomized Rat Skeleton: Dynamic Histomorphometry of Changes in Bone Mass

NASA Technical Reports Server (NTRS)

Jee, W. S. S.; Tang, L.; Ke, H. Z.; Setterberg, R. B.; Kimmel, D. B.

1993-01-01

This experiment contains the crucial data for the Lose, Restore and Maintain (LRM) concept, a practical approach for reversing existing osteoporosis. The LRM concept uses ovariectomy (ox) to lose bone, an anabolic agent to restore bone mass and then switches to an antiresorptive agent to maintain bone mass. We ox'd or sham-ox'd rats for 150 days (Loss Phase), treated them with 6 mg PGE(sub 2)kg/d for 75 days to restore lost cancellous bone mass (Restore Phase) and then stopped PGE(sub 2) treatment and began treatment with 1 or 5 micrograms/kg Risedronate, a bisphosphonate twice a week for 60 days (Maintain Phase). During the Loss Phase, cancellous bone volumes of the Proximal Tibial Metaphysis (PTM) in the ox'd rat fell to 19% of initial controls. During the Restore Phase, the PTM bone volume in ox'd rats doubled. However, when PGE(sub 2) treatment was stopped, the PGE(sub 2)-induced cancellous bone disappeared. In contrast, 5 miligrams of Risedronate inhibited the bone loss and maintained it at the PGE(sub 2) treatment level. The key dynamic histomorphometry value for the Restore (R) and Maintenance (M) phases was the ratio of bone formation to resorption rates. The ratio was elevated to 5.8 in the R phase and depressed to 0.4 for no and 1 miligram Risedronate treated M phase and to a ratio of near unity of 1.1 for the 5miligrams Risedronate treatment. These findings indicate that we were successful in maintaining the new PTM bone induced by PGE(sub 2) after discontinuing PGE(sub 2) by administering enough Risedronate, a resorption inhibitor. We concluded that the LRM concept is correct and such an approach should be considered when employing anabolic agents or growth factors in the treatment of osteoporosis. Continued use of an anabolic agent may not be appropriate because of cost, potential adverse side effects and a loss of efficacy.

Risk-Seeking Versus Risk-Avoiding Investments in Noisy Periodic Environments

NASA Astrophysics Data System (ADS)

Navarro-Barrientos, J. Emeterio; Walter, Frank E.; Schweitzer, Frank

We study the performance of various agent strategies in an artificial investment scenario. Agents are equipped with a budget, x(t), and at each time step invest a particular fraction, q(t), of their budget. The return on investment (RoI), r(t), is characterized by a periodic function with different types and levels of noise. Risk-avoiding agents choose their fraction q(t) proportional to the expected positive RoI, while risk-seeking agents always choose a maximum value qmax if they predict the RoI to be positive ("everything on red"). In addition to these different strategies, agents have different capabilities to predict the future r(t), dependent on their internal complexity. Here, we compare "zero-intelligent" agents using technical analysis (such as moving least squares) with agents using reinforcement learning or genetic algorithms to predict r(t). The performance of agents is measured by their average budget growth after a certain number of time steps. We present results of extensive computer simulations, which show that, for our given artificial environment, (i) the risk-seeking strategy outperforms the risk-avoiding one, and (ii) the genetic algorithm was able to find this optimal strategy itself, and thus outperforms other prediction approaches considered.

Early Observations on Possible Defenses by the Emerging Threat Agent Project

DTIC Science & Technology

2011-01-01

approach would involve the following: • Seek to dissuade adversary development of new CB capabilities. Dissuasion seeks to affect the adversary’s... fruit , it would be unwise in the short term to divert much funding from the agent-specific approach to the second track. The track 2 mechanistic...agents to enhance their effectiveness – genetic manipulation of innocuous (and perhaps ubiquitous) bacteria, viruses, or fungi to make them dangerous

Identifying Potential Therapeutics for Osteoporosis by Exploiting the Relationship between Mevalonate Pathway and Bone Metabolism.

PubMed

Wan Hasan, Wan Nuraini; Chin, Kok-Yong; Jolly, James Jam; Abd Ghafar, Norzana; Soelaiman, Ima Nirwana

2018-04-23

Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling. This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential. Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans. mevalonate pathway can be exploited to develop effective antiosteoporosis agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Design and development of novel hyaluronate-modified nanoparticles for combo-delivery of curcumin and alendronate: Fabrication, characterization, and cellular and molecular evidence of enhanced bone regeneration.

PubMed

Dong, Jinlei; Thu, Hnin Ei; Abourehab, Mohammed A S; Hussain, Zahid

2018-05-18

Osteoporosis is a medical condition of fragile bones with an increased susceptibility to bone fracture. Despite having availability of a wide range of pharmacological agents, prevalence of this metabolic disorder is continuously escalating. Owing to excellent biomedical achievements of nanomedicines in the last few decades, we aimed combo delivery of bone anti-resorptive agent, alendronate (ALN), and bone density enhancing drug, curcumin (CUR), in the form of polymeric nanoparticles. To further optimize the therapeutic efficacy, the prepared ALN/CUR nanoparticles were decorated with hyaluronic acid which is a well-documented biomacromolecule having exceptional bone regenerating potential. The optimized nanoformulation was evaluated for bone regeneration efficacy by assessing the time-mannered modulation in the proliferation, differentiation, and mineralization of MC3T3-E1 cells, a pre-osteoblast model. Moreover, the time-mannered expressions of various bone-forming protein biomarkers including bone morphogenetic protein, runt related transcription factor 2, and osteocalcin were assessed in the cell lysates. Results revealed that HA-ALN/CUR NPs provoke remarkable increase in proliferation, differentiation, and mineralization in the ECM of MC3T3-E1 cells which ultimately leads to enhanced bone formation. This new strategy employing simultaneous delivery of anti-resorptive and bone forming agents would open new horizons for the scientists as an efficient alternative pharmacotherapy for the management of osteoporosis. Copyright © 2017. Published by Elsevier B.V.

Psoralen inhibits bone metastasis of breast cancer in mice.

PubMed

Wu, Chunyu; Sun, Zhenping; Ye, Yiyi; Han, Xianghui; Song, Xiaoyun; Liu, Sheng

2013-12-01

Breast cancer is the most common female malignancy and it frequently metastasizes to bone. Metastatic breast cancer continues to be the primary cause of death for women in East and Southeast Asia. Psoralen is a furocoumarin that can be isolated from the seeds of Psoralea corylifolia L. Psoralen exhibits a wide range of biological properties and has been demonstrated as an antioxidant, antidepressant, anticancer, antibacterial, and antiviral agent. Additionally, it is involved in the formation and regulation of bone. This study investigated whether psoralen can inhibit metastasis of breast cancer to bone in vivo. Histological, molecular biological, and imaging analyses revealed that psoralen inhibits bone metastases in mice. Psoralen may function to inhibit breast cancer cell growth in the bone microenvironment and regulate the function of osteoblasts and osteoclasts in tumor-bearing mice. The results of this study suggest that psoralen is a bone-modifying agent and a potential therapeutic to treat patients with bone metastases. © 2013.

Harnessing and Modulating Inflammation in Strategies for Bone Regeneration

PubMed Central

Mountziaris, Paschalia M.; Spicer, Patrick P.; Kasper, F. Kurtis

2011-01-01

Inflammation is an immediate response that plays a critical role in healing after fracture or injury to bone. However, in certain clinical contexts, such as in inflammatory diseases or in response to the implantation of a biomedical device, the inflammatory response may become chronic and result in destructive catabolic effects on the bone tissue. Since our previous review 3 years ago, which identified inflammatory signals critical for bone regeneration and described the inhibitory effects of anti-inflammatory agents on bone healing, a multitude of studies have been published exploring various aspects of this emerging field. In this review, we distinguish between regenerative and damaging inflammatory processes in bone, update our discussion of the effects of anti-inflammatory agents on bone healing, summarize recent in vitro and in vivo studies demonstrating how inflammation can be modulated to stimulate bone regeneration, and identify key future directions in the field. PMID:21615330

Y-90-DOTA-hLL2: An Agent for Radioimmunotherapy of Non-Hodgkin's Lymphoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Griffiths, Gary L.; Govindan, Serengulam V.; Sharkey, Robert M.

2003-01-01

The goal of this work was to determine an optimal radioimmunotherapy agent for non-Hodgkin's lymphoma. We established the stability profile of yttrium-90-labeled humanized LL2 (hLL2) monoclonal antibody prepared with different chelating agents, and from these data estimated the improvement using the most stable yttrium-90 chelate-hLL2 complex. Methods: The complementary-determining region- (cdr)-grafted (humanized) anti-CD22 mAb, hLL2 (epratuzumab), was conjugated to derivatives of DTPA and 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA). The conjugates were labeled with Y-90 and tested against a 10,000-fold molar excess of free DTPA and against human serum. The conjugates were also labeled with Y-88 and compared for biodistribution in normal andmore » lymphoma xenograft-bearing athymic mice. In vivo data were analyzed for uptake of yttrium in bone and washed bone when either the DOTA or the Mx-DTPA chelates were used, and dosimetry calculations were made for each. Results: Y-90-DOTA -mAb were stable to either DTPA or serum challenge. DTPA complexes of hLL2 lost 3-4% of Y-90 (days 1-4) and 10-15% thereafter. In vivo, stability differences showed lower Y-90 uptake in bone using DOTA. Absorbed doses per 37 MBq (1 mCi) Y-90-mAb were 3555 and 5405 cGy for bone, and 2664 and 4524 cGy for washed-bone for 90Y-DOTA-hLL2 and 90Y-MxDTPA-hLL2, respectively, amounting to 52% and 69.8% increases in absorbed radiation doses for bone and washed-bone when switching from a DOTA to a Mx-DTPA chelate. Conclusion: Y-90-hLL2 prepared with the DOTA chelate represents a preferred agent for RAIT of non-Hodgkin's lymphoma, with an in vivo model demonstrating a large reduction in bone-deposited yttrium, as compared to yttrium-90-hLL2 agents prepared with open-chain DTPA-type chelating agents. Dosimetry suggests that this will result in a substantial toxicological advantage for a DOTA-based hLL2 conjugate.« less

Biologic therapies and bone loss in rheumatoid arthritis.

PubMed

Zerbini, C A F; Clark, P; Mendez-Sanchez, L; Pereira, R M R; Messina, O D; Uña, C R; Adachi, J D; Lems, W F; Cooper, C; Lane, N E

2017-02-01

Rheumatoid arthritis (RA) is a common systemic autoimmune disease of unknown cause, characterized by a chronic, symmetric, and progressive inflammatory polyarthritis. One of the most deleterious effects induced by the chronic inflammation of RA is bone loss. During the last 15 years, the better knowledge of the cytokine network involved in RA allowed the development of potent inhibitors of the inflammatory process classified as biological DMARDs. These new drugs are very effective in the inhibition of inflammation, but there are only few studies regarding their role in bone protection. The principal aim of this review was to show the evidence of the principal biologic therapies and bone loss in RA, focusing on their effects on bone mineral density, bone turnover markers, and fragility fractures. Using the PICOST methodology, two coauthors (PC, LM-S) conducted the search using the following MESH terms: rheumatoid arthritis, osteoporosis, clinical trials, TNF- antagonists, infliximab, adalimumab, etanercept, certolizumab, golimumab, IL-6 antagonists, IL-1 antagonists, abatacept, tocilizumab, rituximab, bone mineral density, bone markers, and fractures. The search was conducted electronically and manually from the following databases: Medline and Science Direct. The search period included articles from 2003 to 2015. The selection included only original adult human research written in English. Titles were retrieved and the same two authors independently selected the relevant studies for a full text. The retrieved selected studies were also reviewed completing the search for relevant articles. The first search included 904 titles from which 253 titles were selected. The agreement on the selection among researchers resulted in a Kappa statistic of 0.95 (p < 0.000). Only 248 abstracts evaluated were included in the acronym PICOST. The final selection included only 28 studies, derived from the systematic search. Additionally, a manual search in the bibliography of the selected articles was made and included into the text and into the section of "small molecules of new agents." Treatment with biologic drugs is associated with the decrease in bone loss. Studies with anti-TNF blocking agents show preservation or increase in spine and hip BMD and also a better profile of bone markers. Most of these studies were performed with infliximab. Only three epidemiological studies analyzed the effect on fractures after anti-TNF blocking agent's treatment. IL-6 blocking agents also showed improvement in localized bone loss not seen with anti-TNF agents. There are a few studies with rituximab and abatacept. Although several studies reported favorable actions of biologic therapies on bone protection, there are still unmet needs for studies regarding their actions on the risk of bone fractures.

Early-term and mid-term histologic events during single-level posterolateral intertransverse process fusion with rhBMP-2/collagen carrier and a ceramic bulking agent in a nonhuman primate model: implications for bone graft preparation.

PubMed

Khan, Safdar N; Toth, Jeffrey M; Gupta, Kavita; Glassman, Steven D; Gupta, Munish C

2014-06-01

We used a nonhuman primate lumbar intertransverse process arthrodesis model to evaluate biological cascade of bone formation using different carrier preparation methods with a single dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) at early time points. To examine early-term/mid-term descriptive histologic and computerized tomographic events in single-level uninstrumented posterolateral nonhuman primate spinal fusions using rhBMP-2/absorbable collagen sponge (ACS) combined with ceramic bulking agents in 3 different configurations. rhBMP-2 on an ACS carrier alone leads to consistent posterolateral lumbar spine fusions in lower-order animals; however, these results have been difficult to replicate in nonhuman primates. Twelve skeletally mature, rhesus macaque monkeys underwent single-level posterolateral arthrodesis at L4-L5. A hydroxyapatite/β-tricalcium phosphate ceramic bulking agent in 3 formulations was used in the treatment groups (n=3). When used, rhBMP-2/ACS at 1.5 mg/cm (3.0 mg rhBMP-2) was combined with 2.5 cm of ceramic bulking agent per side. Animals were euthanized at 4 and 12 weeks postoperative. Computerized tomography scans were performed immediately postoperatively and every 4 weeks until they were euthanized. Sagittal histologic sections were evaluated for bone histogenesis and location, cellular infiltration of the graft/substitute, and bone remodeling activity. Significant histologic differences in the developing fusion appeared between the 3 rhBMP-2/ACS treatment groups at 4 and 12 weeks. At 4 weeks, bone formation appeared to originate at the transverse process and the intertransverse membrane. Cellular infiltration was greatest in granular ceramic groups compared with matrix ceramic group. Minimal to no residual ACS was identified at the early time point. At 12 weeks, marked ceramic remodeling was observed with continued bone formation noted in all carrier groups. At the early time period, histology showed that bone formation appeared to originate at the transverse processes and the intertransverse membrane, indicating that the dorsal muscle bed may not be the only location for bone formation. Histology also showed that the collagen carrier for rhBMP-2 is mostly resorbed by 4 weeks. Our results and previous literature indicate that ceramic bulking agents are needed to provide resistance to compression caused by paraspinal muscles on the fusion bed in the posterolateral environment. Histology showed that ceramic bulking agents may offer long-term scaffolding and a structure to supporting bone formation of the developing fusion mass.

Development of Bone Remodeling Model for Spaceflight Bone Physiology Analysis

NASA Technical Reports Server (NTRS)

Pennline, James A.; Werner, Christopher R.; Lewandowski, Beth; Thompson, Bill; Sibonga, Jean; Mulugeta, Lealem

2015-01-01

Current spaceflight exercise countermeasures do not eliminate bone loss. Astronauts lose bone mass at a rate of 1-2% a month (Lang et al. 2004, Buckey 2006, LeBlanc et al. 2007). This may lead to early onset osteoporosis and place the astronauts at greater risk of fracture later in their lives. NASA seeks to improve understanding of the mechanisms of bone remodeling and demineralization in 1g in order to appropriately quantify long term risks to astronauts and improve countermeasures. NASA's Digital Astronaut Project (DAP) is working with NASA's bone discipline to develop a validated computational model to augment research efforts aimed at achieving this goal.

Obstacles in the optimization of bone health outcomes in the female athlete triad.

PubMed

Ducher, Gaele; Turner, Anne I; Kukuljan, Sonja; Pantano, Kathleen J; Carlson, Jennifer L; Williams, Nancy I; De Souza, Mary Jane

2011-07-01

Maintaining low body weight for the sake of performance and aesthetic purposes is a common feature among young girls and women who exercise on a regular basis, including elite, college and high-school athletes, members of fitness centres, and recreational exercisers. High energy expenditure without adequate compensation in energy intake leads to an energy deficiency, which may ultimately affect reproductive function and bone health. The combination of low energy availability, menstrual disturbances and low bone mineral density is referred to as the 'female athlete triad'. Not all athletes seek medical assistance in response to the absence of menstruation for 3 or more months as some believe that long-term amenorrhoea is not harmful. Indeed, many women may not seek medical attention until they sustain a stress fracture. This review investigates current issues, controversies and strategies in the clinical management of bone health concerns related to the female athlete triad. Current recommendations focus on either increasing energy intake or decreasing energy expenditure, as this approach remains the most efficient strategy to prevent further bone health complications. However, convincing the athlete to increase energy availability can be extremely challenging. Oral contraceptive therapy seems to be a common strategy chosen by many physicians to address bone health issues in young women with amenorrhoea, although there is little evidence that this strategy improves bone mineral density in this population. Assessment of bone health itself is difficult due to the limitations of dual-energy X-ray absorptiometry (DXA) to estimate bone strength. Understanding how bone strength is affected by low energy availability, weight gain and resumption of menses requires further investigations using 3-dimensional bone imaging techniques in order to improve the clinical management of the female athlete triad.

Mediators of Inflammation-Induced Bone Damage in Arthritis and Their Control by Herbal Products

PubMed Central

Nanjundaiah, Siddaraju M.; Astry, Brian; Moudgil, Kamal D.

2013-01-01

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints leading to bone and cartilage damage. Untreated inflammatory arthritis can result in severe deformities and disability. The use of anti-inflammatory agents and biologics has been the mainstay of treatment of RA. However, the prolonged use of such agents may lead to severe adverse reactions. In addition, many of these drugs are quite expensive. These limitations have necessitated the search for newer therapeutic agents for RA. Natural plant products offer a promising resource for potential antiarthritic agents. We describe here the cellular and soluble mediators of inflammation-induced bone damage (osteoimmunology) in arthritis. We also elaborate upon various herbal products that possess antiarthritic activity, particularly mentioning the specific target molecules. As the use of natural product supplements by RA patients is increasing, this paper presents timely and useful information about the mechanism of action of promising herbal products that can inhibit the progression of inflammation and bone damage in the course of arthritis. PMID:23476694

Issues in modern bone histomorphometry☆

PubMed Central

Recker, R.R.; Kimmel, D.B.; Dempster, D.; Weinstein, R.S.; Wronski, T.J.; Burr, D.B.

2012-01-01

This review reports on proceedings of a bone histomorphometry session conducted at the Fortieth International IBMS Sun Valley Skeletal Tissue Biology Workshop held on August 1, 2010. The session was prompted by recent technical problems encountered in conducting histomorphometry on bone biopsies from humans and animals treated with anti-remodeling agents such as bisphosphonates and RANKL antibodies. These agents reduce remodeling substantially, and thus cause problems in calculating bone remodeling dynamics using in vivo fluorochrome labeling. The tissue specimens often contain few or no fluorochrome labels, and thus create statistical and other problems in analyzing variables such as mineral apposition rates, mineralizing surface and bone formation rates. The conference attendees discussed these problems and their resolutions, and the proceedings reported here summarize their discussions and recommendations. PMID:21810491

Responding Creatively to Bone and Blaise (2015) through Packaging, Drawing and Assembling

ERIC Educational Resources Information Center

Potts, Miriam

2017-01-01

In this colloquium, the author responds artistically to Bone and Blaise's article "An uneasy assemblage: Prisoners, animals, asylum-seeking children and posthuman packaging," published in "Contemporary Issues in Early Childhood in 2015" (EJ1058615), continuing their trajectory of "different kinds of images than those…

Improving Students' Help-Seeking Skills Using Metacognitive Feedback in an Intelligent Tutoring System

ERIC Educational Resources Information Center

Roll, Ido; Aleven, Vincent; McLaren, Bruce M.; Koedinger, Kenneth R.

2011-01-01

The present research investigated whether immediate metacognitive feedback on students' help-seeking errors can help students acquire better help-seeking skills. The Help Tutor, an intelligent tutor agent for help seeking, was integrated into a commercial tutoring system for geometry, the Geometry Cognitive Tutor. Study 1, with 58 students, found…

Radium-223: From Radiochemical Development to Clinical Applications in Targeted Cancer Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bruland, Oyvind S.; Jonasdottir, Thora J.; Fisher, Darrell R.

2008-09-15

The radiochemical properties of radium-223 (223Ra, T1/2 = 11.4 d) render this alpha-emitting radionuclide promising for targeted cancer therapy. Together with its short-lived daughters, each 223Ra decay produces four alpha-particle emissions—which enhance therapy effectiveness at the cellular level. In this paper, we review the recently published data reported for pre-clinical and clinical use of 223Ra in cancer treatment. We have evaluated two distinct chemical forms of 223Ra in vivo: 1) cationic 223Ra as dissolved RaCl2, and 2) liposome-encapsulated 223Ra. Cationic 223Ra seeks metabolically active osteoblastic bone and tumor lesions with high uptake and strong binding affinity based on its similaritiesmore » to calcium. Based on these properties, we have advanced the clinical use of 223Ra for treating bone metastases from late-stage breast and prostate cancer. The results show impressive anti-tumor activity and improved overall survival in hormone-refractory prostate cancer patients with bone metastases. In other studies, we have evaluated the biodistribution and tumor uptake of liposomally encapsulated 223Ra in mice with human osteosarcoma xenografts, and in dogs with spontaneous osteosarcoma and associated soft tissue metastases. Results indicate excellent biodistributions in both species. In dogs, we found considerable uptake of liposomal 223Ra in cancer metastases in multiple organs, resulting in favorable tumor-to-normal soft tissue ratios. Collectively, these findings show an outstanding potential for 223Ra as a therapeutic agent.« less

Graphite-reinforced bone cement

NASA Technical Reports Server (NTRS)

Knoell, A. C.

1976-01-01

Chopped graphite fibers added to surgical bone cement form bonding agent with mechanical properties closely matched to those of bone. Curing reaction produces less heat, resulting in reduced traumatization of body tissues. Stiffness is increased without affecting flexural strength.

Autoradiographic method for quantitation of deposition and distribution of radiocalcium in bone

PubMed Central

Lawrence Riggs, B; Bassingthwaighte, James B.; Jowsey, Jenifer; Peter Pequegnat, E

2010-01-01

A method is described for quantitating autoradiographs of bone-seeking isotopes in microscopic sections of bone. Autoradiographs of bone sections containing 45Ca and internal calibration standards are automatically scanned with a microdensitometer. The digitized optical density output is stored on magnetic tape and is converted by computer to equivalent activity of 45Ca per gram of bone. The computer determines the total 45Ca uptake in the bone section and, on the basis of optical density and anatomic position, quantitatively divides the uptake into 4 components, each representing a separate physiologic process (bone formation, secondary mineralization, diffuse long-term exchange, and surface short-term exchange). The method is also applicable for quantitative analysis of microradiographs of bone sections for mineral content and density. PMID:5416906

Tin-117m-labeled stannic (Sn.sup.4+) chelates

DOEpatents

Srivastava, Suresh C.; Meinken, George E.; Richards, Powell

1985-01-01

The radiopharmaceutical reagents of this invention and the class of Tin-117m radiopharmaceuticals are therapeutic and diagnostic agents that incorporate gamma-emitting nuclides that localize in bone after intravenous injection in mammals (mice, rats, dogs, and rabbits). Images reflecting bone structure or function can then be obtained by a scintillation camera that detects the distribution of ionizing radiation emitted by the radioactive agent. Tin-117m-labeled chelates of stannic tin localize almost exclusively in cortical bone. Upon intravenous injection of the reagent, the preferred chelates are phosphonate compounds, preferable, PYP, MDP, EHDP, and DTPA. This class of reagents is therapeutically and diagnostically useful in skeletal scintigraphy and for the radiotherapy of bone tumors and other disorders.

Osthole Stimulates Osteoblast Differentiation and Bone Formation by Activation of β-Catenin–BMP Signaling

PubMed Central

Tang, De-Zhi; Hou, Wei; Zhou, Quan; Zhang, Minjie; Holz, Jonathan; Sheu, Tzong-Jen; Li, Tian-Fang; Cheng, Shao-Dan; Shi, Qi; Harris, Stephen E; Chen, Di; Wang, Yong-Jun

2010-01-01

Osteoporosis is defined as reduced bone mineral density with a high risk of fragile fracture. Current available treatment regimens include antiresorptive drugs such as estrogen receptor analogues and bisphosphates and anabolic agents such as parathyroid hormone (PTH). However, neither option is completely satisfactory because of adverse effects. It is thus highly desirable to identify novel anabolic agents to improve future osteoporosis treatment. Osthole, a coumarin-like derivative extracted from Chinese herbs, has been shown to stimulate osteoblast proliferation and differentiation, but its effect on bone formation in vivo and underlying mechanism remain unknown. In this study, we found that local injection of Osthole significantly increased new bone formation on the surface of mouse calvaria. Ovariectomy caused evident bone loss in rats, whereas Osthole largely prevented such loss, as shown by improved bone microarchitecture, histomorphometric parameters, and biomechanical properties. In vitro studies demonstrated that Osthole activated Wnt/β-catenin signaling, increased Bmp2 expression, and stimulated osteoblast differentiation. Targeted deletion of the β-catenin and Bmp2 genes abolished the stimulatory effect of Osthole on osteoblast differentiation. Since deletion of the Bmp2 gene did not affect Osthole-induced β-catenin expression and the deletion of the β-catenin gene inhibited Osthole-regulated Bmp2 expression in osteoblasts, we propose that Osthole acts through β-catenin–BMP signaling to promote osteoblast differentiation. Our findings demonstrate that Osthole could be a potential anabolic agent to stimulate bone formation and prevent estrogen deficiency–induced bone loss. © 2010 American Society for Bone and Mineral Research. PMID:20200936

Computed Tomography and Optical Imaging of Osteogenesis-angiogenesis Coupling to Assess Integration of Cranial Bone Autografts and Allografts.

PubMed

Cohn Yakubovich, Doron; Tawackoli, Wafa; Sheyn, Dmitriy; Kallai, Ilan; Da, Xiaoyu; Pelled, Gadi; Gazit, Dan; Gazit, Zulma

2015-12-22

A major parameter determining the success of a bone-grafting procedure is vascularization of the area surrounding the graft. We hypothesized that implantation of a bone autograft would induce greater bone regeneration by abundant blood vessel formation. To investigate the effect of the graft on neovascularization at the defect site, we developed a micro-computed tomography (µCT) approach to characterize newly forming blood vessels, which involves systemic perfusion of the animal with a polymerizing contrast agent. This method enables detailed vascular analysis of an organ in its entirety. Additionally, blood perfusion was assessed using fluorescence imaging (FLI) of a blood-borne fluorescent agent. Bone formation was quantified by FLI using a hydroxyapatite-targeted probe and µCT analysis. Stem cell recruitment was monitored by bioluminescence imaging (BLI) of transgenic mice that express luciferase under the control of the osteocalcin promoter. Here we describe and demonstrate preparation of the allograft, calvarial defect surgery, µCT scanning protocols for the neovascularization study and bone formation analysis (including the in vivo perfusion of contrast agent), and the protocol for data analysis. The 3D high-resolution analysis of vasculature demonstrated significantly greater angiogenesis in animals with implanted autografts, especially with respect to arteriole formation. Accordingly, blood perfusion was significantly higher in the autograft group by the 7(th) day after surgery. We observed superior bone mineralization and measured greater bone formation in animals that received autografts. Autograft implantation induced resident stem cell recruitment to the graft-host bone suture, where the cells differentiated into bone-forming cells between the 7(th) and 10(th) postoperative day. This finding means that enhanced bone formation may be attributed to the augmented vascular feeding that characterizes autograft implantation. The methods depicted may serve as an optimal tool to study bone regeneration in terms of tightly bounded bone formation and neovascularization.

Deregulation of Bone Forming Cells in Bone Diseases and Anabolic Effects of Strontium-Containing Agents and Biomaterials

PubMed Central

Tan, Shuang; Zhang, Binbin; Zhu, Xiaomei; Ao, Ping; Guo, Huajie; Yi, Weihong; Zhou, Guang-Qian

2014-01-01

Age-related bone loss and osteoporosis are associated with bone remodeling changes that are featured with decreased trabecular and periosteal bone formation relative to bone resorption. Current anticatabolic therapies focusing on the inhibition of bone resorption may not be sufficient in the prevention or reversal of age-related bone deterioration and there is a big need in promoting osteoblastogenesis and bone formation. Enhanced understanding of the network formed by key signaling pathways and molecules regulating bone forming cells in health and diseases has therefore become highly significant. The successful development of agonist/antagonist of the PTH and Wnt signaling pathways are profits of the understanding of these key pathways. As the core component of an approved antiosteoporosis agent, strontium takes its effect on osteoblasts at multilevel through multiple pathways, representing a good example in revealing and exploring anabolic mechanisms. The recognition of strontium effects on bone has led to its expected application in a variety of biomaterial scaffolds used in tissue engineering strategies aiming at bone repairing and regeneration. While summarizing the recent progress in these respects, this review also proposes the new approaches such as systems biology in order to reveal new insights in the pathology of osteoporosis as well as possible discovery of new therapies. PMID:24800251

Transdermal drug delivery: feasibility for treatment of superficial bone stress fractures.

PubMed

Aghazadeh-Habashi, Ali; Yang, Yang; Tang, Kathy; Lőbenberg, Raimar; Doschak, Michael R

2015-12-01

Transdermal drug delivery offers the promise of effective drug therapy at selective sites of pathology whilst reducing systemic exposure to the pharmaceutical agents in off-target organs and tissues. However, that strategy is often limited to cells comprising superficial tissues of the body (rarely to deeper bony structures) and mostly indicated with small hydrophobic pharmacological agents, such as steroid hormones and anti-inflammatory gels to skin, muscle, and joints. Nonetheless, advances in transdermal liposomal formulation have rendered the ability to readily incorporate pharmacologically active hydrophilic drug molecules and small peptide biologics into transdermal dosage forms to impart the effective delivery of those bioactive agents across the skin barrier to underlying superficial tissue structures including bone, often enhanced by some form of electrical, chemical, and mechanical facilitation. In the following review, we evaluate transdermal drug delivery systems, with a particular focus on delivering therapeutic agents to treat superficial bone pain, notably stress fractures. We further introduce and discuss several small peptide hormones active in bone (such as calcitonins and parathyroid hormone) that have shown potential for transdermal delivery, often under the added augmentation of transdermal drug delivery systems that employ lipo/hydrophilicity, electric charge, and/or microprojection facilitation across the skin barrier.

Electrical stimulation at the dorsal root ganglion preserves trabecular bone mass and microarchitecture of the tibia in hindlimb-unloaded rats.

PubMed

Lau, Y-C; Qian, X; Po, K-T; Li, L-M; Guo, X

2015-02-01

This study seeks to investigate the effect of electrical stimulation (ES) at dorsal root ganglion (DRG) on disuse bone loss in a rat model. Hindlimb unloading for 14 days resulted in significant bone loss in rat tibia while rats with ES at DRG showed a significant reduced bone loss Mechanical unloading induces osteoporosis in both human and animals. Previous studies demonstrated that electrical stimulation (ES) to dorsal root ganglion (DRG) could trigger secretion of calcitonin gene-related peptide (CGRP) which plays an important role in bone modeling and remodeling. This study seeks to investigate the effect of ES to DRG on disuse bone loss in a rat model. Twenty-four rats were randomly assigned in three experimental groups: cage control (CC), hindlimb unloading (HU), and hindlimb unloading with ES (HUES). ES was applied via implantable micro-electrical stimulators (IMES) to right DRGs at vertebral levels L4-L6 in HUES group. Hindlimb unloading for 14 days resulted in 25.9% decrease in total bone mineral content (BMC), 29.2% decrease in trabecular BMD and trabecular microarchitecture and connectivity were significantly deteriorated in the proximal tibia metaphysis in HU group, while rats with ES at DRG showed significant reduced bone loss that there was 3.8% increase in total BMC, 2.3% decrease in trabecular BMD, and significant improvement in trabecular microarchitecture. There was a concurrent enhancement of expression of CGRP in stimulated DRGs. The results confirm the effect of ES at DRG on enhancing CGRP expression and suggest potential applications of IMES for the prevention and treatment of disuse bone loss.

Bone effects of biologic drugs in rheumatoid arthritis.

PubMed

Corrado, Addolorata; Neve, Anna; Maruotti, Nicola; Cantatore, Francesco Paolo

2013-01-01

Biologic agents used in the treatment of rheumatoid arthritis (RA) are able to reduce both disease activity and radiographic progression of joint disease. These drugs are directed against several proinflammatory cytokines (TNF α , IL-6, and IL-1) which are involved both in the pathogenesis of chronic inflammation and progression of joint structural damage and in systemic and local bone loss typically observed in RA. However, the role of biologic drugs in preventing bone loss in clinical practice has not yet clearly assessed. Many clinical studies showed a trend to a positive effect of biologic agents in preventing systemic bone loss observed in RA. Although the suppression of inflammation is the main goal in the treatment of RA and the anti-inflammatory effects of biologic drugs exert a positive effect on bone metabolism, the exact relationship between the prevention of bone loss and control of inflammation has not been clearly established, and if the available biologic drugs against TNF α , IL-1, and IL-6 can exert their effect on systemic and local bone loss also through a direct mechanism on bone cell metabolism is still to be clearly defined.

Nanocomposite scaffolds with tunable mechanical and degradation capabilities: co-delivery of bioactive agents for bone tissue engineering.

PubMed

Cattalini, Juan P; Roether, Judith; Hoppe, Alexander; Pishbin, Fatemeh; Haro Durand, Luis; Gorustovich, Alejandro; Boccaccini, Aldo R; Lucangioli, Silvia; Mouriño, Viviana

2016-10-21

Novel multifunctional nanocomposite scaffolds made of nanobioactive glass and alginate crosslinked with therapeutic ions such as calcium and copper were developed for delivering therapeutic agents, in a highly controlled and sustainable manner, for bone tissue engineering. Alendronate, a well-known antiresorptive agent, was formulated into microspheres under optimized conditions and effectively loaded within the novel multifunctional scaffolds with a high encapsulation percentage. The size of the cation used for the alginate crosslinking impacted directly on porosity and viscoelastic properties, and thus, on the degradation rate and the release profile of copper, calcium and alendronate. According to this, even though highly porous structures were created with suitable pore sizes for cell ingrowth and vascularization in both cases, copper-crosslinked scaffolds showed higher values of porosity, elastic modulus, degradation rate and the amount of copper and alendronate released, when compared with calcium-crosslinked scaffolds. In addition, in all cases, the scaffolds showed bioactivity and mechanical properties close to the endogenous trabecular bone tissue in terms of viscoelasticity. Furthermore, the scaffolds showed osteogenic and angiogenic properties on bone and endothelial cells, respectively, and the extracts of the biomaterials used promoted the formation of blood vessels in an ex vivo model. These new bioactive nanocomposite scaffolds represent an exciting new class of therapeutic cell delivery carrier with tunable mechanical and degradation properties; potentially useful in the controlled and sustainable delivery of therapeutic agents with active roles in bone formation and angiogenesis, as well as in the support of cell proliferation and osteogenesis for bone tissue engineering.

Use of Alendronate Sodium (Fosamax) to Ameliorate Osteoporosis in Renal Transplant Patients: A Case-Control Study

PubMed Central

Huang, Wen-Hung; Lee, Shen-Yang; Weng, Cheng-Hao; Lai, Ping-Chin

2012-01-01

Background Renal transplant patients often have severe bone and mineral deficiencies. While the clinical effects of immunosuppressive agents like calcineurin inhibitors (CIs) and sirolimus on bone turnover are unclear, bisphosphonates are effective in bone recovery in these patients. Gender is significantly associated with osteoporosis and affects bone turnover, which is different in women and men. The effective gender-related site of action of bisphosphonates is unknown. Methods Initially, we enrolled 84 kidney recipients who had received their transplants at least 5 months ago; of these, 8 were excluded and 76 were finally included in the study. First bone mineral density (BMD) at the lumbar spine, hip, and femoral neck was determined using dual-energy X-ray absorptiometry (DXA) between September 2008 and March 2009. These 76 patients underwent a repeat procedure after a mean period 14 months. Immunosuppressive agents, bisphosphonates, patients' characteristics, and biochemical factors were analyzed on the basis of the BMD determined using DXA. Results After the 14-month period, the BMD of lumbar spine increased significantly (from 0.9 g/cm2 to 0.92 g/cm2, p<0.001), whereas that of the hip and femoral neck did not. Ordinal logistic regression analysis was used to show that Fosamax improved bone condition, as defined by WHO (p = 0.007). The use of immunosuppressive agents did not affect bone turnover (p>0.05). Moreover, in subgroup analysis, Fosamax increased the BMD at the lumbar spine and the hipbone in males (p = 0.028 and 0.03, respectively) but only at the lumbar spine in females (p = 0.022). Conclusion After a long periods after renal transplantation, the detrimental effects of steroid and immunosuppressive agents on bone condition diminished. Short-term Fosamax administration effectively improves BMD in these patients. The efficacy of Fosamax differed between male and female renal transplant patients. PMID:23185261

Bonelike apatite formation on ethylene-vinyl alcohol copolymer modified with silane coupling agent and calcium silicate solutions.

PubMed

Oyane, Ayako; Kawashita, Masakazu; Nakanishi, Kazuki; Kokubo, Tadashi; Minoda, Masahiko; Miyamoto, Takeaki; Nakamura, Takashi

2003-05-01

An ethylene-vinyl alcohol copolymer (EVOH) was treated with a silane coupling agent and calcium silicate solutions, and then soaked in a simulated body fluid (SBF) with ion concentrations approximately equal to those of human blood plasma. A smooth and uniform bonelike apatite layer was successfully formed on both the EVOH plate and the EVOH-knitted fibers in SBF within 2 days. Part of the structure of the resulting apatite-EVOH fiber composite was similar to that of natural bone. If this kind of composite can be fabricated into a three-dimensional structure similar to natural bone, the resultant composite is expected to exhibit both mechanical properties analogous to those of natural bone and bone-bonding ability. Hence, it has great potential as a bone substitute. Copyright 2003 Elsevier Science Ltd.

EANM guidelines for radionuclide therapy of bone metastases with beta-emitting radionuclides.

PubMed

Handkiewicz-Junak, Daria; Poeppel, Thorsten D; Bodei, Lisa; Aktolun, Cumali; Ezziddin, Samer; Giammarile, Francesco; Delgado-Bolton, Roberto C; Gabriel, Michael

2018-05-01

The skeleton is the most common metastatic site in patients with advanced cancer. Pain is a major healthcare problem in patients with bone metastases. Bone-seeking radionuclides that selectively accumulate in the bone are used to treat cancer-induced bone pain and to prolong survival in selected groups of cancer patients. The goals of these guidelines are to assist nuclear medicine practitioners in: (a) evaluating patients who might be candidates for radionuclide treatment of bone metastases using beta-emitting radionuclides such as strontium-89 ( 89 Sr), samarium-153 ( 153 Sm) lexidronam ( 153 Sm-EDTMP), and phosphorus-32 ( 32 P) sodium phosphate; (b) performing the treatments; and ©) understanding and evaluating the treatment outcome and side effects.

Automated trabecular bone histomorphometry

NASA Technical Reports Server (NTRS)

Polig, E.; Jee, W. S. S.

1985-01-01

The toxicity of alpha-emitting bone-seeking radionuclides and the relationship between bone tumor incidence and the local dosimetry of radionuclides in bone are investigated. The microdistributions of alpha-emitting radionuclides in the trabecular bone from the proximal humerus, distal humerus, proximal ulna, proximal femur, and distal femur of six young adult beagles injected with Am-241 (three with 2.8 micro-Ci/kg and three with 0.9 micro-Ci/kg) are estimated using a computer-controlled microscope photometer system; the components of the University of Utah Optical Track Scanner are described. The morphometric parameters for the beagles are calculated and analyzed. It is observed that the beagles injected with 0.9 micro-Ci of Am-241/kg showed an increase in the percentage of bone and trabecular bone thickness, and a reduction in the width of the bone marrow space and surface/volume ratio. The data reveal that radiation damage causes abnormal bone structure.

Agent-Based Deterministic Modeling of the Bone Marrow Homeostasis.

PubMed

Kurhekar, Manish; Deshpande, Umesh

2016-01-01

Modeling of stem cells not only describes but also predicts how a stem cell's environment can control its fate. The first stem cell populations discovered were hematopoietic stem cells (HSCs). In this paper, we present a deterministic model of bone marrow (that hosts HSCs) that is consistent with several of the qualitative biological observations. This model incorporates stem cell death (apoptosis) after a certain number of cell divisions and also demonstrates that a single HSC can potentially populate the entire bone marrow. It also demonstrates that there is a production of sufficient number of differentiated cells (RBCs, WBCs, etc.). We prove that our model of bone marrow is biologically consistent and it overcomes the biological feasibility limitations of previously reported models. The major contribution of our model is the flexibility it allows in choosing model parameters which permits several different simulations to be carried out in silico without affecting the homeostatic properties of the model. We have also performed agent-based simulation of the model of bone marrow system proposed in this paper. We have also included parameter details and the results obtained from the simulation. The program of the agent-based simulation of the proposed model is made available on a publicly accessible website.

Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss

NASA Technical Reports Server (NTRS)

LeBlanc, Adrian; Matsumoto, Toshio; Jones, Jeffrey A.; Shapiro, Jay; Lang, Thomas F.; Smith, Scott M.; Shackelford, Linda C.; Sibonga, Jean; Evans, Harlan; Spector, Elisabeth;

Personality and Cultural Modeling for Agent-Based Representation of a Terrorist Cell, Phase 1

DTIC Science & Technology

2003-01-01

domains of Neuroticism, Extroversion, Openness, Agreeableness and Conscientiousness into six 5 facets each. The six facets alone provide a level of...confident confident timid--- bold no easily embarrassed---not easily embarrassed doubting---confident OK defensive---open OK inhibited---expressive...working alone pleasure-seeking---not no pleasure-seeking involved---aloof OK seeks out others---seeks isolation talkative---reticent OK spontaneous---not

Information-Seeking Practices of County Extension Agents

ERIC Educational Resources Information Center

Bailey, Nikki; Hill, Alexandra; Arnold, Shannon

2014-01-01

The purpose of the study reported here was to examine the educational resources used by Montana State University Extension county agents. An online survey was administered to evaluate agents' informational needs. Agents reported client questions (93.8%) and program/workshop planning and presentations (91.7%) as the main reasons for seeking…

Scaffold-based Anti-infection Strategies in Bone Repair

PubMed Central

Johnson, Christopher T.; García, Andrés J.

2014-01-01

Bone fractures and non-union defects often require surgical intervention where biomaterials are used to correct the defect, and approximately 10% of these procedures are compromised by bacterial infection. Currently, treatment options are limited to sustained, high doses of antibiotics and surgical debridement of affected tissue, leaving a significant, unmet need for the development of therapies to combat device-associated biofilm and infections. Engineering implants to prevent infection is a desirable material characteristic. Tissue engineered scaffolds for bone repair provide a means to both regenerate bone and serve as a base for adding antimicrobial agents. Incorporating anti-infection properties into regenerative medicine therapies could improve clinical outcomes and reduce the morbidity and mortality associated with biomaterial implant-associated infections. This review focuses on current animal models and technologies available to assess bone repair in the context of infection, antimicrobial agents to fight infection, the current state of antimicrobial scaffolds, and future directions in the field. PMID:25476163

Friendship, Status, and Repayment as Factors in Seeking Help.

ERIC Educational Resources Information Center

Shapiro, E. Gary

Three variables, derived from Blau's (1955) analysis of consultation networks among federal agents and Homans' (1961) social exchange analysis, were manipulated to observe their effects on help seeking. Subjects were presented with a hypothetical situation where help was needed. Subjects indicated that they would be more likely to seek help from a…

Evaluation of Ga-DOTA-(D-Asp)n as bone imaging agents: D-aspartic acid peptides as carriers to bone.

PubMed

Ogawa, Kazuma; Ishizaki, Atsushi; Takai, Kenichiro; Kitamura, Yoji; Makino, Akira; Kozaka, Takashi; Kiyono, Yasushi; Shiba, Kazuhiro; Odani, Akira

2017-10-25

67 Ga-DOTA-(L-Asp) 11 and 67 Ga-DOTA-(L-Asp) 14 , which have been developed as bone imaging agents, showed a high accumulation in bone and a rapid blood clearance in mice. However, peptides composed of D-amino acids are more stable in vivo than those composed of their L-equivalents. In this study, 67 Ga-DOTA-(D-Asp) n (n = 2, 5, 8, 11, or 14) were synthesized using the Fmoc-based solid-phase methodology and evaluated. In hydroxyapatite binding assay, binding of 67 Ga-DOTA-(D-Asp) n tended to increase with increasing length of the amino acid chain. 67 Ga-DOTA-(D-Asp) 11 and 67 Ga-DOTA-(D-Asp) 14 caused a high accumulation of radioactivity in the bones of the mice. However, the results for 67 Ga-DOTA-(D-Asp) n and 67 Ga-DOTA-(L-Asp) n were comparable. In urine analyses, the proportion of intact complex after injection of 67 Ga-DOTA-(D-Asp) 14 was significantly higher than that of 67 Ga-DOTA-(L-Asp) 14 . Although 67 Ga-DOTA-(D-Asp) 14 was more stable than 67 Ga-DOTA-(L-Asp) 14 , the properties of 67 Ga-DOTA-(D-Asp) n and 67 Ga-DOTA-(L-Asp) n as bone imaging agents may be comparable.

Bone scaffolds with homogeneous and discrete gradient mechanical properties.

PubMed

Jelen, C; Mattei, G; Montemurro, F; De Maria, C; Mattioli-Belmonte, M; Vozzi, G

2013-01-01

Bone TE uses a scaffold either to induce bone formation from surrounding tissue or to act as a carrier or template for implanted bone cells or other agents. We prepared different bone tissue constructs based on collagen, gelatin and hydroxyapatite using genipin as cross-linking agent. The fabricated construct did not present a release neither of collagen neither of genipin over its toxic level in the surrounding aqueous environment. Each scaffold has been mechanically characterized with compression, swelling and creep tests, and their respective viscoelastic mechanical models were derived. Mechanical characterization showed a practically elastic behavior of all samples and that compressive elastic modulus basically increases as content of HA increases, and it is strongly dependent on porosity and water content. Moreover, by considering that gradients in cellular and extracellular architecture as well as in mechanical properties are readily apparent in native tissues, we developed discrete functionally graded scaffolds (discrete FGSs) in order to mimic the graded structure of bone tissue. These new structures were mechanically characterized showing a marked anisotropy as the native bone tissue. Results obtained have shown FGSs could represent valid bone substitutes. Copyright © 2012 Elsevier B.V. All rights reserved.

Kinetochore identification in micronuclei in mouse bone-marrow erythrocytes: an assay for the detection of aneuploidy-inducing agents.

PubMed

Gudi, R; Sandhu, S S; Athwal, R S

1990-10-01

An in vivo micronucleus assay using mouse bone marrow for identifying the ability of chemicals to induce aneuploidy and/or chromosome breaks is described. Micronucleus formation in bone-marrow erythrocytes of mice is commonly used as an index for evaluating the clastogenicity of environmental agents. However, micronuclei may also originate from intact lagging chromosomes resulting from the effect of aneuploidy-inducing agents. We have used immunofluorescent staining using anti-kinetochore antibodies to classify micronuclei for the presence or absence of kinetochores. Micronuclei positive for kinetochores are assumed to contain intact chromosomes and result from induced aneuploidy; while those negative for kinetochores contain acentric chromosomal fragments and originate from clastogenic events. The assay was evaluated using X-irradiation (a known clastogen) and vincristine sulfate (an aneuploidy-inducing agent). A dose-related response for the induction of micronuclei was observed for both agents. Micronuclei induced by X-irradiation were negative for kinetochores while the majority of the micronuclei resulting from vincristine treatment contained kinetochores. Thus, the micronucleus assay in combination with immunofluorescent staining for kinetochores may provide a useful method to simultaneously assess the ability of chemicals to induce aneuploidy and/or chromosome breaks.

Tin-117m-labeled stannic (Sn/sup 4 +/) chelate of diethylenetriamine pentaacetic acid (DTPA) for application in diagnosis and therapy

DOEpatents

Srivastava, S.C.; Meinken, G.E.; Richards, P.

1983-08-25

The radiopharmaceutical reagents of this invention and the class of Tin-117m radiopharmaceuticals are therapeutic and diagnostic agents that incorporate gamma-emitting nuclides that localize in bone after intravenous injection in mammals (mice, rats, dogs, and rabbits). Images reflecting bone structure or function can then be obtained by a scintillation camera that detects the distribution of ionizing radiation emitted by the radioactive agent. Tin-117m-labeled chelates of stannic tin localize almost exclusively in cortical bone. Upon intravenous injection of the reagent, the preferred chelates are phosphonate compounds, preferable, PYP, MDP, EHDP, and DTPA. This class of reagents is therapeutically and diagnostically useful in skeletal scintigraphy and for the radiotherapy of bone tumors and other disorders.

Radionuclide studies in Hodgkin's disease and lymphomas.

PubMed

Richman, S D; Levenson, S M; Jones, A E; Johnston, G S

1975-01-01

A rational, multidisciplinary approach to Hodgkin's disease and the non-Hodgkin's lymphomas has been responsible for major advances in therapy. Invasive diagnostic procedures and exploratory laparotomy, with their associated complications, make nontraumatic radionuclide imaging most appealing in both the clinical staging of disease and in evaluating therapy. Gallium-67-citrate, the tumor scanning agent of the early 1970's, has demonstrated a marked affinity for Hodgkin's disease and the other lymphomas. False positives are few, with sensitivity greater than 70% throughout the spectrum of Hodgkin's disease and the histiocytic lymphomas. In addition to confirming sites of suspected neoplasm, this agent has proved useful in the detection of occult involvement. Moreover, resolution of abnormal gallium-67 concentrations on follow-up studies functions as a visual ancillary index of therapeutic response. The value of wholebody gallium-67 scintigraphy is further enhanced when used in conjunction with routine technetium brain, bone, liver, and spleen scans. While the diagnostic accuracy of gallium-67 studies has been limited in the abdomen due to bowel activity, our attempts to improve these results with the tumor-seeking radiopharmaceutical indium-111-Bleomycin were unrewarding and subsequently were discontinued. Finally, radionuclide lymphography has also been explored. Its diagnostic usefulness in detecting pelvic and abdominal lymph node involvement warrants further investigation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herring, G. M.; Vaughan, Janet; Williamson, Margaret

Characteristics of bone surfaces are discussed in relation to the uptake of bone-seeking isotopes. The alkaline earths are concentrated behind the osteoid border of active surfaces. Yttrium, americium, and plutonium are concentrated on quiescent and resorbing surfaces; traces only occur in and beneath the osteoid border. In view of evidence of mucoproteins at sites where the latter elemerts are found in concentration, a separation of the mucoproteins in cortical bone was undertaken. Mucosubstances have been isolated which give the same reaction with certain reagents as the bone surfaces in question. One of these, a sialoprotein, might be expected, in viewmore » of its acidic nature, to be capable of metal binding.« less

Synergistic effects of green tea polyphenols and alphacalcidol on chronic inflammation-induced bone loss in female rats

USDA-ARS?s Scientific Manuscript database

Summary: Studies suggest that green tea polyphenols (GTP) or alphacalcidol is promising agent for preventing bone loss. Findings that GTP supplementation in the drinking water plus alphacalcidol administration resulted in increased bone mass via a decrease of oxidative stress and inflammation sugges...

Repression of Multiple Myeloma Growth and Preservation of Bone with Combined Radiotherapy and Anti-angiogenic Agent

PubMed Central

Jia, Dan; Koonce, Nathan A.; Halakatti, Roopa; Li, Xin; Yaccoby, Shmuel; Swain, Frances L.; Suva, Larry J.; Hennings, Leah; Berridge, Marc S.; Apana, Scott M.; Mayo, Kevin; Corry, Peter M.; Griffin, Robert J.

2011-01-01

The effects of ionizing radiation, with or without the antiangiogenic agent anginex (Ax), on multiple myeloma growth were tested in a SCID-rab mouse model. Mice carrying human multiple myeloma cell-containing pre-implanted bone grafts were treated weekly with various regimens for 8 weeks. Rapid multiple myeloma growth, assessed by bioluminescence intensity (IVIS), human lambda Ig light chain level in serum (ELISA), and the volume of bone grafts (caliper), was observed in untreated mice. Tumor burden in mice receiving combined therapy was reduced to 59% (by caliper), 43% (by ELISA), and 2% (by IVIS) of baseline values after 8 weeks of treatment. Ax or radiation alone slowed but did not stop tumor growth. Four weeks after the withdrawal of the treatments, tumor burden remained minimal in mice given Ax + radiation but increased noticeably in the other three groups. Multiple myeloma suppression by Ax + radiation was accompanied by a marked decrease in the number and activity of osteoclasts in bone grafts assessed by histology. Bone graft integrity was preserved by Ax + radiation but was lost in the other three groups, as assessed by microCT imaging and radiography. These results suggest that radiotherapy, when primed by anti-angiogenic agents, may be a potent therapy for focal multiple myeloma. PMID:20518660

Management of beta-thalassemia-associated osteoporosis.

PubMed

Giusti, Andrea; Pinto, Valeria; Forni, Gian Luca; Pilotto, Alberto

2016-03-01

Beta-Thalassemia-associated osteoporosis is a multifactorial and complex condition. Different acquired and genetic factors are involved in its pathogenesis. These factors produce an imbalance in bone remodeling by inhibiting osteoblast activity and increasing osteoclast function, leading to bone loss and increased fracture risk. The management of patients presenting with thalassemia-associated osteoporosis should consist of the implementation of general measures and the prescription of a specific pharmacological agent, with the aim of reducing fracture risk and preventing disability and deterioration of quality of life. General measures include control of anemia, adequate chelation therapy, healthy nutrition and lifestyle, regular exercise, adequate management of comorbid conditions, hormone replacement therapy in patients with hypogonadism, and vitamin D supplementation/therapy. Among the pharmacological agents currently available for the management of osteoporosis in postmenopausal women and men, bisphosphonates have been shown to improve bone mineral density, to reduce bone turnover, and to decrease bone/back pain in patients with thalassemia-associated osteoporosis, with a good profile of safety and tolerability. On the other hand, there are limited experiences with other pharmacological agents (e.g., denosumab or teriparatide). The complexity of this condition presents diagnostic and therapeutic challenges and underscores the importance of a comprehensive and multidisciplinary approach. © 2016 New York Academy of Sciences.

Detecting microdamage in bone.

PubMed

Lee, T C; Mohsin, S; Taylor, D; Parkesh, R; Gunnlaugsson, T; O'Brien, F J; Giehl, M; Gowin, W

2003-08-01

Fatigue-induced microdamage in bone contributes to stress and fragility fractures and acts as a stimulus for bone remodelling. Detecting such microdamage is difficult as pre-existing microdamage sustained in vivo must be differentiated from artefactual damage incurred during specimen preparation. This was addressed by bulk staining specimens in alcohol-soluble basic fuchsin dye, but cutting and grinding them in an aqueous medium. Nonetheless, some artefactual cracks are partially stained and careful observation under transmitted light, or epifluorescence microscopy, is required. Fuchsin lodges in cracks, but is not site-specific. Cracks are discontinuities in the calcium-rich bone matrix and chelating agents, which bind calcium, can selectively label them. Oxytetracycline, alizarin complexone, calcein, calcein blue and xylenol orange all selectively bind microcracks and, as they fluoresce at different wavelengths and colours, can be used in sequence to label microcrack growth. New agents that only fluoresce when involved in a chelate are currently being developed--fluorescent photoinduced electron transfer (PET) sensors. Such agents enable microdamage to be quantified and crack growth to be measured and are useful histological tools in providing data for modelling the material behaviour of bone. However, a non-invasive method is needed to measure microdamage in patients. Micro-CT is being studied and initial work with iodine dyes linked to a chelating group has shown some promise. In the long term, it is hoped that repeated measurements can be made at critical sites and microdamage accumulation monitored. Quantification of microdamage, together with bone mass measurements, will help in predicting and preventing bone fracture failure in patients with osteoporosis.

Detecting microdamage in bone

PubMed Central

Lee, TC; Mohsin, S; Taylor, D; Parkesh, R; Gunnlaugsson, T; O'Brien, FJ; Giehl, M; Gowin, W

2003-01-01

Fatigue-induced microdamage in bone contributes to stress and fragility fractures and acts as a stimulus for bone remodelling. Detecting such microdamage is difficult as pre-existing microdamage sustained in vivo must be differentiated from artefactual damage incurred during specimen preparation. This was addressed by bulk staining specimens in alcohol-soluble basic fuchsin dye, but cutting and grinding them in an aqueous medium. Nonetheless, some artefactual cracks are partially stained and careful observation under transmitted light, or epifluorescence microscopy, is required. Fuchsin lodges in cracks, but is not site-specific. Cracks are discontinuities in the calcium-rich bone matrix and chelating agents, which bind calcium, can selectively label them. Oxytetracycline, alizarin complexone, calcein, calcein blue and xylenol orange all selectively bind microcracks and, as they fluoresce at different wavelengths and colours, can be used in sequence to label microcrack growth. New agents that only fluoresce when involved in a chelate are currently being developed – fluorescent photoinduced electron transfer (PET) sensors. Such agents enable microdamage to be quantified and crack growth to be measured and are useful histological tools in providing data for modelling the material behaviour of bone. However, a non-invasive method is needed to measure microdamage in patients. Micro-CT is being studied and initial work with iodine dyes linked to a chelating group has shown some promise. In the long term, it is hoped that repeated measurements can be made at critical sites and microdamage accumulation monitored. Quantification of microdamage, together with bone mass measurements, will help in predicting and preventing bone fracture failure in patients with osteoporosis. PMID:12924817

Bone grafts.

PubMed

Hubble, Matthew J W

2002-09-01

Bone grafts are used in musculoskeletal surgery to restore structural integrity and enhance osteogenic potential. The demand for bone graft for skeletal reconstruction in bone tumor, revision arthroplasty, and trauma surgery, couple with recent advances in understanding and application of the biology of bone transplantation, has resulted in an exponential increase in the number of bone-grafting procedures performed over the last decade. It is estimated that 1.5 million bone-grafting procedures are currently performed worldwide each year, compared to a fraction of that number 20 years ago. Major developments also have resulted in the harvesting, storage, and use of bone grafts and production of graft derivatives, substitutes, and bone-inducing agents.

Biomechanical forces in the skeleton and their relevance to bone metastasis: biology and engineering considerations

PubMed Central

Lynch, Maureen; Fischbach, Claudia

2014-01-01

Bone metastasis represents the leading cause of breast cancer related-deaths. However, the effect of skeleton-associated biomechanical signals on the initiation, progression, and therapy response of breast cancer bone metastasis is largely unknown. This review seeks to highlight possible functional connections between skeletal mechanical signals and breast cancer bone metastasis and their contribution to clinical outcome. It provides an introduction to the physical and biological signals underlying bone functional adaptation and discusses the modulatory roles of mechanical loading and breast cancer metastasis in this process. Following a definition of biophysical design criteria, in vitro and in vivo approaches from the fields of bone biomechanics and tissue engineering will be reviewed that may be suitable to investigate breast cancer bone metastasis as a function of varied mechano-signaling. Finally, an outlook of future opportunities and challenges associated with this newly emerging field will be provided. PMID:25174311

Bone density in limb-immobilized beagles: An animal model for bone loss in weightlessness

NASA Technical Reports Server (NTRS)

Wolinsky, Ira

1987-01-01

Prolonged weightlessness is man in space flight results in a slow progressive demineralization of bone accompanied by an increased calcium output in the urine resulting in negative calcium balances. This possibly irreversible bone loss may constitute a serious limiting factor to long duration manned space flight. In order to seek and test preventative measures an appropriate ground based animal model simulating weightlessness is necessary. Use of the mature Beagle in limb immobilization has been documented as an excellent model for orthopedic research since this animal most closely simulates the phenomenom of bone loss with regards to growth, remodeling, structure, chemistry and mineralization. The purpose of this project is to develop a research protocol for the study of bone loss in Beagles during and after cast immobilization of a hindleg; research will then be initiated.

Carcinogenicity and teratogenicity vs. psychogenicity: Psychological characteristics associated with self-reported Agent Orange exposure among Vietnam combat veterans who seek treatment for substance abuse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robinowitz, R.; Roberts, W.R.; Dolan, M.P.

1989-09-01

This study asked, What are the psychological characteristics of Vietnam combat veterans who claim Agent Orange exposure when compared with combat-experienced cohorts who do not report such contamination The question was researched among 153 heroin addicts, polydrug abusers, and chronic alcoholics who were seeking treatment: 58 reported moderate to high defoliant exposure while in combat; 95 reported minimal to no exposure while in Vietnam. The null hypothesis was accepted for measures of childhood and present family social climate, premilitary backgrounds, reasons for seeking treatment, patterns and types of illicit drug and alcohol use, interpersonal problems, intellectual functioning, and short-term memory.more » The null hypothesis was rejected for personality differences, however, those who self-reported high Agent Orange exposure scored significantly higher on MMPI scales F, Hypochondriasis, Depression, Paranoia, Psychasthenia, Schizophrenia, Mania, and Social interoversion. The results suggest that clinicians carefully assess attributional processing of those who report traumatic experience.« less

Charcot Foot

MedlinePlus

... occur in people who have significant nerve damage (neuropathy). The bones are weakened enough to fracture, and ... living with diabetes—a disease often associated with neuropathy—take preventive measures and seek immediate care if ...

New Antiresorptive Therapies for Postmenopausal Osteoporosis

PubMed Central

2015-01-01

Osteoporosis is a systemic skeletal disease whose risk increases with age and it is common among postmenopausal women. Currently, almost all pharmacological agents for osteoporosis target the bone resorption component of bone remodeling activity. Current antiresorptive agents are effective, but the effectiveness of some agents is limited by real or perceived intolerance, longterm adverse events (AEs), coexisting comorbidities, and inadequate long-term adherence. New antiresorptive therapies that may expand options for the prevention and treatment of osteoporosis include denosumab, combination of conjugated estrogen/bazedoxifene and cathepsin K inhibitors. However, the long-term efficacy and AEs of these antiresorptive therapies need to be confirmed in studies with a longer follow-up period. PMID:26046031

Design of calcium phosphate ceramics for drug delivery applications in bone diseases: A review of the parameters affecting the loading and release of the therapeutic substance.

PubMed

Parent, Marianne; Baradari, Hiva; Champion, Eric; Damia, Chantal; Viana-Trecant, Marylène

2017-04-28

Effective treatment of critical-size defects is a key challenge in restorative surgery of bone. The strategy covers the implantation of biocompatible, osteoconductive, bioactive and biodegradable devices which (1) well interact with native tissue, mimic multi-dimensional and hierarchical structure of bone and (2) are able to enhance bone repair, treating post implantation pathologies or bone diseases by local delivery of therapeutic agents. Among different options, calcium phosphate biomaterials are found to be attractive choices, due to their excellent biocompatibility, customisable bioactivity and biodegradability. Several approaches have been established to enhance this material ability to be loaded with a therapeutic agent, in order to obtain an in situ controlled release that meets the clinical needs. This article reviews the most important factors influencing on both drug loading and release capacity of porous calcium phosphate bone substitutes. Characteristics of the carrier, drug/carrier interactions, experimental conditions of drug loading and evaluation of drug delivery are considered successively. Copyright © 2017 Elsevier B.V. All rights reserved.

Alkylating chemotherapeutic agents cyclophosphamide and melphalan cause functional injury to human bone marrow-derived mesenchymal stem cells.

PubMed

Kemp, Kevin; Morse, Ruth; Sanders, Kelly; Hows, Jill; Donaldson, Craig

2011-07-01

The adverse effects of melphalan and cyclophosphamide on hematopoietic stem cells are well-known; however, the effects on the mesenchymal stem cells (MSCs) residing in the bone marrow are less well characterised. Examining the effects of chemotherapeutic agents on patient MSCs in vivo is difficult due to variability in patients and differences in the drug combinations used, both of which could have implications on MSC function. As drugs are not commonly used as single agents during high-dose chemotherapy (HDC) regimens, there is a lack of data comparing the short- or long-term effects these drugs have on patients post treatment. To help address these problems, the effects of the alkylating chemotherapeutic agents cyclophosphamide and melphalan on human bone marrow MSCs were evaluated in vitro. Within this study, the exposure of MSCs to the chemotherapeutic agents cyclophosphamide or melphalan had strong negative effects on MSC expansion and CD44 expression. In addition, changes were seen in the ability of MSCs to support hematopoietic cell migration and repopulation. These observations therefore highlight potential disadvantages in the use of autologous MSCs in chemotherapeutically pre-treated patients for future therapeutic strategies. Furthermore, this study suggests that if the damage caused by chemotherapeutic agents to marrow MSCs is substantial, it would be logical to use cultured allogeneic MSCs therapeutically to assist or repair the marrow microenvironment after HDC.

The prevention of fragility fractures in patients with non-metastatic prostate cancer: a position statement by the international osteoporosis foundation

PubMed Central

Cianferotti, Luisella; Bertoldo, Francesco; Carini, Marco; Kanis, John A.; Lapini, Alberto; Longo, Nicola; Martorana, Giuseppe; Mirone, Vincenzo; Reginster, Jean-Yves; Rizzoli, Rene; Brandi, Maria Luisa

2017-01-01

Androgen deprivation therapy is commonly employed for the treatment of non-metastatic prostate cancer as primary or adjuvant treatment. The skeleton is greatly compromised in men with prostate cancer during androgen deprivation therapy because of the lack of androgens and estrogens, which are trophic factors for bone. Men receiving androgen deprivation therapy sustain variable degrees of bone loss with an increased risk of fragility fractures. Several bone antiresorptive agents have been tested in randomized controlled trials in these patients. Oral bisphosphonates, such as alendronate and risedronate, and intravenous bisphosphonates, such as pamidronate and zoledronic acid, have been shown to increase bone density and decrease the risk of fractures in men receiving androgen deprivation therapy. Denosumab, a fully monoclonal antibody that inhibits osteoclastic-mediated bone resorption, is also effective in increasing bone mineral density and reducing fracture rates in these patients. The assessment of fracture risk, T-score and/or the evaluation of prevalent fragility fractures are mandatory for the selection of patients who will benefit from antiresorptive therapy. In the future, new agents modulating bone turnover and skeletal muscle metabolism will be available for testing in these subjects. PMID:29088899

The prevention of fragility fractures in patients with non-metastatic prostate cancer: a position statement by the international osteoporosis foundation.

PubMed

Cianferotti, Luisella; Bertoldo, Francesco; Carini, Marco; Kanis, John A; Lapini, Alberto; Longo, Nicola; Martorana, Giuseppe; Mirone, Vincenzo; Reginster, Jean-Yves; Rizzoli, Rene; Brandi, Maria Luisa

2017-09-26

Androgen deprivation therapy is commonly employed for the treatment of non-metastatic prostate cancer as primary or adjuvant treatment. The skeleton is greatly compromised in men with prostate cancer during androgen deprivation therapy because of the lack of androgens and estrogens, which are trophic factors for bone. Men receiving androgen deprivation therapy sustain variable degrees of bone loss with an increased risk of fragility fractures. Several bone antiresorptive agents have been tested in randomized controlled trials in these patients. Oral bisphosphonates, such as alendronate and risedronate, and intravenous bisphosphonates, such as pamidronate and zoledronic acid, have been shown to increase bone density and decrease the risk of fractures in men receiving androgen deprivation therapy. Denosumab, a fully monoclonal antibody that inhibits osteoclastic-mediated bone resorption, is also effective in increasing bone mineral density and reducing fracture rates in these patients. The assessment of fracture risk, T-score and/or the evaluation of prevalent fragility fractures are mandatory for the selection of patients who will benefit from antiresorptive therapy. In the future, new agents modulating bone turnover and skeletal muscle metabolism will be available for testing in these subjects.

[New methods for the evaluation of bone quality. Assessment of bone structural property using imaging.

PubMed

Ito, Masako

Structural property of bone includes micro- or nano-structural property of the trabecular and cortical bone, and macroscopic geometry. Radiological technique is useful to analyze the bone structural property;multi-detector row CT(MDCT)or high-resolution peripheral QCT(HR-pQCT)is available to analyze human bone in vivo . For the analysis of hip geometry, CT-based hip structure analysis(HSA)is available as well as DXA-based HSA. These structural parameters are related to biomechanical property, and these assessment tools provide information of pathological changes or the effects of anti-osteoporotic agents on bone.

Bone vascularization: a way to study bone microarchitecture?

NASA Astrophysics Data System (ADS)

Blery, P.; Autrusseau, F.; Crauste, E.; Freuchet, Erwan; Weiss, Pierre; Guédon, J.-P.; Amouriq, Y.

2014-03-01

Trabecular bone and its microarchitecture are of prime importance for health. Studying vascularization helps to better know the relationship between bone and vascular microarchitecture. This research is an animal study (nine Lewis rats), based on the perfusion of vascularization by a contrast agent (a mixture of 50% barium sulfate with 1.5% of gelatin) before euthanasia. The samples were studied by micro CT at a resolution of 9μm. Softwares were used to show 3D volumes of bone and vessels, to calculate bone and vessels microarchitecture parameters. This study aims to understand simultaneously the bone microarchitecture and its vascular microarchitecture.

Help Helps, but Only so Much: Research on Help Seeking with Intelligent Tutoring Systems

ERIC Educational Resources Information Center

Aleven, Vincent; Roll, Ido; McLaren, Bruce M.; Koedinger, Kenneth R.

2016-01-01

Help seeking is an important process in self-regulated learning (SRL). It may influence learning with intelligent tutoring systems (ITSs), because many ITSs provide help, often at the student's request. The Help Tutor was a tutor agent that gave in-context, real-time feedback on students' help-seeking behavior, as they were learning with an ITS.…

Bone Blood Flow During Simulated Microgravity: Physiological and Molecular Mechanisms

NASA Technical Reports Server (NTRS)

Bloomfield, Susan A.

1999-01-01

Blood flow to bone has been shown to affect bone mass and presumably bone strength. Preliminary data indicate that blood flow to the rat femur decreases after 14 days of simulated microgravity, using hindlimb suspension (HLS). If adult rats subjected to HLS are given dobutamine, a synthetic catecholamine which can cause peripheral vasodilation and increased blood flow, the loss of cortical bone area usually observed is prevented. Further, mechanisms exist at the molecular level to link changes in bone blood flow to changes in bone cell activity, particularly for vasoactive agents like nitric oxide (NO). The decreases in fluid shear stress created by fluid flow associated with the shifts of plasma volume during microgravity may result in alterations in expression of vasoactive agents such as NO, producing important functional effects on bone cells. The primary aim of this project is to characterize changes in 1) bone blood flow, 2) indices of bone mass, geometry, and strength, and 3) changes in gene expression for modulators of nitric oxide activity (e.g., nitric oxide synthase) and other candidate genes involved in signal transduction of mechanical loading after 3, 7, 14, 21, and 28 days of HLS in the adult rat. Using a rat of at least 5 months of age avoids inadvertently studying effects of simulated microgravity on growing, rather than adult, bone. Utilizing the results of these studies, we will then define how altered blood flow contributes to changes in bone with simulated microgravity by administering a vasodilatory agent (which increases blood flow to tissues) during hindlimb suspension. In all studies, responses in the unloaded hindlimb bones (tibial shaft, femoral neck) will be compared with those in the weightbearing humeral shaft and the non-weightbearing calvarium (skull) from the same animal. Bone volumetric mineral density and geometry will be quantified by peripheral quantitative CT; structural and material properties of the long bones will be determined by 3-point bending (tibia, humerus) or compression (femoral neck) testing to failure. A unique aspect of these studies will be defining the time course of changes in gene expression in bone cell populations with unloading, accomplished with Northern blots, in situ hybridization, and immunohistochemistry. These studies have high relevance for concurrent protocols being proposed by investigators on NSBRI Cardiovascular and Muscle teams, with blood flow data available on a number of tissues other than bone. Further, dobutamine and other Beta-agonists have been tested as countermeasures for altered muscle and cardiovascular function. Results of the intervention tested in our studies have potential relevance for a number of systemic changes seen with prolonged spaceflight.

Contrast Agents for Micro-Computed Tomography of Microdamage in Bone

DTIC Science & Technology

2011-01-01

solution from DI water (or PBS). For the second model, a 5 mm cube of cortical bone tissue was embedded in polymethylmethacrylate and sectioned...radiography1 and as a radiopacifer in polymethylmethacrylate bone cement.2 Current commercial products for either application use microscale BaSO4 particles... polymethylmethacrylate bone cement (Lewis, 1997). The objective of this study was to non-destructively and three-dimensionally image microdamage

Concern and Risk Perception: Effects on Osteoprotective Behaviour

PubMed Central

Barcenilla-Wong, A. L.; Chen, J. S.; March, L. M.

2014-01-01

This study aimed to determine the effect that level of concern for osteoporosis, as well as self-perceived risk of osteoporosis and fracture, has on supplementation use, seeking medical advice, bone mineral density (BMD) testing, and antiosteoporosis medication (AOM) use. Study subjects were 1,095 female Australian participants of the Global Longitudinal study of Osteoporosis in Women (GLOW) untreated for osteoporosis at baseline. Study outcomes from self-administered questionnaires included calcium and vitamin D supplementation, self-reported seeking of medical advice regarding osteoporosis, BMD testing, and AOM use in the last 12 months at the late assessment. Logistic regression was used in the analysis. Concern significantly increased the likelihood of seeking medical advice and, however, had no significant impact on screening or treatment. Heightened self-perceived risks of osteoporosis and fracture both significantly increased the likelihood of seeking medical advice and BMD testing while elevated self-perceived risk of fracture increased AOM use. Supplementation use was not significantly associated with concern levels and risk perception. Concern and risk perceptions to osteoporosis and fracture were significantly associated with certain bone-protective behaviours. However, the disconnect between perceived osteoporosis risk and AOM use illustrates the need to emphasize the connection between osteoporosis and fracture in future education programs. PMID:25276471

[Homeostasis and Disorder of Musculoskeletal System.Cellular dynamics in musculoskeletal system visualized by intravital imaging techniques.

PubMed

Kikuta, Junichi; Ishii, Masaru

Bone is continually remodeled by bone-resorbing osteoclasts and bone-forming osteoblasts. Although it has long been believed that bone homeostasis is tightly regulated by communication between osteoclasts and osteoblasts, the fundamental process and dynamics have remained elusive. We originally established an advanced imaging system to visualize living bone tissues using intravital two-photon microscopy. By means of this system, we revealed the in vivo behavior of bone-resorbing osteoclasts and bone-forming osteoblasts in bone tissues. This approach facilitates investigation of cellular dynamics in the pathogenesis of musculoskeletal disorders, and would thus be useful for evaluating the efficacy of novel therapeutic agents.

Biomimetic fiber mesh scaffolds based on gelatin and hydroxyapatite nano-rods: Designing intrinsic skills to attain bone reparation abilities.

PubMed

Sartuqui, Javier; Gravina, A Noel; Rial, Ramón; Benedini, Luciano A; Yahia, L'Hocine; Ruso, Juan M; Messina, Paula V

2016-09-01

Intrinsic material skills have a deep effect on the mechanical and biological performance of bone substitutes, as well as on its associated biodegradation properties. In this work we have manipulated the preparation of collagenous derived fiber mesh frameworks to display a specific composition, morphology, open macroporosity, surface roughness and permeability characteristics. Next, the effect of the induced physicochemical attributes on the scaffold's mechanical behavior, bone bonding potential and biodegradability were evaluated. It was found that the scaffold microstructure, their inherent surface roughness, and the compression strength of the gelatin scaffolds can be modulated by the effect of the cross-linking agent and, essentially, by mimicking the nano-scale size of hydroxyapatite in natural bone. A clear effect of bioactive hydroxyapatite nano-rods on the scaffolds skills can be appreciated and it is greater than the effect of the cross-linking agent, offering a huge perspective for the upcoming progress of bone implant technology. Copyright © 2016 Elsevier B.V. All rights reserved.

[Action of Calendula officinalis essence on bone preservation after the extraction].

PubMed

Uribe-Fentanes, Laura K; Soriano-Padilla, Fernando; Pérez-Frutos, Jorge Raúl; Veras-Hernández, Miriam Alejandra

2018-01-01

Calendula officinalis is a phytodrug used as analgesic, antiseptic and wound-healing agent due to its collagenogenic effect, which is why it is a convenient and affordable treatment that promotes alveolar bone preservation after tooth extraction in vivo. The aim of this study was to use Calendula officinalis during and after tooth extraction to determine its ability to preserve bone after this procedure. We established two groups matched by age, gender and position of the third molar. We used with patients on the experimental group Calendula officinalis diluted 10% as an irrigant during surgical extraction of third molars. We performed the conventional way with the control group irrigating with saline solution. Subsequently, both groups continued to make mouthwash for a week with the irrigating agent. Every week for a month, each patient underwent periapical radiography, out of which we took measurements of alveolar ridges and depth of alveolar bone, which were compared. There is statistically significant evidence to state that Calendula officinalis favorably affects bone preservation after extraction.

Juvenile Gaucher disease simulating osteomyelitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, J.H.; Ortega, J.A.; Heisel, M.A.

1981-10-01

A case in which several imaging procedures suggested juvenile Gaucher disease in a child who presented with symptomatology of osteomyelitis is discussed. The 20-month girl was given a Technetium-99m radionuclide skeletal examination which revealed intense uptake of tracer agents along the shaft of the right femur. It was also found that the liver and spleen were dramatically Ga-67 avid. The bone pain symptomatology suggested an osteomyelitis of the femur, but skeletal scintigraphy with Tc-99m-labeled bone tracer demonstrated photopenic areas involving the femur, suggesting that the bone pain may have been due to marrow packed with Gaucher cells. This overexpansion ofmore » the marrow may lead to microfractures with remodeling seen radiographically as periosteal new bone and scintigraphically as increased periosteal deposition of tracer agent. The radiogallium study was useful to exclude an underlying osteomyelitis in the involved femurs. Although juvenile Gaucher disease is unusual, it should be considered in any child who presents with the constellation of hepatosplenomegaly and bone pain simulating osteomyelitis.« less

Efficacy and safety of emtricitabine/tenofovir alafenamide (FTC/TAF) vs. emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as a backbone for treatment of HIV-1 infection in virologically suppressed adults: subgroup analysis by third agent of a randomized, double-blind, active-controlled phase 3 trial^.

PubMed

Post, Frank A; Yazdanpanah, Yazdan; Schembri, Gabriel; Lazzarin, Adriano; Reynes, Jacques; Maggiolo, Franco; Yan, Mingjin; Abram, Michael E; Tran-Muchowski, Cecilia; Cheng, Andrew; Rhee, Martin S

2017-05-01

FTC/TAF was shown to be noninferior to FTC/TDF with advantages in markers of renal and bone safety. To evaluate the efficacy and safety of switching to FTC/TAF from FTC/TDF by third agent (boosted protease inhibitor [PI] vs. unboosted third agent). We conducted a 48-week subgroup analysis based on third agent from a randomized, double blind study in virologically suppressed adults on a FTC/TDF-containing regimen who switched to FTC/TAF vs. continued FTC/TDF while remaining on the same third agent. We randomized (1:1) 663 participants to either switch to FTC/TAF (N = 333) or continue FTC/TDF (N = 330), each with baseline third agent stratifying by class of third agent in the prior treatment regimen (boosted PI 46%, unboosted third agent 54%). At week 48, significant differences in renal biomarkers and bone mineral density were observed favoring FTC/TAF over FTC/TDF (p < 0.05 for all), with similar improvements in the FTC/TAF arm in those who received boosted PI vs. unboosted third agents. At week 48, virologic success rates were similar between treatment groups for those who received a boosted PI (FTC/TAF 92%, FTC/TDF 93%) and for those who received an unboosted third agent (97% vs. 93%). In virologically suppressed patients switching to FTC/TAF from FTC/TDF, high rates of virologic suppression were maintained, while renal and bone safety parameters improved, regardless of whether participants were receiving a boosted PI or an unboosted third agent. FTC/TAF offers safety advantages over FTC/TDF and can be an important option as an NRTI backbone given with a variety of third agents.

Vertebral osteoporosis: perfused animal cadaver model for testing new vertebroplastic agents.

PubMed

Hoell, Thomas; Huschak, Gerald; Beier, Andre; Holzhausen, Hans-Juergen; Meisel, Hans-Joerg; Emmrich, Frank

2010-12-01

Experimental study. It was aimed to establish a cadaver model to imitate osteoporotic perfused vertebral bone and to allow for transpedicular transfer of bone cement and various new materials into vertebrae. The model was perfused to simulate vertebroplasty in the presence of transvertebral blood flow. The injection of bone cement into vertebrae bears the risk of irreversible discharge of material into the venous system of the spinal canal. The bovine cadaver model studied allows visual studies of material distribution in a vertebral bone, the potential spill-out of material, and quantification of washout and disintegration phenomena. Thoracic and lumbar vertebrae from 1-year-old calves were cut transversally into 5 mm slices, macerated, and decalcified. The softened bone slices were compressed between 2 transparent plastic discs. A standard vertebroplasty cannula (outer diameter 3.5 mm, inner diameter 2.5 mm) was inserted into the vertebral body via the pedicle to transfer the different vertebroplasty materials. Arterial blood flow was simulated by means of liquid irrigation via 2 needles in the ventral part of the vertebral body slice. Metal powder was mixed with the solution to indicate the blood flow in the bone. The model was evaluated with the vertebroplasty cement polymethylmethacrylate. The model permitted visualization of the insertion and distribution of vertebroplasty materials. Liquid bone cement was effused into the spinal canal as in the clinical situation. Higher modulus cement acted in the same way as in clinical vertebroplasty. Rigid vertebroplasty agents led to trabecular fractures and stable mechanical interactions with the bone and eventually moved dorsal bone fragments into the spinal canal. Sedimentation of the metal powder indicated regions of perfusion. The model simulated the clinical behavior of liquid and higher modulus vertebroplasty agents in the presence of blood flow. It enabled safe ex vivo testing of the mechanical and physical properties of alternative vertebroplasty materials under flow conditions.

Prevent and cure disuse bone loss

NASA Technical Reports Server (NTRS)

Jee, Webster S. S.

1994-01-01

Anabolic agents like parathyroid hormone and postagladin E-like substances were studied in dogs and rats to determine their effectiveness in the prevention and cure of bone loss due to immobilization. It was determined that postagladin E2 administration prevented immobilization while at the same time it added extra bone in a dose responsive manner. Although bone mass returns, poor trabecular architecture remains after normal ambulation recovery from immobilization. Disuse related bone loss and poor trabecular architecture were cured by post-immobilization postagladin E2 treatment.

Severe hypocalcaemia as a cause of seemingly idiopathic bilateral lower limb oedema.

PubMed

Hung, Aaron Karnell Dachuan

2014-01-10

The existing scientific literature has not drawn a link between severe hypocalcaemia and its role in recalcitrant peripheral oedema. This phenomenon is particularly relevant in oncological and geriatric medicine as bone strengthening but serum calcium-lowering agents such as bisphosphonates and denosumab are used for osteoporosis and/or bone metastasis. This case report, through metastatic prostate cancer in a 66-year-old man with bone metastasis being treated with a monoclonal antibody denosumab, proposes the mechanism of hypocalcaemic oedema as being akin to calcium deprivation such as those induced by calcium channel antagonism. It demonstrates the importance of calcium supplementation as a concurrent treatment while patients are on these osteoclast inhibiting agents.

Polymeric scaffolds as stem cell carriers in bone repair.

PubMed

Rossi, Filippo; Santoro, Marco; Perale, Giuseppe

2015-10-01

Although bone has a high potential to regenerate itself after damage and injury, the efficacious repair of large bone defects resulting from resection, trauma or non-union fractures still requires the implantation of bone grafts. Materials science, in conjunction with biotechnology, can satisfy these needs by developing artificial bones, synthetic substitutes and organ implants. In particular, recent advances in polymer science have provided several innovations, underlying the increasing importance of macromolecules in this field. To address the increasing need for improved bone substitutes, tissue engineering seeks to create synthetic, three-dimensional scaffolds made from polymeric materials, incorporating stem cells and growth factors, to induce new bone tissue formation. Polymeric materials have shown a great affinity for cell transplantation and differentiation and, moreover, their structure can be tuned in order to maintain an adequate mechanical resistance and contemporarily be fully bioresorbable. This review emphasizes recent progress in polymer science that allows relaible polymeric scaffolds to be synthesized for stem cell growth in bone regeneration. Copyright © 2013 John Wiley & Sons, Ltd.

A primer of bone metastases management in breast cancer patients.

PubMed

Petrut, B; Trinkaus, M; Simmons, C; Clemons, M

2008-01-01

Bone is the most common site for distant spread of breast cancer. Following a diagnosis of metastatic bone disease, patients can suffer from significant morbidity because of pain and skeletal related events (SRES). Bisphosphonates are potent inhibitors of osteoclastic function and the mainstay of bone-directed therapy for bone metastases. The aims of bisphosphonates are to prevent and delay SRES, to reduce bone pain, and to improve quality of life. Bisphosphonate therapy appears to have revolutionized treatment of bone metastases, but bisphosphonate use has several limitations. Those limitations include the high cost of the agents and the need for return trips to the clinic for intravenous treatment. Moreover, many uncertainties surround bisphosphonate use-for example, the timing of bisphosphonate initiation, the choice of bisphosphonate to use, the optimal duration of treatment, and the appropriate means to identify patients who will and will not benefit. In addition, potentially serious adverse effects have been associated with bisphosphonate use-for example, renal toxicity, gastrointestinal side effects, and osteonecrosis of the jaw. The present review is intended as a primer for oncology specialists who treat patients with bone metastases secondary to breast cancer. It focuses on bisphosphonate treatment guidelines, the evidence for those guidelines, and a discussion of new therapeutic agents. It also discusses the use of biochemical markers of bone metabolism, which show promise for predicting the risk of a patient's developing a SRE and of benefiting from bisphosphonate treatment.

Bone vascularization and bone micro-architecture characterizations according to the μCT resolution

NASA Astrophysics Data System (ADS)

Crauste, E.; Autrusseau, F.; Guédon, Jp.; Pilet, P.; Amouriq, Y.; Weiss, P.; Giumelli, B.

2015-03-01

Trabecular bone and its micro-architecture are of prime importance for health. Changes of bone micro-architecture are linked to different pathological situations like osteoporosis and begin now to be understood. In a previous paper [12], we started to investigate the relationships between bone and vessels and proposed some indices of characterization for the vessels issued from those used for the bone. Our main objective in this paper is to qualify the classical values used for bone as well as those we proposed for vessels according to different acquisition parameters and for several thresholding methods used to separate bone vessels and background. This study is also based on vessels perfusion by a contrast agent (barium sulfate mixed with gelatin) before euthanasia on rats. Femurs and tibias as well as mandibles were removed after rat's death and were imaged by microCT (Skyscan 1272, Bruker, Belgium) with a resolution ranging from 18 to 3μm. The so obtained images were analyzed with various softwares (NRecon Reconstruction, CtAn, and CtVox from Bruker) in order to calculate bone and vessels micro-architecture parameters (density of bone/blood within the volume), and to know if the results both for bone and vascular micro-architecture are constant along the chosen pixel resolution. The result is clearly negative. We found a very different characterization both for bone and vessels with the 3μm acquisition. Tibia and mandibles bones were also used to show results that can be visually assessed. The largest portions of the vascular tree are orthogonal to the obtained slices of the bone. Therefore, the contrast agent appears as cylinders of various sizes.

Bone-seeking TRAP conjugates: surprising observations and their implications on the development of gallium-68-labeled bisphosphonates

PubMed Central

2012-01-01

Background Bisphosphonates possess strong affinity to bone. 99mTc bisphosphonate complexes are widely used for bone scintigraphy. For positron emission tomography (PET) bone imaging, Ga-68-based PET tracers based on bisphosphonates are highly desirable. Findings Two trimeric bisphosphonate conjugates of the triazacyclononane-phosphinate (TRAP) chelator were synthesized, labeled with Ga-68, and used for microPET imaging of bone in male Lewis rats. Both Ga-68 tracers show bone uptake and, thus, are suitable for PET bone imaging. Surprisingly, Ga-71 nuclear magnetic resonance data prove that Ga(III) is not located in the chelating cavity of TRAP and must therefore be bound by the conjugated bisphosphonate units. Conclusion The intrinsic Ga-68 chelating properties of TRAP are not needed for Ga-68 PET bone imaging with TRAP-bisphosphonate conjugates. Here, TRAP serves only as a trimeric scaffold. For preparation of Ga-68-based bone seekers for PET, it appears sufficient to equip branched scaffolds with multiple bisphosphonate units, which serve both Ga-68-binding and bone-targeting purposes. PMID:22464278

Cancer-associated bone disease.

PubMed

Rizzoli, R; Body, J-J; Brandi, M-L; Cannata-Andia, J; Chappard, D; El Maghraoui, A; Glüer, C C; Kendler, D; Napoli, N; Papaioannou, A; Pierroz, D D; Rahme, M; Van Poznak, C H; de Villiers, T J; El Hajj Fuleihan, G

2013-12-01

Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence-based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non-communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancer-associated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidence-based care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations.

Radiopharmaceuticals in the elderly cancer patient: Practical considerations, with a focus on prostate cancer therapy: A position paper from the International Society of Geriatric Oncology Task Force.

PubMed

Prior, John O; Gillessen, Silke; Wirth, Manfred; Dale, William; Aapro, Matti; Oyen, Wim J G

2017-05-01

Molecular imaging using radiopharmaceuticals has a clear role in visualising the presence and extent of tumour at diagnosis and monitoring response to therapy. Such imaging provides prognostic and predictive information relevant to management, e.g. by quantifying active tumour mass using positron emission tomography/computed tomography (PET/CT). As these techniques require only pharmacologically inactive doses, age and potential frailty are generally not important. However, this may be different for therapy involving radionuclides because the radiation can impact normal bodily function (e.g. myelosuppression). Since the introduction of Iodine-131 as a targeted therapy in thyroid cancer, several radiopharmaceuticals have been widely used. These include antibodies and peptides targeting specific epitopes on cancer cells. Among therapeutic bone seeking agents, radium-223 ( 223 Ra) stands out as it results in survival gains in patients with castration-resistant prostate cancer and symptomatic bone metastases. The therapeutic use of radiopharmaceuticals in elderly cancer patients specifically has received little attention. In elderly prostate cancer patients, there may be advantages in radionuclides' ease of use and relative lack of toxicity compared with cytotoxic and cytostatic drugs. When using radionuclide therapies, close coordination between oncology and nuclear medicine is needed to ensure safe and effective use. Bone marrow reserve has to be considered. As most radiopharmaceuticals are cleared renally, dose adjustment may be required in the elderly. However, compared with younger patients there is less, if any, concern about adverse long-term radiation effects such as radiation-induced second cancers. Issues regarding the safety of medical staff, care givers and the wider environment can be managed by current precautions. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Automated processing of human bone marrow can result in a population of mononuclear cells capable of achieving engraftment following transplantation.

PubMed

Areman, E M; Cullis, H; Spitzer, T; Sacher, R A

1991-10-01

A concentrate of mononuclear bone marrow cells is often desired for ex vivo treatment with pharmacologic agents, monoclonal antibodies, cytokines, and other agents prior to transplantation. A method has been developed for automated separation of mononuclear cells from large volumes of harvested bone marrow. A programmable instrument originally designed for clinical ex vivo cell separation and the plasma-pheresis of patients and blood donors was adapted to permit rapid preparation, in a closed sterile system, of a bone marrow product enriched with mononuclear cells. A mean (+/- SEM) of 53 +/- 30 percent of the original mononuclear cells was recovered in a volume of 125 +/- 42 mL containing 82 +/- 12 percent mononuclear cells. This technique removed 95 +/- 9 percent of the red cells in the original marrow. No density gradient materials or sedimenting agents were employed in this process. Of 36 marrows processed by this technique, 19 autologous (6 of which were purged with 4-hydroperoxycyclophosphamide) and 7 allogeneic marrows have been transplanted, with all evaluable patients achieving a neutrophil count of 0.5 x 10(9) per L in a mean (+/- SEM) of 21 +/- 6 days.

[Chemoembolization of symptomatic bone metastases: technical considerations and therapeutic effectiveness].

PubMed

Clarençon, F; Cormier, E; Di Maria, F; Sourour, N-A; Szatmary, Z; Rose, M; Chiras, J

2011-09-01

Chemoembolization of bone metastases is defined by the intraarterial perfusion of a chemotherapy agent followed by microparticles embolization to improve tissue impregnation. This technique increases the local concentration of the chemotherapy agent. Tumor response (stable or reduced tumor size) is achieved in 30-80% of cases with symptomatic relief in over 80% of cases. The indications, technical considerations, and effectiveness of this procedure will be reviewed. Copyright © 2011 Elsevier Masson SAS and Éditions françaises de radiologie. All rights reserved.

Detection, Isolation and Characterization of an Agent from Febrile Patients in Malaysia Serologically Reactive with Rickettsia sennetsu.

DTIC Science & Technology

1983-12-01

sennetsu by inoculating mice with the blood and bone marrow homogenates of a patient suffering from "Japanese infectious mononucleosis ." Tanaka and...Rickettsia sennetsu in Cell Culture System. Jpn. J. Microbiol. 9:75-86. Misao, T., and Kobayashi, Y. 1954. Studies on Infectious Mononucleosis . I...Isolation of Etiologic Agent from Blood, Bone Marrow and Lymph Node of a Patient with Infectious Mononucleosis by Using Mice. Tokyo Iji Shinshi 71:683-686

Protective effects of total saponins from stem and leaf of Panax ginseng against cyclophosphamide-induced genotoxicity and apoptosis in mouse bone marrow cells and peripheral lymphocyte cells.

PubMed

Zhang, Qiu Hua; Wu, Chun Fu; Duan, Lian; Yang, Jing Yu

2008-01-01

Cyclophosphamide (CP), commonly used anti-cancer, induces oxidative stress and is cytotoxic to normal cells. It is very important to choice the protective agent combined CP to reduce the side effects in cancer treatment. Ginsenosides are biological active constituents of Panax ginseng C.A. Meyer that acts as the tonic agent for the cancer patients to reduce the side effects in the clinic application. Because CP is a pro-oxidant agent and induces oxidative stress by the generation of free radicals to decrease the activities of anti-oxidant enzymes, the protective effects of the total saponins from stem and leaf of P. ginseng C.A. Meyer (TSPG) act as an anti-oxidant agent against the decreased anti-oxidant enzymes, the genotoxicity and apoptosis induced by CP was carried out. The alkaline single cell gel electrophoresis was employed to detect DNA damage; flow cytometry assay and AO/EB staining assay were employed to measure cell apoptosis; the enzymatic anti-oxidants (T-SOD, CAT and GPx) and non-enzymatic anti-oxidant (GSH) were measured by the various colorimetric methods. CP induced the significant DNA damage in mouse peripheral lymphocytes in time- and dose-dependent manners, inhibited the activities of T-SOD, GPx and CAT, and decreased the contents of GSH in mouse blood, triggered bone marrow cell apoptosis at 6 and 12h. TSPG significantly reduced CP-induced DNA damages in bone marrow cells and peripheral lymphocyte cells, antagonized CP-induced reduction of T-SOD, GPx, CAT activities and the GSH contents, decreased the bone marrow cell apoptosis induced by CP. TSPG, significantly reduced the genotoxicity of CP in bone marrow cells and peripheral lymphocyte cells, and decreased the apoptotic cell number induced by CP in bone marrow cells. The effects of TSPG on T-SOD, GPx, CAT activities and GSH contents might partially contribute to its protective effects on CP-induced cell toxicities.

Is cortical bone hip? What determines cortical bone properties?

PubMed

Epstein, Sol

2007-07-01

Increased bone turnover may produce a disturbance in bone structure which may result in fracture. In cortical bone, both reduction in turnover and increase in hip bone mineral density (BMD) may be necessary to decrease hip fracture risk and may require relatively greater proportionate changes than for trabecular bone. It should also be noted that increased porosity produces disproportionate reduction in bone strength, and studies have shown that increased cortical porosity and decreased cortical thickness are associated with hip fracture. Continued studies for determining the causes of bone strength and deterioration show distinct promise. Osteocyte viability has been observed to be an indicator of bone strength, with viability as the result of maintaining physiological levels of loading and osteocyte apoptosis as the result of a decrease in loading. Osteocyte apoptosis and decrease are major factors in the bone loss and fracture associated with aging. Both the osteocyte and periosteal cell layer are assuming greater importance in the process of maintaining skeletal integrity as our knowledge of these cells expand, as well being a target for pharmacological agents to reduce fracture especially in cortical bone. The bisphosphonate alendronate has been seen to have a positive effect on cortical bone by allowing customary periosteal growth, while reducing the rate of endocortical bone remodeling and slowing bone loss from the endocortical surface. Risedronate treatment effects were attributed to decrease in bone resorption and thus a decrease in fracture risk. Ibandronate has been seen to increase BMD as the spine and femur as well as a reduced incidence of new vertebral fractures and non vertebral on subset post hoc analysis. And treatment with the anabolic agent PTH(1-34) documented modeling and remodelling of quiescent and active bone surfaces. Receptor activator of nuclear factor kappa B ligand (RANKL) plays a key role in bone destruction, and the human monoclonal antibody denosumab binds to RANKL, inhibiting its action and thus improving BMD significantly.

Massive Bone Loss Due to Orchidectomy and Localized Disuse: Preventive Effects of a Biosphonsphonate

NASA Astrophysics Data System (ADS)

Libouban, H.; Moreau, M. F.; Chappard, D.

2008-06-01

Orchidectomy (ORX) and hindlimb paralysis induced by botulinum neurotoxin (BTX) were combined to see if their effects were cumulative and if bone loss could be prevented by an antiresorptive agent (risedronate) or testosterone. Four groups of mature rats were studied for 1 month: SHAM operated; ORX and right hindlimb immobilization (BTX); ORX+BTX+risedronate or testosterone. Bone loss and microarchitecture deterioration were maximized on the immobilized bone. Risedronate but not testosterone prevented trabecular bone loss but was less effective on cortical bone loss. ORX and BTX had additive effects on bone loss which can be prevented by risedronate but not testosterone.

Seeking new acne treatment from natural products, devices and synthetic drug discovery.

PubMed

Yang, Ji Hoon; Yoon, Ji Young; Kwon, Hyuck Hoon; Min, Seonguk; Moon, Jungyoon; Suh, Dae Hun

2017-01-01

Despite lots of research on the pathogenesis of acne, the development of new therapeutic agents is still stagnant. Conventional agents which target multiple pathological processes have some serious side effects and this makes seeking new treatment options important for treating acne. As new therapeutic options, researchers are focusing on natural products, synthetic drugs and devices. From natural products, epigallocatechin-3 gallate, lupeol, cannabidiol and Lactobacillus fermented Chamaecyperis obtusa were reported to be possible candidates for novel drugs, targeting multiple pathogenic factors. Synthetic anti- P.acnes agent, nitric oxide nanoparticles and α-mangostin nanoparticles are shown to be effective in acne treatment. Device or procedural methods such as fractional microneedling radiofrequency, cryolysis, photothermolysis and daylight photodynamic therapy have potential as new treatment options for acne. Further large clinical trials comparing these new treatments with existing agents will be necessary in the future.

Seeking new acne treatment from natural products, devices and synthetic drug discovery

PubMed Central

Yoon, Ji Young; Kwon, Hyuck Hoon; Min, Seonguk; Suh, Dae Hun

2017-01-01

ABSTRACT Despite lots of research on the pathogenesis of acne, the development of new therapeutic agents is still stagnant. Conventional agents which target multiple pathological processes have some serious side effects and this makes seeking new treatment options important for treating acne. As new therapeutic options, researchers are focusing on natural products, synthetic drugs and devices. From natural products, epigallocatechin-3 gallate, lupeol, cannabidiol and Lactobacillus fermented Chamaecyperis obtusa were reported to be possible candidates for novel drugs, targeting multiple pathogenic factors. Synthetic anti-P.acnes agent, nitric oxide nanoparticles and α-mangostin nanoparticles are shown to be effective in acne treatment. Device or procedural methods such as fractional microneedling radiofrequency, cryolysis, photothermolysis and daylight photodynamic therapy have potential as new treatment options for acne. Further large clinical trials comparing these new treatments with existing agents will be necessary in the future. PMID:29484092

In vitro stabilization of a low-tin bone-imaging agent (99mTc-Sn-HEDP) by ascorbic acid.

PubMed

Tofe, A J; Francis, M D

1976-09-01

The presence of oxidants in the 99mTc-pertechnetate and of oxygen in diagnostic kits containing low concentrations of Sn(II) has a detrimental effect upon in vitro and in vivo stability. Maintaining a nitrogen atmosphere or increasing the Sn(II) concentration inhibits the formation of 99mTcO4-. However, the latter remedy is likely to cause uptake in the reticuloendothelial system and has been associated with false positive or negative brain scans. We used ascorbic acid (an antioxidant) to ensure the in vitro stability with the low-Sn(II) bone agent disodium etidronate. In vitro stability studies by instant thin-layer chromatography, using high-acitivity generators and "instant pertechnetate," yielded less than 2% free pertechnetate at 24 hr after preparation. Distribution studies in guinea pigs show neither altered distribution of the bone agent nor abnormal distribution of ascorbic acid, suggesting its sole function as a noncomplexing stabilizer.

Optical clearing of articular cartilage: a comparison of clearing agents

NASA Astrophysics Data System (ADS)

Bykov, Alexander; Hautala, Tapio; Kinnunen, Matti; Popov, Alexey; Karhula, Sakari; Saarakkala, Simo; Nieminen, Miika T.; Tuchin, Valery

2015-07-01

Optical clearing technique was applied to the problem of OCT imaging of articular cartilage and subchondral bone. We show that optical clearing significantly enhances visualization of articular cartilage and cartilage-bone interface. The effect of different clearing agents was analyzed. For the clearing, iohexol solution and propylene glycol (PG) were used. Clearing was performed in vitro at room temperature by immersion method. Cylindrical osteochondral samples (d=4.8mm) were drilled from bovine lateral femur and stored in phosphate-buffered saline at -20°C until clearing. Monitoring of clearing process was performed using high-speed spectral-domain OCT system providing axial resolution of 5.8μm at 930nm. Total duration of experiment was 90-100min to ensure saturation of clearing. We have shown that iohexol solution and PG are capable to optically clear articular cartilage enabling reliable characterization of cartilagebone interface with OCT. Being a low osmolarity agent, iohexol provides minimal changes to the thickness of cartilage sample. Clearing saturation time for the cartilage sample with the thickness of 0.9 mm measured with OCT is of 50 min. However, less than 15 min is enough to reliably detect the rear cartilage boundary. Alternatively, PG significantly (60%) reduces the cartilage thickness enabling better visualization of subchondral bone. It was observed that PG has higher clearing rate. The clearing saturation time is of 30 min, however less than 5 min is enough to detect cartilage-bone interface. We conclude that iohexol solution is superior for OCT imaging of cartilage and cartilage-bone interface, while PG suits better for subhondral bone visualization.

[New methods for the evaluation of bone quality. Bone anabolic agents and bone quality.

PubMed

Yamamoto, Norio; Tsuchiya, Hiroyuki

Teriparatide(TPTD)products that can be used clinically in Japan include a daily subcutaneous injection form produced by genetic engineering and a weekly subcutaneous injectable TPTD acetate form produced by chemical synthesis. Published reports indicate that both forms exhibit excellent antifracture efficacy, and as the only anabolic agents that promote osteogenesis, TPTD products now occupy a prominent position. However, the two forms differ considerably, not only in frequency of administration, but also in mechanism of action. The daily form stimulates osteogenesis and accompanying resorption through more radical high bone turnover, and early in the course of treatment, intracortical porosity and apatite crystallization decrease, while immature collagen crosslinking increases. However, because daily formulations also produce an increase in cortical surface area or cortical thickness, the effects are counterbalanced, and bone strength is maintained. In contrast, the weekly form prioritizes osteogenesis, and by concurrently lowering turnover below pretreatment levels, improves trabecular bone mass and structure, and enhances strength without leading to cortical porosity and other undesirable phenomena. Abaloparatide, a PTHrP(1-34)analog that is homologous with the biologically active site of PTH drugs, is currently under development, and we eagerly anticipate further clarification of the mechanism of action of each formulation on bone.

The Effects of Cosmos caudatus on Structural Bone Histomorphometry in Ovariectomized Rats

PubMed Central

Mohamed, Norazlina; Gwee Sian Khee, Sharon; Shuid, Ahmad Nazrun; Muhammad, Norliza; Suhaimi, Farihah; Othman, Faizah; Babji, Abdul Salam; Soelaiman, Ima-Nirwana

2012-01-01

Osteoporosis is considered a serious debilitating disease. Cosmos caudatus (ulam raja), a plant containing antioxidant compounds and minerals, may be used to treat and prevent osteoporosis. This study determines the effectiveness of C. caudatus as bone protective agent in postmenopausal osteoporosis rat model. Thirty-two female rats, aged 3 months old, were divided into 4 groups. Group one was sham operated (sham) while group two was ovariectomized. These two groups were given ionized water by forced feeding. Groups three and four were ovariectomized and given calcium 1% ad libitum and force-fed with C. caudatus at the dose of 500 mg/kg, respectively. Treatments were given six days per week for a period of eight weeks. Body weight was monitored every week and structural bone histomorphometry analyses of the femur bones were performed. Ovariectomy decreased trabecular bone volume (BV/TV), decreased trabecular number (Tb.N), and increased trabecular separation (Tb.Sp). Both calcium 1% and 500 mg/kg C. caudatus reversed the above structural bone histomorphometric parameters to normal level. C. caudatus shows better effect compared to calcium 1% on trabecular number (Tb.N) and trabecular separation (Tb.Sp). Therefore, Cosmos caudatus 500 mg/kg has the potential to act as the therapeutic agent to restore bone damage in postmenopausal women. PMID:22924056

The Effects of Cosmos caudatus on Structural Bone Histomorphometry in Ovariectomized Rats.

PubMed

Mohamed, Norazlina; Gwee Sian Khee, Sharon; Shuid, Ahmad Nazrun; Muhammad, Norliza; Suhaimi, Farihah; Othman, Faizah; Babji, Abdul Salam; Soelaiman, Ima-Nirwana

2012-01-01

Osteoporosis is considered a serious debilitating disease. Cosmos caudatus (ulam raja), a plant containing antioxidant compounds and minerals, may be used to treat and prevent osteoporosis. This study determines the effectiveness of C. caudatus as bone protective agent in postmenopausal osteoporosis rat model. Thirty-two female rats, aged 3 months old, were divided into 4 groups. Group one was sham operated (sham) while group two was ovariectomized. These two groups were given ionized water by forced feeding. Groups three and four were ovariectomized and given calcium 1% ad libitum and force-fed with C. caudatus at the dose of 500 mg/kg, respectively. Treatments were given six days per week for a period of eight weeks. Body weight was monitored every week and structural bone histomorphometry analyses of the femur bones were performed. Ovariectomy decreased trabecular bone volume (BV/TV), decreased trabecular number (Tb.N), and increased trabecular separation (Tb.Sp). Both calcium 1% and 500 mg/kg C. caudatus reversed the above structural bone histomorphometric parameters to normal level. C. caudatus shows better effect compared to calcium 1% on trabecular number (Tb.N) and trabecular separation (Tb.Sp). Therefore, Cosmos caudatus 500 mg/kg has the potential to act as the therapeutic agent to restore bone damage in postmenopausal women.

[Frontiers in Live Bone Imaging Researches. Novel drug discovery by means of intravital bone imaging technology].

PubMed

Ishii, Masaru

2015-06-01

Recent advances in intravital bone imaging technology has enabled us to grasp the real cellular behaviors and functions in vivo , revolutionizing the field of drug discovery for novel therapeutics against intractable bone diseases. In this chapter, I introduce various updated information on pharmacological actions of several antibone resorptive agents, which could only be derived from advanced imaging techniques, and also discuss the future perspectives of this new trend in drug discovery.

A Flexible Method for Producing F.E.M. Analysis of Bone Using Open-Source Software

NASA Technical Reports Server (NTRS)

Boppana, Abhishektha; Sefcik, Ryan; Myers, Jerry G.; Lewandowski, Beth

2016-01-01

Individuals who experience decreases in load-bearing bone densities can be subject to a higher risk of bone fracture during daily activity. Astronauts may lose up to nine percent of their load-bearing bone density for every month they spend in space [1]. Because of this, specialized countermeasures reduce percent loss in bone density and reduce fracture risk upon returning to Earth. Astronauts will typically not be at risk for fracture during spaceflight, because of the lesser loads experienced in microgravity conditions. However, once back on Earth, astronauts have an increased risk for bone fracture as a result of weakened bone and return to 1G conditions [2]. It is therefore important to understand the significance of any bone density loss in addition to developing exercises in an attempt to limit losses in bone strength. NASA seeks to develop a deeper understanding of fracture risk through the development of a computational bone strength model to assess the bone fracture risk of astronauts pre-flight and post-flight. This study addresses the several key processes needed to develop such strength analyses using medical image processing and finite element modeling.

Experiments and synthesis of bone-targeting epirubicin with the water-soluble macromolecular drug delivery systems of oxidized-dextran.

PubMed

Yu, Li; Cai, Lin; Hu, Hao; Zhang, Yi

2014-05-01

Epirubicin (EPI) is a broad spectrum antineoplastic drug, commonly used as a chemotherapy method to treat osteosarcoma. However, its application has been limited by many side-effects. Therefore, targeted drug delivery to bone has been the aim of current anti-bone-tumor drug studies. Due to the exceptional affinity of Bisphosphonates (BP) to bone, 1-amino-ethylene-1, 1-dephosphate acid (AEDP) was chosen as the bone targeting moiety for water-soluble macromolecular drug delivery systems of oxidized-dextran (OXD) to transport EPI to bone in this article. The bone targeting drug of AEDP-OXD-EPI was designed for the treatment of malignant bone tumors. The successful conjugation of AEDP-OXD-EPI was confirmed by analysis of FTIR and (1)H-NMR spectra. To study the bone-seeking potential of AEDP-OXD-EPI, an in vitro hydroxyapatite (HAp) binding assay and an in vivo experiment of bone-targeting capacity were established. The effectiveness of AEDP-OXD-EPI was demonstrated by inducing apoptosis and necrosis of MG-63 tumor cell line. The obtained experimental data indicated that AEDP-OXD-EPI is an ideal bone-targeting anti-tumor drug.

Biomechanical forces in the skeleton and their relevance to bone metastasis: biology and engineering considerations.

PubMed

Lynch, Maureen E; Fischbach, Claudia

2014-12-15

Bone metastasis represents the leading cause of breast cancer related-deaths. However, the effect of skeleton-associated biomechanical signals on the initiation, progression, and therapy response of breast cancer bone metastasis is largely unknown. This review seeks to highlight possible functional connections between skeletal mechanical signals and breast cancer bone metastasis and their contribution to clinical outcome. It provides an introduction to the physical and biological signals underlying bone functional adaptation and discusses the modulatory roles of mechanical loading and breast cancer metastasis in this process. Following a definition of biophysical design criteria, in vitro and in vivo approaches from the fields of bone biomechanics and tissue engineering that may be suitable to investigate breast cancer bone metastasis as a function of varied mechano-signaling will be reviewed. Finally, an outlook of future opportunities and challenges associated with this newly emerging field will be provided. Copyright © 2014 Elsevier B.V. All rights reserved.

Hit rates and radiation doses to nuclei of bone lining cells from alpha-particle-emitting radionuclides

NASA Technical Reports Server (NTRS)

Polig, E.; Jee, W. S.; Kruglikov, I. L.

1992-01-01

Factors relating the local concentration of a bone-seeking alpha-particle emitter to the mean hit rate have been determined for nuclei of bone lining cells using a Monte Carlo procedure. Cell nuclei were approximated by oblate spheroids with dimensions and location taken from a previous histomorphometric study. The Monte Carlo simulation is applicable for planar and diffuse labels at plane or cylindrical bone surfaces. Additionally, the mean nuclear dose per hit, the dose mean per hit, the mean track segment length and its second moment, the percentage of stoppers, and the frequency distribution of the dose have been determined. Some basic features of the hit statistics for bone lining cells have been outlined, and the consequences of existing standards of radiation protection with regard to the hit frequency to cell nuclei are discussed.

A primer of bone metastases management in breast cancer patients

PubMed Central

Petrut, B.; Trinkaus, M.; Simmons, C.; Clemons, M.

2008-01-01

Bone is the most common site for distant spread of breast cancer. Following a diagnosis of metastatic bone disease, patients can suffer from significant morbidity because of pain and skeletal related events (sres). Bisphosphonates are potent inhibitors of osteoclastic function and the mainstay of bone-directed therapy for bone metastases. The aims of bisphosphonates are to prevent and delay sres, to reduce bone pain, and to improve quality of life. Bisphosphonate therapy appears to have revolutionized treatment of bone metastases, but bisphosphonate use has several limitations. Those limitations include the high cost of the agents and the need for return trips to the clinic for intravenous treatment. Moreover, many uncertainties surround bisphosphonate use—for example, the timing of bisphosphonate initiation, the choice of bisphosphonate to use, the optimal duration of treatment, and the appropriate means to identify patients who will and will not benefit. In addition, potentially serious adverse effects have been associated with bisphosphonate use—for example, renal toxicity, gastrointestinal side effects, and osteonecrosis of the jaw. The present review is intended as a primer for oncology specialists who treat patients with bone metastases secondary to breast cancer. It focuses on bisphosphonate treatment guidelines, the evidence for those guidelines, and a discussion of new therapeutic agents. It also discusses the use of biochemical markers of bone metabolism, which show promise for predicting the risk of a patient’s developing a sre and of benefiting from bisphosphonate treatment. PMID:18231649

Differences in Bone Quality between High versus Low Turnover Renal Osteodystrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Porter, Daniel S.; Pienkowski, David; Faugere, Marie-Claude

2012-01-01

Abnormal bone turnover is common in chronic kidney disease (CKD), but its effects on bone quality remain unclear. This study sought to quantify the relationship between abnormal bone turnover and bone quality. Iliac crest bone biopsies were obtained from CKD-5 patients on dialysis with low (n=18) or high (n=17) turnover, and from volunteers (n=12) with normal turnover and normal kidney function. Histomorphometric methods were used to quantify the microstructural parameters; Fourier transform infrared spectroscopy and nanoindentation were used to quantify the material and mechanical properties in bone. Reduced mineral-to-matrix ratio, mineral crystal size, stiffness and hardness were observed in bonemore » with high turnover compared to bone with normal or low turnover. Decreased cancellous bone volume and trabecular thickness were seen in bone with low turnover compared to bone with normal or high turnover. Bone quality, as defined by its microstructural, material, and mechanical properties, is related to bone turnover. These data suggest that turnover related alterations in bone quality may contribute to the known diminished mechanical competence of bone in CKD patients, albeit from different mechanisms for bone with high (material abnormality) vs. low (microstructural alteration) turnover. The present findings suggest that improved treatments for renal osteodystrophy should seek to avoid low or high bone turnover and aim for turnover rates as close to normal as possible.« less

Denosumab Reduces Risk of Bone Side Effects in Advanced Prostate Cancer

Cancer.gov

The biological agent denosumab (Xgeva) is more effective than zoledronic acid at decreasing the risk of bone fractures and other skeletal-related events (SRE) in men with castration-resistant metastatic prostate cancer, according to results from a randomi

Teachers as Agents of Change: Promoting Peacebuilding and Social Cohesion in Schools in Rwanda

ERIC Educational Resources Information Center

Rubagiza, Jolly; Umutoni, Jane; Kaleeba, Ali

2016-01-01

Education is seen to play a crucial role in the reconstruction of post-conflict countries, particularly in transforming people's mindsets and rebuilding social relations. In this regard, teachers are often perceived as key agents to bring about this transformative change through their role as agents of peace. This paper seeks to understand how…

Does estrogen play a role in response to adjuvant bone-targeted therapies?

PubMed Central

Russell, Kent; Amir, Eitan; Paterson, Alexander; Josse, Robert; Addison, Christina; Kuchuk, Iryna; Clemons, Mark

2013-01-01

Bone remains the most common site of breast cancer recurrence. The results of population studies, pre-clinical research and clinical studies in patients with metastatic disease provided a rationale for testing bone-targeted agents in the adjuvant setting. Despite the initial optimism, results from eight prospectively designed, randomized control studies powered to assess the value of adjuvant bone-targeted therapy in early breast cancer are conflicting. Data have shown that, where benefit exists, it tends to be in women with a “low estrogen environment”, either through menopause or suppression of ovarian function. In this manuscript, we review clinical data supporting the hypothesis that estrogen levels may play a part in explaining the response of patients to bone-targeted agents in the adjuvant setting. The results presented to date suggest that there may be data supporting a unifying role for estrogen in adjuvant trials. However, in the absence of any prospective randomized trials in which estrogen data has been systematically collected we cannot specifically answer this question. We await the results of the Oxford overview analysis of individual patient data with interest. PMID:26909288

Production, Quality Control and Biological Evaluation of 166Ho-PDTMP as a Possible Bone Palliation Agent

PubMed Central

Zolghadri, Samaneh; Jalilian, Amir Reza; Naseri, Zohreh; Yousefnia, Hassan; Bahrami-Samani, Ali; Ghannadi-Maragheh, Mohammad; Afarideh, Hossein

2013-01-01

Objective(s): In this study, 166Ho-1,2-propylene di-amino tetra(methy1enephosphonicAcid) (166Ho-PDTMP) complex was prepared as a bone palliation agent. Materials and Methods: The complex was successfully prepared using an in-house synthesized EDTMP ligand and 166HoCl3. Ho-166 chloride was obtained by thermal neutron irradiation (1 × 1013 n.cm-2.s-1) of natural Ho(NO3)3 samples followed by radiolabeling and stability studies. Biodistribution in wild type rats was also peformed. Results: The complex was prepared with the specific activity of 278 GBq/mg and high radiochemical purity (>99%, checked by ITLC). 166Ho-PDTMP complex was stabilized in the final preparation and in the presence of human serum (>90%) up to 72 hr. The biodistribution of 166Ho-PDTMP in wild-type rats demonstrated significant bone uptake was up to 48 hr compared to 166HoCl3. Conclusion: The produced 166Ho-PDTMP properties suggest a possible new bone palliative therapeutic to overcome the metastatic bone pains. PMID:23826495

Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1(+/mov13) mouse model of type I Osteogenesis Imperfecta.

PubMed

Jacobsen, Christina M; Schwartz, Marissa A; Roberts, Heather J; Lim, Kyung-Eun; Spevak, Lyudmila; Boskey, Adele L; Zurakowski, David; Robling, Alexander G; Warman, Matthew L

2016-09-01

Osteogenesis Imperfecta (OI) comprises a group of genetic skeletal fragility disorders. The mildest form of OI, Osteogenesis Imperfecta type I, is frequently caused by haploinsufficiency mutations in COL1A1, the gene encoding the α1(I) chain of type 1 collagen. Children with OI type I have a 95-fold higher fracture rate compared to unaffected children. Therapies for OI type I in the pediatric population are limited to anti-catabolic agents. In adults with osteoporosis, anabolic therapies that enhance Wnt signaling in bone improve bone mass, and ongoing clinical trials are determining if these therapies also reduce fracture risk. We performed a proof-of-principle experiment in mice to determine whether enhancing Wnt signaling in bone could benefit children with OI type I. We crossed a mouse model of OI type I (Col1a1(+/Mov13)) with a high bone mass (HBM) mouse (Lrp5(+/p.A214V)) that has increased bone strength from enhanced Wnt signaling. Offspring that inherited the OI and HBM alleles had higher bone mass and strength than mice that inherited the OI allele alone. However, OI+HBM and OI mice still had bones with lower ductility compared to wild-type mice. We conclude that enhancing Wnt signaling does not make OI bone normal, but does improve bone properties that could reduce fracture risk. Therefore, agents that enhance Wnt signaling are likely to benefit children and adults with OI type 1. Copyright © 2016 Elsevier Inc. All rights reserved.

Copper-64 Labeled Liposomes for Imaging Bone Marrow

PubMed Central

Lee, Sang-gyu; Gangangari, Kishore; Kalidindi, Teja Muralidhar; Punzalan, Blesida; Larson, Steven M.; Pillarsetty, Naga Vara Kishore

2016-01-01

Introduction Bone marrow is the soft tissue compartment inside the bones made up of hematopoietic cells, adipocytes, stromal cells, phagocytic cells, stem cells, and sinusoids. While [18F]-FLT has been utilized to image proliferative marrow, to date, there are no reports of particle based positron emission tomography (PET) imaging agents for imaging bone marrow. We have developed copper-64 labeled liposomal formulation that selectively targets bone marrow and therefore serves as an efficient PET probe for imaging bone marrow. Methods Optimized liposomal formulations were prepared with succinyl PE, DSPC, cholesterol, and mPEG-DSPE (69:39:1:10:0.1) with diameters of 90 and 140 nm, and were doped with DOTA-Bn-DSPE for stable 64Cu incorporation into liposomes. Results PET imaging and biodistribution studies with 64Cu-labeled liposomes indicate that accumulation in bone marrow was as high as 15.18 ± 3.69 %ID/g for 90 nm liposomes and 7.01 ± 0.92 %ID/g for 140 nm liposomes at 24 h post-administration. In vivo biodistribution studies in tumor-bearing mice indicate that the uptake of 90 nm particles is approximately 0.89 ± 0.48 %ID/g in tumor and 14.22 ± 8.07 %ID/g in bone marrow, but respective values for Doxil® like liposomes are 0.83 ± 0.49 %ID/g and 2.23 ± 1.00 %ID/g. Conclusion Our results indicate that our novel PET labeled liposomes target bone marrow with very high efficiency and therefore can function as efficient bone marrow imaging agents. PMID:27694056

Treatment with eldecalcitol positively affects mineralization, microdamage, and collagen crosslinks in primate bone.

PubMed

Saito, Mitsuru; Grynpas, Marc D; Burr, David B; Allen, Matthew R; Smith, Susan Y; Doyle, Nancy; Amizuka, Norio; Hasegawa, Tomoka; Kida, Yoshikuni; Marumo, Keishi; Saito, Hitoshi

2015-04-01

Eldecalcitol (ELD), an active form of vitamin D analog approved for the treatment of osteoporosis in Japan, increases lumbar spine bone mineral density (BMD), suppresses bone turnover markers, and reduces fracture risk in patients with osteoporosis. We have previously reported that treatment with ELD for 6 months improved the mechanical properties of the lumbar spine in ovariectomized (OVX) cynomolgus monkeys. ELD treatment increased lumbar BMD, suppressed bone turnover markers, and reduced histomorphometric parameters of both bone formation and resorption in vertebral trabecular bone. In this study, we elucidated the effects of ELD on bone quality (namely, mineralization, microarchitecture, microdamage, and bone collagen crosslinks) in OVX cynomolgus monkeys in comparison with OVX-vehicle control monkeys. Density fractionation of bone powder prepared from lumbar vertebrae revealed that ELD treatment shifted the distribution profile of bone mineralization to a higher density, and backscattered electron microscopic imaging showed improved trabecular bone connectivity in the ELD-treated groups. Higher doses of ELD more significantly reduced the amount of microdamage compared to OVX-vehicle controls. The fractionated bone powder samples were divided according to their density, and analyzed for collagen crosslinks. Enzymatic crosslinks were higher in both the high-density (≥2.0 mg/mL) and low-density (<2.0 mg/mL) fractions from the ELD-treated groups than in the corresponding fractions in the OVX-vehicle control groups. On the other hand, non-enzymatic crosslinks were lower in both the high- and low-density fractions. These observations indicated that ELD treatment stimulated the enzymatic reaction of collagen crosslinks and bone mineralization, but prevented non-enzymatic reaction of collagen crosslinks and accumulation of bone microdamage. Bone anti-resorptive agents such as bisphosphonates slow down bone remodeling so that bone mineralization, bone microdamage, and non-enzymatic collagen crosslinks all increase. Bone anabolic agents such as parathyroid hormone decrease bone mineralization and bone microdamage by stimulating bone remodeling. ELD did not fit into either category. Histological analysis indicated that the ELD treatment strongly suppressed bone resorption by reducing the number of osteoclasts, while also stimulating focal bone formation without prior bone resorption (bone minimodeling). These bidirectional activities of ELD may account for its unique effects on bone quality. Copyright © 2014. Published by Elsevier Inc.

Strontium ranelate: a novel mode of action leading to renewed bone quality.

PubMed

Ammann, Patrick

2005-01-01

Various bone resorption inhibitors and bone stimulators have been shown to decrease the risk of osteoporotic fractures. However, there is still a need for agents promoting bone formation by inducing positive uncoupling between bone formation and bone resorption. In vitro studies have suggested that strontium ranelate enhances osteoblast cell replication and activity. Simultaneously, strontium ranelate dose-dependently inhibits osteoclast activity. In vivo studies indicate that strontium ranelate stimulates bone formation and inhibits bone resorption and prevents bone loss and/or promotes bone gain. This positive uncoupling between bone formation and bone resorption results in bone gain and improvement in bone geometry and microarchitecture, without affecting the intrinsic bone tissue quality. Thus, all the determinants of bone strength are positively influenced. In conclusion, strontium ranelate, a new treatment of postmenopausal osteoporosis, acts through an innovative mode of action, both stimulating bone formation and inhibiting bone resorption, resulting in the rebalancing of bone turnover in favor of bone formation. Strontium ranelate increases bone mass while preserving the bone mineralization process, resulting in improvement in bone strength and bone quality.

HYPOXIA-ACTIVATED PRO-DRUG TH-302 EXHIBITS POTENT TUMOUR SUPPRESSIVE ACTIVITY AND COOPERATES WITH CHEMOTHERAPY AGAINST OSTEOSARCOMA

PubMed Central

Liapis, Vasilios; Labrinidis, Agatha; Zinonos, Irene; Hay, Shelley; Ponomarev, Vladimir; Panagopoulos, Vasilios; DeNichilo, Mark; Ingman, Wendy; Atkins, Gerald J.; Findlay, David M.; Zannettino, Andrew CW.; Evdokiou, Andreas

2015-01-01

Tumour hypoxia is a major cause of treatment failure for a variety of malignancies. However, tumour hypoxia also offers treatment opportunities, exemplified by the development compounds that target hypoxic regions within tumours. TH-302 is a pro-drug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide (Br-IPM). When TH-302 is delivered to regions of hypoxia, Br-IPM, the DNA cross linking toxin, is released. In this study we assessed the cytotoxic activity of TH-302 against osteosarcoma cells in vitro and evaluated its anticancer efficacy as a single agent, and in combination with doxorubicin, in an orthotopic mouse model of human osteosarcoma (OS). In vitro, TH-302 was potently cytotoxic to osteosarcoma cells selectively under hypoxic conditions, whereas primary normal human osteoblasts were protected. Animals transplanted with OS cells directly into their tibiae and left untreated developed mixed osteolytic/osteosclerotic bone lesions and subsequently developed lung metastases. TH-302 reduced tumor burden in bone and cooperated with doxorubicin to protect bone from osteosarcoma induced bone destruction, while it also reduced lung metastases. TH-302 may therefore be an attractive therapeutic agent with strong activity as a single agent and in combination with chemotherapy against OS. PMID:25444931

Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma.

PubMed

Liapis, Vasilios; Labrinidis, Agatha; Zinonos, Irene; Hay, Shelley; Ponomarev, Vladimir; Panagopoulos, Vasilios; DeNichilo, Mark; Ingman, Wendy; Atkins, Gerald J; Findlay, David M; Zannettino, Andrew C W; Evdokiou, Andreas

2015-02-01

Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, tumor hypoxia also offers treatment opportunities, exemplified by the development compounds that target hypoxic regions within tumors. TH-302 is a pro-drug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide (Br-IPM). When TH-302 is delivered to regions of hypoxia, Br-IPM, the DNA cross linking toxin, is released. In this study we assessed the cytotoxic activity of TH-302 against osteosarcoma cells in vitro and evaluated its anticancer efficacy as a single agent, and in combination with doxorubicin, in an orthotopic mouse model of human osteosarcoma (OS). In vitro, TH-302 was potently cytotoxic to osteosarcoma cells selectively under hypoxic conditions, whereas primary normal human osteoblasts were protected. Animals transplanted with OS cells directly into their tibiae and left untreated developed mixed osteolytic/osteosclerotic bone lesions and subsequently developed lung metastases. TH-302 reduced tumor burden in bone and cooperated with doxorubicin to protect bone from osteosarcoma induced bone destruction, while it also reduced lung metastases. TH-302 may therefore be an attractive therapeutic agent with strong activity as a single agent and in combination with chemotherapy against OS. Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.

A Review of the Effect of Anticonvulsant Medications on Bone Mineral Density and Fracture Risk

PubMed Central

Lee, Richard H.; Lyles, Kenneth W.; Colón-Emeric, Cathleen

2011-01-01

Background Osteoporosis and seizure disorders are common diagnoses in older adults and often occur concomitantly. Objective The goal of this review was to discuss the current hypothesis for the pathogenesis of anticonvulsant-induced bone density loss and the evidence regarding the risk for osteoporosis and fractures in older individuals. Methods A review of the literature was performed, searching in MEDLINE and CINAHL for articles published between 1990 and October 2009 with the following search terms: anticonvulsant OR antiepileptic; AND osteoporosis OR bone density OR fracture OR absorptiometry, photon. Studies within the pediatric population, cross-sectional studies, and studies whose results were published in a language other than English were excluded. Results A search of the published literature yielded >300 results, of which 24 met the inclusion and exclusion criteria and were included in this review. Hepatic enzyme induction by certain anticonvulsant medications appears to contribute to increased metabolism of 25-hydroxyvitamin D to inactive metabolites, which results in metabolic bone disease. There is increasing evidence that anticonvulsant use is associated with a higher risk of osteoporosis and clinical fractures, especially among older agents such as phenobarbital, carbamazepine, phenytoin, and valproate. Several observational studies suggest a class effect among anticonvulsant agents, associated with clinically significant reductions in bone mineral density and fracture risk. The use of anticonvulsant medications increases the odds of fracture by 1.2 to 2.4 times. However, only 2 large-scale observational studies have specifically examined the risk among those aged >65 years. This review also identified a randomized controlled trial whose results suggest that supplementation with high-dose vitamin D may be associated with increased bone mineral density in patients taking anticonvulsant medications. However, no randomized controlled trials investigating therapeutic agents to prevent fracture in this population were identified. Consequently, there are no formal practice guidelines for the monitoring, prevention, and management of bone disease among those taking anticonvulsants. Conclusions Observational studies suggest an association between use of anticonvulsant medications, reduced bone mineral density, and increased fracture risk. Randomized clinical trials are needed to guide the management of bone disease among those who use anticonvulsants. PMID:20226391

Help Seeking: Agentic Learners Initiating Feedback

ERIC Educational Resources Information Center

Fletcher, Anna Katarina

2018-01-01

Effective feedback is an essential tool for making learning explicit and an essential feature of classroom practice that promotes learner autonomy. Yet, it remains a pressing challenge for teachers to scaffold the active involvement of students as critical, reflective and autonomous learners who use feedback constructively. This paper seeks to…

[Application of acupoint anatomy localization method with colorful tube in education of acupoint anatomy].

PubMed

Song, Shi-Lin

2013-04-01

To seek a precise and simple method for localization of acupoint in anatomical experiment teaching. Medical bone needles were inserted into acupoints. Then, self-mode copper probe needles were thrust along the center of the bone needles to open the inner structures of acuppoints. And probe needles were replaced by colored plastic tubes. Finally, bone needles were withdrawn so as to fix the plastic tubes into the acupoints to facilitate the later cutting. This method for acupoint anatomic positioning is of low cost with accurate positioning and simple manipulation, which has advantages in strong experimental and innovative values.

Cancer-associated bone disease

PubMed Central

Body, J.-J.; Brandi, M.-L.; Cannata-Andia, J.; Chappard, D.; El Maghraoui, A.; Glüer, C.C.; Kendler, D.; Napoli, N.; Papaioannou, A.; Pierroz, D.D.; Rahme, M.; Van Poznak, C.H.; de Villiers, T.J.; El Hajj Fuleihan, G.

2016-01-01

Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence-based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non-communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancer-associated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidence-based care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations. PMID:24146095

The effects of hemostatic agents on peripheral nerve function: an experimental study.

PubMed

Alkan, Alper; Inal, Samet; Yildirim, Mehmet; Baş, Burcu; Ağar, Erdal

2007-04-01

In the practice of oral and maxillofacial surgery, hemostatic agents are sometimes placed in close proximity to peripheral nerves. In the present study, we evaluated immediate and delayed effects of 4 hemostatic agents (oxidized regenerated cellulose, 5% colloid silver-added gelatine sponge, bovine collagen, bone wax) on peripheral nerve function. A total of 25 rat sciatic nerves were prepared, and the amplitudes were recorded with a physiological data acquisition system. Animals were randomly assigned to 5 groups: control, oxidized regenerated cellulose, gelatine sponge, bone wax, and bovine collagen. The first hour records are defined as immediate effects of these hemostatic agents on nerve function. The animals were then allowed to recover for 4 weeks. At the end of this period, the same surgical and recording procedures were performed. These final records are defined as delayed effects of hemostatic agents on nerve function. According to nerve conduction velocity (NCV) and compound action potential (CAP) values of the experimental groups, early and delayed effects of each hemostatic agent were statistically compared with Bonferroni corrected test (P < .05). Statistically, NCV was significantly reduced, and the CAP was significantly increased 1 hour after surgery (P < .05) in the group of oxidized regenerated cellulose. However, there were no significant differences after 4 weeks compared with the first records. In the gelatine sponge group, CAP was significantly increased 4 weeks after the application. In the bovine collagen and bone wax groups, NCV and CAP values (1 hour and 4 weeks after the application) were not statistically significant compared with initial control records. The present study shows that bovine collagen is the most suitable hemostatic agent applicable for peripheral nerves.

Injectable biomaterials for minimally invasive orthopedic treatments.

PubMed

Jayabalan, M; Shalumon, K T; Mitha, M K

2009-06-01

Biodegradable and injectable hydroxy terminated-poly propylene fumarate (HT-PPF) bone cement was developed. The injectable formulation consisting HT-PPF and comonomer, n-vinyl pyrrolidone, calcium phosphate filler, free radical catalyst, accelerator and radiopaque agent sets rapidly to hard mass with low exothermic temperature. The candidate bone cement attains mechanical strength more than the required compressive strength of 5 MPa and compressive modulus 50 MPa. The candidate bone cement resin elicits cell adhesion and cytoplasmic spreading of osteoblast cells. The cured bone cement does not induce intracutaneous irritation and skin sensitization. The candidate bone cement is tissue compatible without eliciting any adverse tissue reactions. The candidate bone cement is osteoconductive and inductive and allow osteointegration and bone remodeling. HT-PPF bone cement is candidate bone cement for minimally invasive radiological procedures for the treatment of bone diseases and spinal compression fractures.

Revisiting the Pharmacokinetic Profiles of Gadolinium-Based Contrast Agents: Differences in Long-Term Biodistribution and Excretion.

PubMed

Lancelot, Eric

2016-11-01

Gadolinium-based contrast agents (GBCAs) have been used for years for magnetic resonance imaging examinations. Because of their rapid blood clearance, they were considered as very safe products until some of them were shown to induce nephrogenic systemic fibrosis in patients with renal failure and hypersignals on T1-weighted unenhanced brain scans of patients with normal renal function. To date, these adverse effects have been related almost exclusively to the use of low-stability linear agents, which are more prone to release free gadolinium. The aim of the present meta-analysis was to ascertain the existence of a deep compartment for gadolinium storage in the body and to assess whether all the GBCAs present the same toxicokinetic profile. Applying a systematic literature search methodology, all clinical and preclinical studies reporting time-dependent plasma concentrations and renal excretion data of gadolinium were identified and analyzed. Since the individual data were not available, the analysis focused on the average values per groups of subjects or animals, which had received a given GBCA at a given dose. The rate constants of the distribution phase (α), rapid elimination phase (β), and residual excretion phase (γ) of gadolinium were determined in each group from the plasma concentration (Cp) time curves and the relative urinary excretion rate (rER) time curves, taking the 2-hour time point as a reference. Moreover, as bone may represent a reservoir for long-term gadolinium accumulation and slow release into the blood stream, the time curves of the relative concentration in the bone (rCB) of Gd-labeled GBCAs in mice or rats were analyzed taking day 1 concentrations as a reference. The ratio of gadolinium concentrations in the bone marrow (CBM) as compared with the bone (CB) was also calculated. The relative urinary excretion rate (rER) plots revealed a prolonged residual excretion phase of gadolinium in healthy volunteers, consistent with the existence of a deep compartment of distribution for the GBCAs. The rate constant γ of gadoterate meglumine (0.107 hour) is 5 times higher than that of the linear agents (0.020 ± 0.008 hour), indicating a much faster blood clearance for the macrocyclic GBCA. Similar results were obtained in the preclinical studies. A strong correlation was shown between the γ values of the different products and their respective thermodynamic stability constants (Ktherm). Greater clearance rates of Gd from murine bone were also found after gadoterate meglumine or gadoteridol injection (0.131-0.184 day) than after administration of the linear agents (0.004-0.067 day). The concentrations of Gd in the bone marrow (CBM) from animals exposed to either gadoterate meglumine or gadodiamide are higher than those in the bone (CB) for at least 24 hours. Moreover, the ratio of concentrations (CBM/CB) at 4 hours is significantly lower with the former agent than the latter (1.9 vs 6.5, respectively). Using a nonconventional pharmacokinetic approach, we showed that gadoterate meglumine undergoes a much faster residual excretion from the body than the linear GBCAs, a process that seems related to the thermodynamic stability of the different chelates. Gadolinium dissociation occurs in vivo for some linear chelates, a mechanism that may explain their long-term retention and slow release from bone. Potential consequences in terms of bone toxicity warrant further investigations.

Preventing painful age-related bone fractures: Anti-sclerostin therapy builds cortical bone and increases the proliferation of osteogenic cells in the periosteum of the geriatric mouse femur.

PubMed

Thompson, Michelle L; Chartier, Stephane R; Mitchell, Stefanie A; Mantyh, Patrick W

2016-01-01

Age-related bone fractures are usually painful and have highly negative effects on a geriatric patient's functional status, quality of life, and survival. Currently, there are few analgesic therapies that fully control bone fracture pain in the elderly without significant unwanted side effects. However, another way of controlling age-related fracture pain would be to preemptively administer an osteo-anabolic agent to geriatric patients with high risk of fracture, so as to build new cortical bone and prevent the fracture from occurring. A major question, however, is whether an osteo-anabolic agent can stimulate the proliferation of osteogenic cells and build significant amounts of new cortical bone in light of the decreased number and responsiveness of osteogenic cells in aging bone. To explore this question, geriatric and young mice, 20 and 4 months old, respectively, received either vehicle or a monoclonal antibody that sequesters sclerostin (anti-sclerostin) for 28 days. From days 21 to 28, animals also received sustained administration of the thymidine analog, bromodeoxyuridine (BrdU), which labels the DNA of dividing cells. Animals were then euthanized at day 28 and the femurs were examined for cortical bone formation, bone mineral density, and newly borne BrdU+ cells in the periosteum which is a tissue that is pivotally involved in the formation of new cortical bone. In both the geriatric and young mice, anti-sclerostin induced a significant increase in the thickness of the cortical bone, bone mineral density, and the proliferation of newly borne BrdU+ cells in the periosteum. These results suggest that even in geriatric animals, anti-sclerostin therapy can build new cortical bone and increase the proliferation of osteogenic cells and thus reduce the likelihood of painful age-related bone fractures. © The Author(s) 2016.

Bone Regeneration in Critical Bone Defects Using Three-Dimensionally Printed β-Tricalcium Phosphate/Hydroxyapatite Scaffolds Is Enhanced by Coating Scaffolds with Either Dipyridamole or BMP-2

PubMed Central

Ishack, Stephanie; Mediero, Aranzazu; Wilder, Tuere; Ricci, John L.; Cronstein, Bruce N.

2017-01-01

Bone defects resulting from trauma or infection need timely and effective treatments to restore damaged bone. Using specialized three-dimensional (3-D) printing technology we have created custom 3-D scaffolds of hydroxyapatite (HA)/Beta-Tri-Calcium Phosphate (β-TCP) to promote bone repair. To further enhance bone regeneration we have coated the scaffolds with dipyridamole, an agent that increases local adenosine levels by blocking cellular uptake of adenosine. 15% HA:85% β-TCP scaffolds were designed using Robocad software, fabricated using a 3-D Robocasting system, and sintered at 1100°C for 4h. Scaffolds were coated with BMP-2 (200ng/ml), Dypiridamole 100µM or saline and implanted in C57B6 and adenosine A2A receptor knockout (A2AKO) mice with 3mm cranial critical bone defects for 2-8 weeks. Dipyridamole release from scaffold was assayed spectrophotometrically. MicroCT and histological analysis were performed. micro-computed tomography (microCT) showed significant bone formation and remodeling in HA/β-TCP- dipyridamole and HA/β-TCP -BMP-2 scaffolds when compared to scaffolds immersed in vehicle at 2, 4 and 8 weeks (n=5 per group; p≤ 0.05, p≤ 0.05 and p≤ 0.01, respectively). Histological analysis showed increased bone formation and a trend toward increased remodeling in HA/β-TCP- dipyridamole and HA/β-TCP-BMP-2 scaffolds. coating scaffolds with dipyridamole did not enhance bone regeneration in A2AKO mice. In conclusion, scaffolds printed with HA/β-TCP promote bone regeneration in critical bone defects and coating these scaffolds with agents that stimulate A2A receptors and growth factors can further enhance bone regeneration. These coated scaffolds may be very useful for treating critical bone defects due to trauma, infection or other causes. PMID:26513656

Assessment of Bone Quality in Osteoporosis Treatment with Bone Anabolic Agents: Really Something New?

PubMed

Ulivieri, Fabio M; Caudarella, Renata; Camisasca, Marzia; Cabrini, Daniela M; Merli, Ilaria; Messina, Carmelo; Piodi, Luca P

2018-04-20

Osteoporosis is a chronic pathologic condition, particularly of the elderly, in which a reduction of bone mineral density (BMD) weakens bone, leading to the so-called fragility fractures, most often of spine and femur. The gold standard exam for the quantitative measurement of BMD is the dual X-ray photon absorptiometry (DXA), a radiological method. However, a relevant number of fragility fractures occurs in the range of normal BMD values, meaning that also qualitative aspects of bone play a role, namely bone architecture and bone geometry. Bone structure is investigated by microCT and histomorphometry, which necessitate an invasive approach with a biopsy, usually taken at the iliac crest, not the typical site of fragility fractures. New tools, trabecular bone score (TBS) and hip structural analysis (HSA), obtained during DXA, can supply informations about bone structure of spine and femur, respectively, in a not invasive way. Therapy of osteoporosis is based on two types of drugs leading to an increase of BMD: antiresorptive and anabolic treatments. The antiresorptive drugs inhibit the osteoclasts, whereas teriparatide and, in part, strontium ranelate ameliorate bone structure. The present review deals with the relation between the anabolic drugs for osteoporosis and the cited new tools which investigate bone architecture and geometry, in order to clarify if they represent a real advantage in monitoring efficacy of osteoporosis' treatment. Data from the studies show that increases of TBS and HSA values after anabolic therapy are small and very close to their least significant change at the end of the usual period of treatment. Therefore, it is questionable if TBS and HSA are really helpful in monitoring bone quality and in defining reduction of individual fragility fracture risk during osteoporosis treatment with bone anabolic agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Ecological host-range of Lilioceris cheni (Coleoptera: Chrysomelidae), a biological control agent of Dioscorea bulbifera L.

USDA-ARS?s Scientific Manuscript database

Open-field host-specificity testing assesses the host-range of a biological control agent in a setting that permits the agent to use its full complement of host-seeking behaviors. This form of testing, particularly when it includes a no-choice phase in which the target weed is killed, may provide th...

The uptake by the canine tibia of the bone-scanning agent 99mTc-MDP before and after an osteotomy.

PubMed

Hughes, S; Khan, R; Davies, R; Lavender, P

1978-11-01

The residue and extraction of technetium-labelled methylene diphosphonate (99mTc-MDP), a substance used in bone scanning, was examined in the canine tibia and found to be low. Examination of washout curves suggested that there were four compartments in cortical bone, a vascular, a perivascular, a bone fluid and a bone compartment. After an osteotomy in the canine tibia the residue of 99mTc-MDP increased. This was believed to be due to an increase in the blood supply to the bone and to an associated increase in new bone available for exchange. Bone scanning in a fracture is therefore a reflection of the vascular status of the bone being examined and of the uptake by bone. This is dependent on there being an adequate blood supply to the bone and an increased number of mineral-binding sites.

The study of the changes in the biochemical and mineral contents of bones of Catla catla due to lead intoxication.

PubMed

Palaniappan, P L R M; Krishnakumar, N; Vadivelu, M; Vijayasundaram, V

2010-02-01

In the present study, an attempt has been made to analyze the changes in the biochemical and mineral contents of lead-intoxicated bones of Catla catla at subchronic (15.5 ppm) exposure, and also to determine whether the effects of Pb intoxication can be reversed with the chelating agent meso 2, 3-dimercaptosuccinic acid (DMSA) on the bones of freshwater fingerlings Catla catla by using Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), and atomic absorption spectrophotometer techniques. The FT-IR spectra of the lead-exposed bones show significant alteration in the biochemical constituents. The XRD analysis showed a decrease in crystallinity due to lead exposure. Further, the Ca, Mg, and P contents of the lead-exposed bones were less than those of the control group, and there was an increase in the mineral contents of the bones after DMSA treatment. In conclusion, the present study suggests that the subchronic lead exposure results in severe loss of bone minerals. The overall decrease in the FT-IR band intensity of Pb-exposed bones relative to the control indicates a decrease in the biochemical constituents like proteins and lipids. The increase in the band intensity after treatment with chelating agent DMSA indicates increased biochemical constituents, showing that the subchronic effects of lead can be reversed by DMSA. The amide I bands observed at 1654 cm(-1) in the present study suggest that the protein is dominated by alpha-helical structure.

In Silico Investigations of the Anti-Catabolic Effects of Pamidronate and Denosumab on Multiple Myeloma-Induced Bone Disease

PubMed Central

Wang, Yan; Lin, Bo

2012-01-01

It is unclear whether the new anti-catabolic agent denosumab represents a viable alternative to the widely used anti-catabolic agent pamidronate in the treatment of Multiple Myeloma (MM)-induced bone disease. This lack of clarity primarily stems from the lack of sufficient clinical investigations, which are costly and time consuming. However, in silico investigations require less time and expense, suggesting that they may be a useful complement to traditional clinical investigations. In this paper, we aim to (i) develop integrated computational models that are suitable for investigating the effects of pamidronate and denosumab on MM-induced bone disease and (ii) evaluate the responses to pamidronate and denosumab treatments using these integrated models. To achieve these goals, pharmacokinetic models of pamidronate and denosumab are first developed and then calibrated and validated using different clinical datasets. Next, the integrated computational models are developed by incorporating the simulated transient concentrations of pamidronate and denosumab and simulations of their actions on the MM-bone compartment into the previously proposed MM-bone model. These integrated models are further calibrated and validated by different clinical datasets so that they are suitable to be applied to investigate the responses to the pamidronate and denosumab treatments. Finally, these responses are evaluated by quantifying the bone volume, bone turnover, and MM-cell density. This evaluation identifies four denosumab regimes that potentially produce an overall improved bone-related response compared with the recommended pamidronate regime. This in silico investigation supports the idea that denosumab represents an appropriate alternative to pamidronate in the treatment of MM-induced bone disease. PMID:23028650

Diabetes, bone and glucose-lowering agents: clinical outcomes.

PubMed

Schwartz, Ann V

2017-07-01

Older adults with diabetes are at higher risk of fracture and of complications resulting from a fracture. Hence, fracture risk reduction is an important goal in diabetes management. This review is one of a pair discussing the relationship between diabetes, bone and glucose-lowering agents; an accompanying review is provided in this issue of Diabetologia by Beata Lecka-Czernik (DOI 10.1007/s00125-017-4269-4 ). Specifically, this review discusses the challenges of accurate fracture risk assessment in diabetes. Standard tools for risk assessment can be used to predict fracture but clinicians need to be aware of the tendency for the bone mineral density T-score and the fracture risk assessment tool (FRAX) to underestimate risk in those with diabetes. Diabetes duration, complications and poor glycaemic control are useful clinical markers of increased fracture risk. Glucose-lowering agents may also affect fracture risk, independent of their effects on glycaemic control, as seen with the negative skeletal effects of the thiazolidinediones; in this review, the potential effects of glucose-lowering medications on fracture risk are discussed. Finally, the current understanding of effective fracture prevention in older adults with diabetes is reviewed.

The potential role of newer gram-positive antibiotics in the setting of osteomyelitis of adults.

PubMed

Moenster, Ryan P; Linneman, Travis W; Call, William B; Kay, Chad L; McEvoy, Theresa A; Sanders, Jamie L

2013-04-01

To summarize available literature regarding the potential role of linezolid, daptomycin, telavancin, tigecycline and ceftaroline for the treatment of osteomyelitis caused by resistant gram-positive organisms. Literature was obtained through PubMed searches from January 1980 to October 2011 using the terms osteomyelitis, bone, linezolid, daptomycin, telavancin, tigecycline and ceftaroline. Results were limited to those published in English. All articles identified from the PubMed searches were evaluated. Any published data related to bone penetration (animal or human) or clinical outcomes in adult osteomyelitis of these agents were included in the review. Animal models report bone concentrations of 2·3 mcg/dL (vertebral) for linezolid, 0·45 mcg/mL (tibiae) for daptomycin, 0·78 mcg/mL (tibiae) for tigecycline and 0·27 mcg/mL (tibiae) for telavancin; no data are available for ceftaroline. Human studies demonstrate bone concentrations of 4·6, 17·0 and 3·9 mcg/mL (sternal, metatarsal and cancellous bone respectively) for linezolid, 4·7 mcg/mL (metatarsal) for daptomycin and 0·078 mcg/mL (unspecified) for tigecycline; no data are available for telavancin and ceftaroline. Retrospective cohort data, and prospective/retrospective case series support the use of linezolid in this setting; however, side-effects may limit use. Retrospective and prospective cohort data support daptomycin use. A retrospective case series is available supporting the use of telavancin. No data are available supporting clinical effectiveness for ceftaroline or tigecycline in the setting of osteomyelitis. Limited data are available evaluating the safety and efficacy of these agents in osteomyelitis in adults. Daptomycin and telavancin may be potential alternatives or second-line agents to vancomycin in selected patients. Linezolid, because of an increase in clinically important ADRs with prolonged use, should be reserved as a second- or third-line agent. Due to a lack of clinical data and poor bone penetration, along with concerns regarding outcomes in severe infections, tigecycline's potential is limited. Little data exist regarding ceftaroline use in osteomyelitis. © 2013 Blackwell Publishing Ltd.

75 FR 1735 - Section 3504 Agent Employment Tax Liability

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-13

...). SUPPLEMENTARY INFORMATION: Background Federal, State, and local government programs seek to help elderly or disabled individuals maintain their independence by funding home health care and other personal services... with employment tax compliance by helping the service recipients to designate agents to report, file...

Protective effect of egg yolk peptide on bone metabolism.

PubMed

Kim, Hye Kyung; Lee, Sena; Leem, Kang-Hyun

2011-03-01

Osteoporosis is a major health problem worldwide, and most current therapy used in osteoporosis treatment acts by either increasing bone formation or decreasing bone resorption. However, the adverse effects of these therapies may preclude their long-term use. We examined the effects of egg yolk water-soluble peptide (YPEP) on bone metabolism as an alternative to current therapeutic agents in ovariectomized (OVX) rats. In the first step, the in vitro effects of YPEP on bone loss were determined. The proliferation, collagen content, and alkaline phosphatase activity of preosteoblastic MC3T3-E1 cells and osteoclastogenesis from bone marrow-derived precursor cells were measured. The in vivo experiment confirmed the positive effect of YPEP on bone tissue. Three-month-old female Sprague-Dawley rats were either sham operated or ovariectomized and fed commercial chow diet or 0.1% YPEP-supplemented diet for 3 month. YPEP increased preosteoblastic MC3T3-E1 cell proliferation and alkaline phosphatase activity in a dose-dependent manner. Collagen content was also increased by YPEP treatment. Furthermore, YPEP potently suppressed osteoclastogenesis from bone marrow-derived precursor cells. YPEP (100 μg/mL) abolished the formation of osteoclasts positive for tartrate-resistant acid phosphatase. OVX rats supplemented with YPEP showed an osteoprotective effect, as the bone mineral density and cortical thickness in the tibia were increased compared with the OVX controls. Moreover, histological data indicate that YPEP prevented the cancellous bone loss induced by ovariectomy. None of these protective effects were observed in casein-treated rats. The present study suggests that YPEP is a promising alternative to current therapeutic agents for the management of osteoporosis.

Metabolic Bone Diseases and Total Hip Arthroplasty: Preventing Complications.

PubMed

Moya-Angeler, Joaquin; Lane, Joseph M; Rodriguez, Jose A

2017-11-01

Metabolic bone diseases are a diverse group of conditions characterized by abnormalities in calcium metabolism and/or bone cell physiology. These unbalanced processes can eventually lead to bony deformities and altered joint biomechanics, resulting in degenerative joint disease. Not infrequently, patients with metabolic bone diseases have restricting hip joint pain that ultimately necessitates hip arthroplasty. To minimize complications, the surgeon must consider the particular characteristics of these patients. The surgical and medical management of patients with metabolic bone diseases undergoing hip arthroplasty requires appropriate preoperative diagnosis, careful attention to the technical challenges of surgery, and strategies to maximize the long-term results of the surgical intervention, such as the use of bone anabolic and anticatabolic agents.

Bone anabolics in osteoporosis: Actuality and perspectives

PubMed Central

Montagnani, Andrea

2014-01-01

Vertebral and nonvertebral fractures prevention is the main goal for osteoporosis therapy by inhibiting bone resorption and/or stimulating bone formation. Antiresorptive drugs decrease the activation frequency, thereby determining a secondary decrease in bone formation rate and a low bone turnover. Bisphosphonates are today’s mainstay among antiresorptive treatment of osteoporosis. Also, oral selective estrogen receptor modulators and recently denosumab have a negative effect on bone turnover. Agents active on bone formation are considered a better perspective in the treatment of severe osteoporosis. Recombinant-human parathyroid hormone (PTH) has showed to increase bone formation and significantly decrease vertebral fractures in severe patients, but with a modest effect on nonvertebral fractures. The study of Wnt signaling pathway, that induces prevalently an osteoblastic activity, opens large possibilities to antagonists of Wnt-inhibitors, such as sclerostin antibodies and dickkopf-1 antagonists, with potential effects not only on trabecular bone but also on cortical bone. PMID:25035827

Modeling the Chagas’ disease after stem cell transplantation

NASA Astrophysics Data System (ADS)

Galvão, Viviane; Miranda, José Garcia Vivas

2009-04-01

A recent model for Chagas’ disease after stem cell transplantation is extended for a three-dimensional multi-agent-based model. The computational model includes six different types of autonomous agents: inflammatory cell, fibrosis, cardiomyocyte, proinflammatory cytokine tumor necrosis factor- α, Trypanosoma cruzi, and bone marrow stem cell. Only fibrosis is fixed and the other types of agents can move randomly through the empty spaces using the three-dimensional Moore neighborhood. Bone marrow stem cells can promote apoptosis in inflammatory cells, fibrosis regression and can differentiate in cardiomyocyte. T. cruzi can increase the number of inflammatory cells. Inflammatory cells and tumor necrosis factor- α can increase the quantity of fibrosis. Our results were compared with experimental data giving a fairly fit and they suggest that the inflammatory cells are important for the development of fibrosis.

Evasion in the plane

NASA Technical Reports Server (NTRS)

Leitmann, G.; Liu, H. S.

1977-01-01

Dynamic systems were considered subject to control by two agents, one of whom desires that no trajectory of the system emanating from outside a given set, intersects that set no matter what the admissible actions of the other agent. Constructive conditions sufficient to yield a feedback control for the agent seeking avoidance were employed to deduce an evader control for the planar pursuit-evasion problem with bounded normal accelerations.

A Collective Case Study of Secondary Students' Model-Based Inquiry on Natural Selection through Programming in an Agent-Based Modeling Environment

ERIC Educational Resources Information Center

Xiang, Lin

2011-01-01

This is a collective case study seeking to develop detailed descriptions of how programming an agent-based simulation influences a group of 8th grade students' model-based inquiry (MBI) by examining students' agent-based programmable modeling (ABPM) processes and the learning outcomes. The context of the present study was a biology unit on…

In vivo calcium metabolism by IRMS

USDA-ARS?s Scientific Manuscript database

Public policy initiatives related to enhancing the health of populations, increasingly seek to identify meaningful biological outcomes on which to determine age-related nutritional requirements. For calcium, the primary outcome of interest is the availability of calcium in the diet for bone formatio...

Autologous bone marrow purging with LAK cells.

PubMed

Giuliodori, L; Moretti, L; Stramigioli, S; Luchetti, F; Annibali, G M; Baldi, A

1993-12-01

In this study we will demonstrate that LAK cells, in vitro, can lyse hematologic neoplastic cells with a minor toxicity of the staminal autologous marrow cells. In fact, after bone marrow and LAK co-culture at a ratio of 1/1 for 8 hours, the inhibition on the GEMM colonies resulted to be 20% less compared to the untreated marrow. These data made LAK an inviting agent for marrow purging in autologous bone marrow transplantation.

[Therapeutic agents for disorders of bone and calcium metabolism--Parathyroid hormone in weekly subcutaneous injection].

PubMed

Uzawa, Toyonobu

2007-01-01

The parathyroid hormone (PTH) that is marketed outside Japan is for daily administration. It has been proven to increase bone mass and prevent fractures, and the effects are very strong. However, data suggest that daily administration of PTH increases bone resorption. By contrast, weekly administration of PTH, which is being developed in Japan, actually decreases bone resorption, and data suggest that this regimen maintains a good balance between bone formation (predominant) and bone resorption. Furthermore, it has been reported that weekly administration of PTH increases bone mass as much as every day administration of PTH, and as such, weekly administration of PTH has the potential to be a useful regimen with characteristics that are different from those of daily administration of PTH.

45 CFR 302.35 - State parent locator service.

Code of Federal Regulations, 2011 CFR

2011-10-01

... parents, non-parent relatives, and children upon request of authorized individuals specified in paragraph... seek an order against a noncustodial parent for the support and maintenance of a child, or any agent of such court; (3) The resident parent, legal guardian, attorney, or agent of a child who is not receiving...

45 CFR 302.35 - State parent locator service.

Code of Federal Regulations, 2012 CFR

2012-10-01

... parents, non-parent relatives, and children upon request of authorized individuals specified in paragraph... seek an order against a noncustodial parent for the support and maintenance of a child, or any agent of such court; (3) The resident parent, legal guardian, attorney, or agent of a child who is not receiving...

Modulation of O6-alkylating agent induced clastogenicity by enhanced DNA repair capacity of bone marrow cells.

PubMed

Chinnasamy, N; Fairbairn, L J; Laher, J; Willington, M A; Rafferty, J A

1998-08-07

The murine bone marrow micronucleus assay has been used to examine (1) the potentiation of fotemustine and streptozotocin induced-clastogenicity by the O6-alkylguanine-DNA alkyltransferase (ATase) inactivator O6-benzylguanine (O6-beG) and (2) the level of protection afforded against this potentiation by retrovirus-mediated expression of an O6-beG-resistant mutant of human ATase (haTPA/GA) in mouse bone marrow. Both fotemustine and streptozotocin induced significantly higher levels of micronucleated polychromatic erythrocytes (p < 0.001 for the highest doses studied) compared to those seen in vehicle-treated animals. The number of micronuclei produced by either agent was dramatically elevated by pretreatment with O6-beG (p < 0.001). Furthermore, in myeloablated mice reconstituted with bone marrow expressing the O6-beG-resistant hATPA/GA as a result of retroviral gene transfer, the frequency of micronucleus formation following exposure of mice to otherwise clastogenic doses of fotemustine or streptozotocin, in the presence of O6-beG, wash highly significantly reduced (p < 0.001 for both agents) relative to that in mock transduced controls. These data clearly implicate O6-chloroethyl- and O6-methylguanine as clastogenic lesions in vivo and establish ATase as a major protective mechanism operating to reduce the frequency of such damage. The potentiation of drug induced clastogenicity by O6-beG suggests that the clinical use of this inactivator in combination with O6-alkylating agents, could substantially increase the risk of therapy related malignancy. Nevertheless the use of hATPA/GA as a protective mechanism via gene therapy may overcome this risk.

Biodistribution of fracture-targeted GSK3β inhibitor-loaded micelles for improved fracture healing

PubMed Central

Low, Stewart A.; Galliford, Chris V.; Yang, Jiyuan; Low, Philip S.; Kopeček, Jindřich

2016-01-01

Bone fractures constitute a major cause of morbidity and mortality especially in the elderly. Complications associated with osteoporosis drugs and the age of the patient slow bone turnover and render such fractures difficult to heal. Increasing the speed of fracture repair by administration of a fracture-targeted bone anabolic agent could find considerable application. Aspartic acid oligopeptides are negatively charged molecules at physiological pH that adsorb to hydroxyapatite, the mineral portion of bone. This general adsorption is the strongest where bone turnover is highest or where hydroxyapatite is freshly exposed. Importantly, both of these conditions are prominent at fracture sites. GSK3β inhibitors are potent anabolic agents that can promote tissue repair when concentrated in a damaged tissue. Unfortunately, they can also cause significant toxicity when administered systemically and are furthermore difficult to deliver due to their strong hydrophobicity. In this paper, we solve both problems by conjugating the hydrophobic GSK3β inhibitor to a hydrophilic aspartic acid octapeptide using a hydrolyzable bond, thereby generating a bone fracture-targeted water-soluble form of the drug. The resulting amphiphile is shown to assemble into micelles, extending its circulation time while maintaining its fracture-targeting abilities. For measurement of pharmacokinetics, an 125I was introduced at the location of the bromine in the GSK3β inhibitor to minimize any structural differences. Biodistribution studies demonstrate a greater than 4-fold increase in fracture accumulation over healthy bone. PMID:26331790

New approaches to pharmacological treatment of osteoporosis.

PubMed Central

Akesson, Kristina

2003-01-01

Osteoporosis has been recognized as a major public health problem for less than two decades. The increasing incidence of fragility fractures, such as vertebral, hip, and wrist fractures, first became apparent from epidemiological studies in the early and mid-1980s, when effective treatment was virtually unavailable. Pharmacological therapies that effectively reduce the number of fractures by improving bone mass are now available widely in countries around the world. Most current agents inhibit bone loss by reducing bone resorption, but emerging therapies may increase bone mass by directly promoting bone formation--as is the case with parathyroid hormone. Current treatment alternatives include bisphosphonates, calcitonin, and selective estrogen receptor modulators, but sufficient calcium and vitamin D are a prerequisite. The availability of evidence-based data that show reductions in the incidence of fractures of 30-50% during treatment has been a major step forward in the pharmacological prevention of fractures. With all agents, fracture reduction is most pronounced for vertebral fracture in high-risk individuals; alendronate and risedronate also may protect against hip fracture in the elderly. New approaches to pharmacological treatment will include further development of existing drugs, especially with regard to tolerance and frequency of dosing. New avenues for targeting the condition will emerge as our knowledge of the regulatory mechanisms of bone remodelling increases, although issues of tissue specificity may be difficult to solve. In the long term, information gained through knowledge of bone genetics may be used to adapt pharmacological treatments more precisely to each individual. PMID:14710507

Glucocorticoid-induced bone loss can be reversed by the actions of PTH and Risedronate on different pathways for bone formation and mineralization

PubMed Central

Yao, Wei; Cheng, Zhiqiang; Pham, Aaron; Busse, Cheryl; Zimmermann, Elizabeth A.; Ritchie, Robert O.; Lane, Nancy E.

2008-01-01

Glucocorticoid (GC) excess decreases bone mineralization and microarchitecture and lead to reduced bone strength. Both anabolic (PTH) and anti-resorptive agents are used to prevent and treat GC-induced bone loss, yet these bone active agents alter bone turnover by very different mechanisms. Our study objective was to determine how PTH and risedronate (Ris) alter bone quality following GC excess. Five-month-old Swiss-Webster male mice were treated with the glucocorticoid (GC) prednisolone (5 mg/kg 60-day slow-release pellet) or placebo (PL)]. At day 28−56, two groups of GC-treated animals had either PTH (5μg/kg, 5x/wk) or Ris (5μg/kg, 5x/wk) intervention. Bone quality and quantity measurements include x-ray tomography microscopy (XTM) for the degree of bone mineralization (DBM), microCT for bone microarchitecture, compression testing for trabecular bone strength, biochemistry and histomorphometry for bone turnover. In addition, real-time PCR and immunohistochemistry were performed to monitor the expression of several key genes regulating Wnt signaling (bone formation) and mineralization. Results Compared to the placebo treated mice, GC treatment decreased trabecular bone volume (BV/TV) and serum osteocalcin, but increased serum CTX and osteoclast surface with a peak at day 28. GC+PTH increased and GC+Ris restored BV/TV to the PL levels after a 28 day treatment period. Average DBM was lowered after GC treatment (−27%), and it was restored to PL level with GC+Ris and GC+PTH. At day 56, RT-PCR revealed that continuous exposure to GC and GC+PTH increased, while GC+Ris decreased the expression of genes that inhibit bone mineralization (Dmp1 and Phex), compared to the PL group. Wnt signaling antagonists Dkk1, Sost and Wif1 were up-regulated by GC treatment but were down-regulated after GC+PTH treatment. Immunohistochemistry of bone sections found GC increased N terminal dmp-1 while PTH treatment increased both N and C terminal dmp-1 staining around osteocytes. Summary GC excess reduced expression of genes that regulate mineralization and increased expression of genes that inhibit Wnt signaling which were associated with reduced bone formation and bone volume over a 60 day treatment period. The addition of both PTH and Ris improved bone mass, DBM and bone strength during concurrent GC treatment, with PTH lowering expression of Wnt inhibitors and increasing bone formation; while Ris lowered the expression of mineralization inhibitors and reversed the deterioration of bone mineralization induced by GC excess. PMID:18975341

Achilles detachment in rat and stable gastric pentadecapeptide BPC 157: Promoted tendon-to-bone healing and opposed corticosteroid aggravation.

PubMed

Krivic, Andrija; Anic, Tomislav; Seiwerth, Sven; Huljev, Dubravko; Sikiric, Predrag

2006-05-01

Stable gastric pentadecapeptide BPC 157 (BPC 157, as an antiulcer agent in clinical trials for inflammatory bowel disease; PLD-116, PL 14736, Pliva, no toxicity reported) alone (without carrier) ameliorates healing of tendon and bone, respectively, as well as other tissues. Thereby, we focus on Achilles tendon-to-bone healing: tendon to bone could not be healed spontaneously, but it was recovered by this peptide. After the rat's Achilles tendon was sharply transected from calcaneal bone, agents [BPC 157 (10 microg, 10 ng, 10 pg), 6alpha-methylprednisolone (1 mg), 0.9% NaCl (5 mL)] were given alone or in combination [/kg body weight (b.w.) intraperitoneally, once time daily, first 30-min after surgery, last 24 h before analysis]. Tested at days 1, 4, 7, 10, 14, and 21 after Achilles detachment, BPC 157 improves healing functionally [Achilles functional index (AFI) values substantially increased], biomechanically (load to failure, stiffness, and Young elasticity modulus significantly increased), macro/microscopically, immunohistochemistry (better organization of collagen fibers, and advanced vascular appearance, more collagen type I). 6alpha-Methylprednisolone consistently aggravates the healing, while BPC 157 substantially reduces 6alpha-methylprednisolone healing aggravation. Thus, direct tendon-to-bone healing using stabile nontoxic peptide BPC 157 without a carrier might successfully exchange the present reconstructive surgical methods. Copyright 2006 Orthopaedic Research Society.

Subtraction micro-computed tomography of angiogenesis and osteogenesis during bone repair using synchrotron radiation with a novel contrast agent.

PubMed

Matsumoto, Takeshi; Goto, Daichi; Sato, Syota

2013-09-01

Quantitative three-dimensional (3D) imaging of angiogenesis during bone repair remains an experimental challenge. We developed a novel contrast agent containing 0.07- to 0.1-μm particles of zirconium dioxide (ZrCA) and established subtraction μCT using synchrotron radiation (sSRCT) for quantitative imaging of angiogenesis and bone repair. This method was applied to a rat model of tibial bone repair 3 days (DAY3; n = 2), 5 days (DAY5; n = 8), or 10 days (DAY10; n = 8) after drill-hole injury. Using the same drill-hole defect model, its potential use was illustrated by comparison of bone repair between hindlimbs subjected to mechanical unloading (n = 6) and normal weight bearing (n = 6) for 10 days. Following vascular casting with ZrCA, the defect site was scanned with 17.9- and 18.1-keV X-rays. In the latter, image contrast between ZrCA-filled vasculature and bone was enhanced owing to the sharp absorption jump of zirconium dioxide at 18.0 keV (k-edge). The two scan data sets were reconstructed with 2.74-μm voxel resolution, registered by mutual information, and digitally subtracted to extract the contrast-enhanced vascular image. K2HPO4 phantom solutions were scanned at 17.9 keV for quantitative evaluation of bone mineral. Angiogenesis had already started, but new bone formation was not found on DAY3. New bone emerged near the defect boundary on DAY5 and took the form of trabecular-like structure invaded by microvessels on DAY10. Vascular and bone volume fractions, blood vessel and bone thicknesses, and mineralization were higher on DAY10 than on DAY5. All these parameters were found to be decreased after 10 days of hindlimb unloading, indicating the possible involvement of angiogenesis in bone repair impairment caused by reduced mechanical stimuli. In conclusion, the combined technique of sSRCT and ZrCA vascular casting is suitable for quantitative 3D imaging of angiogenesis and its surrounding bone regeneration. This method will be useful for better understanding the linkage between angiogenesis and bone repair.

Bone regeneration in critical bone defects using three-dimensionally printed β-tricalcium phosphate/hydroxyapatite scaffolds is enhanced by coating scaffolds with either dipyridamole or BMP-2.

PubMed

Ishack, Stephanie; Mediero, Aranzazu; Wilder, Tuere; Ricci, John L; Cronstein, Bruce N

2017-02-01

Bone defects resulting from trauma or infection need timely and effective treatments to restore damaged bone. Using specialized three-dimensional (3D) printing technology we have created custom 3D scaffolds of hydroxyapatite (HA)/beta-tri-calcium phosphate (β-TCP) to promote bone repair. To further enhance bone regeneration we have coated the scaffolds with dipyridamole, an agent that increases local adenosine levels by blocking cellular uptake of adenosine. Nearly 15% HA:85% β-TCP scaffolds were designed using Robocad software, fabricated using a 3D Robocasting system, and sintered at 1100°C for 4 h. Scaffolds were coated with BMP-2 (200 ng mL -1 ), dypiridamole 100 µM or saline and implanted in C57B6 and adenosine A2A receptor knockout (A2AKO) mice with 3 mm cranial critical bone defects for 2-8 weeks. Dipyridamole release from scaffold was assayed spectrophotometrically. MicroCT and histological analysis were performed. Micro-computed tomography (microCT) showed significant bone formation and remodeling in HA/β-TCP-dipyridamole and HA/β-TCP-BMP-2 scaffolds when compared to scaffolds immersed in vehicle at 2, 4, and 8 weeks (n = 5 per group; p ≤ 0.05, p ≤ 0.05, and p ≤ 0.01, respectively). Histological analysis showed increased bone formation and a trend toward increased remodeling in HA/β-TCP- dipyridamole and HA/β-TCP-BMP-2 scaffolds. Coating scaffolds with dipyridamole did not enhance bone regeneration in A2AKO mice. In conclusion, scaffolds printed with HA/β-TCP promote bone regeneration in critical bone defects and coating these scaffolds with agents that stimulate A2A receptors and growth factors can further enhance bone regeneration. These coated scaffolds may be very useful for treating critical bone defects due to trauma, infection or other causes. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 366-375, 2017. © 2015 Wiley Periodicals, Inc.

Gastrodin inhibits osteoclastogenesis via down-regulating the NFATc1 signaling pathway and stimulates osseointegration in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Feng; Shen, Yi; Liu, Bo

Bone is a rigid yet dynamic organ, and this dynamism is mediated by the delicate balance between osteoclastic bone resorption and osteoblastic bone formation. However, excessive activation of osteoclasts is responsible for many bone diseases such as osteoporosis, Paget disease, and tumor bone metastasis. Agents that could inhibit osteoclast formation or function are regarded as promising alternatives to treat osteoclast-related diseases. Recently, traditional Chinese medicine has attracted attention because of its multiple activities in bone metabolism. Among them, gastrodin has been reported as an anti-osteoporosis agent that reduces reactive oxygen species. However, the direct action of gastrodin on osteoclast differentiationmore » and bone resorption, and its underlying molecular mechanism, remain unknown. In this study, we investigated the effects of gastrodin on receptor activator NF-κB ligand (RANKL)-activated osteoclasts formation and bone resorption. Our results showed that gastrodin retarded RANKL-induced osteoclast differentiation efficiently by downregulating transcriptional and translational expression of nuclear factor of activated T cells cl (NFATc1), a major factor in RANKL-mediated osteoclastogenesis. Meanwhile, gastrodin prevented osteoclast maturation and migration by inhibiting the gene expression of dendrocyte expressed seven transmembrane protein (DC-STAMP), an osteoclastic-specific gene that controls cells fusion and movement. And gastrodin prevented RANKL-induced osteoclastic bone erosion in vitro. In addition, gastrodin also stimulated bone mesenchymal stem cell (BMSC) spreading and osseointegration in titanium plate. In summary, gastrodin could prevent osteoclasts formation and bone resorption via blockage of NFATc1 activity, and stimulate osseointegration in vitro. Gastrodin could be developed as a potent phytochemical candidate to treat osteolytic diseases. - Highlights: • Gastrodin suppresses osteoclasts formation and function in vitro. • Gastrodin impairs NFATc1 activation. • Gastrodin stimulates osseointegration in vitro. • Gastrodin may be used for treating osteoclast related diseases.« less

Research Advances: Nitric Oxide Synthase Reduces Cr(VI); The Chemistry of Popcorn: It's All About "Pop-Ability"; Nanotubes May Help Heal Broken Bones; New Method Unites Organic Materials and Nanotechnology

NASA Astrophysics Data System (ADS)

King, Angela G.

2005-12-01

An enzyme can reduce chromium ions and increase toxicity. Chemistry may reduce the number of unpopped kernels. Nanotubes provide scaffolding for bone growth. A new method will aid fabrication of drug-delivery agents.

On the rat model of human osteopenias and osteoporoses

NASA Technical Reports Server (NTRS)

Frost, Harold M.; Jee, Webster S. S.

1992-01-01

The idea that rats cannot model human osteopenias errs. The same mechanisms control gains in bone mass (longitudinal bone growth and modeling drifts) and losses (BMU-based remodeling), in young and aged rats and humans. Furthermore, they respond similarly in rats and man to mechanical influences, hormones, drugs and other agents.

Benzofuran-pyran hybrids: A new class of potential bone anabolic agents.

PubMed

Gupta, Sampa; Adhikary, Sulekha; Modukuri, Ram K; Choudhary, Dharmendra; Trivedi, Ritu; Sashidhara, Koneni V

2018-06-01

Benzofuran moiety is an important pharmacophore showing positive effects on bone health. In the present study, sixteen benzofuran-pyran hybrids were synthesized and were evaluated for their osteogenic effects on primary osteoblast cells isolated from calvaria. Compounds 22 and 24 were found potent in stimulating osteoblast differentiation as assessed by the alkaline phosphatase activity. These compounds were also found to be nontoxic to osteoblast cells as compared to the control cells in MTT assay. Further, Alizarin Red-S staining for visualization of calcium nodules demonstrated compounds 22 and 34 as active in enhancing mineralization in osteoblast cells. Additionally, transcriptional analysis of these compounds on osteoblast cells revealed that compound 22 up-regulated the expression of osteogenic genes RUNX2, BMP-2, COL-1, thus substantiating that compound 22 having two geminal methyl groups in its R 3 position is a potent osteogenic agent. Additionally, compound 22 enhanced the ability of bone marrow stromal cells to differentiate towards osteoblast lineage and therefore can be further studied in vivo in bone loss model. Copyright © 2018 Elsevier Ltd. All rights reserved.

Self-assembled high-strength hydroxyapatite/graphene oxide/chitosan composite hydrogel for bone tissue engineering.

PubMed

Yu, Peng; Bao, Rui-Ying; Shi, Xiao-Jun; Yang, Wei; Yang, Ming-Bo

2017-01-02

Graphene hydrogel has shown greatly potentials in bone tissue engineering recently, but it is relatively weak in the practical use. Here we report a facile method to synthesize high strength composite graphene hydrogel. Graphene oxide (GO), hydroxyapatite (HA) nanoparticles (NPs) and chitosan (CS) self-assemble into a 3-dimensional hydrogel with the assistance of crosslinking agent genipin (GNP) for CS and reducing agent sodium ascorbate (NaVC) for GO simultaneously. The dense and oriented microstructure of the resulted composite gel endows it with high mechanical strength, high fixing capacity of HA and high porosity. These properties together with the good biocompatibility make the ternary composite gel a promising material for bone tissue engineering. Such a simultaneous crosslinking and reduction strategy can also be applied to produce a variety of 3D graphene-polymer based nanocomposites for biomaterials, energy storage materials and adsorbent materials. Copyright © 2016 Elsevier Ltd. All rights reserved.

The effect of tissue decalcification on mRNA retention within bone for in-situ hybridization studies.

PubMed

Walsh, L; Freemont, A J; Hoyland, J A

1993-06-01

Tissue decalcification is a routine part of the preparation of bone tissue for histological studies. Although in-situ hybridization has been employed to localize mRNA of collagenous and non-collagenous bone related proteins in skeletal tissue, little is known regarding the effects of decalcifying agents on mRNA retention within tissue. In this study in-situ hybridization using an oligonucleotide probe (i.e. a poly d(T) probe) to detect total messenger RNA has been employed to investigate the effects of the decalcifying agents nitric acid, formic acid and EDTA on mRNA retention compared to undeacalcified tissue. The results show that formalin fixation and EDTA decalcification preserve substantial amounts of mRNA within the tissue. In particular, this study illustrates that it is possible to perform in-situ hybridization on formalin fixed decalcified paraffin embedded tissue.

Smad4 is required to inhibit osteoclastogenesis and maintain bone mass.

PubMed

Morita, Mayu; Yoshida, Shigeyuki; Iwasaki, Ryotaro; Yasui, Tetsuro; Sato, Yuiko; Kobayashi, Tami; Watanabe, Ryuichi; Oike, Takatsugu; Miyamoto, Kana; Takami, Masamichi; Ozato, Keiko; Deng, Chu-Xia; Aburatani, Hiroyuki; Tanaka, Sakae; Yoshimura, Akihiko; Toyama, Yoshiaki; Matsumoto, Morio; Nakamura, Masaya; Kawana, Hiromasa; Nakagawa, Taneaki; Miyamoto, Takeshi

2016-10-12

Bone homeostasis is maintained as a delicate balance between bone-resorption and bone-formation, which are coupled to maintain appropriate bone mass. A critical question is how bone-resorption is terminated to allow bone-formation to occur. Here, we show that TGFβs inhibit osteoclastogenesis and maintain bone-mass through Smad4 activity in osteoclasts. We found that latent-TGFβ1 was activated by osteoclasts to inhibit osteoclastogenesis. Osteoclast-specific Smad4 conditional knockout mice (Smad4-cKO) exhibited significantly reduced bone-mass and elevated osteoclast formation relative to controls. TGFβ1-activation induced expression of Irf8 and Bcl6, both of which encode factors inhibiting osteoclastogenesis, by blocking their negative regulator, Prdm1, in osteoclasts in a Smad4-dependent manner. Reduced bone-mass and accelerated osteoclastogenesis seen in Smad4-cKO were abrogated by Prdm1 deletion. Administration of latent-TGFβ1-Fc to wild-type mice antagonized LPS-induced bone destruction in a model of activated osteoclast-mediated bone destruction. Thus, latent-TGFβ1-Fc could serve as a promising new therapeutic agent in bone diseases marked by excessive resorption.

Cell specific radiation dosimetry in skeleton from life-span carcinogenesis studies. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Webster, S.S.J.

1993-04-05

The osteogenic sarcoma is the dominant life-threatening pathology in lifespan studies of beagles exposed to alpha-emitting bone-seeking radionuclides. It was deduced from these studies that certain skeletal sites are more prone to develop tumors. This project sought to determine the bone cells at risk and their cell-specific radiation dose. The cell-specific radiation dose values are related to loss and high Ra-226 and Pu-239 induced osteogenic sarcoma sites, to test different dose response hypothesis and predict the extent of effects in humans.

Cell specific radiation dosimetry in skeleton from life-span carcinogenesis studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Webster, S.S.J.

1993-04-05

The osteogenic sarcoma is the dominant life-threatening pathology in lifespan studies of beagles exposed to alpha-emitting bone-seeking radionuclides. It was deduced from these studies that certain skeletal sites are more prone to develop tumors. This project sought to determine the bone cells at risk and their cell-specific radiation dose. The cell-specific radiation dose values are related to loss and high Ra-226 and Pu-239 induced osteogenic sarcoma sites, to test different dose response hypothesis and predict the extent of effects in humans.

Content modification attacks on consensus seeking multi-agent system with double-integrator dynamics.

PubMed

Dong, Yimeng; Gupta, Nirupam; Chopra, Nikhil

2016-11-01

In this paper, vulnerability of a distributed consensus seeking multi-agent system (MAS) with double-integrator dynamics against edge-bound content modification cyber attacks is studied. In particular, we define a specific edge-bound content modification cyber attack called malignant content modification attack (MCoMA), which results in unbounded growth of an appropriately defined group disagreement vector. Properties of MCoMA are utilized to design detection and mitigation algorithms so as to impart resilience in the considered MAS against MCoMA. Additionally, the proposed detection mechanism is extended to detect the general edge-bound content modification attacks (not just MCoMA). Finally, the efficacies of the proposed results are illustrated through numerical simulations.

Content modification attacks on consensus seeking multi-agent system with double-integrator dynamics

NASA Astrophysics Data System (ADS)

Dong, Yimeng; Gupta, Nirupam; Chopra, Nikhil

2016-11-01

In this paper, vulnerability of a distributed consensus seeking multi-agent system (MAS) with double-integrator dynamics against edge-bound content modification cyber attacks is studied. In particular, we define a specific edge-bound content modification cyber attack called malignant content modification attack (MCoMA), which results in unbounded growth of an appropriately defined group disagreement vector. Properties of MCoMA are utilized to design detection and mitigation algorithms so as to impart resilience in the considered MAS against MCoMA. Additionally, the proposed detection mechanism is extended to detect the general edge-bound content modification attacks (not just MCoMA). Finally, the efficacies of the proposed results are illustrated through numerical simulations.

Bone scintiscanning updated.

PubMed

Lentle, B C; Russell, A S; Percy, J S; Scott, J R; Jackson, F I

1976-03-01

Use of modern materials and methods has given bone scintiscanning a larger role in clinical medicine, The safety and ready availability of newer agents have led to its greater use in investigating both benign and malignant disease of bone and joint. Present evidence suggests that abnormal accumulation of 99mTc-polyphosphate and its analogues results from ionic deposition at crystal surfaces in immature bone, this process being facilitated by an increase in bone vascularity. There is, also, a component of matrix localization. These factors are in keeping with the concept that abnormal scintiscan sites represent areas of increased osteoblastic activity, although this may be an oversimplification. Increasing evidence shows that the bone scintiscan is more sensitive than conventional radiography in detecting focal disease of bone, and its ability to reflect the immediate status of bone further complements radiographic findings. The main limitation of this method relates to nonspecificity of the results obtained.

Review of ectodermal dysplasia: case report on treatment planning and surgical management of oligodontia with implant restorations.

PubMed

Li, Dehua; Liu, Yanpu; Ma, Wei; Song, Yingliang

2011-10-01

Dental implants have proven to be a reliable modality for the rehabilitation of missing teeth. However, there are limited reports on managing anodontia related to ectodermal dysplasia in the scientific literature. The severely reduced bone quantity due to the congenital absence of multiple natural teeth is the biggest challenge for the surgeon. There are a variety of bone augmentation procedures to establish adequate bone quantity, and the surgical planning should be used on an individual case basis. This is a report of a 19-year-old male patient affected by hypohidrotic ectodermal dysplasia. Oligodontia associated with severe atrophy of jaws was the chief complaint for seeking treatment. Based on clinical and radiographic examinations, 2 bone augmentation procedures were used to obtain sufficient width of alveolus for implant placement by performing an onlay bone graft in the maxilla and vertical distraction osteogenesis in the mandible. The treatment planning was discussed and informed consent was obtained.

Intestinal microbiota: a potential target for the treatment of postmenopausal osteoporosis

PubMed Central

Xu, Xin; Jia, Xiaoyue; Mo, Longyi; Liu, Chengcheng; Zheng, Liwei; Yuan, Quan; Zhou, Xuedong

2017-01-01

Postmenopausal osteoporosis (PMO) is a prevalent metabolic bone disease characterized by bone loss and structural destruction, which increases the risk of fracture in postmenopausal women. Owing to the high morbidity and serious complications of PMO, many efforts have been devoted to its prophylaxis and treatment. The intestinal microbiota is the complex community of microorganisms colonizing the gastrointestinal tract. Probiotics, which are dietary or medical supplements consisting of beneficial intestinal bacteria, work in concert with endogenous intestinal microorganisms to maintain host health. Recent studies have revealed that bone loss in PMO is closely related to host immunity, which is influenced by the intestinal microbiota. The curative effects of probiotics on metabolic bone diseases have also been demonstrated. The effects of the intestinal microbiota on bone metabolism suggest a promising target for PMO management. This review seeks to summarize the critical effects of the intestinal microbiota and probiotics on PMO, with a focus on the molecular mechanisms underlying the pathogenic relationship between bacteria and host, and to define the possible treatment options. PMID:28983411

8 CFR 287.7 - Detainer provisions under section 287(d)(3) of the Act.

Code of Federal Regulations, 2010 CFR

2010-01-01

... advise another law enforcement agency that the Department seeks custody of an alien presently in the... detainers: (1) Border patrol agents, including aircraft pilots; (2) Special agents; (3) Deportation officers... with this section, the criminal justice agency requesting such action or informing the Department of a...

25 CFR 88.2 - Employment by tribes or individual claimants.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 25 Indians 1 2012-04-01 2011-04-01 true Employment by tribes or individual claimants. 88.2 Section... ATTORNEYS AND AGENTS TO REPRESENT CLAIMANTS § 88.2 Employment by tribes or individual claimants. All such attorneys or agents seeking approval of their employment by Indian tribes or desiring to represent...

25 CFR 88.2 - Employment by tribes or individual claimants.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 25 Indians 1 2011-04-01 2011-04-01 false Employment by tribes or individual claimants. 88.2... ATTORNEYS AND AGENTS TO REPRESENT CLAIMANTS § 88.2 Employment by tribes or individual claimants. All such attorneys or agents seeking approval of their employment by Indian tribes or desiring to represent...

25 CFR 88.2 - Employment by tribes or individual claimants.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 25 Indians 1 2014-04-01 2014-04-01 false Employment by tribes or individual claimants. 88.2... ATTORNEYS AND AGENTS TO REPRESENT CLAIMANTS § 88.2 Employment by tribes or individual claimants. All such attorneys or agents seeking approval of their employment by Indian tribes or desiring to represent...

25 CFR 88.2 - Employment by tribes or individual claimants.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false Employment by tribes or individual claimants. 88.2... ATTORNEYS AND AGENTS TO REPRESENT CLAIMANTS § 88.2 Employment by tribes or individual claimants. All such attorneys or agents seeking approval of their employment by Indian tribes or desiring to represent...

25 CFR 88.2 - Employment by tribes or individual claimants.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 25 Indians 1 2013-04-01 2013-04-01 false Employment by tribes or individual claimants. 88.2... ATTORNEYS AND AGENTS TO REPRESENT CLAIMANTS § 88.2 Employment by tribes or individual claimants. All such attorneys or agents seeking approval of their employment by Indian tribes or desiring to represent...

A bone marrow toxicity model for 223Ra alpha-emitter radiopharmaceutical therapy

NASA Astrophysics Data System (ADS)

Hobbs, Robert F.; Song, Hong; Watchman, Christopher J.; Bolch, Wesley E.; Aksnes, Anne-Kirsti; Ramdahl, Thomas; Flux, Glenn D.; Sgouros, George

2012-05-01

Ra-223, an α-particle emitting bone-seeking radionuclide, has recently been used in clinical trials for osseous metastases of prostate cancer. We investigated the relationship between absorbed fraction-based red marrow dosimetry and cell level-dosimetry using a model that accounts for the expected localization of this agent relative to marrow cavity architecture. We show that cell level-based dosimetry is essential to understanding potential marrow toxicity. The GEANT4 software package was used to create simple spheres representing marrow cavities. Ra-223 was positioned on the trabecular bone surface or in the endosteal layer and simulated for decay, along with the descendants. The interior of the sphere was divided into cell-size voxels and the energy was collected in each voxel and interpreted as dose cell histograms. The average absorbed dose values and absorbed fractions were also calculated in order to compare those results with previously published values. The absorbed dose was predominantly deposited near the trabecular surface. The dose cell histogram results were used to plot the percentage of cells that received a potentially toxic absorbed dose (2 or 4 Gy) as a function of the average absorbed dose over the marrow cavity. The results show (1) a heterogeneous distribution of cellular absorbed dose, strongly dependent on the position of the cell within the marrow cavity; and (2) that increasing the average marrow cavity absorbed dose, or equivalently, increasing the administered activity resulted in only a small increase in potential marrow toxicity (i.e. the number of cells receiving more than 4 or 2 Gy), for a range of average marrow cavity absorbed doses from 1 to 20 Gy. The results from the trabecular model differ markedly from a standard absorbed fraction method while presenting comparable average dose values. These suggest that increasing the amount of radioactivity may not substantially increase the risk of toxicity, a result unavailable to the absorbed fraction method of dose calculation.

A Novel Growth Factor and Anti-Apoptotic Agent for Promoting Lung Development and Treating Lung Disease | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at the NCI have developed a new therapeutic strategy for lung cancer using secretoglobin family 3A member 2 (SCGB3A2), as a cell proliferative and anti-apoptotic agent. SCGB3A2 can be used to inhibit lung damage that results from treatment with anti-cancer agents. NCI seeks parties to license or co-develop this technology.

NPS Collaborative Technology Testbed for ONR CKM Program

DTIC Science & Technology

2005-01-11

or have access to the MIT E-Wall hosted by the TOC. The combination of E-Wall and agents lend themselves to the dynamic gathering and display of...display, intuitive icons or menus that is easy to activate and customize , and automatically seeks and connects to other like services/networks/agents...integration creates network- centric memory mechanism for developing shared understanding of SA events Data Base Integration of Sensor-DM Agents and

Longitudinal Effects of Teriparatide or Zoledronic Acid on Bone Modeling- and Remodeling-Based Formation in the SHOTZ Study.

PubMed

Dempster, David W; Zhou, Hua; Ruff, Valerie A; Melby, Thomas E; Alam, Jahangir; Taylor, Kathleen A

2018-04-01

Previously, we reported on bone histomorphometry, biochemical markers, and bone mineral density distribution after 6 and 24 months of treatment with teriparatide (TPTD) or zoledronic acid (ZOL) in the SHOTZ study. The study included a 12-month primary study period, with treatment (TPTD 20 μg/d by subcutaneous injection or ZOL 5 mg/yr by intravenous infusion) randomized and double-blind until the month 6 biopsy (TPTD, n = 28; ZOL, n = 30 evaluable), then open-label, with an optional 12-month extension receiving the original treatment. A second biopsy (TPTD, n = 10; ZOL, n = 9) was collected from the contralateral side at month 24. Here we present data on remodeling-based bone formation (RBF), modeling-based bone formation (MBF), and overflow modeling-based bone formation (oMBF, modeling overflow adjacent to RBF sites) in the cancellous, endocortical, and periosteal envelopes. RBF was significantly greater after TPTD versus ZOL in all envelopes at 6 and 24 months, except the periosteal envelope at 24 months. MBF was significantly greater with TPTD in all envelopes at 6 months but not at 24 months. oMBF was significantly greater at 6 months in the cancellous and endocortical envelopes with TPTD, with no significant differences at 24 months. At 6 months, total bone formation surface was also significantly greater in each envelope with TPTD treatment (all p < 0.001). For within-group comparisons from 6 to 24 months, no statistically significant changes were observed in RBF, MBF, or oMBF in any envelope for either the TPTD or ZOL treatment groups. Overall, TPTD treatment was associated with greater bone formation than ZOL. Taken together the data support the view that ZOL is a traditional antiremodeling agent, wheareas TPTD is a proremodeling anabolic agent that increases bone formation, especially that associated with bone remodeling, including related overflow modeling, with substantial modeling-based bone formation early in the course of treatment. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

Contrast Agents for Micro-Computed Tomography of Microdamage in Bone

DTIC Science & Technology

2008-01-01

4 × 50–60 mm, were sectioned from the cortex at the mid-diaphysis of a single bovine tibia. Two symmetric notches were machined on the periosteal ...endosteal surface, 0.6 mm from the periosteal surface and 0.2 mm from the beam sides (Fig. 2). Gaussian smoothing was applied to suppress noise and 3D...microdamage in trabecular bone with barium sulfate (BaSO4); (2) apply the technique to detect microdamage induced in bovine tibial trabecular bone specimens

On-chip synthesis of fine-tuned bone-seeking hybrid nanoparticles.

PubMed

Hasani-Sadrabadi, Mohammad Mahdi; Dashtimoghadam, Erfan; Bahlakeh, Ghasem; Majedi, Fatemeh S; Keshvari, Hamid; Van Dersarl, Jules J; Bertsch, Arnaud; Panahifar, Arash; Renaud, Philippe; Tayebi, Lobat; Mahmoudi, Morteza; Jacob, Karl I

2015-01-01

Here we report a one-step approach for reproducible synthesis of finely tuned targeting multifunctional hybrid nanoparticles (HNPs). A microfluidic-assisted method was employed for controlled nanoprecipitation of bisphosphonate-conjugated poly(D,L-lactide-co-glycolide) chains, while coencapsulating superparamagnetic iron oxide nanoparticles and the anticancer drug Paclitaxel. Smaller and more compact HNPs with narrower size distribution and higher drug loading were obtained at microfluidic rapid mixing regimen compared with the conventional bulk method. The HNPs were shown to have a strong affinity for hydroxyapatite, as demonstrated in vitro bone-binding assay, which was further supported by molecular dynamics simulation results. In vivo proof of concept study verified the prolonged circulation of targeted microfluidic HNPs. Biodistribution as well as noninvasive bioimaging experiments showed high tumor localization and suppression of targeted HNPs to the bone metastatic tumor. The hybrid bone-targeting nanoparticles with adjustable characteristics can be considered as promising nanoplatforms for various theragnostic applications.

75 FR 81332 - Health Outcomes Not Associated With Exposure to Certain Herbicide Agents; Veterans and Agent...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-27

... are limited by the inconsistency of the results, the lack of controls, and other methodological... ducts); pancreatic cancer; bone and joint cancer; melanoma; non-melanoma skin cancer (basal cell and... cancers; colorectal cancer; hepatobiliary cancer, melanoma, non-melanoma skin cancer; cancers of the...

The Process of Care-seeking for Myocardial Infarction Among Patients With Diabetes

PubMed Central

Ängerud, Karin Hellström; Brulin, Christine; Eliasson, Mats; Näslund, Ulf; Hörnsten, Åsa

2015-01-01

Background: People with diabetes have a higher risk for myocardial infarction (MI) than do people without diabetes. It is extremely important that patients with MI seek medical care as soon as possible after symptom onset because the shorter the time from symptom onset to treatment, the better the prognosis. Objective: The aim of this study was to explore how people with diabetes experience the onset of MI and how they decide to seek care. Methods: We interviewed 15 patients with diabetes, 7 men and 8 women, seeking care for MI. They were interviewed 1 to 5 days after their admission to hospital. Five of the participants had had a previous MI; 5 were being treated with insulin; 5, with a combination of insulin and oral antidiabetic agents; and 5, with oral agents only. Data were analyzed according to grounded theory. Results: The core category that emerged, “becoming ready to act,” incorporated the related categories of perceiving symptoms, becoming aware of illness, feeling endangered, and acting on illness experience. Our results suggest that responses in each of the categories affect the care-seeking process and could be barriers or facilitators in timely care-seeking. Many participants did not see themselves as susceptible to MI and MI was not expressed as a complication of diabetes. Conclusions: Patients with diabetes engaged in a complex care-seeking process, including several delaying barriers, when they experienced symptoms of an MI. Education for patients with diabetes should include discussions about their increased risk of MI, the range of individual variation in symptoms and onset of MI, and the best course of action when possible symptoms of MI occur. PMID:25325370

"Two Handfuls of Bone and Ash": Teaching Our Children about Hiroshima.

ERIC Educational Resources Information Center

Kazemek, Francis E.

1994-01-01

Textbook treatments of Hiroshima bombing inadequately convey this event's horrors and complexities. Many adults and children are desensitized to war's horrors by media's depersonalized language, i.e., using "collateral damage" to describe Desert Storm civilian casualties. Educators should seek alternative resources, such as Toshi…

HIV Infection and Bone Abnormalities.

PubMed

Ahmad, Aamir N; Ahmad, Shahid N; Ahmad, Nafees

2017-01-01

More than 36 million people are living with human immunodeficiency virus (HIV) infection worldwide and 50% of them have access to antiretroviral therapy (ART). While recent advances in HIV therapy have reduced the viral load, restored CD4 T cell counts and decreased opportunistic infections, several bone-related abnormalities such as low bone mineral density (BMD), osteoporosis, osteopenia, osteomalacia and fractures have emerged in HIV-infected individuals. Of all classes of antiretroviral agents, HIV protease inhibitors used in ART combination showed a higher frequency of osteopenia, osteoporosis and low BMD in HIV-infected patients. Although the mechanisms of HIV and/or ART associated bone abnormalities are not known, it is believed that the damage is caused by a complex interaction of T lymphocytes with osteoclasts and osteoblasts, likely influenced by both HIV and ART. In addition, infection of osteoclasts and bone marrow stromal cells by HIV, including HIV Gp120 induced apoptosis of osteoblasts and release of proinflammatory cytokines have been implicated in impairment of bone development and maturation. Several of the newer antiretroviral agents currently used in ART combination, including the widely used tenofovir in different formulations show relative adverse effects on BMD. In this context, switching the HIV-regimen from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) showed improvement in BMD of HIV-infected patients. In addition, inclusion of integrase inhibitor in ART combination is associated with improved BMD in patients. Furthermore, supplementation of vitamin D and calcium with the initiation of ART may mitigate bone loss. Therefore, levels of vitamin D and calcium should be part of the evaluation of HIV-infected patients.

Fatty acid is a potential agent for bone tissue induction: In vitro and in vivo approach.

PubMed

Cardoso, Guinea Bc; Chacon, Erivelto; Chacon, Priscila Gl; Bordeaux-Rego, Pedro; Duarte, Adriana Ss; Saad, Sara T Olalla; Zavaglia, Cecilia Ac; Cunha, Marcelo R

2017-12-01

Our hypothesis was to investigate the fatty acid potential as a bone induction factor. In vitro and in vivo studies were performed to evaluate this approach. Oleic acid was used in a 0.5 wt.% concentration. Polycaprolactone was used as the polymeric matrix by combining solvent-casting and particulate-leaching techniques, with a final porosity of 70 wt.%, investigated by SEM images. Contact angle measurements were produced to investigate the influence of oleic acid on polycaprolactone chains. Cell culture was performed using adipocyte-derived stem cells to evaluate biocompatibility and bioactivity properties. In addition, in vivo studies were performed to evaluate the induction potential of oleic acid addition. Adipocyte-derived stem cells were used to provide differentiation after 21 days of culture. Likewise, information were obtained with in vivo data and cellular invagination was observed on both scaffolds (polycaprolactone and polycaprolactone /oleic acid); interestingly, the scaffold with oleic acid addition demonstrated that cellular migrations are not related to the surrounding tissue, indicating bioactive potential. Our hypothesis is that fatty acid may be used as a potential induction factor for bone tissue engineering. The study's findings indicate oleic acid as a possible agent for bone induction, according to data on cell differentiation, proliferation, and migration. Impact statement The biomaterial combined in this study on bone regeneration is innovative and shows promising results in the treatment of bone lesions. Polycaprolactone (PCL) and oleic acid have been studied separately. In this research, we combined biomaterials to assess the stimulus and the speed of bone healing.

The Transplantation of hBM-MSCs Increases Bone Neo-Formation and Preserves Hearing Function in the Treatment of Temporal Bone Defects - on the Experience of Two Month Follow Up.

PubMed

Školoudík, Lukáš; Chrobok, Viktor; Kočí, Zuzana; Popelář, Jiří; Syka, Josef; Laco, Jan; Filipová, Alžběta; Syková, Eva; Filip, Stanislav

2018-06-03

Temporal bone reconstruction is a persisting problem following middle ear cholesteatoma surgery. Seeking to advance the clinical transfer of stem cell therapy we attempted the reconstruction of temporal bone using a composite bioartificial graft based on a hydroxyapatite bone scaffold combined with human bone marrow-derived mesenchymal stromal cells (hBM-MSCs). The aim of this study was to evaluate the effect of the combined biomaterial on the healing of postoperative temporal bone defects and the preservation of physiological hearing functions in a guinea pig model. The treatment's effect could be observed at 1 and 2 months after implantation of the biomaterial, as opposed to the control group. The clinical evaluation of our results included animal survival, clinical signs of an inflammatory response, and exploration of the tympanic bulla. Osteogenesis, angiogenesis, and inflammation were evaluated by histopathological analyses, whereas hBM-MSCs survival was evaluated by immunofluorescence assays. Hearing capacity was evaluated by objective audiometric methods, i.e. auditory brainstem responses and otoacoustic emission. Our study shows that hBM-MSCs, in combination with hydroxyapatite scaffolds, improves the repair of bone defects providing a safe and effective alternative in their treatment following middle ear surgery due to cholesteatoma.

Current and potential future drug treatments for osteoporosis.

PubMed Central

Patel, S

1996-01-01

There has been a major interest in the drug treatment of osteoporosis and an increase in the number of drugs available in most countries. The ideal drug (one which increases or restores bone density and trabecular connectivity) is still not available. However, in patients with relatively preserved trabecular connectivity and moderately reduced bone density, several agents have shown substantial clinical benefit. Oestrogens are still the mainstay of drug treatment, but the risks of breast cancer versus the cardiovascular and skeletal benefits with long term use have to be assessed in the individual. Newer tissue specific oestrogens show some promise in this respect. The bisphosphonates and possibly fluoride are likely to be the major alternatives to oestrogens in the medium term. The newer bisphosphonates, alendronate and in the future risedronate, are likely to supersede etidronate. Calcitriol probably has a limited role, confined to those patients in whom HRT or bisphosphonates are not appropriate. Calcium supplementation, or an increase in dietary intake if deficient, irrespective of which agent is used, is also of benefit. In older patients there is considerable support for using a combination of calcium and vitamin D. Whether combination treatment, for example oestrogens, bisphosphonates, and calcium together, will result in greater efficacy remains to be conclusively shown, but may be an attractive option in younger patients with higher bone turnover. Apart from fluoride, bone formation stimulators are unlikely to have a major role until the next century, although it may be possible to use growth factors as part of an ADFR regimen (A = activate remodelling, D = depress resorption, F = free formation, and R = repeat). This is still an important theoretical approach and needs further work with newer agents to see if increased efficacy can be found. In addition sequential treatment may be necessary in view of the limited time periods over which particular agents, such as intermittent fluoride (four years), have been examined, and this will have to be individually tailored. Other approaches include trying to increase peak bone mineral density, although influencing the young to prevent a disease that may not manifest itself for half a century is daunting. PMID:8984934

Engineering bioactive polymers for the next generation of bone repair

NASA Astrophysics Data System (ADS)

Ho, Emily Y.

Bone disease is a serious health condition among the aged population. In some cases of bone damage it becomes necessary to replace, recontour, and assist in the healing of the bone. Many materials have been proposed as useful replacements but none have been proven to be ideal. In this thesis, two bioactive composites were investigated for bone replacements. First reported material is a hydroxyapatite (HA) particle reinforced polymethylmethacrylate (PMMA) composite treated with a co-polymer coupling agent for mandible augmentations. The influence of the coupling agent on the local mechanical properties of the system before and after simulated biological conditions was determined by applying nano-indentation at the cross-sectional HA/PMMA interface. The local interfacial results were indicative of the global quasi static compression test results. While the coupling agent improved the interfacial and global mechanical properties before and after 24 hours in vitro immersion, it did not affect the surface bioactivity of the system. However, the addition of coupling agent did not provide long term in vitro improvement of both local and global mechanical properties of the composite. An alternative approach of combining a bioactive phase into polymer matrix was developed. The second analyzed material is an injectable composite with osteoconductivity and ideal mechanical biocompatibility for vertebral fracture fixations which we formulated and fabricated. A bioactive component was engineered into the macromolecular structure to facilitate the formation of apatite nucleation sites on a thermo-sensitive polymer, poly(N-isopropylacryamide)-co-poly(ethyleneglycol) dimethacrylate (PNIPAAm-PEGDM), through incorporation of tri-methacryloxypropyltrimethoxysilane (MPS). PNIPAAm-PEGDM is capable of liquid to solid phase transformation at 32°C. In this study, the phase transformation temperature (LCSTs), the in vitro mechanical properties, swelling characteristics and bioactivity of the polymers were evaluated. The addition of NIPS to the polymer encouraged apatite formation and increased its compressive modulus while its LCST remained unchanged. The challenge of this material system is to balance the network-forming and bioactivity inducing MPS with the gain in elastic recovery induced by PEGDM addition to the PNIPAAm base, all while maintaining an injectable material system. This material platform offers a family of polymers that have a range of mechanical properties for various tissue replacements.

Cellular Mechanisms of Multiple Myeloma Bone Disease

PubMed Central

Oranger, Angela; Carbone, Claudia; Izzo, Maddalena; Grano, Maria

2013-01-01

Multiple myeloma (MM) is a hematologic malignancy of differentiated plasma cells that accumulates and proliferates in the bone marrow. MM patients often develop bone disease that results in severe bone pain, osteolytic lesions, and pathologic fractures. These skeletal complications have not only a negative impact on quality of life but also a possible effect in overall survival. MM osteolytic bone lesions arise from the altered bone remodeling due to both increased osteoclast activation and decreased osteoblast differentiation. A dysregulated production of numerous cytokines that can contribute to the uncoupling of bone cell activity is well documented in the bone marrow microenvironment of MM patients. These molecules are produced not only by malignant plasma cells, that directly contribute to MM bone disease, but also by bone, immune, and stromal cells interacting with each other in the bone microenvironment. This review focuses on the current knowledge of MM bone disease biology, with particular regard on the role of bone and immune cells in producing cytokines critical for malignant plasma cell proliferation as well as in osteolysis development. Therefore, the understanding of MM pathogenesis could be useful to the discovery of novel agents that will be able to both restore bone remodelling and reduce tumor burden. PMID:23818912

Contributions of Raman spectroscopy to the understanding of bone strength.

PubMed

Mandair, Gurjit S; Morris, Michael D

2015-01-01

Raman spectroscopy is increasingly commonly used to understand how changes in bone composition and structure influence tissue-level bone mechanical properties. The spectroscopic technique provides information on bone mineral and matrix collagen components and on the effects of various matrix proteins on bone material properties as well. The Raman spectrum of bone not only contains information on bone mineral crystallinity that is related to bone hardness but also provides information on the orientation of mineral crystallites with respect to the collagen fibril axis. Indirect information on collagen cross-links is also available and will be discussed. After a short introduction to bone Raman spectroscopic parameters and collection methodologies, advances in in vivo Raman spectroscopic measurements for animal and human subject studies will be reviewed. A discussion on the effects of aging, osteogenesis imperfecta, osteoporosis and therapeutic agents on bone composition and mechanical properties will be highlighted, including genetic mouse models in which structure-function and exercise effects are explored. Similarly, extracellular matrix proteins, proteases and transcriptional proteins implicated in the regulation of bone material properties will be reviewed.

Impacts of extended laboratory rearing on female fitness in Florida colonies of the parasitoid spalangia cameroni (Hymenoptera: Pteromalidae) with an analysis of wolbachia strains

USDA-ARS?s Scientific Manuscript database

Spalangia cameroni is used as a biological control agent of filth flies. These parasitoids are reared commercially, but little is known about the impact of colony age on host-seeking and life history parameters. Host-seeking in equine shavings and manure was analyzed with two colony ages established...

Biomaterial delivery of morphogens to mimic the natural healing cascade in bone

PubMed Central

Mehta, Manav; Schmidt-Bleek, Katharina; Duda, Georg N; Mooney, David J

2012-01-01

Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing. PMID:22626978

Prostaglandin E2 Prevents Bone Loss and Adds Extra Bone to Immobilized Distal Femoral Metaphysis in Female Rats

NASA Technical Reports Server (NTRS)

Akamine, T.; Jee, W. S. S.; Ke, H. Z.; Li, X. J.; Lin, B. Y.

1992-01-01

The object of this study was to determine whether prostaglandin E2 (PGE2) can prevent disuse (underloading)-induced cancellous bone loss. Thirteen-month-old retired female Sprague-Dawley breeders served as controls or were subjected to right hindlimb immobilization by bandaging and simultaneously treated subcutaneously daily with 0, 1, 3, or 6 mg PGE2/kg/d for two and six weeks. Histomorphometric analyses were performed on the cancellous bone using double-fluorescent labeled, 20 micron thick, undecalcified distal femoral metaphysis sections. We found that PGE2 administration not only prevented disuse-induced bone loss, but also added extra bone to disuse cancellous bone in a dose-response manner. PGE2 prevented the disuse-induced osteopenia by stimulating more bone formation than and shortening the period of bone remodeling. It activated woven bone formation, stimulated lamellar bone formation, and increased the eroded bone surface above that caused by disuse alone. While underloading increased the remodeling period (sigma), PGE2 treatment of underloaded bone shortened the time for osteoclastic bone resorption and bone remodeling, and thus reduced the remodeling space. The study shows that PGE2 is a powerful anabolic agent that prevents disuse-induced osteopenia and adds extra bone to these same bones.

Tools for Using Citizen Science in Environmental, Agricultural, and Natural Resources Extension Programs

ERIC Educational Resources Information Center

Stofer, Kathryn A.

2017-01-01

Citizen science is quickly becoming a valuable tool in the Extension professional's tool kit. This is the case whether you are a 4-H agent looking to involve youth in agriscience and agriculture-related science, technology, engineering, and math experiential learning activities or an agriculture and natural resources agent seeking to help…

Dietary nutraceuticals as backbone for bone health.

PubMed

Pandey, Manoj K; Gupta, Subash C; Karelia, Deepkamal; Gilhooley, Patrick J; Shakibaei, Mehdi; Aggarwal, Bharat B

2018-03-27

Bone loss or osteoporosis, is a slow-progressing disease that results from dysregulation of pro-inflammatory cytokines. The FDA has approved number of drugs for bone loss prevention, nonetheless all are expensive and have multiple side effects. The nutraceuticals identified from dietary agents such as butein, cardamonin, coronarin D curcumin, diosgenin, embelin, gambogic acid, genistein, plumbagin, quercetin, reseveratrol, zerumbone and more, can modulate cell signaling pathways and reverse/slow down osteoporosis. Most of these nutraceuticals are inexpensive; show no side effect while still possessing anti-inflammatory properties. This review provides various mechanisms of osteoporosis and how nutraceuticals can potentially prevent the bone loss. Published by Elsevier Inc.

Osteoporosis: An Update on Pathogenesis and Treatment

PubMed Central

Josse, Robert G.

1983-01-01

Both hormonal and nonhormonal factors appear to contribute to bone loss in osteoporosis. Decreased estrogen production, not enough calcium and too much protein, phosphorus and caffeine in the diet all have a probable effect. Aims of treatment include giving symptomatic relief, rehabilitation, arresting further bone loss, increasing the useful bone mass and restoring damaged skeletal architecture where possible. Current treatment includes ensuring that the patient avoids excess protein and caffeine and has adequate calcium in her diet. Estrogen therapy is still subject to debate, but does seem to prevent bone loss if initiated within three to five years of menopause. Much research is currently being done on sodium fluoride, the only agent that appears actually able to produce new bone. PMID:21283471

Scaffold Design for Bone Regeneration

PubMed Central

Polo-Corrales, Liliana; Latorre-Esteves, Magda; Ramirez-Vick, Jaime E.

2014-01-01

The use of bone grafts is the standard to treat skeletal fractures, or to replace and regenerate lost bone, as demonstrated by the large number of bone graft procedures performed worldwide. The most common of these is the autograft, however, its use can lead to complications such as pain, infection, scarring, blood loss, and donor-site morbidity. The alternative is allografts, but they lack the osteoactive capacity of autografts and carry the risk of carrying infectious agents or immune rejection. Other approaches, such as the bone graft substitutes, have focused on improving the efficacy of bone grafts or other scaffolds by incorporating bone progenitor cells and growth factors to stimulate cells. An ideal bone graft or scaffold should be made of biomaterials that imitate the structure and properties of natural bone ECM, include osteoprogenitor cells and provide all the necessary environmental cues found in natural bone. However, creating living tissue constructs that are structurally, functionally and mechanically comparable to the natural bone has been a challenge so far. This focus of this review is on the evolution of these scaffolds as bone graft substitutes in the process of recreating the bone tissue microenvironment, including biochemical and biophysical cues. PMID:24730250

Cytologic Effects of Air Force Chemicals

DTIC Science & Technology

1979-08-01

mitomycin C (MMC, Sigma), a well known bifunctional DNA alkylating agent . Figure 3 shows typical metaphase spreads of a rat lymphocyte and a rat bone...monofunctional DNA alkylating agents and well known mutagens, are shown in Figures 7 and 8, respectively. Fig- ure 9 shows the induction of micronuclei by MMC...a bifunctional alkyl - ating agent . These three chemicals serve as positive controls for the in vitro exposures. In all three figures, the general

The effects of corrosive substances on human bone, teeth, hair, nails, and soft tissue.

PubMed

Hartnett, Kristen M; Fulginiti, Laura C; Di Modica, Frank

2011-07-01

This research investigates the effects of household chemicals on human tissues. Five different human tissues (bone, tooth, hair, fingernails, and skin/muscle/fat) were immersed into six different corrosive agents. These agents consisted of hydrochloric acid, sulfuric acid, lye, bleach, organic septic cleaner, and Coca-Cola(®) soda. Tap water was used as a control. Tissue samples were cut to consistent sizes and submerged in the corrosive liquids. Over time, the appearance, consistency, and weight were documented. Hydrochloric acid was the most destructive agent in this study, consuming most tissues within 24 h. Sulfuric acid was the second most destructive agent in this study. Bleach, lye, and cola had no structural effects on the hard tissues of the body, but did alter the appearance or integrity of the hair, nails, or flesh in some way. The organic septic cleaner and tap water had no effect on any of the human tissue tested during the timeframe of the study. 2011 American Academy of Forensic Sciences. Published 2011. This article is a U.S. Government work and is in the public domain in the U.S.A.

[Bone marrow stromal damage mediated by immune response activity].

PubMed

Vojinović, J; Kamenov, B; Najman, S; Branković, Lj; Dimitrijević, H

1994-01-01

The aim of this work was to estimate influence of activated immune response on hematopoiesis in vitro, using the experimental model of BCG immunized BALB/c mice and in patients with chronic immunoactivation: long-lasting infections, autoimmunity or malignancy. We correlated changes in long term bone marrow cultures (Dexter) and NBT reduction with appearance of anemia in patients and experimental model of immunization by BCG. Increased spontaneous NBT reduction pointed out role of macrophage activation in bone marrow stroma damage. Long-term bone marrow cultures showed reduced number of hematopoietic cells, with predomination of fibroblasts and loss of fat cells. This results correlated with anemia and leucocytosis with stimulated myelopoiesis in peripheral blood. Activation of immune response, or acting of any agent that directly changes extracellular matrix and cellularity of bone marrow, may result in microenviroment bone marrow damage that modify hematopoiesis.

Can we improve fixation and outcomes? Use of bone substitutes.

PubMed

Moroni, Antonio; Larsson, Sune; Hoang Kim, Amy; Gelsomini, Letizia; Giannoudis, Peter V

2009-07-01

Hip fractures secondary to osteoporosis are common in the elderly. Stabilizing these fractures until union is achieved is a challenge due to poor bone stock and insufficient purchase of the implant to the bone. The reported high rate of complications has prompted extensive research in the development of fixation techniques. Furthermore, manipulation of both the local fracture environment in terms of application of growth factors, scaffolds, and mesenchymal cells and the systemic administration of agents promoting bone formation and bone strength has been considered as a treatment option with promising results. There are only a few evidence-based studies reporting on fixation augmentation techniques. This article reports on the efficacy of bone graft substitutes for the fixation of hip fractures, in particular calcium phosphates, which have been used as granules, cements, and implant coatings.

Osteoclast-targeting small molecules for the treatment of neoplastic bone metastases.

PubMed

Kawatani, Makoto; Osada, Hiroyuki

2009-11-01

Osteoclasts are highly specialized cells that resorb bone, and their abnormal activity is implicated in a variety of human bone diseases. In neoplastic bone metastasis, the bone destruction caused by osteoclasts is not only associated with the formation and progression of metastatic lesions, but also could contribute to frequent complications such as severe pain and pathological fractures, which greatly diminish the quality of life of patients. Bisphosphonates, potent antiresorptive drugs, have been shown to have efficacy for treating bone metastases in many types of cancer, and the development of various molecularly targeted agents is currently proceeding. Thus, inhibition of osteoclast function is now established as an important treatment strategy for bony metastases. This review focuses on promising small molecules that disrupt osteoclast function and introduces our chemical/biological approach for identifying osteoclast-targeting small molecular inhibitors.

Complex ankle arthrodesis: Review of the literature

PubMed Central

Rabinovich, Remy V; Haleem, Amgad M; Rozbruch, S Robert

2015-01-01

Complex ankle arthrodesis is defined as an ankle fusion that is at high risk of delayed and nonunion secondary to patient comorbidities and/or local ankle/hindfoot factors. Risk factors that contribute to defining this group of patients can be divided into systemic factors and local factors pertaining to co-existing ankle or hindfoot pathology. Orthopaedic surgeons should be aware of these risk factors and their association with patients’ outcomes after complex ankle fusions. Both external and internal fixations have demonstrated positive outcomes with regards to achieving stable fixation and minimizing infection. Recent innovations in the application of biophysical agents and devices have shown promising results as adjuncts for healing. Both osteoconductive and osteoinductive agents have been effectively utilized as biological adjuncts for bone healing with low complication rates. Devices such as pulsed electromagnetic field bone stimulators, internal direct current stimulators and low-intensity pulsed ultrasound bone stimulators have been associated with faster bone healing and improved outcomes scores when compared with controls. The aim of this review article is to present a comprehensive approach to the management of complex ankle fusions, including the use of biophysical adjuncts for healing and a proposed algorithm for their treatment. PMID:26396936

Technetium-99m and rhenium-188 complexes with one and two pendant bisphosphonate groups for imaging arterial calcification.

PubMed

Bordoloi, Jayanta Kumar; Berry, David; Khan, Irfan Ullah; Sunassee, Kavitha; de Rosales, Rafael Torres Martin; Shanahan, Catherine; Blower, Philip J

2015-03-21

The first (99m)Tc and (188)Re complexes containing two pendant bisphosphonate groups have been synthesised, based on the mononuclear M(v) nitride core with two dithiocarbamate ligands each with a pendant bisphosphonate. The structural identity of the (99)Tc and stable rhenium analogues as uncharged, mononuclear nitridobis(dithiocarbamate) complexes was determined by electrospray mass spectrometry. The (99m)Tc complex showed greater affinity for synthetic and biological hydroxyapatite, and greater stability in biological media, than the well-known but poorly-characterised and inhomogeneous bone imaging agent (99m)Tc-MDP. It gave excellent SPECT images of both bone calcification (mice and rats) and vascular calcification (rat model), but the improved stability and the availability of two pendant bisphosphonate groups conferred no dramatic advantage in imaging over the conventional (99m)Tc-MDP agent in which the bisphosphonate group is bound directly to Tc. The (188)Re complex also showed preferential uptake in bone. These tracers and the biological model of vascular calcification offer the opportunity to study the biological interpretation and clinical potential of radionuclide imaging of vascular calcification and to deliver radionuclide therapy to bone metastases.

A combined chitosan/nano-size hydroxyapatite system for the controlled release of icariin.

PubMed

Fan, Junjun; Bi, Long; Wu, Tao; Cao, Liangguo; Wang, Dexin; Nan, Kaihui; Chen, Jingdi; Jin, Dan; Jiang, Shan; Pei, Guoxian

2012-02-01

Icariin, a plant-derived flavonol glycoside, has been proved as an osteoinductive agent for bone regeneration. For this reason, we developed an icariin-loaded chitosan/nano-sized hydroxyapatite (IC-CS/HA) system which controls the release kinetics of icariin to enhance bone repairing. First, by Fourier transform infrared spectroscopy, we found that icariin was stable in the system developed without undergoing any chemical changes. On the other hand, X-ray diffraction, scanning electron microscopy and mechanical test revealed that the introduction of icariin did not remarkably change the phase, morphology, porosity and mechanical strength of the CS/HA composite. Then the hydrolytic degradation and drug release kinetics in vitro were investigated by incubation in phosphate buffered saline solution. The results indicated that the icariin was released in a temporally controlled manner and the release kinetics could be governed by degradation of both chitosan and hydroxyapatite matrix. Finally the in vitro bioactivity assay revealed that the loaded icariin was biologically active as evidenced by stimulation of bone marrow derived stroma cell alkaline phosphatase activity and formation of mineralized nodules. This successful IC-CS/HA system offers a new delivery method of osteoinductive agents and a useful scaffold design for bone regeneration.

An introduction to Na(18)F bone scintigraphy: basic principles, advanced imaging concepts, and case examples.

PubMed

Bridges, Robert L; Wiley, Chris R; Christian, John C; Strohm, Adam P

2007-06-01

Na(18)F, an early bone scintigraphy agent, is poised to reenter mainstream clinical imaging with the present generations of stand-alone PET and PET/CT hybrid scanners. (18)F PET scans promise improved imaging quality for both benign and malignant bone disease, with significantly improved sensitivity and specificity over conventional planar and SPECT bone scans. In this article, basic acquisition information will be presented along with examples of studies related to oncology, sports medicine, and general orthopedics. The use of image fusion of PET bone scans with CT and MRI will be demonstrated. The objectives of this article are to provide the reader with an understanding of the history of early bone scintigraphy in relation to Na(18)F scanning, a familiarity with basic imaging techniques for PET bone scanning, an appreciation of the extent of disease processes that can be imaged with PET bone scanning, an appreciation for the added value of multimodality image fusion with bone disease, and a recognition of the potential role PET bone scanning may play in clinical imaging.

The short-term effects of cisplatin chemotherapy on bone turnover.

PubMed

Young, D R; Virolainen, P; Inoue, N; Frassica, F J; Chao, E Y

1997-11-01

Cisplatin is an effective agent in the treatment of osteosarcoma of bone but little is known of its effects on normal bone turnover. Twenty-four dogs divided into three study groups were used to study the effect of cisplatin on normal bone turnover at the distant site of surgery. Group 1 served as the control group, group 2 received four cycles of cisplatin every 3 weeks before the surgery, and group 3 received four cycles postoperatively. The bone turnover rate was evaluated by measuring levels of systemic bone markers, osteocalcin, alkaline phospohatase, urine pyridinoline cross-links, and by determination histomorphometric indices. Histomorphological analysis showed poor correlation on bone formation with systemic bone markers at distant sites of surgery. Histomorphometrically normal bone turnover was affected by administration of cisplatin, but the effect was temporary, late, and less significant than what occurred at the surgical site. Our data showed that significant effects of cisplatin are observed at the site of active cellular induction and proliferation, such as implant-host interface, and less effects are seen at the sites of normal bone turnover.

Application of platelet-rich plasma with stem cells in bone and periodontal tissue engineering

PubMed Central

Fernandes, Gabriela; Yang, Shuying

2016-01-01

Presently, there is a high paucity of bone grafts in the United States and worldwide. Regenerating bone is of prime concern due to the current demand of bone grafts and the increasing number of diseases causing bone loss. Autogenous bone is the present gold standard of bone regeneration. However, disadvantages like donor site morbidity and its decreased availability limit its use. Even allografts and synthetic grafting materials have their own limitations. As certain specific stem cells can be directed to differentiate into an osteoblastic lineage in the presence of growth factors (GFs), it makes stem cells the ideal agents for bone regeneration. Furthermore, platelet-rich plasma (PRP), which can be easily isolated from whole blood, is often used for bone regeneration, wound healing and bone defect repair. When stem cells are combined with PRP in the presence of GFs, they are able to promote osteogenesis. This review provides in-depth knowledge regarding the use of stem cells and PRP in vitro, in vivo and their application in clinical studies in the future. PMID:28018706

Stimulation of fibroblast growth factor 23 by metabolic acidosis requires osteoblastic intracellular calcium signaling and prostaglandin synthesis.

PubMed

Krieger, Nancy S; Bushinsky, David A

2017-10-01

Serum fibroblast growth factor 23 (FGF23) increases progressively in chronic kidney disease (CKD) and is associated with increased mortality. FGF23 is synthesized in osteoblasts and osteocytes; however, the factors regulating its production are not clear. Patients with CKD have decreased renal acid excretion leading to metabolic acidosis (MET). During MET, acid is buffered by bone with release of mineral calcium (Ca) and phosphate (P). MET increases intracellular Ca signaling and cyclooxygenase 2 (COX2)-induced prostaglandin production in the osteoblast, leading to decreased bone formation and increased bone resorption. We found that MET directly stimulates FGF23 in mouse bone organ cultures and primary osteoblasts. We hypothesized that MET increases FGF23 through similar pathways that lead to bone resorption. Neonatal mouse calvariae were incubated in neutral (NTL, pH = 7.44, Pco 2 = 38 mmHg, [HCO 3 - ] = 27 mM) or acid (MET, pH = 7.18, Pco 2 = 37 mmHg, [HCO 3 - ] = 13 mM) medium without or with 2-APB (50 μM), an inhibitor of intracellular Ca signaling or NS-398 (1 μM), an inhibitor of COX2. Each agent significantly inhibited MET stimulation of medium FGF23 protein and calvarial FGF23 RNA as well as bone resorption at 48 h. To exclude the potential contribution of MET-induced bone P release, we utilized primary calvarial osteoblasts. In these cells each agent inhibited MET stimulation of FGF23 RNA expression at 6 h. Thus stimulation of FGF23 by MET in mouse osteoblasts utilizes the same initial signaling pathways as MET-induced bone resorption. Therapeutic interventions directed toward correction of MET, especially in CKD, have the potential to not only prevent bone resorption but also lower FGF23 and perhaps decrease mortality. Copyright © 2017 the American Physiological Society.

Bone formation transcripts dominate the differential gene expression profile in an equine osteoporotic condition associated with pulmonary silicosis.

PubMed

Zavodovskaya, Regina; Stover, Susan M; Murphy, Brian G; Katzman, Scott; Durbin-Johnson, Blythe; Britton, Monica; Finno, Carrie J

2018-01-01

Osteoporosis has been associated with pulmonary silicosis in California horses exposed to soils rich in cytotoxic silica dioxide crystals, a syndrome termed silicate associated osteoporosis (SAO). The causal mechanism for the development of osteoporosis is unknown. Osteoporotic lesions are primarily located in bone marrow-rich sites such as ribs, scapula and pelvis. Gene transcription patterns within bone marrow and pulmonary lymph nodes of affected horses may offer clues to disease pathobiology. Bone marrow core and tracheobronchial lymph node tissue samples harvested postmortem from affected and unaffected horses were examined histologically and subjected to RNA sequencing (RNA-seq). Sequenced data were analyzed for differential gene expression and gene ontology. Metatranscriptomic and metagenomic assays evaluated samples for infectious agents. Thirteen of 17 differentially expressed transcripts in bone marrow were linked to bone and cartilage formation such as integrin binding bone sialoprotein (log2FC = 3.39, PFDR = 0.013) and chondroadherin (log2FC = 4.48, PFDR = 0.031). Equus caballus solute carrier family 9, subfamily A2 (log2FC = 3.77, PFDR = 0.0034) was one of the four differentially expressed transcripts linked to osteoclast activity. Osteoblasts were hyperplastic and hypertrophic in bone marrow from affected horses. Biological pathways associated with skeletal morphogenesis were significantly enriched in affected horses. The 30 differentially expressed genes in affected lymph nodes were associated with inflammatory responses. Evidence of infectious agents was not found. The SAO affected bone marrow molecular signature demonstrated increased transcription and heightened activation of osteoblasts. Increased osteoblastic activity could be part of the pathological mechanism for osteoporosis or a compensatory response to the accelerated osteolysis. Transcriptome data offer gene targets for inquiries into the role of osteocytes and osteoblasts in SAO pathogenesis. Viral or bacterial infectious etiology in SAO is less likely based on metatranscriptomic and metagenomic data but cannot be completely ruled out.

Nonlinear electric reaction arising in dry bone subjected to 4-point bending

NASA Astrophysics Data System (ADS)

Murasawa, Go; Cho, Hideo; Ogawa, Kazuma

2007-04-01

Bone is a smart, self-adaptive and also partly self-repairing tissue. In recent years, many researchers seek to find how to give the effective mechanical stimulation to bone, because it is the predominant loading that determines the bone shape and macroscopic structure. However, the trial of regeneration of bone is still under way. On the other hand, it has been known that electrical potential generates from bone by mechanical stimulation (Yasuda, 1977; Williams, 1982; Starkebaum, 1979; Cochran, 1968; Lanyon, 1977; Salzstein, 1987a,b; Friedenberg, 1966). This is called "stress-generated potential (SGP)". The process of information transfer between "strain" and "cells" is not still clear. But, there is some possibility that SGP has something to do with the process of information transfer. If the electrical potential is more clear under some mechanical loadings, we will be able to regenerate bone artificially and freely. Therefore, it is important to investigate SGP in detail. The aim of present study is to investigate the electric reaction arising in dry bone subjected to mechanical loadings at high amplitude and low frequency strain. Firstly, specimen is fabricated from femur of cow. Next, the speeds of wave propagation in bone are tried to measure by laser ultra sonic technique and wavelet transform, because these have relationship with bone density. Secondary, 4-point bending test is conducted up to fracture. Then, electric reaction arising in bone is measured during loading. Finally, cyclic 4-point bending tests are conducted to investigate the electric reaction arising in bone at low frequency strain.

Estrogen Receptors in Breast and Bone: from Virtue of Remodeling to Vileness of Metastasis

PubMed Central

Bado, Igor; Gugala, Zbigniew; Fuqua, Suzanne A. W.; Zhang, Xiang H.-F.

2017-01-01

Bone metastasis is a prominent cause of morbidity and mortality in cancer. High rates of bone colonization in breast cancer, especially in the subtype expressing estrogen receptors (ERs), suggests tissue-specific proclivities for metastatic tumor formation. The mechanisms behind this subtype-specific organ-tropism remains largely elusive. Interestingly, as the major driver of ER+ breast cancer, ERs also play important roles in bone development and homeostasis. Thus, any agents targeting ER will also inevitably affect the microenvironment, i.e., the osteoblasts and osteoclasts. Yet, how such microenvironmental effects are integrated with direct therapeutic responses of cancer cells remain poorly understood. Recent findings on ER mutations, especially their enrichment in bone metastasis, raised even more provocative questions on the role of ER in cancer-bone interaction. In this review, we evaluate the importance of estrogen receptors (ERs) in bone metastasis and discuss new avenues of investigation for bone metastasis treatment based on current knowledge. PMID:28368409

Non-canonical Wnt4 prevents skeletal aging and inflammation by inhibiting NF-κB

PubMed Central

Yu, Bo; Chang, Jia; Liu, Yunsong; Li, Jiong; Kevork, Kareena; Al-Hezaimi, Khalid; Graves, Dana T; Park, No-Hee; Wang, Cun-Yu

2014-01-01

Aging-related bone loss and osteoporosis affect millions of patients worldwide. Chronic inflammation associated with aging and arthritis promotes bone resorption and impairs bone formation. Here we show that Wnt4 attenuated bone loss in osteoporosis and skeletal aging by inhibiting nuclear factor-kappa B (NF-κB) via non-canonical Wnt signaling. Transgenic mice expressing Wnt4 from osteoblasts were significantly protected from bone loss and chronic inflammation induced by ovariectomy, tumor necrosis factor or natural aging. In addition to promoting bone formation, Wnt4 could inhibit osteoclast formation and bone resorption. Mechanistically, Wnt4 inhibited transforming growth factor beta-activated kinase 1-mediated NF-κB activation in macrophages and osteoclast precursors independent of β-catenin. Moreover, recombinant Wnt4 proteins were able to alleviate osteoporotic bone loss and inflammation by inhibiting NF-κB in vivo. Taken together, our results suggest that Wnt4 might be used as a therapeutic agent for treating osteoporosis by attenuating NF-κB. PMID:25108526

Amodiaquine induced agranulocytosis: inhibition of colony growth in bone marrow by antimalarial agents.

PubMed Central

Rhodes, E G; Ball, J; Franklin, I M

1986-01-01

Bone marrow was cultured in vitro for colonies of granulocytes and macrophages five months after a patient had recovered from amodiaquine induced agranulocytosis. The addition of amodiaquine, chloroquine, and sulfadoxine to the culture was followed by a dose dependent inhibition of colony growth in the patient's marrow but not in normal control bone marrow. Colony growth was, however, unaffected by proguanil, pyrimethamine, and quinine. These findings show that in vitro marrow culture may have important predictive value in some cases of drug induced agranulocytosis. PMID:3082409

Calcium phosphate cement with biofunctional agents and stem cell seeding for dental and craniofacial bone repair.

PubMed

Thein-Han, WahWah; Liu, Jun; Xu, Hockin H K

2012-10-01

Calcium phosphate cement (CPC) can be injected to harden in situ and is promising for dental and craniofacial applications. However, human stem cell attachment to CPC is relatively poor. The objectives of this study were to incorporate biofunctional agents into CPC, and to investigate human umbilical cord mesenchymal stem cell (hUCMSC) seeding on biofunctionalized CPC for osteogenic differentiation for the first time. Five types of biofunctional agents were used: RGD (Arg-Gly-Asp) peptides, human fibronectin (Fn), fibronectin-like engineered polymer protein (FEPP), extracellular matrix Geltrex, and human platelet concentrate. Five biofunctionalized CPC scaffolds were fabricated: CPC-RGD, CPC-Fn, CPC-FEPP, CPC-Geltrex, and CPC-Platelets. The hUCMSC attachment, proliferation, osteogenic differentiation and mineral synthesis were measured. The hUCMSCs on biofunctionalized CPCs had much better cell attachment, proliferation, actin fiber expression, osteogenic differentiation and mineral synthesis, compared to the traditional CPC control. Cell proliferation was increased by an order of magnitude via incorporation of biofunctional agents in CPC (p<0.05). Mineral synthesis on biofunctionalized CPCs was 3-5 folds of those of control (p<0.05). hUCMSCs differentiated with high alkaline phosphatase, Runx2, osteocalcin, and collagen I gene expressions. Mechanical properties of biofunctionalized CPC matched the reported strength and elastic modulus of cancellous bone. A new class of biofunctionalized CPCs was developed, including CPC-RGD, CPC-Fn, CPC-FEPP, CPC-Geltrex, and CPC-Platelets. hUCMSCs on biofunctionalized CPCs had cell density, cell proliferation, actin fiber density, and bone mineralization that were dramatically better than those on traditional CPC. Novel biofunctionalized CPC scaffolds with greatly enhanced human stem cell proliferation and differentiation are promising to facilitate bone regeneration in a wide range of dental, craniofacial and orthopedic applications. Copyright © 2012 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Entrainment and motor emulation approaches to joint action: Alternatives or complementary approaches?

PubMed

Colling, Lincoln J; Williamson, Kellie

2014-01-01

Joint actions, such as music and dance, rely crucially on the ability of two, or more, agents to align their actions with great temporal precision. Within the literature that seeks to explain how this action alignment is possible, two broad approaches have appeared. The first, what we term the entrainment approach, has sought to explain these alignment phenomena in terms of the behavioral dynamics of the system of two agents. The second, what we term the emulator approach, has sought to explain these alignment phenomena in terms of mechanisms, such as forward and inverse models, that are implemented in the brain. They have often been pitched as alternative explanations of the same phenomena; however, we argue that this view is mistaken, because, as we show, these two approaches are engaged in distinct, and not mutually exclusive, explanatory tasks. While the entrainment approach seeks to uncover the general laws that govern behavior the emulator approach seeks to uncover mechanisms. We argue that is possible to do both and that the entrainment approach must pay greater attention to the mechanisms that support the behavioral dynamics of interest. In short, the entrainment approach must be transformed into a neuroentrainment approach by adopting a mechanistic view of explanation and by seeking mechanisms that are implemented in the brain.

Methods of Treating or Preventing Demyelation Using Thrombin Inhibitors | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (“NICHD”), seek CRADA partner or collaboration for development of agents to treat multiple sclerosis or other conditions associated with myelin remodeling by administering an agent that inhibits cleavage of Neurofascin 155 or Caspr1. The agent could be a thrombin inhibitor, an agent that inhibits thrombin expression, an anti-thrombin antibody that specifically inhibits thrombin mediated cleavage of Neurofascin 155, a mutated version or fragment of Neurofascin 155 or Caspr1, or antibodies to Neurofascin 155 or Caspr1.

Validation of a simple and fast method to quantify in vitro mineralization with fluorescent probes used in molecular imaging of bone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moester, Martiene J.C.; Schoeman, Monique A.E.; Oudshoorn, Ineke B.

2014-01-03

Highlights: •We validate a simple and fast method of quantification of in vitro mineralization. •Fluorescently labeled agents can detect calcium deposits in the mineralized matrix of cell cultures. •Fluorescent signals of the probes correlated with Alizarin Red S staining. -- Abstract: Alizarin Red S staining is the standard method to indicate and quantify matrix mineralization during differentiation of osteoblast cultures. KS483 cells are multipotent mouse mesenchymal progenitor cells that can differentiate into chondrocytes, adipocytes and osteoblasts and are a well-characterized model for the study of bone formation. Matrix mineralization is the last step of differentiation of bone cells and ismore » therefore a very important outcome measure in bone research. Fluorescently labelled calcium chelating agents, e.g. BoneTag and OsteoSense, are currently used for in vivo imaging of bone. The aim of the present study was to validate these probes for fast and simple detection and quantification of in vitro matrix mineralization by KS483 cells and thus enabling high-throughput screening experiments. KS483 cells were cultured under osteogenic conditions in the presence of compounds that either stimulate or inhibit osteoblast differentiation and thereby matrix mineralization. After 21 days of differentiation, fluorescence of stained cultures was quantified with a near-infrared imager and compared to Alizarin Red S quantification. Fluorescence of both probes closely correlated to Alizarin Red S staining in both inhibiting and stimulating conditions. In addition, both compounds displayed specificity for mineralized nodules. We therefore conclude that this method of quantification of bone mineralization using fluorescent compounds is a good alternative for the Alizarin Red S staining.« less

Characterizing the Lower Paleolithic bone industry from Schöningen 12 II: A multi-proxy study.

PubMed

Julien, Marie-Anne; Hardy, Bruce; Stahlschmidt, Mareike C; Urban, Brigitte; Serangeli, Jordi; Conard, Nicholas J

2015-12-01

Although preservation of Paleolithic faunal assemblages from open-air settings is often poor, the Lower Paleolithic sites of Schöningen provide exceptionally well-preserved mammalian faunal material for investigating hominin/animal relationships. Pleistocene fossil assemblages, however, usually reflect a complex taphonomic history in which natural and anthropogenic processes are often superimposed. A number of examples of osseous finds that resemble tools were recently discovered in the MIS 9 deposits of Schöningen 12 II. Non-anthropogenic agents are known to produce surface modifications mimicking human artifacts and the identification of osseous remains used and/or deliberately modified by ancient hominins is often controversial in such old contexts. Multiple lines of evidence are thus useful for distinguishing between osseous artifacts and "eco-facts". In this paper, the recognition of the use of bone for different technological purposes by late Middle Pleistocene hominins is addressed through a multi-proxy study combining geoarcheology, bone taphonomy, zooarcheology, and use-wear analysis. This allowed the identification of the processes and agents responsible for the formation and modification of the different bone assemblages of Schöningen 12 II. Our analysis points to different types of bones having been likely used as tools. These results expand the diversity of the organic technological repertoire of the Middle Pleistocene hominins, making Schöningen 12 II a remarkable new source of information on osseous technology long before the Upper Paleolithic, the period traditionally viewed as the start of the systematic use of bone tools. Together with other observations of bone tools documented during the Lower and Middle Paleolithic, the results from Schöningen show that archeologists may have underestimated the diversity and importance of osseous technology among archaic hominins. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Idea Storming Cube: Evaluating the Effects of Using Game and Computer Agent to Support Divergent Thinking

ERIC Educational Resources Information Center

Huang, Chun-Chieh; Yeh, Ting-Kuang; Li, Tsai-Yen; Chang, Chun-Yen

2010-01-01

The objective of this article is to evaluate the effectiveness of a collaborative and online brainstorming game, Idea Storming Cube (ISC), which provides users with a competitive game-based environment and a peer-like intelligent agent. The program seeks to promote students' divergent thinking to aid in the process of problem solving. The…

Human Aided Reinforcement Learning in Complex Environments

DTIC Science & Technology

learn to solve tasks through a trial -and- error process. As an agent takes ...task faster andmore accurately, a human expert can be added to the system to guide an agent in solving the task. This project seeks to expand on current...theenvironment, which works particularly well for reactive tasks . In more complex tasks , these systems do not work as intended. The manipulation

Teaching Social Change Agents in Educational Leadership, School and Agency Counseling and Human Service Administration

ERIC Educational Resources Information Center

Tripses, Jenny S.; Hatfield, Kevin; Risen, D. Michael

2005-01-01

This article describes the authors' journey as three educational leadership professors implementing a program to improve teaching for social justice. The social change agents they seek to nurture in their graduate program are individuals who are keenly aware of inequities in society and possess the knowledge, skills, and will to make a difference…

Clinical Development of VEGF Signaling Pathway Inhibitors in Childhood Solid Tumors

PubMed Central

Yamashiro, Darrell J.; Fox, Elizabeth

2011-01-01

Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers. PMID:22042784

Tridax procumbens flavonoids: a prospective bioactive compound increased osteoblast differentiation and trabecular bone formation.

PubMed

Al Mamun, Md Abdullah; Hosen, Mohammad Jakir; Khatun, Amina; Alam, M Masihul; Al-Bari, Md Abdul Alim

2017-09-08

The Tridax procumbens extracts (TPE) are known for their ethno-medicinal properties to increase osteogenic functioning in mesenchymal stem cells. Recently, we found that the T. procumbens flavonoids (TPF) significantly suppressed the RANKL-induced osteoclasts differentiation and bone resorption. The TPF also promoted osteoblasts differentiation and bone formation demonstrated by increasing bone formation markers in cultured mouse primary osteoblasts. However, the effects of the TPF on in vivo bone formation remain unclear. In this study, we investigated the effects of the TPF on in vivo bone formation, injected the TPF (20 mg/kg) twice a day in the low calcium diet mice and killed them after 21 day. Radiographic and histomorphometric analyses were performed on the dissected bones to determine the anabolic effects of the TPF. Bone mineral density and bone mineral content of the TPF-treated mice were significantly increased compared to the control mice. Bone formation-related indices like osteoblast number, osteoblast surface, bone volume, mineralizing surface, mineral apposition rate and bone formation rate were significantly increased in the TPF-treated mice compared to the control mice. Our findings point towards the stimulation of bone formation by TPF, suggested that the TPF could be a potential natural anabolic agent to treat patients with bone loss-associated diseases such as osteoporosis.

Technetium-99m-labeled ceftizoxime loaded long-circulating and pH-sensitive liposomes used to identify osteomyelitis.

PubMed

Ferreira, Soraya Maria Zandim Maciel Dias; Domingos, Giselle Pires; Ferreira, Diego dos Santos; Rocha, Talita Guieiro Ribeiro; Serakides, Rogéria; de Faria Rezende, Cleuza Maria; Cardoso, Valbert Nascimento; Fernandes, Simone Odília Antunes; Oliveira, Mônica Cristina

2012-07-15

Osteomyelitis is an infectious disease located in the bone or bone marrow. Long-circulating and pH-sensitive liposomes containing a technetium-99m-labeled antibiotic, ceftizoxime, (SpHL-(99m)Tc-CF) were developed to identify osteomyelitis foci. Biodistribution studies and scintigraphic images of bone infection or non infection-bearing rats that had been treated with these liposomes were performed. A high accumulation in infectious foci and high values in the target-non target ratio could be observed. These results indicate the potential of SpHL-(99m)Tc-CF as a potential agent for the diagnosis of bone infections. Copyright © 2012 Elsevier Ltd. All rights reserved.

Preventing Bacterial Infections using Metal Oxides Nanocoatings on Bone Implant

NASA Astrophysics Data System (ADS)

Duceac, L. D.; Straticiuc, S.; Hanganu, E.; Stafie, L.; Calin, G.; Gavrilescu, S. L.

2017-06-01

Nowadays bone implant removal is caused by infection that occurs around it possibly acquired after surgery or during hospitalization. The purpose of this study was to reveal some metal oxides applied as coatings on bone implant thus limiting the usual antibiotics-resistant bacteria colonization. Therefore ZnO, TiO2 and CuO were synthesized and structurally and morphologically analized in order to use them as an alternative antimicrobial agents deposited on bone implant. XRD, SEM, and FTIR characterization techniques were used to identify structure and texture of these nanoscaled metal oxides. These metal oxides nanocoatings on implant surface play a big role in preventing bacterial infection and reducing surgical complications.

Bone tissue engineering: state of the art and future trends.

PubMed

Salgado, António J; Coutinho, Olga P; Reis, Rui L

2004-08-09

Although several major progresses have been introduced in the field of bone regenerative medicine during the years, current therapies, such as bone grafts, still have many limitations. Moreover, and in spite of the fact that material science technology has resulted in clear improvements in the field of bone substitution medicine, no adequate bone substitute has been developed and hence large bone defects/injuries still represent a major challenge for orthopaedic and reconstructive surgeons. It is in this context that TE has been emerging as a valid approach to the current therapies for bone regeneration/substitution. In contrast to classic biomaterial approach, TE is based on the understanding of tissue formation and regeneration, and aims to induce new functional tissues, rather than just to implant new spare parts. The present review pretends to give an exhaustive overview on all components needed for making bone tissue engineering a successful therapy. It begins by giving the reader a brief background on bone biology, followed by an exhaustive description of all the relevant components on bone TE, going from materials to scaffolds and from cells to tissue engineering strategies, that will lead to "engineered" bone. Scaffolds processed by using a methodology based on extrusion with blowing agents.

The orally available Btk inhibitor ibrutinib (PCI-32765) protects against osteoclast-mediated bone loss.

PubMed

Shinohara, Masahiro; Chang, Betty Y; Buggy, Joseph J; Nagai, Yusuke; Kodama, Tatsuhiko; Asahara, Hiroshi; Takayanagi, Hiroshi

2014-03-01

Bone-resorbing osteoclasts play an essential role in normal bone homeostasis, as well as in various bone disorders such as osteoporosis and rheumatoid arthritis. Previously we showed that the Tec family of tyrosine kinases is essential for the differentiation of osteoclasts and the inhibition of Btk is a promising strategy for the prevention of the bone loss in osteoclast-associated bone disorders. Here we demonstrate that an orally available Btk inhibitor, ibrutinib (PCI-32765), suppresses osteoclastic bone resorption by inhibiting both osteoclast differentiation and function. Ibrutinib downregulated the expression of NFATc1, the key transcription factor for osteoclastogenesis, and disrupted the formation of the actin ring in mature osteoclasts. In addition, genome-wide screening revealed that Btk regulates the expression of the genes involved in osteoclast differentiation and function in both an NFATc1-dependent and -independent manner. Finally, we showed that ibrutinib administration ameliorated the bone loss that developed in a RANKL-induced osteoporosis mouse model. Thus, this study suggests ibrutinib to be a promising therapeutic agent for osteoclast-associated bone diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

Anabolic activity of ursolic acid in bone: Stimulating osteoblast differentiation in vitro and inducing new bone formation in vivo.

PubMed

Lee, Su-Ui; Park, Sang-Joon; Kwak, Han Bok; Oh, Jaemin; Min, Yong Ki; Kim, Seong Hwan

2008-01-01

In the field of osteoporosis, there has been growing interest in anabolic agents that enhance bone mass and improve bone architecture. In this study, we demonstrated that the ubiquitous plant triterpenoid, ursolic acid, enhances differentiation and mineralization of osteoblasts in vitro. We found that ursolic acid induced the expression of osteoblast-specific genes with the activation of mitogen-activated protein kinases, nuclear factor-kappaB, and activator protein-1. Additionally, noggin, an antagonist of bone morphogenetic proteins (BMPs), inhibited ursolic acid-induced osteoblast differentiation. Noggin also inhibited the activation of Smad and the induction of BMP-2 mRNA expression by ursolic acid in the late stage of osteoblast differentiation. Importantly, ursolic acid was shown to have bone-forming activity in vivo in a mouse calvarial bone formation model. A high proportion of positive immunostaining of BMP-2 was found in the nuclear region of woven bone formed by ursolic acid. These results suggested that ursolic acid has the anabolic potential to stimulate osteoblast differentiation and enhance new bone formation.

Biodegradable Scaffolds for Bone Regeneration Combined with Drug-Delivery Systems in Osteomyelitis Therapy

PubMed Central

Dorati, Rossella; DeTrizio, Antonella; Modena, Tiziana; Conti, Bice; Benazzo, Francesco; Gastaldi, Giulia; Genta, Ida

2017-01-01

A great deal of research is ongoing in the area of tissue engineering (TE) for bone regeneration. A possible improvement in restoring damaged tissues involves the loading of drugs such as proteins, genes, growth factors, antibiotics, and anti-inflammatory drugs into scaffolds for tissue regeneration. This mini-review is focused on the combination of the local delivery of antibiotic agents with bone regenerative therapy for the treatment of a severe bone infection such as osteomyelitis. The review includes a brief explanation of scaffolds for bone regeneration including scaffolds characteristics and types, a focus on severe bone infections (especially osteomyelitis and its treatment), and a literature review of local antibiotic delivery by the combination of scaffolds and drug-delivery systems. Some examples related to published studies on gentamicin sulfate-loaded drug-delivery systems combined with scaffolds are discussed, and future perspectives are highlighted. PMID:29231857

Efficiency of High Molecular Weight Backbone Degradable HPMA Copolymer – Prostaglandin E1 Conjugate in Promotion of Bone Formation in Ovariectomized Rats

PubMed Central

Pan, Huaizhong; Sima, Monika; Miller, Scott C.; Kopečková, Pavla; Yang, Jiyuan; Kopeček, Jindřich

2013-01-01

Multiblock, high molecular weight, linear, backbone degradable HPMA copolymer-prostaglandin E1 (PGE1) conjugate has been synthesized by RAFT polymerization mediated by a new bifunctional chain transfer agent (CTA), which contains an enzymatically degradable oligopeptide sequence flanked by two dithiobenzoate groups, followed by post-polymerization aminolysis and thiol-ene chain extension. The multiblock conjugate contains Asp8 as the bone-targeting moiety and enzymatically degradable bonds in the polymer backbone; in vivo degradation produces cleavage products that are below the renal threshold. Using an ovariectomized (OVX) rat model, the accumulation in bone and efficacy to promote bone formation was evaluated; low molecular weight conjugates served as control. The results indicated a higher accumulation in bone, greater enhancement of bone density, and higher plasma osteocalcin levels for the backbone degradable conjugate. PMID:23731780

Lessons from rare diseases of cartilage and bone.

PubMed

Gallagher, James A; Ranganath, Lakshminarayan R; Boyde, Alan

2015-06-01

Studying severe phenotypes of rare syndromes can elucidate disease mechanisms of more common disorders and identify potential therapeutic targets. Lessons from rare bone diseases contributed to the development of the most successful class of bone active agents, the bisphosphonates. More recent research on rare bone diseases has helped elucidate key pathways and identify new targets in bone resorption and bone formation including cathepsin K and sclerostin, for which drugs are now in clinical trials. By contrast, there has been much less focus on rare cartilage diseases and osteoarthritis (OA) remains a common disease with no effective therapy. Investigation of rare cartilage syndromes is identifying new potential targets in OA including GDF5 and lubricin. Research on the arthropathy of the ultra-rare disease alkaptonuria has identified several new features of the OA phenotype, including high density mineralized protrusions (HDMPs) which constitute a newly identified mechanism of joint destruction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of hydrazine based deproteination protocol on bone mineral crystal structure.

PubMed

Karampas, I A; Orkoula, M G; Kontoyannis, C G

2012-05-01

In several bone deproteination protocols the chemical agent used for protein cleavage is hydrazine. The effect of hydrazine deproteination method on the crystal size and crystallinity of the bone mineral was studied. Bovine bones were subjected to this protocol and the crystal size and crystallinity of the remaining bone mineral were determined by X-ray Diffraction (XRD), by measuring the width at the half of the maximum intensity of the (002) reflection. It was found that hydrazine deproteination induces noteworthy increase of crystal size and crystallinity. The effect was enhanced by increasing hydrazine temperature from 25 to 55°C. Furthermore, infrared spectroscopy revealed that hydrazine facilitates the removal of carbonate and acid phosphate ions from bone mineral. It is proposed that the mechanism of modification of crystal size and crystallinity lies on the removal of these ions thus, resulting in crystal re-organization.

[Effect of anti-osteoporotic agents on cortical microstructure].

PubMed

Ito, Masako

2013-07-01

The incidence of non-vertebral fracture increases in old age, and the deterioration of cortical micro-structure is considered to be one of important reason to cause non-vertebral fracture. In this chapter, the age-related change of cortical microstructure, relationship with bone strength are discussed as well as the effect of anti-osteoporotic drugs on cortical bone ; bisphosphonate, teriparatide, active vitamin D3, and denosumab.

Clinical Investigations

DTIC Science & Technology

1977-09-30

90F ork Unit No. 76/24 (FY76, 0) An Investination of the Effect of Supplemental Oxygen on Chemically Induced Fat Embolization ...accepted as criteria for determination of the presence of fat embolism syndrome. In this study laboratory parameters and lung scans are obtained for a 5...91 Work Unit No. 76/31 (FY76, 0) Early Detection of Fatiaue Fracture by Bone Scannina with Tc-99 Bone Scan Agents

Preparation, quality control and biodistribution assessment of ¹⁵³Sm-BPAMD as a novel agent for bone pain palliation therapy.

PubMed

Rabie, Ali; Enayati, Razieh; Yousefnia, Hassan; Jalilian, Amir Reza; Shamsaei, Mojtaba; Zolghadri, Samaneh; Bahrami-Samani, Ali; Hosntalab, Mohammad

2015-12-01

Various phosphonate ligands labeled with β(-)-emitting radionuclides have shown good efficacy for bone pain palliation. In this study, a new agent for bone pain palliation has been developed. ¹⁵³Sm-(4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (¹⁵³Sm-BPAMD) complex was prepared using BPAMD ligand and ¹⁵³SmCl3. The effect of various parameters on the labeling yield of ¹⁵³Sm-BPAMD including ligand concentration, pH, temperature and reaction time were studied. Radiochemical purity of the radiolabeled complex was checked by instant thin layer chromatography (ITLC). Stability studies of the complex in the final preparation and in the presence of human serum were performed up to 48 h. Partition coefficient and hydroxyapatite (HA) binding of the complex were investigated and biodistribution studies (SPECT imaging and scarification) were performed after injection of the complex to Syrian mice up to 48 h post-injection. The biodistribution of the complex was compared with the biodistribution of the ¹⁵³Sm cation in the same type mice. ¹⁵³Sm-BPAMD was prepared in high radiochemical purity >98% and specific activity of 267 GBq/mmol at the optimal conditions. The complex demonstrated significant stability at room temperature and in human serum at least for 48 h. HA binding assay demonstrated that at the amount of more than 5 mg, approximately, all radiolabeled complex was bound to HA. At the pH 7.4, LogP o/w was -1.86 ± 0.02. Both SPECT and scarification showed major accumulation of the labeled compound in the bone tissue. The results show that ¹⁵³Sm-BPAMD has interesting characteristics as an agent for bone pain palliation; however, further biological studies in other mammals are still needed.

Biomaterial delivery of morphogens to mimic the natural healing cascade in bone.

PubMed

Mehta, Manav; Schmidt-Bleek, Katharina; Duda, Georg N; Mooney, David J

2012-09-01

Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing. Copyright © 2012 Elsevier B.V. All rights reserved.

Development of Novel Radiogallium-Labeled Bone Imaging Agents Using Oligo-Aspartic Acid Peptides as Carriers

PubMed Central

Ogawa, Kazuma; Ishizaki, Atsushi; Takai, Kenichiro; Kitamura, Yoji; Kiwada, Tatsuto; Shiba, Kazuhiro; Odani, Akira

2013-01-01

68Ga (T 1/2 = 68 min, a generator-produced nuclide) has great potential as a radionuclide for clinical positron emission tomography (PET). Because poly-glutamic and poly-aspartic acids have high affinity for hydroxyapatite, to develop new bone targeting 68Ga-labeled bone imaging agents for PET, we used 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) as a chelating site and conjugated aspartic acid peptides of varying lengths. Subsequently, we compared Ga complexes, Ga-DOTA-(Asp)n (n = 2, 5, 8, 11, or 14) with easy-to-handle 67Ga, with the previously described 67Ga-DOTA complex conjugated bisphosphonate, 67Ga-DOTA-Bn-SCN-HBP. After synthesizing DOTA-(Asp)n by a Fmoc-based solid-phase method, complexes were formed with 67Ga, resulting in 67Ga-DOTA-(Asp)n with a radiochemical purity of over 95% after HPLC purification. In hydroxyapatite binding assays, the binding rate of 67Ga-DOTA-(Asp)n increased with the increase in the length of the conjugated aspartate peptide. Moreover, in biodistribution experiments, 67Ga-DOTA-(Asp)8, 67Ga-DOTA-(Asp)11, and 67Ga-DOTA-(Asp)14 showed high accumulation in bone (10.5±1.5, 15.1±2.6, and 12.8±1.7% ID/g, respectively) but were barely observed in other tissues at 60 min after injection. Although bone accumulation of 67Ga-DOTA-(Asp)n was lower than that of 67Ga-DOTA-Bn-SCN-HBP, blood clearance of 67Ga-DOTA-(Asp)n was more rapid. Accordingly, the bone/blood ratios of 67Ga-DOTA-(Asp)11 and 67Ga-DOTA-(Asp)14 were comparable with those of 67Ga-DOTA-Bn-SCN-HBP. In conclusion, these data provide useful insights into the drug design of 68Ga-PET tracers for the diagnosis of bone disorders, such as bone metastases. PMID:24391942

The Growing Reliance of Ontario Colleges of Applied Arts and Technology on Educational Agents for the Recruitment of International Students

ERIC Educational Resources Information Center

Legusov, Oleg

2017-01-01

The number of international students seeking educational opportunities at Ontario colleges of applied arts and technology (CAATs) has grown at an unprecedented rate in the past 10 years. It appears that as the number of the international college students has increased, colleges have also been relying more heavily on educational agents to recruit…

Extension or Communication?--The Perceptions of Southern Brazilian Tobacco Farmers and Rural Agents about Rural Extension and Framework Convention on Tobacco Control.

ERIC Educational Resources Information Center

Troian, Alessandra; Eichler, Marcelo Leandro

2012-01-01

This article attempts to critique the current process of extension through an investigation that seeks to demonstrate and analyze the perceptions held by farmers and rural agents about some aspects of tobacco cultivation in the municipality of Arvorezinha (Little Tree) in southern Brazil. The research has been taking place during the last four…

Systemic Treatment with Strontium Ranelate Accelerates the Filling of a Bone Defect and Improves the Material Level Properties of the Healing Bone

PubMed Central

Zacchetti, Giovanna; Rizzoli, René

2014-01-01

Rapid bone defect filling with normal bone is a challenge in orthopaedics and dentistry. Strontium ranelate (SrRan) has been shown to in vitro decrease bone resorption and increase bone formation, and represents a potential agent with the capacity to accelerate bone defect filling. In this study, bone tibial defects of 2.5 mm in diameter were created in 6-month-old female rats orally fed SrRan (625 mg/kg/d; 5/7 days) or vehicle for 4, 8, or 12 weeks (10 rats per group per time point) from the time of surgery. Tibias were removed. Micro-architecture was determined by micro-computed tomography (µCT) and material level properties by nanoindentation analysis. µCT analysis showed that SrRan administration significantly improved microarchitecture of trabecular bone growing into the defect after 8 and 12 weeks of treatment compared to vehicle. SrRan treatment also accelerated the growth of cortical bone over the defect, but with different kinetics compared to trabecular bone, as the effects were already significant after 4 weeks. Nanoindentation analysis demonstrated that SrRan treatment significantly increased material level properties of both trabecular bone and cortical bone filling the defect compared to vehicle. SrRan accelerates the filling of bone defect by improving cortical and trabecular bone microarchitecture both quantitatively and qualitatively. PMID:25243150

Novel therapeutic agents for osteosarcoma.

PubMed

O'Day, Kathleen; Gorlick, Richard

2009-04-01

Osteosarcoma is the most common malignant primary bone tumor in childhood. Despite multiagent chemotherapy and aggressive surgical resection, 30% of patients with localized disease and 80% of patients with metastatic disease at diagnosis will relapse. Survival for these patients has remained unchanged over the past 20 years. A number of novel agents in various stages of development hold promise for improving therapy for patients with osteosarcoma. This article will focus on novel therapeutic approaches, including agents targeting signal-transduction pathways, inhibitors of the tumor microenvironment and immunomodulatory agents, as well as overcoming resistance mechanisms and the use of novel delivery mechanisms.

Cell apoptosis, autophagy and necroptosis in osteosarcoma treatment

PubMed Central

Li, Dongqi; Li, Huiling; Ren, Mingyan; Liao, Yedan; Yu, Shunling; Chen, Yanjin; Yang, Yihao; Zhang, Ya

2016-01-01

Osteosarcoma is the most common primary bone tumor in children and adolescents. Although combined therapy including surgery and multi-agent chemotherapy have resulted in great improvements in the overall survival of patients, chemoresistance remains an obstacle for the treatment of osteosarcoma. Molecular targets or effective agents that are actively involved in cell death including apoptosis, autophagy and necroptosis have been studied. We summarized how these agents (novel compounds, miRNAs, or proteins) regulate apoptotic, autophagic and necroptotic pathways; and discussed the current knowledge on the role of these new agents in chemotherapy resistance in osteosarcoma. PMID:27007056

Monte Carlo simulation of age-dependent radiation dose from alpha- and beta-emitting radionuclides to critical trabecular bone and bone marrow targets

NASA Astrophysics Data System (ADS)

Dant, James T.; Richardson, Richard B.; Nie, Linda H.

2013-05-01

Alpha (α) particles and low-energy beta (β) particles present minimal risk for external exposure. While these particles can induce leukemia and bone cancer due to internal exposure, they can also be beneficial for targeted radiation therapies. In this paper, a trabecular bone model is presented to investigate the radiation dose from bone- and marrow-seeking α and β emitters to different critical compartments (targets) of trabecular bone for different age groups. Two main issues are addressed with Monte Carlo simulations. The first is the absorption fractions (AFs) from bone and marrow to critical targets within the bone for different age groups. The other issue is the application of 223Ra for the radiotherapy treatment of bone metastases. Both a static model and a simulated bone remodeling process are established for trabecular bone. The results show significantly lower AFs from radionuclide sources in the bone volume to the peripheral marrow and the haematopoietic marrow for adults than for newborns and children. The AFs from sources on the bone surface and in the bone marrow to peripheral marrow and haematopoietic marrow also varies for adults and children depending on the energy of the particles. Regarding the use of 223Ra as a radionuclide for the radiotherapy of bone metastases, the simulations show a significantly higher dose from 223Ra and its progeny in forming bone to the target compartment of bone metastases than that from two other more commonly used β-emitting radiopharmaceuticals, 153Sm and 89Sr. There is also a slightly lower dose from 223Ra in forming bone to haematopoietic marrow than that from 153Sm and 89Sr. These results indicate a higher therapy efficiency and lower marrow toxicity from 223Ra and its progeny. In conclusion, age-related changes in bone dimension and cellularity seem to significantly affect the internal dose from α and β emitters in the bone and marrow to critical targets, and 223Ra may be a more efficient radiopharmaceutical for the treatment of bone metastases than 153Sm and 89Sr, if the diffusion of 219Rn to the bone marrow is insignificant.

Nitroxyl (HNO) Releasing Therapeutics | NCI Technology Transfer Center | TTC

Cancer.gov

The National Cancer Institute's Cancer and Inflammation Program is seeking statements of capability or interest from parties interested in licensing therapeutic agents that generate Nitroxyl (HNO) in physiological media.

Role of Hypomethylating Agents in the Treatment of Bone Marrow Failure

DTIC Science & Technology

2015-10-01

and clonal somatic mutations that occur in myeloid malignancies. 15. SUBJECT TERMS Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML...Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), hypomethylating agents (HMA), azacitidine, decitabine, TET2 mutations 3...of this project is to develop novel approaches to the treatment of acute myeloid leukemia based on combinations of lenalidomide with additional

Non-viral gene therapy for bone tissue engineering.

PubMed

Wegman, Fiona; Oner, F Cumhur; Dhert, Wouter J A; Alblas, Jacqueline

2013-01-01

The possibilities of using gene therapy for bone regeneration have been extensively investigated. Improvements in the design of new transfection agents, combining vectors and delivery/release systems to diminish cytotoxicity and increase transfection efficiencies have led to several successful in vitro, ex vivo and in vivo strategies. These include growth factor or short interfering ribonucleic acid (siRNA) delivery, or even enzyme replacement therapies, and have led to increased osteogenic differentiation and bone formation in vivo. These results provide optimism to consider use in humans with some of these gene-delivery strategies in the near future.

Bone Marrow Stromal Cells Generate Muscle Cells and Repair Muscle Degeneration

NASA Astrophysics Data System (ADS)

Dezawa, Mari; Ishikawa, Hiroto; Itokazu, Yutaka; Yoshihara, Tomoyuki; Hoshino, Mikio; Takeda, Shin-ichi; Ide, Chizuka; Nabeshima, Yo-ichi

2005-07-01

Bone marrow stromal cells (MSCs) have great potential as therapeutic agents. We report a method for inducing skeletal muscle lineage cells from human and rat general adherent MSCs with an efficiency of 89%. Induced cells differentiated into muscle fibers upon transplantation into degenerated muscles of rats and mdx-nude mice. The induced population contained Pax7-positive cells that contributed to subsequent regeneration of muscle upon repetitive damage without additional transplantation of cells. These MSCs represent a more ready supply of myogenic cells than do the rare myogenic stem cells normally found in muscle and bone marrow.

Phosphonated Near-Infrared Fluorophores for Biomedical Imaging of Bone**

PubMed Central

Hyun, Hoon; Wada, Hideyuki; Bao, Kai; Gravier, Julien; Yadav, Yogesh; Laramie, Matt; Henary, Maged; Frangioni, John V.

2014-01-01

The conventional method for creating targeted contrast agents is to conjugate separate targeting and fluorophore domains. In this study we report a new strategy based on incorporation of targeting moieties into the non-resonant structure of pentamethine and heptamethine indocyanines. Using the known affinity of phosphonates for bone minerals as a model system, we have synthesized two families of bifunctional molecules that target bone without the need for a traditional bisphosphonate. With peak fluorescence emission at ≈ 700 nm or ≈ 800 nm, these molecules can be used for FLARE dual-channel imaging. Longitudinal FLARE studies in mice demonstrate that phosphonated near-infrared fluorophores remain stable in bone for over 5 weeks, and histological analysis demonstrates incorporation into bone matrix. Taken together, we describe a new strategy for creating ultracompact, targeted, near-infrared fluorophores for various bioimaging applications. PMID:25139079

Enhanced anti-tumor activity and safety profile of targeted nano-scaled HPMA copolymer-alendronate-TNP-470 conjugate in the treatment of bone malignances

PubMed Central

Segal, Ehud; Pan, Huaizhong; Benayoun, Liat; Kopečková, Pavla; Shaked, Yuval; Kopeček, Jindčrich; Satchi-Fainaro, Ronit

2015-01-01

Bone neoplasms, such as osteosarcoma, exhibit a propensity for systemic metastases resulting in adverse clinical outcome. Traditional treatment consisting of aggressive chemotherapy combined with surgical resection, has been the mainstay of these malignances. Therefore, bone-targeted non-toxic therapies are required. We previously conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. HPMA copolymer-ALN-TNP-470 conjugate exhibited improved anti-angiogenic and anti-tumor activity compared with the combination of free ALN and TNP-470 when evaluated in a xenogeneic model of human osteosarcoma. The immune system has major effect on toxicology studies and on tumor progression. Therefore, in this manuscript we examined the safety and efficacy profiles of the conjugate using murine osteosarcoma syngeneic model. Toxicity and efficacy evaluation revealed superior anti-tumor activity and decreased organ-related toxicities of the conjugate compared with the combination of free ALN plus TNP-470. Finally, comparative anti-angiogenic activity and specificity studies, using surrogate biomarkers of circulating endothelial cells (CEC), highlighted the advantage of the conjugate over the free agents. The therapeutic platform described here may have clinical translational relevance for the treatment of bone-related angiogenesis-dependent malignances. PMID:21429572

Osthole inhibits bone metastasis of breast cancer

PubMed Central

Guo, Baofeng; Ye, Yiyi; Han, Xianghui; Qin, Yuenong; Liu, Sheng

2017-01-01

Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potential mechanism of this inhibition. In the murine model of breast cancer osseous metastasis, mice that received osthole developed significantly less bone metastases and displayed decreased tumor burden when compared with mice in the control group. Osthole inhibited breast cancer cell growth, migration, and invasion, and induced apoptosis of breast cancer cells. Additionally, it also regulated OPG/RANKL signals in the interactions between bone cells (osteoblasts and osteoclasts) and cancer cells. Besides, it also inhibited TGF-β/Smads signaling in breast cancer metastasis to bone in MDA-231BO cells. The results of this study suggest that osthole has real potential as a therapeutic candidate in the treatment of breast cancer patients with bone metastases. PMID:28938572

Biomimetic coatings for bone tissue engineering of critical-sized defects.

PubMed

Liu, Yuelian; Wu, Gang; de Groot, Klaas

2010-10-06

The repair of critical-sized bone defects is still challenging in the fields of implantology, maxillofacial surgery and orthopaedics. Current therapies such as autografts and allografts are associated with various limitations. Cytokine-based bone tissue engineering has been attracting increasing attention. Bone-inducing agents have been locally injected to stimulate the native bone-formation activity, but without much success. The reason is that these drugs must be delivered slowly and at a low concentration to be effective. This then mimics the natural method of cytokine release. For this purpose, a suitable vehicle was developed, the so-called biomimetic coating, which can be deposited on metal implants as well as on biomaterials. Materials that are currently used to fill bony defects cannot by themselves trigger bone formation. Therefore, biological functionalization of such materials by the biomimetic method resulted in a novel biomimetic coating onto different biomaterials. Bone morphogenetic protein 2 (BMP-2)-incorporated biomimetic coating can be a solution for a large bone defect repair in the fields of dental implantology, maxillofacial surgery and orthopaedics. Here, we review the performance of the biomimetic coating both in vitro and in vivo.

Elevated levels of STAT1 in Fanconi anemia group A lymphoblasts correlate with the cells’ sensitivity to DNA interstrand crosslinking drugs

PubMed Central

Prieto-Remón, Inés; Sánchez-Carrera, Dámaso; López-Duarte, Mónica; Richard, Carlos; Pipaón, Carlos

2013-01-01

Progressive bone marrow failure starting in the first decade of life is one of the main characteristics of Fanconi anemia. Along with the bone marrow failure, this pathology is characterized by congenital malformations, endocrine dysfunction and an extraordinary predisposition to develop cancer. The fact that hematopoietic progenitor cells from subjects with Fanconi anemia are sensitive to both DNA-interstrand crosslinking agents and inflammatory cytokines, which are aberrantly overproduced in these patients, has led to different explanations for the causes of the bone marrow failure. We analyzed STAT1 expression in lymphoblastoid cell lines derived from patients with Fanconi anemia group A and correlated this with aspects of the Fanconi anemia phenotype such as sensitivity to genotoxic agents or to inhibitory cytokines. We provide evidence of overexpression of STAT1 in FANCA-deficient cells which has both transcriptional and post-translational components, and is related to the constitutive activation of ERK in Fanconi anemia group A cells, since it can be reverted by treatment with U0126. STAT1 phosphorylation was not defective in the lymphoblasts, so these cells accumulated higher levels of active STAT1 in response to interferon gamma, probably in relation to their greater sensitivity to this cytokine. On the other hand, inhibition of STAT1 by genetic or chemical means reverted the hypersensitivity of Fanconi anemia group A lymphoblasts to DNA interstrand crosslinking agents. Our data provide an explanation for the mixed sensitivity of Fanconi anemia group A cells to both genotoxic stress and inflammatory cytokines and indicate new targets for the treatment of bone marrow failure in these patients. PMID:23585528

Mechanical behaviour of degradable phosphate glass fibres and composites-a review.

PubMed

Colquhoun, R; Tanner, K E

2015-12-23

Biodegradable materials are potentially an advantageous alternative to the traditional metallic fracture fixation devices used in the reconstruction of bone tissue defects. This is due to the occurrence of stress shielding in the surrounding bone tissue that arises from the absence of mechanical stimulus to the regenerating bone due to the mismatch between the elastic modulus of bone and the metal implant. However although degradable polymers may alleviate such issues, these inert materials possess insufficient mechanical properties to be considered as a suitable alternative to current metallic devices at sites of sufficient mechanical loading. Phosphate based glasses are an advantageous group of materials for tissue regenerative applications due to their ability to completely degrade in vivo at highly controllable rates based on the specific glass composition. Furthermore the release of the glass's constituent ions can evoke a therapeutic stimulus in vivo (i.e. osteoinduction) whilst also generating a bioactive response. The processing of these materials into fibres subsequently allows them to act as reinforcing agents in degradable polymers to simultaneously increase its mechanical properties and enhance its in vivo response. However despite the various review articles relating to the compositional influences of different phosphate glass systems, there has been limited work summarising the mechanical properties of different phosphate based glass fibres and their subsequent incorporation as a reinforcing agent in degradable composite materials. As a result, this review article examines the compositional influences behind the development of different phosphate based glass fibre compositions intended as composite reinforcing agents along with an analysis of different potential composite configurations. This includes variations in the fibre content, matrix material and fibre architecture as well as other novel composites designs.

The role of bisphosphonates or denosumab in light of the availability of new therapies for prostate cancer.

PubMed

Saad, Fred; Sternberg, Cora N; Mulders, Peter F A; Niepel, Daniela; Tombal, Bertrand F

2018-05-03

Most men with advanced prostate cancer will develop bone metastases, which have a substantial impact on quality of life. Bone metastases can lead to skeletal-related events (SREs), which place a burden on patients and healthcare systems. For men with castration-resistant prostate cancer (CRPC) and bone metastases, the treatment landscape has evolved rapidly over the past few years. The relatively recent approvals of the hormonal agents abiraterone acetate and enzalutamide, second-line chemotherapy cabazitaxel, and the radiopharmaceutical radium-223 dichloride (radium-223), have provided clinicians with a greater choice of treatments. These compounds have benefits in terms of overall survival based on the results of pivotal phase 3 studies. The bisphosphonate zoledronic acid and the RANK ligand inhibitor denosumab are indicated for the prevention of SREs in men with metastatic CRPC but studies of these compounds have not demonstrated a survival benefit. The important question of the role of bisphosphonates or denosumab in combination with these new agents has thus materialised. Current and emerging evidence from clinical studies of abiraterone acetate, enzalutamide and radium-223, suggest that addition of bisphosphonates or denosumab to these new therapies may provide further clinical benefits for patients with prostate cancer and bone metastases. This evidence may help to shape clinical practice but are based largely on post hoc analyses of clinical trial data. It is therefore apparent that further data are required from both clinical studies and real-world settings to enable physicians to understand the efficacy and safety of combination therapy with the new agents plus bisphosphonates or denosumab. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Demeter, persephone, and the search for emergence in agent-based models.

DOE Office of Scientific and Technical Information (OSTI.GOV)

North, M. J.; Howe, T. R.; Collier, N. T.

2006-01-01

In Greek mythology, the earth goddess Demeter was unable to find her daughter Persephone after Persephone was abducted by Hades, the god of the underworld. Demeter is said to have embarked on a long and frustrating, but ultimately successful, search to find her daughter. Unfortunately, long and frustrating searches are not confined to Greek mythology. In modern times, agent-based modelers often face similar troubles when searching for agents that are to be to be connected to one another and when seeking appropriate target agents while defining agent behaviors. The result is a 'search for emergence' in that many emergent ormore » potentially emergent behaviors in agent-based models of complex adaptive systems either implicitly or explicitly require search functions. This paper considers a new nested querying approach to simplifying such agent-based modeling and multi-agent simulation search problems.« less

Biomaterials approaches to treating implant-associated osteomyelitis

PubMed Central

Inzana, Jason A.; Schwarz, Edward M.; Kates, Stephen L.; Awad, Hani A.

2016-01-01

Orthopaedic devices are the most common surgical devices associated with implant-related infections and Staphylococcus aureus (S. aureus) is the most common causative pathogen in chronic bone infections (osteomyelitis). Treatment of these chronic bone infections often involves combinations of antibiotics given systemically and locally to the affected site via a biomaterial spacer. The gold standard biomaterial for local antibiotic delivery against osteomyelitis, poly(methyl methacrylate) (PMMA) bone cement, bears many limitations. Such shortcomings include limited antibiotic release, incompatibility with many antimicrobial agents, and the need for follow-up surgeries to remove the non-biodegradable cement before surgical reconstruction of the lost bone. Therefore, extensive research pursuits are targeting alternative, biodegradable materials to replace PMMA in osteomyelitis applications. Herein, we provide an overview of the primary clinical treatment strategies and emerging biodegradable materials that may be employed for management of implant-related osteomyelitis. We performed a systematic review of experimental biomaterials systems that have been evaluated for treating established S. aureus osteomyelitis in an animal model. Many experimental biomaterials were not decisively more efficacious for infection management than PMMA when delivering the same antibiotic. However, alternative biomaterials have reduced the number of follow-up surgeries, enhanced the antimicrobial efficacy by delivering agents that are incompatible with PMMA, and regenerated bone in an infected defect. Understanding the advantages, limitations, and potential for clinical translation of each biomaterial, along with the conditions under which it was evaluated (e.g. animal model), is critical for surgeons and researchers to navigate the plethora of options for local antibiotic delivery. PMID:26724454

THE PROTECTIVE EFFECT OF LOCAL BONE MARROW ASPHYXIA IN ACUTE RADIATION SICKNESS IN ANIMALS (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zherebchenko, P.G.; Krasnykh, I.G.; Lebkova, N.P.

1960-10-01

In experiments on mice, rats, and dogs, a study was made of the effect of local bone marrow asphyxia on the course and outcome of radiation sickness. Asphyxia was induced by applying a hemostatic tourniquet on the extremity of animals during irradiation. It was established that local asphyxia of the bone marrow alleviates the severity of acute radiation sickness and increases the survival of animals. It is shown that at the basis of the radioprotective action lies the reduced degeneration of the bone marrow, subsequently facilitating the regeneration of hematopeiesis. Data are obtained relative to the intensification of the effectmore » of local asphyxia with the aid of prophylactic (mercamine) and curative (streptomycin) agents. (auth)« less

Improved Mobilization of Exogenous Mesenchymal Stem Cells to Bone for Fracture Healing and Sex Difference

PubMed Central

Yao, Wei; Evan Lay, Yu-An; Kot, Alexander; Liu, Ruiwu; Zhang, Hongliang; Chen, Haiyan; Lam, Kit; Lane, Nancy E.

2017-01-01

Mesenchymal stem cell (MSC) transplantation has been tested in animal and clinical fracture studies. We have developed a bone-seeking compound, LLP2A-Alendronate (LLP2A-Ale) that augments MSC homing to bone. The purpose of this study was to determine whether treatment with LLP2A-Ale or a combination of LLP2A-Ale and MSCs would accelerate bone healing in a mouse closed fracture model and if the effects are sex dependent. A right mid-femur fracture was induced in two-month-old osterix-mCherry (Osx-mCherry) male and female reporter mice. The mice were subsequently treated with placebo, LLP2A-Ale (500 µg/kg, IV), MSCs derived from wild-type female Osx-mCherry adipose tissue (ADSC, 3 × 105, IV) or ADSC + LLP2A-Ale. In phosphate buffered saline-treated mice, females had higher systemic and surface-based bone formation than males. However, male mice formed a larger callus and had higher volumetric bone mineral density and bone strength than females. LLP2A-Ale treatment increased exogenous MSC homing to the fracture gaps, enhanced incorporation of these cells into callus formation, and stimulated endochondral bone formation. Additionally, higher engraftment of exogenous MSCs in fracture gaps seemed to contribute to overall fracture healing and improved bone strength. These effects were sex-independent. There was a sex-difference in the rate of fracture healing. ADSC and LLP2A-Ale combination treatment was superior to on callus formation, which was independent of sex. Increased mobilization of exogenous MSCs to fracture sites accelerated endochondral bone formation and enhanced bone tissue regeneration. PMID:27334693

Cyclic, low-dose total body irradiation for metastatic neuroblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

D'Angio, G.J.; Evans, A.E.

1983-12-01

Total body irradiation (TBI) can be thought of as a systemic anticancer agent. It therefore might best be given like an adjuvant drug, i.e., in tolerable doses, cyclically. The therapeutic ratio between normal bone marrow stem cells and suitably sensitive cancer cells should be widened by these means. Fourteen children with advanced (Stage IV) neuroblastomas were given 100-150 rad TBI in 50 rad daily fractions along with each three-week cycle of standard triple-agent chemotherapy (vincristine, DTIC, cyclophosphamide). Two patients died of toxicity and one is still undergoing therapy. Four of the remaining 12 survive free of disease for 12+ tomore » 31+ months. The regimen is well tolerated, but prolonged, pronounced bone marrow depression, especially thrombocytopenia, commonly occurs after doses of 300-450 rad.« less

A Spontaneous 3D Bone-On-a-Chip for Bone Metastasis Study of Breast Cancer Cells.

PubMed

Hao, Sijie; Ha, Laura; Cheng, Gong; Wan, Yuan; Xia, Yiqiu; Sosnoski, Donna M; Mastro, Andrea M; Zheng, Si-Yang

2018-03-01

Bone metastasis occurs at ≈70% frequency in metastatic breast cancer. The mechanisms used by tumors to hijack the skeleton, promote bone metastases, and confer therapeutic resistance are poorly understood. This has led to the development of various bone models to investigate the interactions between cancer cells and host bone marrow cells and related physiological changes. However, it is challenging to perform bone studies due to the difficulty in periodic sampling. Herein, a bone-on-a-chip (BC) is reported for spontaneous growth of a 3D, mineralized, collagenous bone tissue. Mature osteoblastic tissue of up to 85 µm thickness containing heavily mineralized collagen fibers naturally formed in 720 h without the aid of differentiation agents. Moreover, co-culture of metastatic breast cancer cells is examined with osteoblastic tissues. The new bone-on-a-chip design not only increases experimental throughput by miniaturization, but also maximizes the chances of cancer cell interaction with bone matrix of a concentrated surface area and facilitates easy, frequent observation. As a result, unique hallmarks of breast cancer bone colonization, previously confirmed only in vivo, are observed. The spontaneous 3D BC keeps the promise as a physiologically relevant model for the in vitro study of breast cancer bone metastasis. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Artificial Gravity: Will it Preserve Bone Health on Long-Duration Missions?

NASA Technical Reports Server (NTRS)

Davis-Street, Janis; Paloski, William H.

2005-01-01

Prolonged microgravity exposure disrupts bone, muscle, and cardiovascular homeostasis, sensory-motor coordination, immune function, and behavioral performance. Bone loss, in particular, remains a serious impediment to the success of exploration-class missions by increasing the risks of bone fracture and renal stone formation for crew members. Current countermeasures, consisting primarily of resistive and aerobic exercise, have not yet proven fully successful for preventing bone loss during long-duration spaceflight. While other bone-specific countermeasures, such as pharmacological therapy and dietary modifications, are under consideration, countermeasure approaches that simultaneously address multiple physiologic systems may be more desirable for exploration-class missions, particularly if they can provide effective protection at reduced mission resource requirements (up-mass, power, crew time, etc). The most robust of the multi-system approaches under consideration, artificial gravity (AG), could prevent all of the microgravity-related physiological changes from occurring. The potential methods for realizing an artificial gravity countermeasure are reviewed, as well as selected animal and human studies evaluating the effects of artificial gravity on bone function. Future plans for the study of the multi-system effects of artificial gravity include a joint, cooperative international effort that will systematically seek an optimal prescription for intermittent AG to preserve bone, muscle, and cardiovascular function in human subjects deconditioned by 6 degree head-down-tilt-bed rest. It is concluded that AG has great promise as a multi-system countermeasure, but that further research is required to determine the appropriate parameters for implementation of such a countermeasure for exploration-class missions.

The feasibility of in vivo detection of lanthanum using a 241Am K x-ray fluorescence system.

PubMed

Nguyen, Joanna; Keldani, Zaid; Da Silva, Eric; Pejović-Milić, Ana; Gräfe, James L

2017-08-21

Lanthanum (La) is commonly used in phosphate binders in the form of lanthanum carbonate in patients with end-stage kidney disease undergoing hemodialysis treatments. With this administration, there is the potential for La storage in the body with bone being the main site of concern. However, the long-term effects of residual La in the body on bone health are not yet known. In this work, we investigate the feasibility of using a K x-ray fluorescence (K-XRF) spectroscopy system to measure bone La in vivo. A series of hydroxyapatite (HAp) bone mineral phantoms were created to represent human bone. A 1.09 GBq 241 Am source was used to excite the HAp phantoms doped with various known concentrations of La placed in a 90° geometry relative to the photon source and high-purity germanium (HPGe) detector. For a detector live time of 2000 s, the minimum detection limit was calculated to be 1.7 µg La g -1 Ca or 0.7 µg La g -1 HAp and is comparable to previously reported in vivo bone La concentrations. The technique developed in this study shows promising results and provides an alternative method to invasive biopsy sampling techniques to monitor the accumulation of bone La. To the best of our knowledge, this is the first reported work that seeks to non-invasively measure bone La via in vivo XRF.

Molecular stress-inducing compounds increase osteoclast formation in a heat shock factor 1 protein-dependent manner.

PubMed

Chai, Ryan C; Kouspou, Michelle M; Lang, Benjamin J; Nguyen, Chau H; van der Kraan, A Gabrielle J; Vieusseux, Jessica L; Lim, Reece C; Gillespie, Matthew T; Benjamin, Ivor J; Quinn, Julian M W; Price, John T

2014-05-09

Many anticancer therapeutic agents cause bone loss, which increases the risk of fractures that severely reduce quality of life. Thus, in drug development, it is critical to identify and understand such effects. Anticancer therapeutic and HSP90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) causes bone loss by increasing osteoclast formation, but the mechanism underlying this is not understood. 17-AAG activates heat shock factor 1 (Hsf1), the master transcriptional regulator of heat shock/cell stress responses, which may be involved in this negative action of 17-AAG upon bone. Using mouse bone marrow and RAW264.7 osteoclast differentiation models we found that HSP90 inhibitors that induced a heat shock response also enhanced osteoclast formation, whereas HSP90 inhibitors that did not (including coumermycin A1 and novobiocin) did not affect osteoclast formation. Pharmacological inhibition or shRNAmir knockdown of Hsf1 in RAW264.7 cells as well as the use of Hsf1 null mouse bone marrow cells demonstrated that 17-AAG-enhanced osteoclast formation was Hsf1-dependent. Moreover, ectopic overexpression of Hsf1 enhanced 17-AAG effects upon osteoclast formation. Consistent with these findings, protein levels of the essential osteoclast transcription factor microphthalmia-associated transcription factor were increased by 17-AAG in an Hsf1-dependent manner. In addition to HSP90 inhibitors, we also identified that other agents that induced cellular stress, such as ethanol, doxorubicin, and methotrexate, also directly increased osteoclast formation, potentially in an Hsf1-dependent manner. These results, therefore, indicate that cellular stress can enhance osteoclast differentiation via Hsf1-dependent mechanisms and may significantly contribute to pathological and therapeutic related bone loss.

Preclinical studies in support of defibrotide for the treatment of multiple myeloma and other neoplasias.

PubMed

Mitsiades, Constantine S; Rouleau, Cecile; Echart, Cinara; Menon, Krishna; Teicher, Beverly; Distaso, Maria; Palumbo, Antonio; Boccadoro, Mario; Anderson, Kenneth C; Iacobelli, Massimo; Richardson, Paul G

2009-02-15

Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantation-related toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective effect on endothelium, we investigated whether defibrotide protects tumor cells from cytotoxic antitumor agents. Further, given its antiadhesive properties, we evaluated whether defibrotide modulates the protection conferred to multiple myeloma cells by bone marrow stromal cells. Defibrotide lacks significant single-agent in vitro cytotoxicity on multiple myeloma or solid tumor cells and does not attenuate their in vitro response to dexamethasone, bortezomib, immunomodulatory thalidomide derivatives, and conventional chemotherapeutics, including melphalan and cyclophosphamide. Importantly, defibrotide enhances in vivo chemosensitivity of multiple myeloma and mammary carcinoma xenografts in animal models. In cocultures of multiple myeloma cells with bone marrow stromal cells in vitro, defibrotide enhances the multiple myeloma cell sensitivity to melphalan and dexamethasone, and decreases multiple myeloma-bone marrow stromal cell adhesion and its sequelae, including nuclear factor-kappaB activation in multiple myeloma and bone marrow stromal cells, and associated cytokine production. Moreover, defibrotide inhibits expression and/or function of key mediators of multiple myeloma interaction with bone marrow stromal cell and endothelium, including heparanase, angiogenic cytokines, and adhesion molecules. Defibrotide's in vivo chemosensitizing properties and lack of direct in vitro activity against tumor cells suggest that it favorably modulates antitumor interactions between bone marrow stromal cells and endothelia in the tumor microenvironment. These data support clinical studies of defibrotide in combination with conventional and novel therapies to potentially improve patient outcome in multiple myeloma and other malignancies.

Androgens and bone health.

PubMed

Hansen, K A; Tho, S P

1998-01-01

Osteoporosis is one of the most common metabolic bone diseases in the adult population and its prevalence will continue to rise as our population grows older. In both sexes, hypogonadism is associated with accelerated loss of bone and development of osteoporosis. Adrenal and gonadal androgen levels decline with advancing age in both sexes. Androgens act by either directly binding to androgen receptors, or by aromatization of androgens to estrogens and subsequently interacting with estrogen receptors. Both pathways are important for skeletal health. Direct androgen binding to an androgen receptor may play a more important role in early skeletal development and determination of sexual dimorphic traits. While bone remodeling, which is important in maintaining healthy bone through life, is primarily stimulated by estrogen, studies in the rat and human support the complex action of androgens and estrogens in bone modeling and remodeling, and hence the development and maintenance of healthy bone. In postmenopausal females, the addition of androgens to hormone replacement therapy results in significant additional improvement in bone mineral density compared to estrogen replacement alone. Accumulating evidence indicate that androgens play an important role in the health of bone and the potential benefit of adding these agents to hormone replacement regimens.

Method of coating a substrate with a calcium phosphate compound

DOEpatents

Gao, Yufei; Campbell, Allison A.

2000-01-01

The present invention is a method of coating a substrate with a calcium phosphate compound using plasma enhanced MOCVD. The substrate is a solid material that may be porous or non-porous, including but not limited to metal, ceramic, glass and combinations thereof. The coated substrate is preferably used as an implant, including but not limited to orthopaedic, dental and combinations thereof. Calcium phosphate compound includes but is not limited to tricalcium phosphate (TCP), hydroxyapatite (HA) and combinations thereof. TCP is preferred on a titanium implant when implant resorbability is desired. HA is preferred when the bone bonding of new bone tissue into the structure of the implant is desired. Either or both of TCP and/or HA coated implants may be placed into a solution with an agent selected from the group of protein, antibiotic, antimicrobial, growth factor and combinations thereof that can be adsorbed into the coating before implantation. Once implanted, the release of TCP will also release the agent to improve growth of new bone tissues and/or to prevent infection.

Meeting Report From the Prostate Cancer Foundation Scientific Working Group on Radium-223.

PubMed

Miyahira, Andrea K; Morris, Michael; Soule, Howard R

2017-02-01

The Prostate Cancer Foundation (PCF) convened a Scientific Working Group Meeting on Radium-223 on September 8, 2016, at The Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center. The meeting was attended by 18 investigators with expertise in radium-223, bone biology, molecular imaging, biomarkers, and prostate cancer clinical trials. The goal of this meeting was to discuss the known and unknown surroundings the therapeutic effects of the bone targeting agent radium-223, in bone metastatic prostate cancer therapy, and to outline the most critical studies needed to improve the clinical use of this agent. Three major topic areas were discussed: (1) the basic science of radium; (2) immuno-adjuvant properties of radium therapy; and (3) high impact clinical trials and correlative science. This article reviews the major topics discussed at the meeting for the purpose of accelerating studies that will improve the use of radium-223 in the treatment of prostate cancer patients. Prostate 77:245-254, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

[Growing up with bone marrow transplantation: repercussions for the quality of life of children and adolescents].

PubMed

Anders, Jane Cristina; Lima, Regina Aparecida Garcia de

2004-01-01

Nowadays, various knowledge areas take an increasing interest in the discussion about the quality of life of people submitted to bone marrow transplantation-BMT. This study aims to describe the experiences of children and adolescents who survived this kind of transplantation and to discover how this therapy mode influenced their quality of life. Study participants were 14 children/adolescents who survived BMT. In this qualitative research, data were collected by means of interviews, which were held at the participants' homes or when they returned to hospital. We identified their life as permeated by insecurity, changed body image, physical and emotional problems. These data indicate the importance of understanding the experience of children/adolescents living with bone marrow transplantation, seeking to identify aspects for the intervention and planning of nursing care, so as to contribute to their reinsertion and a better quality of life.

Managing the patient with osteogenesis imperfecta: a multidisciplinary approach

PubMed Central

Marr, Caroline; Seasman, Alison; Bishop, Nick

2017-01-01

Osteogenesis imperfecta (OI) is a heterogeneous heritable connective tissue disorder characterized by low bone density. The type and severity of OI are variable. The primary manifestations are fractures, bone deformity, and bone pain, resulting in reduced mobility and function to complete everyday tasks. OI affects not only the physical but also the social and emotional well-being of children, young people, and their families. As such, medical, surgical, and allied health professionals’ assessments all play a role in the management of these children. The multidisciplinary approach to the treatment of children and young people living with OI seeks to provide well-coordinated, comprehensive assessments, and interventions that place the child and family at the very center of their care. The coordinated efforts of a multidisciplinary team can support children with OI to fulfill their potential, maximizing function, independence, and well-being. PMID:28435282

Quantitative evaluation of bone resorption activity of osteoclast-like cells by measuring calcium phosphate resorbing area using incubator-facilitated and video-enhanced microscopy.

PubMed

Morimoto, Yoshitaka; Hoshino, Hironobu; Sakurai, Takashi; Terakawa, Susumu; Nagano, Akira

2009-04-01

Quantitative evaluation of the ability of bone resorption activity in live osteoclast-like cells (OCLs) has not yet been reported on. In this study, we observed the sequential morphological change of OCLs and measured the resorbing calcium phosphate (CP) area made by OCLs alone and with the addition of elcatonin utilizing incubator facilitated video-enhanced microscopy. OCLs, which were obtained from a coculture of ddy-mouse osteoblastic cells and bone marrow cells, were cultured on CP-coated quartz cover slips. The CP-free area increased constantly in the OCLs alone, whereas it did not increase after the addition of elcatonin. This study showed that analysis of the resorbed areas under the OCL body using this method enables the sequential quantitative evaluation of the bone resorption activity and the effect of several therapeutic agents on bone resorption in vitro.

Efficacy of teriparatide vs neridronate in adults with osteogenesis imperfecta type I: a prospective randomized international clinical study

PubMed Central

Leali, Paolo Tranquilli; Balsano, Massimo; Maestretti, Gianluca; Brusoni, Matteo; Amorese, Veronica; Ciurlia, Emanuele; Andreozzi, Matteo; Caggiari, Gianfilippo; Doria, Carlo

2017-01-01

Summary Osteogenesis imperfecta (OI) is an hereditary disease characterized by low bone mass, increased bone fragility, short stature, and skeletal deformities, few treatment options are currently available. Neridronate is an amino-bisphosphonate, licensed in Italy for the treatment of OI and Paget’s disease of bone. A characteristic property of neridronate is that it can be administered both intravenously and intramuscularly, providing an useful system for administration in homecare. Neridronate appears to increase Bone Mineral Density (BMD) in adults with OI and reduces bone resorption by inhibition of osteoclastic activity. Teriparatide (recombinant 1–34 N terminal sequence of human parathyroid hormone) is the first anabolic agent approved for the treatment of patients with osteoporosis and has been reported to increase bone formation by stimulating osteoblast differentiation, osteoblast function, and survival. The results of this study showed a promising role of teriparatide in the therapy of OI type I. PMID:29263724

Protective Effects of Selected Botanical Agents on Bone.

PubMed

Jolly, James Jam; Chin, Kok-Yong; Alias, Ekram; Chua, Kien Hui; Soelaiman, Ima Nirwana

2018-05-11

Osteoporosis is a serious health problem affecting more than 200 million elderly people worldwide. The early symptoms of this disease are hardly detectable. It causes progressive bone loss, which ultimately renders the patients susceptible to fractures. Osteoporosis must be prevented because the associated fragility fractures result in high morbidity, mortality, and healthcare costs. Many plants used in herbal medicine contain bioactive compounds possessing skeletal protective effects. This paper explores the anti-osteoporotic properties of selected herbal plants, including their actions on osteoblasts (bone forming cells), osteoclasts (bone resorbing cells), and bone remodelling. Some of the herbal plant families included in this review are Berberidaceae, Fabaceae, Arecaceae, Labiatae, Simaroubaceaea, and Myrsinaceae. Their active constituents, mechanisms of action, and pharmaceutical applications were discussed. The literature shows that very few herbal plants have undergone human clinical trials to evaluate their pharmacological effects on bone to date. Therefore, more intensive research should be performed on these plants to validate their anti-osteoporotic properties so that they can complement the currently available conventional drugs in the battle against osteoporosis.

Inhibition of Osteoclast Differentiation and Bone Resorption by N-Methylpyrrolidone*

PubMed Central

Ghayor, Chafik; Correro, Rita M.; Lange, Katrin; Karfeld-Sulzer, Lindsay S.; Grätz, Klaus W.; Weber, Franz E.

2011-01-01

Regulation of RANKL (receptor activator of nuclear factor κB ligand)-induced osteoclast differentiation is of current interest in the development of antiresorptive agents. Osteoclasts are multinucleated cells that play a crucial role in bone resorption. In this study, we investigated the effects of N-methylpyrrolidone (NMP) on the regulation of RANKL-induced osteoclastogenesis. NMP inhibited RANKL-induced tartrate-resistant acid phosphatase activity and the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. The RANKL-induced expression of NFATc1 (nuclear factor of activated T cells, cytoplasmic 1) and c-Fos, which are key transcription factors for osteoclastogenesis, was also reduced by treatment with NMP. Furthermore, NMP induced disruption of the actin rings and decreased the mRNAs of cathepsin K and MMP-9 (matrix metalloproteinase-9), both involved in bone resorption. Taken together, these results suggest that NMP inhibits osteoclast differentiation and attenuates bone resorption. Therefore, NMP could prove useful for the treatment of osteoporosis or other bone diseases associated with excessive bone resorption. PMID:21613210

Graded porous polyurethane foam: a potential scaffold for oro-maxillary bone regeneration.

PubMed

Giannitelli, S M; Basoli, F; Mozetic, P; Piva, P; Bartuli, F N; Luciani, F; Arcuri, C; Trombetta, M; Rainer, A; Licoccia, S

2015-06-01

Bone tissue engineering applications demand for biomaterials offering a substrate for cell adhesion, migration, and proliferation, while inferring suitable mechanical properties to the construct. In the present study, polyurethane (PU) foams were synthesized to develop a graded porous material-characterized by a dense shell and a porous core-for the treatment of oro-maxillary bone defects. Foam was synthesized via a one-pot reaction starting from a polyisocyanate and a biocompatible polyester diol, using water as a foaming agent. Different foaming conditions were examined, with the aim of creating a dense/porous functional graded material that would perform at the same time as an osteoconductive scaffold for bone defect regeneration and as a membrane-barrier to gingival tissue ingrowth. The obtained PU was characterized in terms of morphological and mechanical properties. Biocompatibility assessment was performed in combination with bone-marrow-derived human mesenchymal stromal cells (hBMSCs). Our findings confirm that the material is potentially suitable for guided bone regeneration applications. Copyright © 2015 Elsevier B.V. All rights reserved.

Novel bone wax based on poly(ethylene glycol)-calcium phosphate cement mixtures.

PubMed

Brückner, Theresa; Schamel, Martha; Kübler, Alexander C; Groll, Jürgen; Gbureck, Uwe

2016-03-01

Classic bone wax is associated with drawbacks such as the risk of infection, inflammation and hindered osteogenesis. Here, we developed a novel self-setting bone wax on the basis of hydrophilic poly(ethylene glycol) (PEG) and hydroxyapatite (HA) forming calcium phosphate cement (CPC), to overcome the problems that are linked to the use of conventional beeswax systems. Amounts of up to 10 wt.% of pregelatinized starch were additionally supplemented as hemostatic agent. After exposure to a humid environment, the PEG phase dissolved and was exchanged by penetrating water that interacted with the HA precursor (tetracalcium phosphate (TTCP)/monetite) to form highly porous, nanocrystalline HA via a dissolution/precipitation reaction. Simultaneously, pregelatinized starch could gel and supply the bone wax with liquid sealing features. The novel bone wax formulation was found to be cohesive, malleable and after hardening under aqueous conditions, it had a mechanical performance (∼2.5 MPa compressive strength) that is comparable to that of cancellous bone. It withstood systolic blood pressure conditions for several days and showed antibacterial properties for almost one week, even though 60% of the incorporated drug vancomycin hydrochloride was already released after 8h of deposition by diffusion controlled processes. The study investigated the development of alternative bone waxes on the basis of a hydroxyapatite (HA) forming calcium phosphate cement (CPC) system. Conventional bone waxes are composed of non-biodegradable beeswax/vaseline mixtures that are often linked to infection, inflammation and hindered osteogenesis. We combined the usage of bioresorbable polymers, the supplementation with hemostatic agents and the incorporation of a mineral component to overcome those drawbacks. Self-setting CPC precursors (tetracalcium phosphate (TTCP), monetite) were embedded in a resorbable matrix of poly(ethylene glycol) (PEG) and supplemented with pregelatinized starch. This formulation was found to be malleable and cohesive underwater. While immersion in an aqueous environment, CPC precursors formed highly porous, nanocrystalline HA via dissolution/precipitation reaction as water penetrated the novel wax formulation and PEG molecules simultaneously dissolved. The bone wax further withstood blood pressure conditions. After hardening, mechanical performance was comparable to that of cancellous bone and we also successfully provided the bone wax with antibacterial properties. In our opinion, the described bone wax formulation outmatches conventional bone waxes, as it circumvents the detriments being associated with the term "bone wax". Our wax has a novel composition and would broaden the application of CPC and besides, the general interest in bone waxes will increase, as they were long considered as a "first-line treatment" to avoid. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Synergistic Combination Agent for Cancer Therapy | NCI Technology Transfer Center | TTC

Cancer.gov

The Nanotechnology Characterization Laboratory of the Frederick National Laboratory for Biomedical Research seeks parties interested in collaborative research to co-develop a ceramide and vinca alkaloid combination therapy for treatment of cancer.

Cytokine expression in response to root repair agents.

PubMed

Oliveira, R R; Tavares, W L F; Reis, A L; Silva, V A; Vieira, L Q; Ribeiro Sobrinho, A P

2018-05-06

To evaluate the expression of TNF-α, IL-6, IFN-γ, TGF-β, IL-4, IL-10, RANKL, RANK and OPG on mouse calvarial bone treated with MTA, Geristore ® and Emdogain ® . Bone wounds were made on the heads of C57BL/6 mice, breaking the periosteum and the cortical surface of the calvaria. Each repair agent was inserted into sectioned Eppendorf microtubes and placed on the bone wound, and soft tissues were sutured. At 14 and 21 days, animals were sacrificed and the treated region was dissected. The calvaria bone was removed, and RNA was extracted. mRNA expression of the aforementioned cytokines was assessed using real-time PCR. Data were analysed by nonparametric methods, including the Mann-Whitney and Kruskal-Wallis tests (p<0.05). Following treatment with Emdogain ® and MTA, mRNA expression of RANKL, RANK and OPG increased significantly (p <0.05) between days 14 to 21. Geristore ® did not alter the basal expression of these mediators during the same period of evaluation. While treatment with Emdogain ® did cause a significant increase in TNF-α mRNA expression between days 14 and 21 (p <0.05), treatment with MTA did not alter the basal expression of this cytokine at either experimental time point. However, TNF-α mRNA expression was down-regulated significantly at day 21 (p <0.05) when Geristore ® was applied. A significant increase in the mRNA expression of IL-6, TGF-β, IL-10, IL-4 and IFN-γ was observed with Emdogain ® and MTA treatment between days 14 to 21, whereas Geristore ® reduced significantly the expression of IL-6, TGF-β and IL-4 (p <0.05). The clinical indication of these repair agents depends on the root resorption diagnosis. While MTA and Emdogain ® induce a pro- and anti-inflammatory response early and late, respectively, Geristore ® was not associated with an inflammatory reaction when compared to both repair agents. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Hypercalciuric Bone Disease

NASA Astrophysics Data System (ADS)

Favus, Murray J.

2008-09-01

Hypercalciuria plays an important causal role in many patients with calcium oxalate (CaOx) stones. The source of the hypercalciuria includes increased intestinal Ca absorption and decreased renal tubule Ca reabsorption. In CaOx stone formers with idiopathic hypercalciuria (IH), Ca metabolic balance studies have revealed negative Ca balance and persistent hypercalciuria in the fasting state and during low dietary Ca intake. Bone resorption may also contribute to the high urine Ca excretion and increase the risk of bone loss. Indeed, low bone mass by DEXA scanning has been discovered in many IH patients. Thiazide diuretic agents reduce urine Ca excretion and may increase bone mineral density (BMD), thereby reducing fracture risk. Dietary Ca restriction that has been used unsuccessfully in the treatment of CaOx nephrolithiasis in the past may enhance negative Ca balance and accelerate bone loss. DEXA scans may demonstrate low BMD at the spine, hip, or forearm, with no predictable pattern. The unique pattern of bone histologic changes in IH differs from other causes of low DEXA bone density including postmenopausal osteoporosis, male hypogonadal osteoporosis, and glucocorticoid-induced osteoporosis. Hypercalciuria appears to play an important pathologic role in the development of low bone mass, and therefore correction of urine Ca losses should be a primary target for treatment of the bone disease accompanying IH.

Pattern of uptake of americium-241 by the rat skeleton and its subsequent redistribution and retention: implications for human dosimetry and toxicology.

PubMed

Priest, N D; Howells, G; Green, D; Haines, J W

1983-01-01

The distribution and retention of intravenously injected 241Am in the skeleton of the female rat has been investigated using autoradiographic and radiochemical techniques. The studies were designed to assess the dosimetric and toxicologic implications of an 241Am intake by man. They showed that in the rat approximately one third of the intravenously injected 241Am was deposited in the skeleton where it appeared to be retained with a long biological half-time. The studies also showed: 1 241Am is initially deposited onto all types of bone surface including endosteal surfaces, periosteal surfaces and those of the vascular canals within cortical bone, but seems to be preferentially deposited onto those that are resorbing, 2 Bone accretion results in the burial of surface deposits of 241Am, 3 Bone resorption causes the removal of 241Am from surfaces, 4 Resorbed 241Am is retained by phagocytic cells (probably macrophages) in the bone marrow, 5 The transfer of 241Am from the phagocytic cells in the marrow to adjacent bone surfaces seems to occur, (local recycling). 6 The possibility that some of the 241Am removed from the bone surfaces enters the blood and is redeposited in bone, (systemic recycling) cannot be dismissed. These results show that 241Am deposition and redistribution in bone shares many characteristics with other 'bone surface-seeking radionuclides' typified by 239Pu. Consequently, it is suggested that a similar model to that used to calculate annual limits of intake for 239Pu in man would be suitable for the calculation of corresponding values for the 241Am isotopes.

Insulin antagonises pigment epithelium-derived factor (PEDF)-induced modulation of lineage commitment of myocytes and heterotrophic ossification.

PubMed

Carnagarin, Revathy; Elahy, Mina; Dharmarajan, Arun M; Dass, Crispin R

2017-12-16

Extensive bone defects arising as a result of trauma, infection and tumour resection and other bone pathologies necessitates the identification of effective strategies in the form of tissue engineering, gene therapy and osteoinductive agents to enhance the bone repair process. PEDF is a multifunctional glycoprotein which plays an important role in regulating osteoblastic differentiation and bone formation. PEDF treatment of mice and human skeletal myocytes at physiological concentration inhibited myogenic differentiation and activated Erk1/2 MAPK- dependent osteogenic transdifferentiation of myocytes. In mice, insulin, a promoter of bone regeneration, attenuated PEDF-induced expression of osteogenic markers such as osteocalcin, alkaline phosphatase and mineralisation for bone formation in the muscle and surrounding adipose tissue. These results provide new insights into the molecular aspects of the antagonising effect of insulin on PEDF-dependent modulation of the differentiation commitment of musculoskeletal environment into osteogenesis, and suggest that PEDF may be developed as an effective clinical therapy for bone regeneration as its heterotopic ossification can be controlled via co-administration of insulin. Copyright © 2017 Elsevier B.V. All rights reserved.

A Method for Decentralised Optimisation in Networks

NASA Astrophysics Data System (ADS)

Saramäki, Jari

2005-06-01

We outline a method for distributed Monte Carlo optimisation of computational problems in networks of agents, such as peer-to-peer networks of computers. The optimisation and messaging procedures are inspired by gossip protocols and epidemic data dissemination, and are decentralised, i.e. no central overseer is required. In the outlined method, each agent follows simple local rules and seeks for better solutions to the optimisation problem by Monte Carlo trials, as well as by querying other agents in its local neighbourhood. With proper network topology, good solutions spread rapidly through the network for further improvement. Furthermore, the system retains its functionality even in realistic settings where agents are randomly switched on and off.

The effect of antiresorptives on bone quality.

PubMed

Recker, Robert R; Armas, Laura

2011-08-01

Currently, antiresorptive therapy in the treatment and prevention of osteoporosis includes bisphosphonates, estrogen replacement, selective estrogen receptor modulators (raloxifene), and denosumab (a human antibody that inactivates RANKL). The original paradigm driving the development of antiresorptive therapy was that inhibition of bone resorption would allow bone formation to continue and correct the defect. However, it is now clear increases in bone density account for little of the antifracture effect of these treatments. We examined the antifracture benefit of antiresorptives deriving from bone quality changes. We searched the archive of nearly 30,000 articles accumulated over more than 40 years in our research center library using a software program (Refman™). Approximately 250 publications were identified in locating the 69 cited here. The findings document antiresorptive agents are not primarily anabolic. All cause a modest increase in bone density due to a reduction in the bone remodeling space; however, the majority of their efficacy is due to suppression of the primary cause of osteoporosis, ie, excessive bone remodeling not driven by mechanical need. All of them improve some element(s) of bone quality. Antiresorptive therapy reduces risk of fracture by improving bone quality through halting removal of bone tissue and the resultant destruction of microarchitecture of bone and, perhaps to some extent, by improving the intrinsic material properties of bone tissue. Information presented here may help clinicians to improve selection of patients for antiresorptive therapy by avoiding them in cases clearly not due to excessive bone remodeling.

[Recent research advance on bone marrow microenvironment-mediated leukemia drug resistant mechanism].

PubMed

Fu, Bing; Ling, Yan-Juan

2011-06-01

The bone marrow microenvironment consists of bone marrow stromal cells, osteoblasts and osteoclasts which facilities the survival, differentiation and proliferation of hematopoietic cells through secreting soluble factors and extracellular matrix proteins that mediate these functions. This environment not only supports the growth of normal and malignant hematopoietic cells, but also protects them against the damage from chemotherapeutic agents through the secretion of soluble cytokines, cell adhesion, up-regulation of resistant genes and changes of cell cycle. In this review, the research advances on drug-resistance mechanisms mediated by bone marrow microenvironment are summarized briefly, including soluble factors mediating drug resistance, intercellular adhesion inducing drug resistance, up-regulation of some drug resistance genes, regulation in metabolism of leukemic cells, changes in cell cycles of tumor cells and so on.

Electromagnetic irradiation may be a new approach to therapy for peri-implantitis.

PubMed

Cao, Zhensheng; Chen, Yijia; Chen, Yuxue; Zhao, Qing; Xu, Xiaomei; Chen, Yangxi

2012-03-01

Peri-implantitis can lead to bone destruction around a dental implant through inflammation and immune reactions caused by bacteria adhering to the surface of the implant abutment. Electromagnetic irradiation can inhibit bacterial growth, increase bone formation, decrease bone resorption and reduce the inflammatory response. Our hypothesis is that electromagnetic irradiation may be a new treatment approach for peri-implantitis and may simultaneously maintain bone mass around the dental implant. The results would be more significant when combined with other agents, because the effect of some antibiotics and anti-inflammatory drugs is strengthened by electromagnetic irradiation. This non-invasive therapy is expected to be conducted in a convenient manner, and even by patients at home, thereby facilitating the prevention and treatment of peri-implantitis. Copyright © 2011 Elsevier Ltd. All rights reserved.

Apoptosis and Self-Destruct: A Contribution to Autonomic Agents?

NASA Technical Reports Server (NTRS)

Sterritt, Roy; Hinchey, Mike

2004-01-01

Autonomic Computing (AC), a self-managing systems initiative based on the biological metaphor of the autonomic nervous system, is increasingly gaining momentum as the way forward in designing reliable systems. Agent technologies have been identified as a key enabler for engineering autonomicity in systems, both in terms of retrofitting autonomicity into legacy systems and designing new systems. The AC initiative provides an opportunity to consider other biological systems and principles in seeking new design strategies. This paper reports on one such investigation; utilizing the apoptosis metaphor of biological systems to provide a dynamic health indicator signal between autonomic agents.

Requirements for facilities transferring or receiving select agents. Final rule.

PubMed

2001-08-31

CDC administers regulations that govern the transfer of certain biological agents and toxins ("select agents"). These regulations require entities that transfer or receive select agents to register with CDC and comply with biosafety standards contained in the Third Edition of the CDC/NIH publication "Biosafety in Microbiological and Biomedical Laboratories ("BMBL")." On October 28,1999, CDC published a Notice of Proposed Rulemaking ("NPRM") seeking both to revise the biosafety standards facilities must follow when handling select agents and to provide new biosecurity standards for such facilities. These new standards are contained in the Fourth Edition of BMBL, which the NPRM proposed to incorporate by reference, thereby replacing the Third Edition. No comments were received in response to this proposal. CDC is therefore amending its regulations to incorporate the Fourth Edition.

Targeting mast cells in gastric cancer with special reference to bone metastases

PubMed Central

Leporini, Christian; Ammendola, Michele; Marech, Ilaria; Sammarco, Giuseppe; Sacco, Rosario; Gadaleta, Cosmo Damiano; Oakley, Caroline; Russo, Emilio; De Sarro, Giovambattista; Ranieri, Girolamo

2015-01-01

Bone metastases from gastric cancer (GC) are considered a relatively uncommon finding; however, they are related to poorer prognosis. Both primary GC and its metastatic progression rely on angiogenesis. Several lines of evidence from GC patients strongly support the involvement of mast cells (MCs) positive to tryptase (MCPT) in primary gastric tumor angiogenesis. Recently, we analyzed infiltrating MCs and neovascularization in bone tissue metastases from primary GC patients, and observed a significant correlation between infiltrating MCPT and angiogenesis. Such a finding suggested the involvement of peritumoral MCPT by infiltrating surrounding tumor cells, and in bone metastasis angiogenesis from primary GC. Thus, an MCPT-stimulated angiogenic process could support the development of metastases in bone tissue. From this perspective, we aim to review the hypothetical involvement of tumor-infiltrating, peritumoral MCPT in angiogenesis-mediated GC cell growth in the bone microenvironment and in tumor-induced osteoclastic bone resorption. We also focus on the potential use of MCPT targeting agents, such as MCs tryptase inhibitors (gabexate mesylate, nafamostat mesylate) or c-KitR tyrosine kinase inhibitors (imatinib, masitinib), as possible new anti-angiogenic and anti-resorptive strategies for the treatment of GC patients affected by bone metastases. PMID:26457010

Bisphosphonates and osteonecrosis of the jaw.

PubMed

Shannon, Jodi; Shannon, John; Modelevsky, Steven; Grippo, Anne A

2011-12-01

Bisphosphonates are used worldwide as a successful treatment for people with osteoporosis, which is the major underlying cause of fractures in postmenopausal women and older adults. These agents are successful at increasing bone mass and bone trabecular thickness, decreasing the risk of fracture, and decreasing bone pain, enabling individuals to have better quality of life. Bisphosphonates are also used to treat multiple myeloma, bone metastasis, and Paget's disease; however, bisphosphonate treatment may result in negative side effects, including osteonecrosis of the jaw (ONJ). ONJ involves necrotic, exposed bone in the jaw, pain, possible secondary infection, swelling, painful lesions, and various dysesthesias, although less-severe cases may be asymptomatic. First-generation bisphosphonates, which do not contain nitrogen, are metabolized into a nonfunctional, cytotoxic analogue of adenosine triphosphate and cause osteoclast death by starvation. Second-generation bisphosphonates are nitrogen-containing agents; these inhibit osteoclast vesicular trafficking, membrane ruffling, morphology, and cytoskeletal arrangement by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. Physicians treating older adults with osteoporosis and cancer should work together with dental practitioners, pharmacists, and other clinicians to inform individuals receiving bisphosphonates of their possible side effects and to suggest precautionary steps that may minimize the risk of osteonecrosis, particularly of the jaw. These include practicing good oral hygiene; scheduling regular dental examinations and cleanings; and cautioning people who are scheduling treatment for periodontal disease, oral and maxillofacial therapy, endodontics, implant placement, restorative dentistry, and prosthodontics. Recommendations for management of people with ONJ include an oral rinse, such as chlorhexidine, and antibiotics. © 2011, Copyright the Authors Journal compilation © 2011, The American Geriatrics Society.

Efficacy of Various Analgesics on Shoulder Function and Rotator Cuff Tendon-to-Bone Healing in a Rat (Rattus norvegicus) Model

PubMed Central

Caro, Adam C; Tucker, Jennica J; Yannascoli, Sarah M; Dunkman, Andrew A; Thomas, Stephen J; Soslowsky, Louis J

2014-01-01

Although relief of postoperative pain is an imperative aspect of animal welfare, analgesics that do not interfere with the scientific goals of the study must be used. Here we compared the efficacy of different analgesic agents by using an established rat model of supraspinatus tendon healing and a novel gait-analysis system. We hypothesized that different analgesic agents would all provide pain relief in this model but would cause differences in tendon-to-bone healing and gait parameters. Buprenorphine, ibuprofen, tramadol–gabapentin, and acetaminophen were compared with a no-analgesia control group. Gait measures (stride length and vertical force) on the operative forelimb differed between the control group and both the buprenorphine (2 and 4 d postsurgery) and ibuprofen (2 d postsurgery) groups. Step length was different in the control group as compared with the tramadol–gabapentin (2 d after surgery), buprenorphine (2 and 4 d after surgery), and ibuprofen (2 d after surgery) groups. Regarding tendon-to-bone healing, the ibuprofen group showed less stiffness at the insertion site; no other differences in tendon-to-bone healing were detected. In summary, the analgesics evaluated were associated with differences in both animal gait and tendon-to-bone healing. This information will be useful for improving the management of postsurgical pain without adversely affecting tissue healing. Given its ability to improve gait without impeding healing, we recommend use of buprenorphine for postsurgical pain management in rats. In addition, our gait-analysis system can be used to evaluate new analgesics. PMID:24602546

Biomaterials approaches to treating implant-associated osteomyelitis.

PubMed

Inzana, Jason A; Schwarz, Edward M; Kates, Stephen L; Awad, Hani A

2016-03-01

Orthopaedic devices are the most common surgical devices associated with implant-related infections and Staphylococcus aureus (S. aureus) is the most common causative pathogen in chronic bone infections (osteomyelitis). Treatment of these chronic bone infections often involves combinations of antibiotics given systemically and locally to the affected site via a biomaterial spacer. The gold standard biomaterial for local antibiotic delivery against osteomyelitis, poly(methyl methacrylate) (PMMA) bone cement, bears many limitations. Such shortcomings include limited antibiotic release, incompatibility with many antimicrobial agents, and the need for follow-up surgeries to remove the non-biodegradable cement before surgical reconstruction of the lost bone. Therefore, extensive research pursuits are targeting alternative, biodegradable materials to replace PMMA in osteomyelitis applications. Herein, we provide an overview of the primary clinical treatment strategies and emerging biodegradable materials that may be employed for management of implant-related osteomyelitis. We performed a systematic review of experimental biomaterials systems that have been evaluated for treating established S. aureus osteomyelitis in an animal model. Many experimental biomaterials were not decisively more efficacious for infection management than PMMA when delivering the same antibiotic. However, alternative biomaterials have reduced the number of follow-up surgeries, enhanced the antimicrobial efficacy by delivering agents that are incompatible with PMMA, and regenerated bone in an infected defect. Understanding the advantages, limitations, and potential for clinical translation of each biomaterial, along with the conditions under which it was evaluated (e.g. animal model), is critical for surgeons and researchers to navigate the plethora of options for local antibiotic delivery. Copyright © 2015 Elsevier Ltd. All rights reserved.

Immunotherapeutics for Pediatric Solid Tumors | NCI Technology Transfer Center | TTC

Cancer.gov

The National Cancer Institute’s Pediatric Oncology Branch seeks partners interested in licensing or collaborative research to co-develop new immunotherapeutic agents based on chimeric antigen receptor (CARs) for the treatment of pediatric solid tumors.

76 FR 53882 - Proposed Information Collection; Comment Request; Trade Fair Certification Program Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-30

... agents or distributors; market research and exposure; and joint venture and licensing opportunities for...-sector firms. The TFC Program seeks to broaden the base of U.S. firms, particularly new-to-market...

PARP Inhibitor and NO-Donor Dual Prodrugs as Anticancer Agents | NCI Technology Transfer Center | TTC

Cancer.gov

The National Cancer Institute’s Chemical Biology Laboratory seeks partners interested in collaborative research to co-develop PARP inhibitor and NO-donor hybrid prodrugs for the treatment of cancer.

Control of Hemotropic Diseases of Dogs.

DTIC Science & Technology

1979-12-31

and Kobayashi, Y.: Studies on Infectious Mononucleosis . I. Isolation of Etiologic Agent from Blood, Bone Marrow and Lymph Node of a Patient with... Infectious Mononucleosis by Using Mice. Tokyo Iji Shinshi, 71 (1954): 683-686. Ristic, M., Huxsoll, D.L., IWeisiger, R.M., Hildebrandt, P.K., Nyindo, M. B...1030-1036. Tanaka, H. and Hanoaka, M.: Ultrastructurc and Taxonomy of Rickettsia sennetsu (the Causative Agent of "Sennetsu" or Infectious Mononucleosis

A comparison of multiple behavior models in a simulation of the aftermath of an improvised nuclear detonation.

PubMed

Parikh, Nidhi; Hayatnagarkar, Harshal G; Beckman, Richard J; Marathe, Madhav V; Swarup, Samarth

2016-11-01

We describe a large-scale simulation of the aftermath of a hypothetical 10kT improvised nuclear detonation at ground level, near the White House in Washington DC. We take a synthetic information approach, where multiple data sets are combined to construct a synthesized representation of the population of the region with accurate demographics, as well as four infrastructures: transportation, healthcare, communication, and power. In this article, we focus on the model of agents and their behavior, which is represented using the options framework. Six different behavioral options are modeled: household reconstitution, evacuation, healthcare-seeking, worry, shelter-seeking, and aiding & assisting others. Agent decision-making takes into account their health status, information about family members, information about the event, and their local environment. We combine these behavioral options into five different behavior models of increasing complexity and do a number of simulations to compare the models.

A comparison of multiple behavior models in a simulation of the aftermath of an improvised nuclear detonation

PubMed Central

Parikh, Nidhi; Hayatnagarkar, Harshal G.; Beckman, Richard J.; Marathe, Madhav V.; Swarup, Samarth

2016-01-01

We describe a large-scale simulation of the aftermath of a hypothetical 10kT improvised nuclear detonation at ground level, near the White House in Washington DC. We take a synthetic information approach, where multiple data sets are combined to construct a synthesized representation of the population of the region with accurate demographics, as well as four infrastructures: transportation, healthcare, communication, and power. In this article, we focus on the model of agents and their behavior, which is represented using the options framework. Six different behavioral options are modeled: household reconstitution, evacuation, healthcare-seeking, worry, shelter-seeking, and aiding & assisting others. Agent decision-making takes into account their health status, information about family members, information about the event, and their local environment. We combine these behavioral options into five different behavior models of increasing complexity and do a number of simulations to compare the models. PMID:27909393

Immunology of malignant diseases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Byers, V.S.; Baldwin, R.W.

1987-01-01

This book contains 11 chapters. Some of the chapter titles are: Immunoscintigraphy: tumor detection with radiolabelled antitumor monoclonal antibodies; Bone marrow transplantation; Immunomodulating agents; Immunology in bowel cancer; Melanoma; and Immunological features of human bladder cancer.

Poly-cyclodextrin functionalized porous bioceramics for local chemotherapy and anticancer bone reconstruction.

PubMed

Chai, Feng; Abdelkarim, Mohamed; Laurent, Thomas; Tabary, Nicolas; Degoutin, Stephanie; Simon, Nicolas; Peters, Fabian; Blanchemain, Nicolas; Martel, Bernard; Hildebrand, Hartmut F

2014-08-01

The progress in bone cancer surgery and multimodal treatment concept achieve only modest improvement in the overall survival, due to failure in clearing out residual cancer cells at the surgical margin and extreme side-effects of adjuvant postoperative treatments. Our study aims to propose a new method based on cyclodextrin polymer (polyCD) functionalized hydroxyapatite (HA) for achieving a high local drug concentration with a sustained release profile and a better control of residual malignant cells via local drug delivery and promotion of the reconstruction of bone defects. PolyCD, a versatile carrier for therapeutic molecules, can be incorporated into HA (bone regeneration scaffold) through thermal treatment. The parameters of polyCD treatment on the macroporous HA (porosity 65%) were characterized via thermogravimetric analysis. Good cytocompatibility of polyCD functionalized bioceramics was demonstrated on osteoblast cells by cell vitality assay. An antibiotic (gentamicin) and an anticancer agent (cisplatin) were respectively loaded on polyCD functionalized bioceramics for drug release test. The results show that polyCD functionalization leads to significantly improved drug loading quantity (30% more concerning gentamicin and twice more for cisplatin) and drug release duration (7 days longer concerning gentamicin and 3 days longer for cisplatin). Conclusively, this study offers a safe and reliable drug delivery system for bioceramic matrices, which can load anticancer agents (or/and antibiotics) to reduce local recurrence (or/and infection). © 2014 Wiley Periodicals, Inc.

Multifunctional role of osteopontin in directing intrafibrillar mineralization of collagen and activation of osteoclasts

PubMed Central

Rodriguez, Douglas E.; Thula-Mata, Taili; Toro, Edgardo J.; Yeh, Ya-Wen; Holt, Carl; Holliday, L. Shannon; Gower, Laurie B.

2013-01-01

Mineralized collagen composites are of interest because they have the potential to provide a bone-like scaffold that stimulates the natural processes of resorption and remodeling. Working toward this goal, our group has previously shown that the nanostructure of bone can be reproduced using a polymer-induced liquid-precursor (PILP) process, which enables intrafibrillar mineralization of collagen with hydroxyapatite (HA) to be achieved. This prior work used polyaspartic acid (pASP), a simple mimic for acidic non-collagenous proteins (NCPs), to generate nanodroplets/nanoparticles of an amorphous mineral precursor which can infiltrate the interstices of type-I collagen fibrils. In this study we show that osteopontin (OPN) can similarly serve as a process-directing agent for the intrafibrillar mineralization of collagen, even though OPN is generally considered a mineralization inhibitor. We also found that inclusion of OPN in the mineralization process promotes the interaction of mouse marrow-derived osteoclasts with PILP-remineralized bone that was previously demineralized, as measured by actin ring formation. While osteoclast activation occurred when pASP was used as the process-directing agent, using OPN resulted in a dramatic effect on osteoclast activation, presumably because of the inherent arginine-glycine-aspartate acid (RGD) ligands of OPN. By capitalizing on the multifunctionality of OPN, these studies may lead the way to producing biomimetic bone substitutes with the capability of tailorable bioresorption rates. PMID:24140612

Zoledronic acid: a review of its use in the treatment of osteoporosis.

PubMed

Deeks, Emma D; Perry, Caroline M

2008-01-01

Zoledronic acid (Aclasta; Reclast), a third-generation nitrogen-containing bisphosphonate, is the first once-yearly treatment to have been approved for use in patients with postmenopausal osteoporosis or at high risk of fracture. Intravenous zoledronic acid 5 mg once yearly is effective in reducing the risk of several types of fracture in patients with postmenopausal osteoporosis or recent low-trauma hip fracture. Moreover, improvements in bone mineral density (BMD) and reductions in markers of bone turnover are also generally observed. Zoledronic acid is generally well tolerated. Additional comparative data are required to definitively position zoledronic acid with respect to other agents. In the meantime, intravenous zoledronic acid 5 mg once yearly is a convenient and effective treatment option that may have an advantage over some other agents, for which adherence to treatment regimens is a recognized problem.

In Vitro Osteoblast Model for Bone Wound Infections and Antimicrobial Therapy

DTIC Science & Technology

2013-01-01

performed.    In the past, others have developed 3‐D scaffolds with osteoblasts in vitro for bone  regeneration  [3], [4],  [5]. Recently, investigators have...agent to be incorporated in chewing  gum  formulation as it prevented the development of  oral biofilm and inhibit oral pathogens in vitro [55‐57]. The...agent in a chewing  gum  formulation [58]. As KSL‐W is known to have bactericidal activity  against A.baumanni and K.pneumoniae (personal communication

Healing of the bone with anti-fracture drugs.

PubMed

Vannucci, Letizia; Brandi, Maria Luisa

2016-12-01

Fracture healing is a complex physiological process. As impaired fracture healing is more frequent in osteoporotic subjects, anti-osteoporotic drugs could have some impact on this process. Areas covered: We reviewed the current literature to evaluate the effects of these drugs on fracture healing and their potential role in supporting this process, especially when impaired. A PubMed/Medline search was undertaken combining the terms 'fracture healing', 'anti-resorptive drugs', 'anabolic agents', 'anti-osteoporotic drugs'. Expert opinion: As clinical evidence on the role of anti-osteoporotic drugs in the process of fracture healing consists mainly of case reports or studies with a relatively small number of patients, large randomized clinical trials are needed in order to extend to the human setting the promising results on these agents as inductors or co-adjuvants of bone healing derived from animal studies.

Effects of rosiglitazone on bone mineral density and remodelling parameters in Postmenopausal diabetic women: a 2-year follow-up study.

PubMed

Berberoglu, Zehra; Yazici, Ayse C; Demirag, Nilgun G

2010-09-01

To evaluate the effect of rosiglitazone on bone metabolism and bone density. An open-label, randomized, controlled trial of 24-month duration. Patients and measurements Obese, postmenopausal women with newly diagnosed diabetes were studied. Before and after the intervention, metabolic bone markers and bone density were assessed. Twenty-six patients received rosiglitazone (4 mg/day), and 23 remained on diet alone. Serum bone-specific alkaline phosphatase and osteocalcin levels decreased by 17% (P < 0.001 vs control group) and 26% (P < 0.01 vs control group), respectively, in the rosiglitazone group. There were no significant changes in the deoxypyridinoline levels between the two groups. Annual bone loss at the trochanter and at the lumbar spine associated with each year of rosiglitazone use was 2.56% (P = 0.01 vs control group) and 2.18% (P < 0.01 vs control group), respectively. Femoral neck and total hip bone density declined significantly in both groups (P < 0.01, and P = 0.01, respectively) but was not significantly different between the two groups. Rosiglitazone treatment adversely affects bone formation over a 2-year period. It increases bone loss at the lumbar spine and trochanter in postmenopausal, type 2 diabetic women. However, bone loss at the total hip did not differ with use of this agent.

Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts.

PubMed

Uluçkan, Özge; Jimenez, Maria; Karbach, Susanne; Jeschke, Anke; Graña, Osvaldo; Keller, Johannes; Busse, Björn; Croxford, Andrew L; Finzel, Stephanie; Koenders, Marije; van den Berg, Wim; Schinke, Thorsten; Amling, Michael; Waisman, Ari; Schett, Georg; Wagner, Erwin F

2016-03-16

Inflammation has important roles in tissue regeneration, autoimmunity, and cancer. Different inflammatory stimuli can lead to bone loss by mechanisms that are not well understood. We show that skin inflammation induces bone loss in mice and humans. In psoriasis, one of the prototypic IL-17A-mediated inflammatory human skin diseases, low bone formation and bone loss correlated with increased serum IL-17A levels. Similarly, in two mouse models with chronic IL-17A-mediated skin inflammation,K14-IL17A(ind)andJunB(Δep), strong inhibition of bone formation was observed, different from classical inflammatory bone loss where osteoclast activation leads to bone degradation. We show that under inflammatory conditions, skin-resident cells such as keratinocytes, γδ T cells, and innate lymphoid cells were able to express IL-17A, which acted systemically to inhibit osteoblast and osteocyte function by a mechanism involving Wnt signaling. IL-17A led to decreased Wnt signaling in vitro, and importantly, pharmacological blockade of IL-17A rescued Wnt target gene expression and bone formation in vivo. These data provide a mechanism where IL-17A affects bone formation by regulating Wnt signaling in osteoblasts and osteocytes. This study suggests that using IL-17A blocking agents in psoriasis could be beneficial against bone loss in these patients. Copyright © 2016, American Association for the Advancement of Science.

Hardness of the subchondral bone of the patella in the normal state, in chondromalacia, and in osteoarthrosis.

PubMed

Björkström, S; Goldie, I F

1982-06-01

The hardness of bone is its property of withstanding the impact of a penetrating agent. It has been found that articular degenerative changes in, for example, the tibia (knee) are combined with a decrease in the hardness of the subchondral bone. In this investigation the hardness of subchondral bone in chondromalacia and osteoarthrosis of the patella has been analysed and compared with normal subchondral bone. Using an indentation method originally described by Brinell the hardness of the subchondral bone was evaluated in 7 normal patellae, in 20 with chondromalacia and in 33 with osteoarthrosis. A microscopic and microradiographic study of the subchondral bone was carried out simultaneously. Hardness was lowest in the normal material. The mean hardness value beneath the degenerated cartilage differed only slightly from that of the normal material, but the variation of values was increased. The hardness in bone in the chondromalacia area was lower than the hardness in bone covered by surrounding normal cartilage. The mean hardness value in bone beneath normal parts of cartilage in specimens with chondromalacia was higher than the mean hardness value of the normal material. In the microscopic and microradiographic examination it became evident that there was a relationship between trabecular structure and subchondral bone hardness; high values: coarse and solid structure; low values: slender and less regular structure.

Milk thistle: a future potential anti-osteoporotic and fracture healing agent.

PubMed

Mohd Fozi, Nur Farhana; Mazlan, Mazliadiyana; Shuid, Ahmad Nazrun; Isa Naina, Mohamed

2013-12-01

Osteoporosis is a progressive disease of the skeleton characterised by bone fragility due to a reduction in bone mass and possibly to alteration in bone architecture that lead to a propensity to fracture with minimum trauma. Most osteoporotic fractures occur at locations rich in trabecular or cancellous bone and usually related to post menopausal women. Recently, silymarin received attention due to its alternative beneficial effect on bone formation. It is a mixture of flavonoids with powerful antioxidant properties. This review focuses on the use of milk thistle or silymarin for the treatment of osteoporosis that may be related to fracture bone. Silymarin shows potent antioxidant herb that may modulate multiple genes in favour of helping to build bone and prevent bone loss. In the mouse fracture healing model, silymarin supplementation improved tibial healing with elevated BMD and serum levels of ALP and osteocalcin. Silymarin also demonstrated clear estrogenic antiosteoporotic effects in bone structure. Silymarin appears to play a crucial role to prevent bone loss and might regulate osteogenesis and may be beneficial for fracture healing. If silymarin is considered for the use of post menopausal women, it may be used for the treatment of osteoporosis. It would be of great benefit to postmenopausal women to develop an oestrogen antagonist that is as potent and efficacious as oestrogen in preventing bone loss without the major side effect associated with HRT.

Desalted Duck Egg White Peptides Promote Calcium Uptake and Modulate Bone Formation in the Retinoic Acid-Induced Bone Loss Rat and Caco-2 Cell Model.

PubMed

Hou, Tao; Liu, Yanshuang; Kolba, Nikolai; Guo, Danjun; He, Hui

2017-05-12

Desalted duck egg white peptides (DPs) have been proven to promote calcium uptake in Caco-2 cells and rats treated with a calcium-deficient diet. The retinoic acid-induced bone loss model was used to evaluate the effect of DPs on calcium absorption and bone formation. Three-month-old Wistar female rats were treated with 0.9% saline, DPs (800 mg/kg), or alendronate (5 mg/kg) for three weeks immediately after retinoic acid treatment (80 mg/kg) once daily for two weeks. The model group was significantly higher in serum bone alkaline phosphatase than the other three groups ( p < 0.05), but lower in calcium absorption rate, serum osteocalcin, bone weight index, bone calcium content, bone mineral density, and bone max load. After treatment with DPs or alendronate, the absorption rate increased and some serum and bone indices recovered. The morphology results indicated bone tissue form were ameliorated and numbers of osteoclasts decreased after supplementation with DPs or alendronate. The in vitro study showed that the transient receptor potential vanilloid 6 (TRPV6) calcium channel was the main transport pathway of both DPs and Val-Ser-Glu-Glu peptitde (VSEE), which was identified from DPs. Our results indicated that DPs could be a promising alternative to current therapeutic agents for bone loss because of the promotion of calcium uptake and regulation of bone formation.

A Multi-Level Model of Information Seeking in the Clinical Domain

PubMed Central

Hung, Peter W.; Johnson, Stephen B.; Kaufman, David R.; Mendonça, Eneida A.

2008-01-01

Objective: Clinicians often have difficulty translating information needs into effective search strategies to find appropriate answers. Information retrieval systems employing an intelligent search agent that generates adaptive search strategies based on human search expertise could be helpful in meeting clinician information needs. A prerequisite for creating such systems is an information seeking model that facilitates the representation of human search expertise. The purpose of developing such a model is to provide guidance to information seeking system development and to shape an empirical research program. Design: The information seeking process was modeled as a complex problem-solving activity. After considering how similarly complex activities had been modeled in other domains, we determined that modeling context-initiated information seeking across multiple problem spaces allows the abstraction of search knowledge into functionally consistent layers. The knowledge layers were identified in the information science literature and validated through our observations of searches performed by health science librarians. Results: A hierarchical multi-level model of context-initiated information seeking is proposed. Each level represents (1) a problem space that is traversed during the online search process, and (2) a distinct layer of knowledge that is required to execute a successful search. Grand strategy determines what information resources will be searched, for what purpose, and in what order. The strategy level represents an overall approach for searching a single resource. Tactics are individual moves made to further a strategy. Operations are mappings of abstract intentions to information resource-specific concrete input. Assessment is the basis of interaction within the strategic hierarchy, influencing the direction of the search. Conclusion: The described multi-level model provides a framework for future research and the foundation for development of an automated information retrieval system that uses an intelligent search agent to bridge clinician information needs and human search expertise. PMID:18006383

Development of a Model System to Evaluate Local Recurrence in Osteosarcoma and Assessment of the Effects of Bone Morphogenetic Protein-2.

PubMed

Geller, David S; Singh, Michael Y; Zhang, Wendong; Gill, Jonathan; Roth, Michael E; Kim, Mimi Y; Xie, Xianhong; Singh, Christopher K; Dorfman, Howard D; Villanueva-Siles, Esperanza; Park, Amy; Piperdi, Sajida; Gorlick, Richard

2015-07-01

It is increasingly relevant to better define what constitutes an adequate surgical margin in an effort to improve reconstructive longevity and functional outcomes following osteosarcoma surgery. In addition, nonunion remains a challenging problem in some patients following allograft reconstruction. Bone morphogenetic protein-2 (BMP-2) could enhance osseous union, but has been historically avoided due to concerns that it may promote tumor recurrence. An orthotopic xenograft murine model was utilized to describe the natural temporal course of osteosarcoma growth. Tumors were treated either with surgery alone, surgery and single-agent chemotherapy, or surgery and dual-agent chemotherapy to assess the relationship between surgical margin and local recurrence. The effect of BMP-2 on local recurrence was similarly assessed. Osteosarcoma tumor growth was categorized into reproducible phases. Margins greater than 997 μm resulted in local control following surgery alone. Margins greater than 36 μm resulted in local control following surgery and single-agent chemotherapy. Margins greater than 12 μm resulted in local control following surgery and dual-agent chemotherapy. The application of exogenous BMP-2 does not confer an increased risk of local recurrence. This model reliably reproduces the clinical, radiographic, and surgical conditions encountered in human osteosarcoma. It successfully incorporates relevant chemotherapy, further paralleling the human experience. Surgical margins required to achieve local control in osteosarcoma can be reduced using single-agent chemotherapy and further decreased using dual-agent chemotherapy. The application of BMP-2 does not increase local recurrence in this model. ©2014 American Association for Cancer Research.

The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking.

PubMed

Nair, Sunila G; Adams-Deutsch, Tristan; Epstein, David H; Shaham, Yavin

2009-09-01

Relapse to old, unhealthy eating habits is a major problem in human dietary treatments. The mechanisms underlying this relapse are unknown. Surprisingly, until recently this clinical problem has not been systematically studied in animal models. Here, we review results from recent studies in which a reinstatement model (commonly used to study relapse to abused drugs) was employed to characterize the effect of pharmacological agents on relapse to food seeking induced by either food priming (non-contingent exposure to small amounts of food), cues previously associated with food, or injections of the pharmacological stressor yohimbine. We also address methodological issues related to the use of the reinstatement model to study relapse to food seeking, similarities and differences in mechanisms underlying reinstatement of food seeking versus drug seeking, and the degree to which the reinstatement procedure provides a suitable model for studying relapse in humans. We conclude by discussing implications for medication development and future research. We offer three tentative conclusions: (1)The neuronal mechanisms of food-priming- and cue-induced reinstatement are likely different from those of reinstatement induced by the pharmacological stressor yohimbine. (2)The neuronal mechanisms of reinstatement of food seeking are possibly different from those of ongoing food-reinforced operant responding. (3)The neuronal mechanisms underlying reinstatement of food seeking overlap to some degree with those of reinstatement of drug seeking.

Horizontal alveolar bone loss: A periodontal orphan

PubMed Central

Jayakumar, A.; Rohini, S.; Naveen, A.; Haritha, A.; Reddy, Krishnanjeneya

2010-01-01

Background: Attempts to successfully regenerate lost alveolar bone have always been a clinician’s dream. Angular defects, at least, have a fairer chance, but the same cannot be said about horizontal bone loss. The purpose of the present study was to evaluate the prevalence of horizontal alveolar bone loss and vertical bone defects in periodontal patients; and later, to correlate it with the treatment modalities available in the literature for horizontal and vertical bone defects. Materials and Methods: The study was conducted in two parts. Part I was the radiographic evaluation of 150 orthopantomographs (OPGs) (of patients diagnosed with chronic periodontitis and seeking periodontal care), which were digitized and read using the AutoCAD 2006 software. All the periodontitis-affected teeth were categorized as teeth with vertical defects (if the defect angle was ≤45° and defect depth was ≥3 mm) or as having horizontal bone loss. Part II of the study comprised search of the literature on treatment modalities for horizontal and vertical bone loss in four selected periodontal journals. Results: Out of the 150 OPGs studied, 54 (36%) OPGs showed one or more vertical defects. Totally, 3,371 teeth were studied, out of which horizontal bone loss was found in 3,107 (92.2%) teeth, and vertical defects were found only in 264 (7.8%) of the teeth, which was statistically significant (P<.001). Search of the selected journals revealed 477 papers have addressed the treatment modalities for vertical and horizontal types of bone loss specifically. Out of the 477 papers, 461 (96.3%) have addressed vertical bone loss, and 18 (3.7%) have addressed treatment options for horizontal bone loss. Two papers have addressed both types of bone loss and are included in both categories. Conclusion: Horizontal bone loss is more prevalent than vertical bone loss but has been sidelined by researchers as very few papers have been published on the subject of regenerative treatment modalities for this type of bone loss. This study should be an impetus for greater attention to an otherwise ubiquitous periodontal challenge. PMID:21760673

Autologous serum improves bone formation in a primary stable silica-embedded nanohydroxyapatite bone substitute in combination with mesenchymal stem cells and rhBMP-2 in the sheep model

PubMed Central

Boos, Anja M; Weigand, Annika; Deschler, Gloria; Gerber, Thomas; Arkudas, Andreas; Kneser, Ulrich; Horch, Raymund E; Beier, Justus P

2014-01-01

New therapeutic strategies are required for critical size bone defects, because the gold standard of transplanting autologous bone from an unharmed area of the body often leads to several severe side effects and disadvantages for the patient. For years, tissue engineering approaches have been seeking a stable, axially vascularized transplantable bone replacement suitable for transplantation into the recipient bed with pre-existing insufficient conditions. For this reason, the arteriovenous loop model was developed and various bone substitutes have been vascularized. However, it has not been possible thus far to engineer a primary stable and axially vascularized transplantable bone substitute. For that purpose, a primary stable silica-embedded nanohydroxyapatite (HA) bone substitute in combination with blood, bone marrow, expanded, or directly retransplanted mesenchymal stem cells, recombinant human bone morphogenetic protein 2 (rhBMP-2), and different carrier materials (fibrin, cell culture medium, autologous serum) was tested subcutaneously for 4 or 12 weeks in the sheep model. Autologous serum lead to an early matrix change during degradation of the bone substitute and formation of new bone tissue. The best results were achieved in the group combining mesenchymal stem cells expanded with 60 μg/mL rhBMP-2 in autologous serum. Better ingrowth of fibrovascular tissue could be detected in the autologous serum group compared with the control (fibrin). Osteoclastic activity indicating an active bone remodeling process was observed after 4 weeks, particularly in the group with autologous serum and after 12 weeks in every experimental group. This study clearly demonstrates the positive effects of autologous serum in combination with mesenchymal stem cells and rhBMP-2 on bone formation in a primary stable silica-embedded nano-HA bone grafting material in the sheep model. In further experiments, the results will be transferred to the sheep arteriovenous loop model in order to engineer an axially vascularized primary stable bone replacement in clinically relevant size for free transplantation. PMID:25429218

From Roentgen to magnetic resonance imaging: the history of medical imaging.

PubMed

Scatliff, James H; Morris, Peter J

2014-01-01

Medical imaging has advanced in remarkable ways since the discovery of x-rays 120 years ago. Today's radiologists can image the human body in intricate detail using computed tomography, magnetic resonance imaging, positron emission tomography, ultrasound, and various other modalities. Such technology allows for improved screening, diagnosis, and monitoring of disease, but it also comes with risks. Many imaging modalities expose patients to ionizing radiation, which potentially increases their risk of developing cancer in the future, and imaging may also be associated with possible allergic reactions or risks related to the use of intravenous contrast agents. In addition, the financial costs of imaging are taxing our health care system, and incidental findings can trigger anxiety and further testing. This issue of the NCMJ addresses the pros and cons of medical imaging and discusses in detail the following uses of medical imaging: screening for breast cancer with mammography, screening for osteoporosis and monitoring of bone mineral density with dual-energy x-ray absorptiometry, screening for congenital hip dysplasia in infants with ultrasound, and evaluation of various heart conditions with cardiac imaging. Together, these articles show the challenges that must be met as we seek to harness the power of today's imaging technologies, as well as the potential benefits that can be achieved when these hurdles are overcome.

Dipeptidyl Peptidase-4 Inhibitor, Vildagliptin, Improves Trabecular Bone Mineral Density and Microstructure in Obese, Insulin-Resistant, Pre-diabetic Rats.

PubMed

Charoenphandhu, Narattaphol; Suntornsaratoon, Panan; Sa-Nguanmoo, Piangkwan; Tanajak, Pongpan; Teerapornpuntakit, Jarinthorn; Aeimlapa, Ratchaneevan; Chattipakorn, Nipon; Chattipakorn, Siriporn

2018-02-02

Obese insulin resistance and type 2 diabetes mellitus profoundly impair bone mechanical properties and bone quality. However, because several antidiabetes drugs, especially thiazolidinediones, further aggravate bone loss in individuals with diabetes, diabetic osteopathy should not be treated by using simply any glucose-lowering agents. Recently, incretins have been reported to affect osteoblast function positively. The present study aimed to investigate the effects of vildagliptin, an inhibitor of dipeptidyl peptidase-4, on bone of rats with high-fat-diet-induced prediabetes. Male rats were fed a high-fat diet for 12 weeks to induce obese insulin resistance and then treated with vildagliptin for 4 weeks. The effects of the drug on bone were determined by microcomputed tomography and bone histomorphometry. Vildagliptin markedly improved insulin resistance in these obese insulin-resistant rats. It also significantly increased volumetric bone mineral density. Specifically, vildagliptin-treated obese insulin-resistant rats exhibited higher trabecular volumetric bone mineral density than vehicle-treated obese insulin-resistant rats, whereas cortical volumetric bone mineral density, cortical thickness and area were not changed. Bone histomorphometric analysis in a trabecular-rich area (i.e. tibial metaphysis) revealed greater trabecular bone volume and number and less trabecular separation without change in trabecular thickness, osteocyte lacunar area or cortical thickness in the vildagliptin-treated group. Vildagliptin had a beneficial effect on the bone of obese insulin-resistant rats with prediabetes, particularly at the trabecular site. Such benefit probably results from enhanced bone formation rather than from suppressed bone resorption. Copyright © 2018 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

18 F-Fluoride positron emission tomography/computed tomography for noninvasive in vivo quantification of pathophysiological bone metabolism in experimental murine arthritis

PubMed Central

2014-01-01

Introduction Evaluation of disease severity in experimental models of rheumatoid arthritis is inevitably associated with assessment of structural bone damage. A noninvasive imaging technology allowing objective quantification of pathophysiological alterations of bone structure in rodents could substantially extend the methods used to date in preclinical arthritis research for staging of autoimmune disease severity or efficacy of therapeutical intervention. Sodium 18 F-fluoride (18 F-NaF) is a bone-seeking tracer well-suited for molecular imaging. Therefore, we systematically examined the use of 18 F-NaF positron emission tomography/computed tomography (PET/CT) in mice with glucose-6-phosphate isomerase (G6PI)–induced arthritis for quantification of pathological bone metabolism. Methods F-fluoride was injected into mice before disease onset and at various time points of progressing experimental arthritis. Radioisotope accumulation in joints in the fore- and hindpaws was analyzed by PET measurements. For validation of bone metabolism quantified by 18 F-fluoride PET, bone surface parameters of high-resolution μCT measurements were used. Results Before clinical arthritis onset, no distinct accumulation of 18 F-fluoride was detectable in the fore- and hindlimbs of mice immunized with G6PI. In the course of experimental autoimmune disease, 18 F-fluoride bone uptake was increased at sites of enhanced bone metabolism caused by pathophysiological processes of autoimmune disease. Moreover, 18 F-fluoride signaling at different stages of G6PI-induced arthritis was significantly correlated with the degree of bone destruction. CT enabled identification of exact localization of 18 F-fluoride signaling in bone and soft tissue. Conclusions The results of this study suggest that small-animal PET/CT using 18 F-fluoride as a tracer is a feasible method for quantitative assessment of pathophysiological bone metabolism in experimental arthritis. Furthermore, the possibility to perform repeated noninvasive measurements in vivo allows longitudinal study of therapeutical intervention monitoring. PMID:25053370

Clinical guideline on bone conduction implants.

PubMed

Lavilla Martín de Valmaseda, María José; Cavalle Garrido, Laura; Huarte Irujo, Alicia; Núñez Batalla, Faustino; Manrique Rodriguez, Manuel; Ramos Macías, Ángel; de Paula Vernetta, Carlos; Gil-Carcedo Sañudo, Elisa; Lassaleta, Luis; Sánchez-Cuadrado, Isabel; Espinosa Sánchez, Juan Manuel; Batuecas Caletrio, Ángel; Cenjor Español, Carlos

2018-04-13

During the last decade there have been multiple and relevant advances in conduction and mixed hearing loss treatment. These advances and the appearance of new devices have extended the indications for bone-conduction implants. The Scientific Committee of Audiology of the Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello SEORL-CCC (Spanish Society of Otolaryngology and Head and Neck Surgery), together with the Otology and Otoneurology Committees, have undertaken a review of the current state of bone-conduction devices with updated information, to provide a clinical guideline on bone-conduction implants for otorhinolaryngology specialists, health professionals, health authorities and society in general. This clinical guideline on bone-conduction implants contains information on the following: 1) Definition and description of bone-conduction devices; 2) Current and upcoming indications for bone conduction devices: Magnetic resonance compatibility; 3) Organization requirements for a bone-conduction implant programme. The purpose of this guideline is to describe the different bone-conduction implants, their characteristics and their indications, and to provide coordinated instructions for all the above-mentioned agents for decision making within their specific work areas. Copyright © 2018 Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. Publicado por Elsevier España, S.L.U. All rights reserved.

Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression

NASA Technical Reports Server (NTRS)

Lotinun, Sutada; Sibonga, Jean D.; Turner, Russell T.

2002-01-01

A mechanism explaining the differential skeletal effects of intermittent and continuous elevation of serum parathyroid hormone (PTH) remains elusive. Intermittent PTH increases bone formation and bone mass and is being investigated as a therapy for osteoporosis. By contrast, chronic hyperparathyroidism results in the metabolic bone disease osteitis fibrosa characterized by osteomalacia, focal bone resorption, and peritrabecular bone marrow fibrosis. Intermittent and continuous PTH have similar effects on the number of osteoblasts and bone-forming activity. Many of the beneficial as well as detrimental effects of the hormone appear to be mediated by osteoblast-derived growth factors. This hypothesis was tested using cDNA microgene arrays to compare gene expression in tibia of rats treated with continuous and pulsatile administration of PTH. These treatments result in differential expression of many genes, including growth factors. One of the genes whose steady-state mRNA levels was increased by continuous but not pulsatile administration was platelet-derived growth factor-A (PDGF-A). Administration of a PDGF-A antagonist greatly reduced bone resorption, osteomalacia, and bone marrow fibrosis in a rat model for hyperparathyroidism, suggesting that PDGF-A is a causative agent for this disease. These findings suggest that profiling changes in gene expression can help identify the metabolic pathways responsible for the skeletal responses to the hormone.

Dioscin inhibits osteoclast differentiation and bone resorption though down-regulating the Akt signaling cascades

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qu, Xinhua; Zhai, Zanjing; Liu, Xuqiang

Highlights: •A natural-derived compound, dioscin, suppresses osteoclast formation and bone resorption. •Dioscin inhibits osteolytic bone loss in vivo. •Dioscin impairs the Akt signaling cascades pathways during osteoclastogenesis. •Dioscin have therapeutic value in treating osteoclast-related diseases. -- Abstract: Bone resorption is the unique function of osteoclasts (OCs) and is critical for both bone homeostasis and pathologic bone diseases including osteoporosis, rheumatoid arthritis and tumor bone metastasis. Thus, searching for natural compounds that may suppress osteoclast formation and/or function is promising for the treatment of osteoclast-related diseases. In this study, we for the first time demonstrated that dioscin suppressed RANKL-mediated osteoclast differentiationmore » and bone resorption in vitro in a dose-dependent manner. The suppressive effect of dioscin is supported by the reduced expression of osteoclast-specific markers. Further molecular analysis revealed that dioscin abrogated AKT phosphorylation, which subsequently impaired RANKL-induced nuclear factor-kappaB (NF-κB) signaling pathway and inhibited NFATc1 transcriptional activity. Moreover, in vivo studies further verified the bone protection activity of dioscin in osteolytic animal model. Together our data demonstrate that dioscin suppressed RANKL-induced osteoclast formation and function through Akt signaling cascades. Therefore, dioscin is a potential natural agent for the treatment of osteoclast-related diseases.« less

Effects of obesity on bone metabolism.

PubMed

Cao, Jay J

2011-06-15

Obesity is traditionally viewed to be beneficial to bone health because of well-established positive effect of mechanical loading conferred by body weight on bone formation, despite being a risk factor for many other chronic health disorders. Although body mass has a positive effect on bone formation, whether the mass derived from an obesity condition or excessive fat accumulation is beneficial to bone remains controversial. The underline pathophysiological relationship between obesity and bone is complex and continues to be an active research area. Recent data from epidemiological and animal studies strongly support that fat accumulation is detrimental to bone mass. To our knowledge, obesity possibly affects bone metabolism through several mechanisms. Because both adipocytes and osteoblasts are derived from a common multipotential mesenchymal stem cell, obesity may increase adipocyte differentiation and fat accumulation while decrease osteoblast differentiation and bone formation. Obesity is associated with chronic inflammation. The increased circulating and tissue proinflammatory cytokines in obesity may promote osteoclast activity and bone resorption through modifying the receptor activator of NF-κB (RANK)/RANK ligand/osteoprotegerin pathway. Furthermore, the excessive secretion of leptin and/or decreased production of adiponectin by adipocytes in obesity may either directly affect bone formation or indirectly affect bone resorption through up-regulated proinflammatory cytokine production. Finally, high-fat intake may interfere with intestinal calcium absorption and therefore decrease calcium availability for bone formation. Unraveling the relationship between fat and bone metabolism at molecular level may help us to develop therapeutic agents to prevent or treat both obesity and osteoporosis. Obesity, defined as having a body mass index ≥ 30 kg/m2, is a condition in which excessive body fat accumulates to a degree that adversely affects health. The rates of obesity rates have doubled since 1980 and as of 2007, 33% of men and 35% of women in the US are obese. Obesity is positively associated to many chronic disorders such as hypertension, dyslipidemia, type 2 diabetes mellitus, coronary heart disease, and certain cancers. It is estimated that the direct medical cost associated with obesity in the United States is ~$100 billion per year.Bone mass and strength decrease during adulthood, especially in women after menopause. These changes can culminate in osteoporosis, a disease characterized by low bone mass and microarchitectural deterioration resulting in increased bone fracture risk. It is estimated that there are about 10 million Americans over the age of 50 who have osteoporosis while another 34 million people are at risk of developing the disease. In 2001, osteoporosis alone accounted for some $17 billion in direct annual healthcare expenditure. Several lines of evidence suggest that obesity and bone metabolism are interrelated. First, both osteoblasts (bone forming cells) and adipocytes (energy storing cells) are derived from a common mesenchymal stem cell and agents inhibiting adipogenesis stimulated osteoblast differentiation and vice versa, those inhibiting osteoblastogenesis increased adipogenesis. Second, decreased bone marrow osteoblastogenesis with aging is usually accompanied with increased marrow adipogenesis. Third, chronic use of steroid hormone, such as glucocorticoid, results in obesity accompanied by rapid bone loss. Fourth, both obesity and osteoporosis are associated with elevated oxidative stress and increased production of proinflammatory cytokines. At present, the mechanisms for the effects of obesity on bone metabolism are not well defined and will be the focus of this review.

D1 receptors in the nucleus accumbens-shell, but not the core, are involved in mediating ethanol-seeking behavior of alcohol-preferring (P) rats.

PubMed

Hauser, S R; Deehan, G A; Dhaher, R; Knight, C P; Wilden, J A; McBride, W J; Rodd, Z A

2015-06-04

Clinical and preclinical research suggest that activation of the mesolimbic dopamine (DA) system is involved in mediating the rewarding actions of drugs of abuse, as well as promoting drug-seeking behavior. Inhibition of DA D1 receptors in the nucleus accumbens (Acb) can reduce ethanol (EtOH)-seeking behavior of non-selective rats triggered by environmental context. However, to date, there has been no research on the effects of D1 receptor agents on EtOH- seeking behavior of high alcohol-preferring (P) rats following prolonged abstinence. The objective of the present study was to examine the effects of microinjecting the D1 antagonist SCH 23390 or the D1 agonist A-77636 into the Acb shell or Acb core on spontaneous recovery of EtOH-seeking behavior. After 10 weeks of concurrent access to EtOH and water, P rats underwent seven extinction sessions (EtOH and water withheld), followed by 2 weeks in their home cages without access to EtOH or operant sessions. In the 2nd week of the home cage phase, rats were bilaterally implanted with guide cannula aimed at the Acb shell or Acb core; rats were allowed 7d ays to recover before EtOH-seeking was assessed by the Pavlovian Spontaneous Recovery (PSR) model. Administration of SCH23390 (1μg/side) into the Acb shell inhibited responding on the EtOH lever, whereas administration of A-77636 (0.125μg/side) increased responding on the EtOH lever. Microinfusion of D1 receptor agents into the Acb core did not alter responding on the EtOH lever. Responses on the water lever were not altered by any of the treatments. The results suggest that activation of D1 receptors within the Acb shell, but not Acb core, are involved in mediating PSR of EtOH-seeking behavior of P rats. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

μCT-based, in vivo dynamic bone histomorphometry allows 3D evaluation of the early responses of bone resorption and formation to PTH and alendronate combination therapy.

PubMed

de Bakker, Chantal M J; Altman, Allison R; Tseng, Wei-Ju; Tribble, Mary Beth; Li, Connie; Chandra, Abhishek; Qin, Ling; Liu, X Sherry

2015-04-01

Current osteoporosis treatments improve bone mass by increasing net bone formation: anti-resorptive drugs such as bisphosphonates block osteoclast activity, while anabolic agents such as parathyroid hormone (PTH) increase bone remodeling, with a greater effect on formation. Although these drugs are widely used, their role in modulating formation and resorption is not fully understood, due in part to technical limitations in the ability to longitudinally assess bone remodeling. Importantly, it is not known whether or not PTH-induced bone formation is independent of resorption, resulting in controversy over the effectiveness of combination therapies that use both PTH and an anti-resorptive. In this study, we developed a μCT-based, in vivo dynamic bone histomorphometry technique for rat tibiae, and applied this method to longitudinally track changes in bone resorption and formation as a result of treatment with alendronate (ALN), PTH, or combination therapy of both PTH and ALN (PTH+ALN). Correlations between our μCT-based measures of bone formation and measures of bone formation based on calcein-labeled histology (r=0.72-0.83) confirm the accuracy of this method. Bone remodeling parameters measured through μCT-based in vivo dynamic bone histomorphometry indicate an increased rate of bone formation in rats treated with PTH and PTH+ALN, together with a decrease in bone resorption measures in rats treated with ALN and PTH+ALN. These results were further supported by traditional histology-based measurements, suggesting that PTH was able to induce bone formation while bone resorption was suppressed. Copyright © 2014 Elsevier Inc. All rights reserved.

Gallium, a promising candidate to disrupt the vicious cycle driving osteolytic metastases.

PubMed

Strazic-Geljic, Ivana; Guberovic, Iva; Didak, Blanka; Schmid-Antomarchi, Heidy; Schmid-Alliana, Annie; Boukhechba, Florian; Bouler, Jean-Michel; Scimeca, Jean-Claude; Verron, Elise

2016-09-15

Bone metastases of breast cancer typically lead to a severe osteolysis due to an excessive osteoclastic activity. On the other hand, the semi-metallic element gallium (Ga) displays an inhibitory action on osteoclasts, and therefore on bone resorption, as well as antitumour properties. Thus, we explored in vitro Ga effects on osteoclastogenesis in an aggressive bone metastatic environment based on the culture of pre-osteoclast RAW 264.7 cells with conditioned medium from metastatic breast tumour cells, i.e. the breast tumour cell line model MDA-MB-231 and its bone-seeking clone MDA-231BO. We first observed that Ga dose-dependently inhibited the tumour cells-induced osteoclastic differentiation of RAW 264.7 cells. To mimic a more aggressive environment where pro-tumourigenic factors are released from bone matrix due to osteoclastic resorption, metastatic breast tumour cells were stimulated with TGF-β, a mayor cytokine in bone metastasis vicious cycle. In these conditions, we observed that Ga still inhibited cancer cells-driven osteoclastogenesis. Lastly, we evidenced that Ga affected directly and strongly the proliferation/viability of both cancer cell lines, as well as the expression of major osteolytic factors in MDA-231BO cells. With the exception of two small scale clinical studies from 1980s, this is the first time that antitumour properties of Ga have been specifically studied in the context of bone metastases. Our data strongly suggest that, through its action against the vicious cycle involving bone cells and tumour cells, Ga represents a relevant and promising candidate for the local treatment of bone metastases in patients with breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Enhancer of Zeste Homolog 2 Inhibition Stimulates Bone Formation and Mitigates Bone Loss Caused by Ovariectomy in Skeletally Mature Mice*

PubMed Central

Dudakovic, Amel; Camilleri, Emily T.; Riester, Scott M.; Paradise, Christopher R.; Gluscevic, Martina; O'Toole, Thomas M.; Thaler, Roman; Evans, Jared M.; Yan, Huihuang; Subramaniam, Malayannan; Hawse, John R.; Stein, Gary S.; Montecino, Martin A.; McGee-Lawrence, Meghan E.; Westendorf, Jennifer J.; van Wijnen, Andre J.

2016-01-01

Perturbations in skeletal development and bone degeneration may result in reduced bone mass and quality, leading to greater fracture risk. Bone loss is mitigated by bone protective therapies, but there is a clinical need for new bone-anabolic agents. Previous work has demonstrated that Ezh2 (enhancer of zeste homolog 2), a histone 3 lysine 27 (H3K27) methyltransferase, suppressed differentiation of osteogenic progenitors. Here, we investigated whether inhibition of Ezh2 can be leveraged for bone stimulatory applications. Pharmacologic inhibition and siRNA knockdown of Ezh2 enhanced osteogenic commitment of MC3T3 preosteoblasts. Next generation RNA sequencing of mRNAs and real time quantitative PCR profiling established that Ezh2 inactivation promotes expression of bone-related gene regulators and extracellular matrix proteins. Mechanistically, enhanced gene expression was linked to decreased H3K27 trimethylation (H3K27me3) near transcriptional start sites in genome-wide sequencing of chromatin immunoprecipitations assays. Administration of an Ezh2 inhibitor modestly increases bone density parameters of adult mice. Furthermore, Ezh2 inhibition also alleviated bone loss in an estrogen-deficient mammalian model for osteoporosis. Ezh2 inhibition enhanced expression of Wnt10b and Pth1r and increased the BMP-dependent phosphorylation of Smad1/5. Thus, these data suggest that inhibition of Ezh2 promotes paracrine signaling in osteoblasts and has bone-anabolic and osteoprotective potential in adults. PMID:27758858

Weak bones in diabetes mellitus - an update on pharmaceutical treatment options.

PubMed

Lin, Daphne P L; Dass, Crispin R

2018-01-01

Diabetes mellitus is often associated with a number of complications such as nephropathy, neuropathy, retinopathy and foot ulcers. However, weak bone is a diabetic complication that is often overlooked. Although the exact mechanism for weak bones within diabetes mellitus is unclear, studies have shown that the mechanism does differ in both type I (T1DM) and type II diabetes (T2DM). This review, however, investigates the application of mesenchymal stem cells, recombinant human bone morphogenetic protein-2, teriparatide, insulin administration and the effectiveness of a peroxisome proliferator-activated receptor-ϒ modulator, netoglitazone in the context of diabetic weak bones. In T1DM, weak bones may be the result of defective osteoblast activity, the absence of insulin's anabolic effects on bone, the deregulation of the bone-pancreas negative feedback loop and advanced glycation end product (AGE) aggregation within the bone matrix as a result of hyperglycaemia. Interestingly, T2DM patients placed on insulin administration, thiazolidinediones, SGLT2 inhibitors and sulfonylureas have an associated increased fracture risk. T2DM patients are also observed to have high sclerostin levels that impair osteoblast gene transcription, AGE aggregation within bone, which compromises bone strength and a decrease in esRAGE concentration resulting in a negative association with vertebral fractures. Effective treatment options for weak bones in the context of diabetes are currently lacking. There is certainly scope for discovery and development of novel agents that could alleviate this complication in diabetes patients. © 2017 Royal Pharmaceutical Society.

[Subantral augmentation with porous titanium in experiment and clinic].

PubMed

Sirak, S V; Shchetinin, E V; Sletov, A A

2016-01-01

The article discusses the use of porous titanium for subantral augmentation. Experimental study was conducted on 12 yearling rams. Subantral augmentation using porous titanium was performed in 33 patients. In the control group consisting of 14 patients calcium phosphates and bone collagen based agents ("Bio-Оss" and "Collost") were used. In the main and control groups 46 and 32 implant were placed, respectively. Pilot histological and clinical studies proved that the granules of porous titanium are biocompatible with bone tissue, provide the optimal surface microrelief, thus creating good conditions for adhesion, expansion and migration of osteoforming cells, have negligible kinetics of resorption, are porous to ensure effective neovascularization of de novo formed bone tissue. Porous titanium is an effective alternative material for subantral bone augmentation for dental implantation and reconstructive operations on the maxillary sinus.

Radioisotope scanning in osseous sarcoidosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rohatgi, P.K.

1980-01-01

Technetium-99m (/sup 99m/Tc)-labeled pyrophosphate or diphosphonate compounds and gallium-67 citrate (/sup 67/Ga) are two radionuclide scanning agents that are in widespread use in clinical practice. Technetium-99m pyrophosphate is used extensively for bone scanning to detect metastatic bone disease, benign bone tumors, osteomyelitis, benign hypertrophic osteoarthropathy, and Paget's disease. Only two reports describe abnormal /sup 99m/Tc/ pyrophosphate bone scans in four patients with osseous sarcoidosis. Gallium-67 scans are used primarily to localize neoplastic or inflammatory lesions anywhere in the body. In recent years /sup 67/Ga scans have also been used to detect the presence of both pulmonary and extrapulmonary sarcoidosis, butmore » there are no reports describing abnormal uptake of gallium in patients with osseous sarcoidosis. This report describes experience with radioisotope scanning in two patients with osseous sarcoidosis.« less

Treatment of experimental staphylococcal osteomyelitis with rifampin and trimethoprim, alone and in combination.

PubMed Central

Norden, C W; Keleti, E

1980-01-01

Rifampin and trimethoprim were used alone and in combination in the treatment of chronic osteomyelitis due to Staphylococcus aureus in rabbits. Rifampicin levels in infected bone were well above the minimum inhibitory concentration of the infecting strain of S. aureus for at least 4 h after injection. In contrast, trimethoprim levels in diseased bone were below the minimum inhibitory concentration as early as 1 h after injection. Trimethoprim or rifampin, administered alone for 14 days, were ineffective in sterilizing infected rabbit bones. The combination of rifampin plus trimethoprim was significantly more effective (P less than 0.005) than either agents given alone for a comparable duration of time. Staphylococci isolated from the bones of rabbits treated with rifampin alone or rifampin plus trimethoprim were uniformly resistant to rifampin, but retained their susceptibility to trimethoprim. PMID:7396451

Novel Tissue Protective Agents for the Treatment of Acute Radiation-induced BMF

DTIC Science & Technology

2013-03-01

induced apoptosis in the following hematopoietic cell lines: HL-60, NB-4 cells, 32Dc13 and EML cell line. Experimental design and methods: HL-60, a...et al., 1999). EML Cell line (ATCC CRL-11691), a bone marrow cell line obtained by immortalizing bone marrow cells from male BDF1 mice with a...Membrane preparations were made from HL-60, NB-4, 32Dc13 and EML cells attempts were made to co-immunoprecipitate the CD131 molecule with EPOR in

N-cadherin Regulation of Bone Growth and Homeostasis is Osteolineage Stage-Specific

PubMed Central

Fontana, Francesca; Hickman-Brecks, Cynthia L.; Salazar, Valerie S.; Revollo, Leila; Abou-Ezzi, Grazia; Grimston, Susan K.; Jeong, Sung Yeop; Watkins, Marcus; Fortunato, Manuela; Alippe, Yael; Link, Daniel C.; Mbalaviele, Gabriel; Civitelli, Roberto

2017-01-01

N-cadherin inhibits osteogenic cell differentiation and canonical Wnt/β-catenin signaling in vitro. However, in vivo both conditional Cdh2 ablation and overexpression in osteoblasts lead to low bone mass. We tested the hypothesis that N-cadherin has different effects on osteolineage cells depending upon their differentiation stage. Embryonic conditional osteolineage Cdh2 deletion in mice results in defective growth, low bone mass and reduced osteoprogenitor number. These abnormalities are prevented by delaying Cdh2 ablation until 1 month of age, thus targeting only committed and mature osteoblasts, suggesting they are the consequence of N-cadherin deficiency in osteoprogenitors. Indeed, diaphyseal trabecularization actually increases when Cdh2 is ablated postnatally. The sclerostin-insensitive Lrp5A214V mutant, associated with high bone mass, does not rescue the growth defect, but it overrides the low bone mass of embryonically Cdh2 deleted mice, suggesting N-cadherin interacts with Wnt signaling to control bone mass. Finally, bone accrual and β-catenin accumulation after administration of an anti-Dkk1 antibody are enhanced in N-cadherin deficient mice. Thus, while lack of N-cadherin in embryonic and perinatal age is detrimental to bone growth and bone accrual, in adult mice loss of N-cadherin in osteolineage cells favors bone formation. Hence, N-cadherin inhibition may widen the therapeutic window of osteoanabolic agents. PMID:28240364

Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy.

PubMed

Madan, Babita; McDonald, Mitchell J; Foxa, Gabrielle E; Diegel, Cassandra R; Williams, Bart O; Virshup, David M

2018-01-01

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine (PORCN) that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159 (ETC-159) had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably, simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family, mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN inhibitors. Mitigation of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.

Epigenetics of bone diseases.

PubMed

Michou, Laetitia

2017-12-12

Histone deacetylation, DNA methylation, and micro-RNAs (miRNAs) are the three main epigenetic mechanisms that regulate gene expression. All the physiological processes involved in bone remodeling are tightly regulated by epigenetic factors. This review discusses the main epigenetic modifications seen in tumoral and non-tumoral bone diseases, with emphasis on miRNAs. The role for epigenetic modifications of gene expression in the most common bone diseases is illustrated by drawing on the latest publications in the field. In multifactorial bone diseases such as osteoporosis, many epigenetic biomarkers, either alone or in combination, have been associated with bone mineral density or suggested to predict osteoporotic fractures. In addition, treatments designed to modulate bone remodeling by selectively targeting the function of specific miRNAs are being evaluated. Advances in the understanding of epigenetic regulation shed new light on the pathophysiology of other non-tumoral bone diseases, including genetic conditions inherited on a Mendelian basis. Finally, in the area of primary and metastatic bone tumors, the last few years have witnessed considerable progress in elucidating the epigenetic regulation of oncogenesis and its local interactions with bone tissue. These new data may allow the development of epigenetic outcome predictors, which are in very high demand, and of innovative therapeutic agents acting via miRNA modulation. Copyright © 2017 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Si-Wu-tang extract stimulates bone formation through PI3K/Akt/NF-κB signaling pathways in osteoblasts.

PubMed

Wu, Chi-Ming; Chen, Po-Chun; Li, Te-Mao; Fong, Yi-Chin; Tang, Chih-Hsin

2013-10-24

Si-Wu-Tang (SWT), a Traditional Chinese Medicine (TCM) formula, is widely used for the treatment of gynopathies diseases such as menstrual discomfort, climacteric syndrome, dysmenorrhea, and other estrogen-related diseases. Recent studies have shown that SWT can treat primary dysmenorrhea, have anti-pruritic anti-inflammatory effects, and protect against radiation-induced bone marrow damage in an animal model. It has been reported that anti-inflammatory and anti-oxidant agents have the potential to treat osteoporosis by increasing bone formation and/or suppressing bone resorption. However, the effect of SWT on bone cell function has not yet been reported. Alkaline phosphatase (ALP), bone morphogenetic proteins (BMP)-2, and osteopontin (OPN) mRNA expression was analyzed by qPCR. The mechanism of action of SWT extract was investigated using western blotting. The in vivo anti-osteoporotic effect of SWT extract was assessed in ovariectomized mice. Here, we report that SWT increases ALP, BMP-2, and OPN expression as well as bone mineralization. In addition, we show that the PI3K, Akt, and NF-κB signaling pathways may be involved in the SWT-mediated increase in gene expression and bone mineralization. Notably, treatment of mice with SWT extract prevented bone loss induced by ovariectomy in vivo. SWT may be used to stimulate bone formation for the treatment of osteoporosis.

3D printing of biomaterials with mussel-inspired nanostructures for tumor therapy and tissue regeneration.

PubMed

Ma, Hongshi; Luo, Jian; Sun, Zhe; Xia, Lunguo; Shi, Mengchao; Liu, Mingyao; Chang, Jiang; Wu, Chengtie

2016-12-01

Primary bone cancer brings patients great sufferings. To deal with the bone defects resulted from cancer surgery, biomaterials with good bone-forming ability are necessary to repair bone defects. Meanwhile, in order to prevent possible tumor recurrence, it is essential that the remaining tumor cells around bone defects are completely killed. However, there are few biomaterials with the ability of both cancer therapy and bone regeneration until now. Here, we fabricated a 3D-printed bioceramic scaffold with a uniformly self-assembled Ca-P/polydopamine nanolayer surface. Taking advantage of biocompatibility, biodegradability and the excellent photothermal effect of polydopamine, the bifunctional scaffolds with mussel-inspired nanostructures could be used as a satisfactory and controllable photothermal agent, which effectively induced tumor cell death in vitro, and significantly inhibited tumor growth in mice. In addition, owing to the nanostructured surface, the prepared polydopamine-modified bioceramic scaffolds could support the attachment and proliferation of rabbit bone mesenchymal stem cells (rBMSCs), and significantly promoted the formation of new bone tissues in rabbit bone defects even under photothermal treatment. Therefore, the mussel-inspired nanostructures in 3D-printed bioceramic exhibited a remarkable capability for both cancer therapy and bone regeneration, offering a promising strategy to construct bifunctional biomaterials which could be widely used for therapy of tumor-induced tissue defects. Copyright © 2016 Elsevier Ltd. All rights reserved.

Role of Hypomethylating Agents in the Treatment of Bone Marrow Failure

DTIC Science & Technology

2016-10-01

functional studies, as proposed in Aim 2, to find that cells with cohesin gene mutations are sensitized to hypomethylating agents. We used CRISPR /Cas9...screen loss of function mutations in MDS for response to azacitidine. We used CRISPR /Cas9 genome engineering of primary human hematopoietic stem and...investigate whether sites of altered methylation occur at hydroxymethylated loci. We generated isogenic TF-1 cell line clones using CRISPR -Cas9

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ogawa, E.; Suzuki, S.; Tsuzuki, H.

Mice were subcutaneoulsy injected with Sr/sup 90/ or Sr/sup 85/, and effects of various drugs on their 3-day excretion and retention on the 4th day were investigated. Among chelating agents, NaCa citrate, NaMg citrate, NaSr citrate, Achromycin (or tetracycline), and aspartic MgK (alone or in combination with NH/sub 4/Cl) displayed Sr-eliminating effects. ATP increased only the excretion without diminishing the retention in bone. EDTA, DTPA, BADE, tricarballylate, Na citrate and NaPb citrate were not effective. Among salts, Mg salt, sulfite, and thiosulfate were effective in eliminating Sr. The last exerted a greater effect when given concurrently with Mg, Ca, ormore » Sr salt. Ca and Sr salt exerted no effect, and ammonium chloride promoted only urinary secretion, not extending to local or total excretion. Such salts as induce alkalosis conversely exerted inhibitory effects. Among hormones, glucocorticoids had Sreliminating effects. TSH was effective, and antithyroidal drugs conversely seemed to have excretion-diminishing effects. Among vitamins, cocarboxylase increased Sr excretion, but did not decrease the retention in bone. Also metabolic inhibitors were ineffective, and NaF conversely increased bone deposition of Sr. Among diuretics, SHdrugs, and weak chelating agents, there were no effective drugs. (JAIF)« less

Bone wax in Neurosurgery: A Review.

PubMed

Das, Joe M

2018-05-09

In this occasion of 125 years after the so-called "initial" use of bone wax (BW) by Sir Victor Horsley, a review of this age-old hemostatic agent deemed appropriate. The first use of BW for hemostasis is dated back to the 18 th century when modeling or candle wax was used for hemostasis. Though the pioneers in the usage of BW in craniofacial surgeries were Belloq, Professor Khristian Khristianovich Salomon and François Magendie, its first successful use in neurosurgery was demonstrated by Henri Ferdinand Dolbeau in 1864, following the extirpation of a frontal osteoma. This was further popularized by Sir Victor Alexander Haden Horsley, the father of British neurosurgery, who is often incorrectly mentioned as the inventor of BW. Originally derived from bees' wax, the currently available commercial preparation contains paraffin wax and Isopropyl palmitate in addition. The main action being mechanical tamponade, BW has found several other uses in neurosurgery, other than being a hemostatic agent. Though it is cost-effective, the use of BW is associated with several complications also, including ineffective bone healing and infection. So several other alternatives are coming up, but none has yet been able to fully replace "Horsley's wax" till date. Copyright © 2018 Elsevier Inc. All rights reserved.

Cross-talk of MicroRNA and hydrogen sulfide: A novel therapeutic approach for bone diseases

PubMed Central

Zhai, Yuankun; Tyagi, Suresh C.; Tyagi, Neetu

2017-01-01

Bone homeostasis requires a balance between the bone formation of osteoblasts and bone resorption of osteoclasts to maintain ideal bone mass and bone quality. An imbalance in bone remodeling processes results in bone metabolic disorders such as osteoporosis. Hydrogen sulfide (H2S), a gasotransmitter, has attracted the focus of many researchers due to its multiple physiological functions. It has been implicated in anti-inflammatory, vasodilatory, angiogenic, cytoprotective, anti-oxidative and anti-apoptotic mechanisms. H2S has also been shown to exert osteoprotective activity through its anti-inflammatory and anti-oxidative effects. However, the underlying molecular mechanisms by which H2S mitigates bone diseases are not completely understood. Experimental evidence suggests that H2S may regulate signaling pathways by directly influencing a gene in the cascade or interacting with some other gasotransmitter (carbon monoxide or nitric oxide) or both. MicroRNAs (miRNAs) are short non-coding RNAs which regulate gene expression by targeting, binding and suppressing mRNAs; thus controlling cell fate. Certainly, bone remodeling is also regulated by miRNAs expression and has been reported in many studies. MicroRNAs also regulate H2S biosynthesis. The inter-regulation of microRNAs and H2S opens a new possibility for exploring the H2S-microRNA crosstalk in bone diseases. However, the relationship between miRNAs, bone development, and H2S is still not well explained. This review focuses on miRNAs and their roles in regulating bone remodeling and possible mechanisms behind H2S mediated bone loss inhibition, H2S-miRNAs crosstalk in relation to the pathophysiology of bone remodeling, and future perspectives for miRNA-H2S as a therapeutic agent for bone diseases. PMID:28618652

Turning Bone Morphogenetic Protein 2 (BMP2) On and Off in Mesenchymal Cells†

PubMed Central

Rogers, Melissa B.; Shah, Tapan A.; Shaikh, Nadia N.

2016-01-01

The concentration, location, and timing of bone morphogenetic protein 2 (BMP2, HGNC:1069, GeneID: 650) gene expression must be precisely regulated. Abnormal BMP2 levels cause congenital anomalies and diseases involving the mesenchymal cells that differentiate into muscle, fat, cartilage, and bone. The molecules and conditions that influence BMP2 synthesis are diverse. Understandably, complex mechanisms control Bmp2 gene expression. This review includes a compilation of agents and conditions that can induce Bmp2. The currently known trans-regulatory factors and cis-regulatory elements that modulate Bmp2 expression are summarized and discussed. This article is protected by copyright. All rights reserved PMID:25776852

Structural Characterization of Sm(III)(EDTMP).

PubMed

Yang, Y; Pushie, M J; Cooper, D M L; Doschak, M R

2015-11-02

Samarium-153 ethylenediamine-N,N,N',N'-tetrakis(methylenephosphonic acid) ((153)Sm-EDTMP, or samarium lexidronam), also known by its registered trademark name Quadramet, is an approved therapeutic radiopharmaceutical used in the palliative treatment of painful bone metastases. Typically, patients with prostate, breast, or lung cancer are most likely to go on to require bone pain palliation treatment due to bone metastases. Sm(EDTMP) is a bone-seeking drug which accumulates on rapidly growing bone, thereby delivering a highly region-specific dose of radiation, chiefly through β particle emission. Even with its widespread clinical use, the structure of Sm(EDTMP) has not yet been characterized at atomic resolution, despite attempts to crystallize the complex. Herein, we prepared a 1:1 complex of the cold (stable isotope) of Sm(EDTMP) under alkaline conditions and then isolated and characterized the complex using conventional spectroscopic techniques, as well as with extended X-ray absorption fine structure (EXAFS) spectroscopy and density functional structure calculations, using natural abundance Sm. We present the atomic resolution structure of [Sm(III)(EDTMP)-8H](5-) for the first time, supported by the EXAFS data and complementary spectroscopic techniques, which demonstrate that the samarium coordination environment in solution is in agreement with the structure that has long been conjectured.

Occurrence of metastases in beagles with skeletal malignancies induced by internal irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lloyd, R.D.; Angus, W.; Taylor, G.N.

1994-03-01

Metastases from malignant bone tumors often are responsible for the fatal effects of these cancers. Characteristics of primary skeletal malignancies in beagles injected with bone-seeking radionuclides were studied by Thurman (1971) and summarized by Thurman et al. (1971). There were 212 tumors in 186 of these dogs for which we subsequently received information on bone tumor metastases. Evaluation of bone and soft tissue slides from these animals allowed us to compare parameters reported previously with the occurrence of grossly apparent bone tumor metastases. Data included growth-rate of the primary tumor, volume of the primary tumor at death, sex of themore » animal, growth period of the primary tumor, degree of calcification of the primary tumor, skeletal location of the primary tumor, cumulative radiation dose to the skeleton, dose equivalent to the skeleton, and year of death. For most of the comparisons, no significant differences could be established between dogs with and without metastases. However, tumor volume at death appeared to be correlated with probability of metastasis (p < 0.05), with the larger tumors being associated with higher rates of metastasis. Comparisons of dogs with and without metastases as a function of tumor growth-rate did not, for the most part, yield significantly different results between groups. 10 refs., 11 tabs.« less

Optimal management of cancer treatment-induced bone loss: considerations for elderly patients.

PubMed

Tipples, Karen; Robinson, Anne

2011-11-01

Hormone manipulation, commonly used in breast and prostate cancer, can result in significant bone loss. In multiple myeloma (MM), corticosteroids play an important role in therapy but increase the risk of fracture over that expected for any given bone mineral density. These adverse effects on the skeletal system are particularly relevant in the elderly population, in whom osteoporosis can significantly affect not only quality of life but also survival. The associated health and social care costs are becoming increasingly important. Screening with dual energy x-ray absorptiometry (DXA) scans and lifestyle advice on smoking, alcohol and dietary intake are essential parts of the management of patients with cancer treatment-induced bone loss. The value of exercise also cannot be underestimated. A careful drug review should be carried out to eliminate agents that may potentially exacerbate bone toxicity. Therapies to address bone toxicities include bisphosphonates, which have been shown to play an increasingly important role in preventing declines in bone health. The issues of compliance when oral agents are used should not be underestimated. Renal toxicity and osteonecrosis of the jaw are relevant toxicities, especially in the elderly. Cardiac toxicity has not been proven, but there is evidence to suggest that the suppression of bone turnover seen with some, although not all, bisphosphonates is not reversed following cessation of treatment. The implications of this finding need to be borne in mind when treating elderly patients. The possibility of atypical fractures in patients taking bisphosphonates also needs to be given consideration, although this remains a rare complication. Recently, the receptor activator of nuclear factor-κB ligand (RANKL) ligand antibody denosumab has been shown to be of value in fracture prevention, and its subcutaneous route of administration offers a potential advantage. Oncologists should also remember that tamoxifen, which has little effect on bone integrity, remains a useful drug for breast cancer patients. A multidisciplinary approach involving the hospital specialist, general practitioner, nurse and, most importantly, the patient, family and carers should ensure that the maximal benefit is received from the anti-cancer treatment, with minimal cost to the patient. As cancer cure rates increase, late toxicity is increasingly relevant and challenging. The skeletal system warrants more research to maximize the care of all our patients, especially the elderly, who may be most at risk.

Protective Effects of Selected Botanical Agents on Bone

PubMed Central

Jolly, James Jam; Alias, Ekram; Chua, Kien Hui; Soelaiman, Ima Nirwana

2018-01-01

Osteoporosis is a serious health problem affecting more than 200 million elderly people worldwide. The early symptoms of this disease are hardly detectable. It causes progressive bone loss, which ultimately renders the patients susceptible to fractures. Osteoporosis must be prevented because the associated fragility fractures result in high morbidity, mortality, and healthcare costs. Many plants used in herbal medicine contain bioactive compounds possessing skeletal protective effects. This paper explores the anti-osteoporotic properties of selected herbal plants, including their actions on osteoblasts (bone forming cells), osteoclasts (bone resorbing cells), and bone remodelling. Some of the herbal plant families included in this review are Berberidaceae, Fabaceae, Arecaceae, Labiatae, Simaroubaceaea, and Myrsinaceae. Their active constituents, mechanisms of action, and pharmaceutical applications were discussed. The literature shows that very few herbal plants have undergone human clinical trials to evaluate their pharmacological effects on bone to date. Therefore, more intensive research should be performed on these plants to validate their anti-osteoporotic properties so that they can complement the currently available conventional drugs in the battle against osteoporosis. PMID:29751644

A review of fibrin and fibrin composites for bone tissue engineering

PubMed Central

Noori, Alireza; Ashrafi, Seyed Jamal; Vaez-Ghaemi, Roza; Hatamian-Zaremi, Ashraf; Webster, Thomas J

2017-01-01

Tissue engineering has emerged as a new treatment approach for bone repair and regeneration seeking to address limitations associated with current therapies, such as autologous bone grafting. While many bone tissue engineering approaches have traditionally focused on synthetic materials (such as polymers or hydrogels), there has been a lot of excitement surrounding the use of natural materials due to their biologically inspired properties. Fibrin is a natural scaffold formed following tissue injury that initiates hemostasis and provides the initial matrix useful for cell adhesion, migration, proliferation, and differentiation. Fibrin has captured the interest of bone tissue engineers due to its excellent biocompatibility, controllable biodegradability, and ability to deliver cells and biomolecules. Fibrin is particularly appealing because its precursors, fibrinogen, and thrombin, which can be derived from the patient’s own blood, enable the fabrication of completely autologous scaffolds. In this article, we highlight the unique properties of fibrin as a scaffolding material to treat bone defects. Moreover, we emphasize its role in bone tissue engineering nanocomposites where approaches further emulate the natural nanostructured features of bone when using fibrin and other nanomaterials. We also review the preparation methods of fibrin glue and then discuss a wide range of fibrin applications in bone tissue engineering. These include the delivery of cells and/or biomolecules to a defect site, distributing cells, and/or growth factors throughout other pre-formed scaffolds and enhancing the physical as well as biological properties of other biomaterials. Thoughts on the future direction of fibrin research for bone tissue engineering are also presented. In the future, the development of fibrin precursors as recombinant proteins will solve problems associated with using multiple or single-donor fibrin glue, and the combination of nanomaterials that allow for the incorporation of biomolecules with fibrin will significantly improve the efficacy of fibrin for numerous bone tissue engineering applications. PMID:28761338

A review of fibrin and fibrin composites for bone tissue engineering.

PubMed

Noori, Alireza; Ashrafi, Seyed Jamal; Vaez-Ghaemi, Roza; Hatamian-Zaremi, Ashraf; Webster, Thomas J

2017-01-01

Tissue engineering has emerged as a new treatment approach for bone repair and regeneration seeking to address limitations associated with current therapies, such as autologous bone grafting. While many bone tissue engineering approaches have traditionally focused on synthetic materials (such as polymers or hydrogels), there has been a lot of excitement surrounding the use of natural materials due to their biologically inspired properties. Fibrin is a natural scaffold formed following tissue injury that initiates hemostasis and provides the initial matrix useful for cell adhesion, migration, proliferation, and differentiation. Fibrin has captured the interest of bone tissue engineers due to its excellent biocompatibility, controllable biodegradability, and ability to deliver cells and biomolecules. Fibrin is particularly appealing because its precursors, fibrinogen, and thrombin, which can be derived from the patient's own blood, enable the fabrication of completely autologous scaffolds. In this article, we highlight the unique properties of fibrin as a scaffolding material to treat bone defects. Moreover, we emphasize its role in bone tissue engineering nanocomposites where approaches further emulate the natural nanostructured features of bone when using fibrin and other nanomaterials. We also review the preparation methods of fibrin glue and then discuss a wide range of fibrin applications in bone tissue engineering. These include the delivery of cells and/or biomolecules to a defect site, distributing cells, and/or growth factors throughout other pre-formed scaffolds and enhancing the physical as well as biological properties of other biomaterials. Thoughts on the future direction of fibrin research for bone tissue engineering are also presented. In the future, the development of fibrin precursors as recombinant proteins will solve problems associated with using multiple or single-donor fibrin glue, and the combination of nanomaterials that allow for the incorporation of biomolecules with fibrin will significantly improve the efficacy of fibrin for numerous bone tissue engineering applications.

Cancer Therapy Evaluation Program | Office of Cancer Genomics

Cancer.gov

The Cancer Therapy Evaluation Program (CTEP) seeks to improve the lives of cancer patients by finding better treatments, control mechanisms, and cures for cancer. CTEP funds a national program of cancer research, sponsoring clinical trials to evaluate new anti-cancer agents.

Silica-Coated Nanodiamonds for Imaging and Delivery of Therapeutic Agents | NCI Technology Transfer Center | TTC

Cancer.gov

The NCI Radiation Oncology Branch and the NHLBI Laboratory of Single Molecule Biophysics seek parties to co-develop fluorescent nanodiamonds for use as in vivo and in vitro optical tracking probes toward commercialization.

Androgens and osteoporosis.

PubMed

Ebeling, Peter R

2010-06-01

The review is timely given recent advances regarding mechanisms of androgen action on bone cells and in humans. Osteoporosis in men is an important public health problem. An improved understanding of the role of androgens in the pathophysiology of bone loss will lead to new treatments. Androgen receptors are present in most bone cells. Testosterone acts on bone both directly via the androgen receptor and indirectly, following aromatization, via the oestrogen receptor. During skeletal modelling, ERalpha is critical for longitudinal bone growth. For periosteal growth and bone expansion, androgen receptor activation has a positive effect, whereas ERalpha activation is inhibitory. During skeletal remodelling, both receptor pathways generate similar and additive effects on bone.Androgen deficiency is a common secondary cause of osteoporosis in men and should be treated with testosterone, particularly in symptomatic men. However, lack of efficacy data for testosterone in osteoporosis means it is less useful as a first-line treatment in men with age-related declines in testosterone and osteoporosis, when other agents such as bisphosphonates and parathyroid hormone are effective. Randomized, placebo-controlled trials of testosterone therapy in men with age-related declines in testosterone and osteoporosis are needed, and should carefully evaluate potential risks, as well as its efficacy in reducing fractures and other health benefits.

Interconnected porous hydroxyapatite ceramics for bone tissue engineering

PubMed Central

Yoshikawa, Hideki; Tamai, Noriyuki; Murase, Tsuyoshi; Myoui, Akira

2008-01-01

Several porous calcium hydroxyapatite (HA) ceramics have been used clinically as bone substitutes, but most of them possessed few interpore connections, resulting in pathological fracture probably due to poor bone formation within the substitute. We recently developed a fully interconnected porous HA ceramic (IP-CHA) by adopting the ‘foam-gel’ technique. The IP-CHA had a three-dimensional structure with spherical pores of uniform size (average 150 μm, porosity 75%), which were interconnected by window-like holes (average diameter 40 μm), and also demonstrated adequate compression strength (10–12 MPa). In animal experiments, the IP-CHA showed superior osteoconduction, with the majority of pores filled with newly formed bone. The interconnected porous structure facilitates bone tissue engineering by allowing the introduction of mesenchymal cells, osteotropic agents such as bone morphogenetic protein or vasculature into the pores. Clinically, we have applied the IP-CHA to treat various bony defects in orthopaedic surgery, and radiographic examinations demonstrated that grafted IP-CHA gained radiopacity more quickly than the synthetic HA in clinical use previously. We review the accumulated data on bone tissue engineering using the novel scaffold and on clinical application in the orthopaedic field. PMID:19106069

Nanoceramics on osteoblast proliferation and differentiation in bone tissue engineering.

PubMed

Sethu, Sai Nievethitha; Namashivayam, Subhapradha; Devendran, Saravanan; Nagarajan, Selvamurugan; Tsai, Wei-Bor; Narashiman, Srinivasan; Ramachandran, Murugesan; Ambigapathi, Moorthi

2017-05-01

Bone, a highly dynamic connective tissue, consist of a bioorganic phase comprising osteogenic cells and proteins which lies over an inorganic phase predominantly made of CaPO 4 (biological apatite). Injury to bone can be due to mechanical, metabolic or inflammatory agents also owing pathological conditions like fractures, osteomyelitis, osteolysis or cysts may arise in enameloid, chondroid, cementum, or chondroid bone which forms the intermediate tissues of the body. Bone tissue engineering (BTE) applies bioactive scaffolds, host cells and osteogenic signals for restoring damaged or diseased tissues. Various bioceramics used in BTE can be bioactive (like glass ceramics and hydroxyapatite bioactive glass), bioresorbable (like tricalcium phosphates) or bioinert (like zirconia and alumina). Limiting the size of these materials to nano-scale has resulted in a higher surface area to volume ratio thereby improving multi-functionality, solubility, surface catalytic activity, high heat and electrical conductivity. Nanoceramics have been found to induce osteoconduction, osteointegration, osteogenesis and osteoinduction. The present review aims at summarizing the interactions of nanoceramics and osteoblast/stem cells for promoting the proliferation and differentiation of the osteoblast cells by nanoceramics as superior bone substitutes in bone tissue engineering applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Reversible posterior leucoencephalopathy syndrome associated with bone marrow transplantation.

PubMed

Teive, H A; Brandi, I V; Camargo, C H; Bittencourt, M A; Bonfim, C M; Friedrich, M L; de Medeiros, C R; Werneck, L C; Pasquini, R

2001-09-01

Reversible posterior leucoencephalopathy syndrome (RPLS) has previously been described in patients who have renal insufficiency, eclampsia, hypertensive encephalopathy and patients receiving immunosuppressive therapy. The mechanism by which immunosuppressive agents can cause this syndrome is not clear, but it is probably related with cytotoxic effects of these agents on the vascular endothelium. We report eight patients who received cyclosporine A (CSA) after allogeneic bone marrow transplantation or as treatment for severe aplastic anemia (SSA) who developed posterior leucoencephalopathy. The most common signs and symptoms were seizures and headache. Neurological dysfunction occurred preceded by or concomitant with high blood pressure and some degree of acute renal failure in six patients. Computerized tomography studies showed low-density white matter lesions involving the posterior areas of cerebral hemispheres. Symptoms and neuroimaging abnormalities were reversible and improvement occurred in all patients when given lower doses of CSA or when the drug was withdrawn. RPLS may be considered an expression of CSA neurotoxicity.

Encapsulated boron as an osteoinductive agent for bone scaffolds.

PubMed

Gümüşderelioğlu, Menemşe; Tunçay, Ekin Ö; Kaynak, Gökçe; Demirtaş, Tolga T; Aydın, Seda Tığlı; Hakkı, Sema S

2015-01-01

The aim of this study was to develop boron (B)-releasing polymeric scaffold to promote regeneration of bone tissue. Boric acid-doped chitosan nanoparticles with a diameter of approx. 175 nm were produced by tripolyphosphate (TPP)-initiated ionic gelation process. The nanoparticles strongly attached via electrostatic interactions into chitosan scaffolds produced by freeze-drying with approx. 100 μm pore diameter. According to the ICP-OES results, following first 5h initial burst release, fast release of B from scaffolds was observed for 24h incubation period in conditioned medium. Then, slow release of B was performed over 120 h. The results of the cell culture studies proved that the encapsulated boron within the scaffolds can be used as an osteoinductive agent by showing its positive effects on the proliferation and differentiation of MC3T3-E1 preosteoblastic cells. Copyright © 2015 Elsevier GmbH. All rights reserved.

Bone Tumor Environment as a Potential Therapeutic Target in Ewing Sarcoma

PubMed Central

Redini, Françoise; Heymann, Dominique

2015-01-01

Ewing sarcoma is the second most common pediatric bone tumor, with three cases per million worldwide. In clinical terms, Ewing sarcoma is an aggressive, rapidly fatal malignancy that mainly develops not only in osseous sites (85%) but also in extra-skeletal soft tissue. It spreads naturally to the lungs, bones, and bone marrow with poor prognosis in the two latter cases. Bone lesions from primary or secondary (metastases) tumors are characterized by extensive bone remodeling, more often due to osteolysis. Osteoclast activation and subsequent bone resorption are responsible for the clinical features of bone tumors, including pain, vertebral collapse, and spinal cord compression. Based on the “vicious cycle” concept of tumor cells and bone resorbing cells, drugs, which target osteoclasts, may be promising agents as adjuvant setting for treating bone tumors, including Ewing sarcoma. There is also increasing evidence that cellular and molecular protagonists present in the bone microenvironment play a part in establishing a favorable “niche” for tumor initiation and progression. The purpose of this review is to discuss the potential therapeutic value of drugs targeting the bone tumor microenvironment in Ewing sarcoma. The first part of the review will focus on targeting the bone resorbing function of osteoclasts by means of bisphosphonates or drugs blocking the pro-resorbing cytokine receptor activator of NF-kappa B ligand. Second, the role of this peculiar hypoxic microenvironment will be discussed in the context of resistance to chemotherapy, escape from the immune system, or neo-angiogenesis. Therapeutic interventions based on these specificities could be then proposed in the context of Ewing sarcoma. PMID:26779435

Bone Tumor Environment as a Potential Therapeutic Target in Ewing Sarcoma.

PubMed

Redini, Françoise; Heymann, Dominique

2015-01-01

Ewing sarcoma is the second most common pediatric bone tumor, with three cases per million worldwide. In clinical terms, Ewing sarcoma is an aggressive, rapidly fatal malignancy that mainly develops not only in osseous sites (85%) but also in extra-skeletal soft tissue. It spreads naturally to the lungs, bones, and bone marrow with poor prognosis in the two latter cases. Bone lesions from primary or secondary (metastases) tumors are characterized by extensive bone remodeling, more often due to osteolysis. Osteoclast activation and subsequent bone resorption are responsible for the clinical features of bone tumors, including pain, vertebral collapse, and spinal cord compression. Based on the "vicious cycle" concept of tumor cells and bone resorbing cells, drugs, which target osteoclasts, may be promising agents as adjuvant setting for treating bone tumors, including Ewing sarcoma. There is also increasing evidence that cellular and molecular protagonists present in the bone microenvironment play a part in establishing a favorable "niche" for tumor initiation and progression. The purpose of this review is to discuss the potential therapeutic value of drugs targeting the bone tumor microenvironment in Ewing sarcoma. The first part of the review will focus on targeting the bone resorbing function of osteoclasts by means of bisphosphonates or drugs blocking the pro-resorbing cytokine receptor activator of NF-kappa B ligand. Second, the role of this peculiar hypoxic microenvironment will be discussed in the context of resistance to chemotherapy, escape from the immune system, or neo-angiogenesis. Therapeutic interventions based on these specificities could be then proposed in the context of Ewing sarcoma.

Characterization of synthetic foam structures used to manufacture artificial vertebral trabecular bone.

PubMed

Fürst, David; Senck, Sascha; Hollensteiner, Marianne; Esterer, Benjamin; Augat, Peter; Eckstein, Felix; Schrempf, Andreas

2017-07-01

Artificial materials reflecting the mechanical properties of human bone are essential for valid and reliable implant testing and design. They also are of great benefit for realistic simulation of surgical procedures. The objective of this study was therefore to characterize two groups of self-developed synthetic foam structures by static compressive testing and by microcomputed tomography. Two mineral fillers and varying amounts of a blowing agent were used to create different expansion behavior of the synthetic open-cell foams. The resulting compressive and morphometric properties thus differed within and also slightly between both groups. Apart from the structural anisotropy, the compressive and morphometric properties of the synthetic foam materials were shown to mirror the respective characteristics of human vertebral trabecular bone in good approximation. In conclusion, the artificial materials created can be used to manufacture valid synthetic bones for surgical training. Further, they provide novel possibilities for studying the relationship between trabecular bone microstructure and biomechanical properties. Copyright © 2017 Elsevier B.V. All rights reserved.

Bone metabolism in renal transplant patients treated with cyclosporine or sirolimus.

PubMed

Campistol, Josep M; Holt, David W; Epstein, Solomon; Gioud-Paquet, Martine; Rutault, Karine; Burke, James T

2005-09-01

Sirolimus is a new immunosuppressive agent used as treatment to prevent acute renal allograft rejection. One of the complications of renal transplantation and subsequent long-term immunosuppression is bone loss associated with osteoporosis and consequent fracture. Two open-label, randomized, phase 2 studies comparing sirolimus versus cyclosporine (CsA) included indices of bone metabolism as secondary end-points. Markers of bone turnover, serum osteocalcin and urinary N-telopeptides, were measured over a 1-year period in 115 patients receiving either CsA or sirolimus as a primary therapy in combination with azathioprine and glucocorticoids (study A) or mycophenolate mofetil (MMF) and glucocorticoids (study B). Urinary excretion of N-telopeptides and the concentrations of serum osteocalcin were consistently higher in the CsA-treated patients and significantly different at week 24 for N-telopeptides and at weeks 12, 24, and 52 for osteocalcin. In conclusion, future trials are warranted to test whether a sirolimus-based regimen conserves bone mineral density compared with a CsA-based regimen.

Bone protein extraction without demineralization using principles from hydroxyapatite chromatography.

PubMed

Cleland, Timothy P; Vashishth, Deepak

2015-03-01

Historically, extraction of bone proteins has relied on the use of demineralization to better retrieve proteins from the extracellular matrix; however, demineralization can be a slow process that restricts subsequent analysis of the samples. Here, we developed a novel protein extraction method that does not use demineralization but instead uses a methodology from hydroxyapatite chromatography where high concentrations of ammonium phosphate and ammonium bicarbonate are used to extract bone proteins. We report that this method has a higher yield than those with previously published small-scale extant bone extractions, with and without demineralization. Furthermore, after digestion with trypsin and subsequent high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis, we were able to detect several extracellular matrix and vascular proteins in addition to collagen I and osteocalcin. Our new method has the potential to isolate proteins within a short period (4h) and provide information about bone proteins that may be lost during demineralization or with the use of denaturing agents. Copyright © 2014 Elsevier Inc. All rights reserved.

Nash Equilibrium of Social-Learning Agents in a Restless Multiarmed Bandit Game.

PubMed

Nakayama, Kazuaki; Hisakado, Masato; Mori, Shintaro

2017-05-16

We study a simple model for social-learning agents in a restless multiarmed bandit (rMAB). The bandit has one good arm that changes to a bad one with a certain probability. Each agent stochastically selects one of the two methods, random search (individual learning) or copying information from other agents (social learning), using which he/she seeks the good arm. Fitness of an agent is the probability to know the good arm in the steady state of the agent system. In this model, we explicitly construct the unique Nash equilibrium state and show that the corresponding strategy for each agent is an evolutionarily stable strategy (ESS) in the sense of Thomas. It is shown that the fitness of an agent with ESS is superior to that of an asocial learner when the success probability of social learning is greater than a threshold determined from the probability of success of individual learning, the probability of change of state of the rMAB, and the number of agents. The ESS Nash equilibrium is a solution to Rogers' paradox.

Optimising antiresorptive therapies in postmenopausal women: why do we need to give due consideration to the degree of suppression?

PubMed

Karsdal, Morten A; Qvist, Per; Christiansen, Claus; Tankó, László B

2006-01-01

Accelerated bone turnover with bone resorption exceeding bone formation is a major mechanism underlying postmenopausal bone loss and hence the development of osteoporosis. Accordingly, inhibition of bone resorption is a rational approach for the prevention of osteoporosis. In this context, the most logical option, hormone replacement therapy, reverses the rate of bone turnover to premenopausal levels, whereas the magnitude of inhibition by amino-bisphosphonates and the recently introduced anti-receptor activator of NFkappaB ligand (RANKL) antibody often exceeds this. As bone turnover has crucial implications for the continuous renewal of bone tissue, the over-suppression of bone turnover has potential consequences for bone quality and strength. Long-term treatment with potent bisphosphonates has recently been associated with osteonecrosis of the jaw and dose-dependent increases in micro-crack accumulation in animals. Although these observations are the subject of ongoing discussions, it is timely to discuss whether the over-suppression of bone turnover below premenopausal levels is really our ultimate goal when defining the success criteria for antiresorptive agents. In this review, the implications of high and excessively low bone turnover of endogenous origin for bone quality, fracture risk and integrity of the jaw are discussed. In addition, animal and clinical research revealing initial findings regarding the potential adverse effects of drug-induced suppression of bone remodeling are summarised. The inhibition of bone resorption, which is either transient between doses (e.g. with calcitonin) or does not exceed premenopausal levels (with hormone replacement therapy or selective estrogen receptor modulators), is preferable because it not only provides similar antifracture efficacy but can also assist in the maintenance of the dynamic repair of micro-cracks/micro-fractures.

Differential effects of PPAR-{gamma} activation versus chemical or genetic reduction of DPP-4 activity on bone quality in mice.

PubMed

Kyle, Kimberly A; Willett, Thomas L; Baggio, Laurie L; Drucker, Daniel J; Grynpas, Marc D

2011-02-01

Patients with type 2 diabetes mellitus have an increased risk of fracture that can be further exacerbated by thiazolidinediones. A new class of antidiabetic agents control glucose through reduction of dipeptidyl peptidase-4 (DPP-4) activity; however the importance of DPP-4 for the control of bone quality has not been extensively characterized. We compared the effects of the thiazolidinedione pioglitazone and the DPP-4 inhibitor sitagliptin on bone quality in high-fat diet (HFD)-fed wild-type mice. In complementary studies, we examined bone quality in Dpp4(+/+) vs. Dpp4(-/-) mice. Pioglitazone produced yellow bones with greater bone marrow adiposity and significantly reduced vertebral bone mechanics in male, female, and ovariectomized (OVX) HFD fed female mice. Pioglitazone negatively affected vertebral volumetric bone mineral density, trabecular architecture, and mineral apposition rate in male mice. Sitagliptin treatment of HFD-fed wild-type mice significantly improved vertebral volumetric bone mineral density and trabecular architecture in female mice, but these improvements were lost in females after OVX. Genetic inactivation of Dpp4 did not produce a major bone phenotype in male and female Dpp4(-/-) mice; however, OVX Dpp4(-/-) mice exhibited significantly reduced femoral size and mechanics. These findings delineate the skeletal consequences of pharmacological and genetic reduction of DPP-4 activity and reveal significant differences in the effects of pioglitazone vs. sitagliptin vs. genetic Dpp4 inactivation on bone mechanics in mice.

A national portfolio of bone oncology trials—The Canadian experience in 2012

PubMed Central

Kuchuk, I.; Simos, D.; Addison, C.L.; Clemons, M.

2012-01-01

Background The impact of both cancer and its treatment on bone is an essential component of oncological practice. Bone oncology not only affects patients with both early stage and metastatic disease but also covers the entire spectrum of tumour types. We therefore decided to review and summarise bone oncology-related trials that are currently being conducted in Canada. Method We assessed ongoing and recently completed trials in Canada. We used available North American and Canadian cancer trial websites and also contacted known investigators in this field for their input. Results Twenty seven clinical trials were identified. Seven pertained to local treatment of bone metastasis from any solid tumour type. Seven were systemic treatment trials, five focused on bone biology and predictive factors, three evaluated safety of bone-targeted agents, three were adjuvant trials and two trials investigated impact of cancer therapy on bone health. The majority of trials were related to systemic treatment and bone biology in breast cancer. Most were small, single centre, grant-funded studies. Not surprisingly the larger safety and adjuvant studies were pharmaceutical company driven. Discussion Despite the widespread interest in bone-targeted therapies our survey would suggest that most studies are single centre and breast cancer focused. If major advances in bone oncology are to be made then collaborative strategies are needed to not only increase current sample sizes but to also expand these studies into non-breast cancer populations. PMID:26909263

A simple and effective approach to prepare injectable macroporous calcium phosphate cement for bone repair: Syringe-foaming using a viscous hydrophilic polymeric solution.

PubMed

Zhang, Jingtao; Liu, Weizhen; Gauthier, Olivier; Sourice, Sophie; Pilet, Paul; Rethore, Gildas; Khairoun, Khalid; Bouler, Jean-Michel; Tancret, Franck; Weiss, Pierre

2016-02-01

In this study, we propose a simple and effective strategy to prepare injectable macroporous calcium phosphate cements (CPCs) by syringe-foaming via hydrophilic viscous polymeric solution, such as using silanized-hydroxypropyl methylcellulose (Si-HPMC) as a foaming agent. The Si-HPMC foamed CPCs demonstrate excellent handling properties such as injectability and cohesion. After hardening the foamed CPCs possess hierarchical macropores and their mechanical properties (Young's modulus and compressive strength) are comparable to those of cancellous bone. Moreover, a preliminary in vivo study in the distal femoral sites of rabbits was conducted to evaluate the biofunctionality of this injectable macroporous CPC. The evidence of newly formed bone in the central zone of implantation site indicates the feasibility and effectiveness of this foaming strategy that will have to be optimized by further extensive animal experiments. A major challenge in the design of biomaterial-based injectable bone substitutes is the development of cohesive, macroporous and self-setting calcium phosphate cement (CPC) that enables rapid cell invasion with adequate initial mechanical properties without the use of complex processing and additives. Thus, we propose a simple and effective strategy to prepare injectable macroporous CPCs through syringe-foaming using a hydrophilic viscous polymeric solution (silanized-hydroxypropyl methylcellulose, Si-HPMC) as a foaming agent, that simultaneously meets all the aforementioned aims. Evidence from our in vivo studies shows the existence of newly formed bone within the implantation site, indicating the feasibility and effectiveness of this foaming strategy, which could be used in various CPC systems using other hydrophilic viscous polymeric solutions. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

In Vivo, Non-Invasive Characterization of Human Bone by Hybrid Broadband (600-1200 nm) Diffuse Optical and Correlation Spectroscopies.

PubMed

Konugolu Venkata Sekar, Sanathana; Pagliazzi, Marco; Negredo, Eugènia; Martelli, Fabrizio; Farina, Andrea; Dalla Mora, Alberto; Lindner, Claus; Farzam, Parisa; Pérez-Álvarez, Núria; Puig, Jordi; Taroni, Paola; Pifferi, Antonio; Durduran, Turgut

2016-01-01

Non-invasive in vivo diffuse optical characterization of human bone opens a new possibility of diagnosing bone related pathologies. We present an in vivo characterization performed on seventeen healthy subjects at six different superficial bone locations: radius distal, radius proximal, ulna distal, ulna proximal, trochanter and calcaneus. A tailored diffuse optical protocol for high penetration depth combined with the rather superficial nature of considered tissues ensured the effective probing of the bone tissue. Measurements were performed using a broadband system for Time-Resolved Diffuse Optical Spectroscopy (TRS) to assess mean absorption and reduced scattering spectra in the 600-1200 nm range and Diffuse Correlation Spectroscopy (DCS) to monitor microvascular blood flow. Significant variations among tissue constituents were found between different locations; with radius distal rich of collagen, suggesting it as a prominent location for bone related measurements, and calcaneus bone having highest blood flow among the body locations being considered. By using TRS and DCS together, we are able to probe the perfusion and oxygen consumption of the tissue without any contrast agents. Therefore, we predict that these methods will be able to evaluate the impairment of the oxygen metabolism of the bone at the point-of-care.

In Vivo, Non-Invasive Characterization of Human Bone by Hybrid Broadband (600-1200 nm) Diffuse Optical and Correlation Spectroscopies

PubMed Central

Pagliazzi, Marco; Negredo, Eugènia; Martelli, Fabrizio; Farina, Andrea; Dalla Mora, Alberto; Lindner, Claus; Farzam, Parisa; Pérez-Álvarez, Núria; Puig, Jordi; Taroni, Paola; Pifferi, Antonio; Durduran, Turgut

2016-01-01

Non-invasive in vivo diffuse optical characterization of human bone opens a new possibility of diagnosing bone related pathologies. We present an in vivo characterization performed on seventeen healthy subjects at six different superficial bone locations: radius distal, radius proximal, ulna distal, ulna proximal, trochanter and calcaneus. A tailored diffuse optical protocol for high penetration depth combined with the rather superficial nature of considered tissues ensured the effective probing of the bone tissue. Measurements were performed using a broadband system for Time-Resolved Diffuse Optical Spectroscopy (TRS) to assess mean absorption and reduced scattering spectra in the 600–1200 nm range and Diffuse Correlation Spectroscopy (DCS) to monitor microvascular blood flow. Significant variations among tissue constituents were found between different locations; with radius distal rich of collagen, suggesting it as a prominent location for bone related measurements, and calcaneus bone having highest blood flow among the body locations being considered. By using TRS and DCS together, we are able to probe the perfusion and oxygen consumption of the tissue without any contrast agents. Therefore, we predict that these methods will be able to evaluate the impairment of the oxygen metabolism of the bone at the point-of-care. PMID:27997565

R-Spondin 1 promotes vibration-induced bone formation in mouse models of osteoporosis

PubMed Central

Wang, Haitao; Brennan, Tracy A.; Russell, Elizabeth; Kim, Jung-Hoon; Egan, Kevin P.; Chen, Qijun; Israelite, Craig; Schultz, David C.; Johnson, Frederick B.; Pignolo, Robert J.

2013-01-01

Bone tissue adapts to its functional environment by optimizing its morphology for mechanical demand. Among the mechanosensitive cells that recognize and respond to forces in the skeleton are osteocytes, osteoblasts, and mesenchymal progenitor cells (MPCs). Therefore, the ability to use mechanical signals to improve bone health through exercise and devices that deliver mechanical signals is an attractive approach to age-related bone loss; however, the extracellular or circulating mediators of such signals are largely unknown. Using SDS-PAGE separation of proteins secreted by MPCs in response to low magnitude mechanical signals and in-gel trypsin digestion followed by HPLC and mass spectroscopy, we identified secreted proteins up-regulated by vibratory stimulation. We exploited a cell senescence-associated secretory phenotype screen, and reasoned that a subset of vibration-induced proteins with diminished secretion by senescent MPCs will have the capacity to promote bone formation in vivo. We identified one such vibration-induced bone-enhancing (vibe) gene as R-Spondin 1, a Wnt pathway modulator, and demonstrated that it has the capacity to promote bone formation in three mouse models of age-related bone loss. By virtue of their secretory status, some vibe proteins may be candidates for pre-clinical development as anabolic agents for the treatment of osteoporosis. PMID:23974989

Effect of radioactive iodine-induced hypothyroidism on longitudinal bone growth during puberty in immature female rats.

PubMed

Choi, Hyeonhae; Ryu, Ki-Young; Roh, Jaesook; Bae, Jaeman

2018-05-22

Thyroid cancer in children, the most common endocrine malignancy, shows aggressive behavior and has a high recurrence rate after surgical ablation. Radioactive iodine (RAI) treatment is the most effective primary modality for medical ablation of juvenile thyroid cancer, and leads to intentional hypothyroidism. Although several negative impacts of hypothyroidism have been reported in children in response to other antithyroid agents, the combined effects of RAI exposure and hypothyroidism, on growing bones specifically, are unknown. In this study, we investigated the effect of RAI-induced hypothyroidism on the long bones during the pubertal growth spurt using immature female rats. Female Sprague-Dawley rats were randomly divided into a control group, and an RAI-treated group fed with RAI (0.37 MBq/g body weight) twice via gavage. After 4 weeks, we observed a significantly-reduced serum free thyroxine level in the RAI group. The latter group also displayed decreased body weight gain compared to the control. In addition, the lengths of long bones, such as the leg bones and vertebral column, as well as bone mineral content, were reduced in the RAI-treated animals. Our results confirm the negative impacts of RAI-induced thyroid deficiency during puberty on longitudinal bone growth and bone mineralization.

Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats

PubMed Central

Zhang, Qing; Miller, Christopher; Bible, Jesse; Li, Jiliang; Xu, Xiaoqing; Mehta, Nozer; Gilligan, James; Vignery, Agnès; Scholz, Jodi A Carlson

2012-01-01

Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH or vehicle for four weeks. Both femurs from each rat were analyzed by X-ray and pQCT, then analyzed either by microCT, histology or biomechanical testing. Marrow ablation alone induced transient bone formation of low abundance that persisted over four weeks, while marrow ablation followed by PTH induced bone formation of high abundance that also persisted over four weeks. Our data confirms that the osteo-inducive effect of marrow ablation and the additive effect of marrow ablation, followed by PTH, occurs in aged rats. Our observations open new avenues of investigations in the field of tissue regeneration. Local marrow ablation, in conjunction with an anabolic agent, might provide a new platform for rapid site-directed bone growth in areas of high bone loss, such as in the hip and wrist, which are subject to fracture. PMID:24710549

Effect of collagen sponge and fibrin glue on bone repair

PubMed Central

SANTOS, Thiago de Santana; ABUNA, Rodrigo Paolo Flores; de ALMEIDA, Adriana Luisa Gonçalves; BELOTI, Marcio Mateus; ROSA, Adalberto Luiz

2015-01-01

ABSTRACT The ability of hemostatic agents to promote bone repair has been investigated using in vitro and in vivo models but, up to now, the results are inconclusive. Objective In this context, the aim of this study was to compare the potential of bone repair of collagen sponge with fibrin glue in a rat calvarial defect model. Material and Methods Defects of 5 mm in diameter were created in rat calvariae and treated with either collagen sponge or fibrin glue; untreated defects were used as control. At 4 and 8 weeks, histological analysis and micro-CT-based histomorphometry were carried out and data were compared by two-way ANOVA followed by Student-Newman-Keuls test when appropriated (p≤0.05). Results Three-dimensional reconstructions showed increased bone formation in defects treated with either collagen sponge or fibrin glue compared with untreated defects, which was confirmed by the histological analysis. Morphometric parameters indicated the progression of bone formation from 4 to 8 weeks. Additionally, fibrin glue displayed slightly higher bone formation rate when compared with collagen sponge. Conclusion Our results have shown the benefits of using collagen sponge and fibrin glue to promote new bone formation in rat calvarial bone defects, the latter being discreetly more advantageous. PMID:26814464

Anti-DKK1 antibody promotes bone fracture healing through activation of β-catenin signaling

PubMed Central

Jin, Hongting; Wang, Baoli; Li, Jia; Xie, Wanqing; Mao, Qiang; Li, Shan; Dong, Fuqiang; Sun, Yan; Ke, Hua-Zhu; Babij, Philip; Tong, Peijian; Chen, Di

2015-01-01

In this study we investigated if Wnt/β-catenin signaling in mesenchymal progenitor cells plays a role in bone fracture repair and if DKK1-Ab promotes fracture healing through activation of β-catenin signaling. Unilateral open transverse tibial fractures were created in CD1 mice and in β-cateninPrx1ER conditional knockout (KO) and Cre-negative control mice (C57BL/6 background). Bone fracture callus tissues were collected and analyzed by radiography, micro-CT (μCT), histology, biomechanical testing and gene expression analysis. The results demonstrated that treatment with DKK1-Ab promoted bone callus formation and increased mechanical strength during the fracture healing processinCD1 mice. DKK1-Ab enhanced fracture repair by activation of endochondral ossification. The normal rate of bone repair was delayed when the β-catenin gene was conditionally deleted in mesenchymal progenitor cells during the early stages of fracture healing. DKK1-Ab appeared to act through β-catenin signaling to enhance bone repair since the beneficial effect of DKK1-Ab was abrogated in β-cateninPrx1ER conditional KO mice. Further understanding of the signaling mechanism of DKK1-Ab in bone formation and bone regeneration may facilitate the clinical translation of this anabolic agent into therapeutic intervention. PMID:25263522

In vitro simulation of pathological bone conditions to predict clinical outcome of bone tissue engineered materials

NASA Astrophysics Data System (ADS)

Nguyen, Duong Thuy Thi

According to the Centers for Disease Control, the geriatric population of ≥65 years of age will increase to 51.5 million in 2020; 40% of white women and 13% of white men will be at risk for fragility fractures or fractures sustained under normal stress and loading conditions due to bone disease, leading to hospitalization and surgical treatment. Fracture management strategies can be divided into pharmaceutical therapy, surgical intervention, and tissue regeneration for fracture prevention, fracture stabilization, and fracture site regeneration, respectively. However, these strategies fail to accommodate the pathological nature of fragility fractures, leading to unwanted side effects, implant failures, and non-unions. Compromised innate bone healing reactions of patients with bone diseases are exacerbated with protective bone therapy. Once these patients sustain a fracture, bone healing is a challenge, especially when fracture stabilization is unsuccessful. Traditional stabilizing screw and plate systems were designed with emphasis on bone mechanics rather than biology. Bone grafts are often used with fixation devices to provide skeletal continuity at the fracture gap. Current bone grafts include autologous bone tissue and donor bone tissue; however, the quality and quantity demanded by fragility fractures sustained by high-risk geriatric patients and patients with bone diseases are not met. Consequently, bone tissue engineering strategies are advancing towards functionalized bone substitutes to provide fracture reconstruction while effectively mediating bone healing in normal and diseased fracture environments. In order to target fragility fractures, fracture management strategies should be tailored to allow bone regeneration and fracture stabilization with bioactive bone substitutes designed for the pathological environment. The clinical outcome of these materials must be predictable within various disease environments. Initial development of a targeted treatment strategy should focus on simulating, in vitro, a physiological bone environment to predict clinical effectiveness of engineered bone and understand cellular responses due to the proposed agents and bioactive scaffolds. An in vitro test system can be the necessary catalyst to reduce implant failures and non-unions in fragility fractures.

Multifunctional pH sensitive 3D scaffolds for treatment and prevention of bone infection.

PubMed

Cicuéndez, Mónica; Doadrio, Juan C; Hernández, Ana; Portolés, M Teresa; Izquierdo-Barba, Isabel; Vallet-Regí, María

2018-01-01

Multifunctional-therapeutic three-dimensional (3D) scaffolds have been prepared. These biomaterials are able to destroy the S. aureus bacterial biofilm and to allow bone regeneration at the same time. The present study is focused on the design of pH sensitive 3D hierarchical meso-macroporous 3D scaffolds based on MGHA nanocomposite formed by a mesostructured glassy network with embedded hydroxyapatite nanoparticles, whose mesopores have been loaded with levofloxacin (Levo) as antibacterial agent. These 3D platforms exhibit controlled and pH-dependent Levo release, sustained over time at physiological pH (7.4) and notably increased at infection pH (6.7 and 5.5), which is due to the different interaction rate between diverse Levo species and the silica matrix. These 3D systems are able to inhibit the S. aureus growth and to destroy the bacterial biofilm without cytotoxic effects on human osteoblasts and allowing an adequate colonization and differentiation of preosteoblastic cells on their surface. These findings suggest promising applications of these hierarchical MGHA nanocomposite 3D scaffolds for the treatment and prevention of bone infection. Multifunctional 3D nanocomposite scaffolds with the ability for loading and sustained delivery of an antimicrobial agent, to eliminate and prevent bone infection and at the same time to contribute to bone regeneration process without cytotoxic effects on the surrounding tissue has been proposed. These 3D scaffolds exhibit a sustained levofloxacin delivery at physiological pH (pH 7.4), which increasing notably when pH decreases to characteristic values of bone infection process (pH 6.7 and pH 5.5). In vitro competitive assays between preosteoblastic and bacteria onto the 3D scaffold surface demonstrated an adequate osteoblast colonization in entire scaffold surface together with the ability to eliminate bacteria contamination. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

The approval process for biosimilar erythropoiesis-stimulating agents.

PubMed

Wish, Jay B

2014-09-05

A biosimilar drug or follow-on biologic drug is defined by the Public Health Service Act as a product that is "highly similar to the reference product notwithstanding minor differences in clinically active components and there are no clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity and potency of the product." The advantage of biosimilar drugs is that they are significantly less expensive than the reference products, allowing for increased accessibility and cost savings. Recognizing these advantages, the US Congress passed the Biologics Price Competition and Innovation Act in 2009 as part of health care reform. The Biologics Price Competition and Innovation Act allows sponsors of biosimilar agents to seek approval by showing structural and functional similarity to the reference agent, with the extent of required clinical studies to be determined on the basis of the degree of biosimilarity with the reference product. The goal is to bring biosimilar agents to the market more efficiently while still protecting the safety of the public. The European Union has had such a process in place for a number of years. Two biosimilar epoetin agents have been approved in the European Union since 2007, and their companies are conducting trials to seek approval in the United States, because Amgen's patent protection for epoetin alfa expires in 2014. Trials completed for European Union approval of both agents showed similar efficacy and safety to the reference epoetin alfa. As with all biologics, immunogenicity concerns may persist because of the fragility of the manufacturing process and the worldwide experience with pure red cell aplasia as a result of epoetin therapy. The uptake of biosimilar epoetins after approval in the United States will depend on the balance of cost advantage against safety concerns. Competition in the marketplace will likely decrease the cost of the reference agent as well. Copyright © 2014 by the American Society of Nephrology.

Predicting the impact of combined therapies on myeloma cell growth using a hybrid multi-scale agent-based model.

PubMed

Ji, Zhiwei; Su, Jing; Wu, Dan; Peng, Huiming; Zhao, Weiling; Nlong Zhao, Brian; Zhou, Xiaobo

2017-01-31

Multiple myeloma is a malignant still incurable plasma cell disorder. This is due to refractory disease relapse, immune impairment, and development of multi-drug resistance. The growth of malignant plasma cells is dependent on the bone marrow (BM) microenvironment and evasion of the host's anti-tumor immune response. Hence, we hypothesized that targeting tumor-stromal cell interaction and endogenous immune system in BM will potentially improve the response of multiple myeloma (MM). Therefore, we proposed a computational simulation of the myeloma development in the complicated microenvironment which includes immune cell components and bone marrow stromal cells and predicted the effects of combined treatment with multi-drugs on myeloma cell growth. We constructed a hybrid multi-scale agent-based model (HABM) that combines an ODE system and Agent-based model (ABM). The ODEs was used for modeling the dynamic changes of intracellular signal transductions and ABM for modeling the cell-cell interactions between stromal cells, tumor, and immune components in the BM. This model simulated myeloma growth in the bone marrow microenvironment and revealed the important role of immune system in this process. The predicted outcomes were consistent with the experimental observations from previous studies. Moreover, we applied this model to predict the treatment effects of three key therapeutic drugs used for MM, and found that the combination of these three drugs potentially suppress the growth of myeloma cells and reactivate the immune response. In summary, the proposed model may serve as a novel computational platform for simulating the formation of MM and evaluating the treatment response of MM to multiple drugs.

Liquid-solid phase transition alloy as reversible and rapid molding bone cement.

PubMed

Yi, Liting; Jin, Chao; Wang, Lei; Liu, Jing

2014-12-01

Acrylic bone cement has been an essential non-metallic implant used as fixing agent in the cemented total joint arthroplasty (THA). However, the currently available materials based mainly on polymethylmethacrylate (PMMA) still encounter certain limitations, such as time-consuming polymerization, thermal and chemical necrosis and troublesome revision procedure. Here from an alternative way, we proposed for the first time to adopt the injectable alloy cement to address such tough issues through introducing its unique liquid-solid phase transition mechanism. A typical cement along this way is thus made of an alloy Bi/In/Sn/Zn with a specifically designed low melting point 57.5 °C, which enables its rapid molding into various desired shapes with high plasticity and ultimate metallic behaviors. The fundamental characteristics including the mechanical strength, biocompatibility and phase transition-induced thermal effects have been clarified to demonstrate the importance of such alloy as unconventional cement with favorable merits. In addition, we also disclosed its advantage as an excellent contrast agent for radiation imaging on the bone interior structure which is highly beneficial for guiding the surgery and monitoring the therapeutic effects. Particularly, the proposed alloy cement with reversible phase transition feature significantly simplifies the revision of the cement and prosthesis. This study opens the way for employing the injectable alloy materials as reversible bone cement to fulfill diverse clinical needs in the coming time. Copyright © 2014 Elsevier Ltd. All rights reserved.

Protection against the Acute and Delayed Toxicity of Mustards and Mustard-Like Compounds.

DTIC Science & Technology

1983-09-01

Edition, A. G. Gilman, L. S. Goodman, and A. Gilman (eds.), Macmillan, New York, 1980, pp. 1256-1313. * 2. Ludlum, D. B., Alkylating Agents and the...chemical warfare agents . They are acutely toxic to the skin, respiratory tract, eyes, bone marrow, and, in large doses, to other organs as well...related to the alkylating activity of sulfur mustards and, specifically, to alkylation of DNA (1). Investigations of related compounds have led to the

Molecular radiotheragnostics in prostate cancer.

PubMed

Du, Yong; Dizdarevic, Sabina

2017-10-01

Two different molecular radio-theragnostic principles are applied in prostate cancer, providing a personalised management for those patients. Firstly, radiopharmaceuticals with the same or similar mechanism of action but different energy (gamma-γ, eg 99m Tc-diphosphonates or positron-β+, eg 18F-NaF emitting isotopes) can be used to identify patients with osteoblastic metastases for a treatment with bone seeking beta (β-) or alpha (α-) emitting radionuclides to deliver targeted molecular radiotherapy. A number of such β- emitting molecules have been used for bone palliation. More recently, an alpha emitting 223 Ra-dicholoride demonstrated not only symptomatic relief but also significantly improved overall survival in castration-resistant prostate cancer with predominant bone metastases. The second principle involves utilisation of the same prostatic specific membrane antigen (PSMA) or similar compound (eg PSMA-11, PSMA-617), but different label with either β+ ( 68 Ga) or γ ( 99m Tc) emitting radioisotope for imaging and subsequently β- ( 177 Lu) or α ( 225 Ac) emitting radionuclide for treatment. © Royal College of Physicians 2017. All rights reserved.

Transient recycling of resected bone to facilitate mandibular reconstruction--a technical note.

PubMed

Lee, Jing-Wei; Tsai, Shin-Sheng; Kuo, Yao-Lung

2006-10-01

Mandibular reconstruction requires considerable sculptural skills. The intriguingly complex configuration of the structure is difficult to reproduce. It is thus imperative for surgeons to seek a technique that improves the precision of the reconstruction. A 55-year-old male presented with a full thickness cancer (T4+) of his left cheek. Radical ablative surgery resulted in an extensive loss of bone and soft tissue mandating major reconstruction. The resected bony specimen was thoroughly denuded, autoclaved, and then placed back into its original site so that the mandible resumed its pre-surgical configuration. A reconstruction plate was applied to maintain structural stability, then the "recycled bone" was used as a template and replaced with a free fibular graft. The patient fared well and a follow-up panoramic radiograph demonstrated good alignment and symmetry of the reconstructed mandible. This method is a viable option for segmental mandibulectomy defect repair in selected cases. Using this technique, it is possible to restore the original bony contour expediently and accurately.

Possible benefits of strontium ranelate in complicated long bone fractures.

PubMed

Alegre, Duarte Nuno; Ribeiro, Costa; Sousa, Carlos; Correia, João; Silva, Luís; de Almeida, Luís

2012-02-01

Osteoporosis drugs are prescribed to prevent fragility fractures, which is the principal aim of the management of osteoporosis. However, if fracture does occur, then it is also important to promote a fast and uneventful healing process. Despite this, little is known about the effect of osteoporosis drugs on bone healing in humans. Strontium ranelate is an osteoporosis agent that increases bone formation and reduces bone resorption and may therefore be beneficial in fracture healing. We report four cases of fracture non-union for up to 20 months. Treatment with strontium ranelate (2 g/day) for between 6 weeks and 6 months appeared to contribute to bone consolidation in the four cases. Animal studies support beneficial effects of strontium ranelate on bone healing via improvement of bone material properties and microarchitecture in the vicinity of the fracture. The clinical cases described herein provide new information on these effects, in the absence of randomized controlled studies on the clinical efficacy of pharmacological treatments in osteoporosis in fracture repair. Further studies are necessary. Fracture healing is an important topic in orthopedic research and is also a concern for patients with postmenopausal osteoporosis. Evidence from case reports and animal studies suggests that strontium ranelate improves bone microarchitecture and accelerates fracture healing. A positive effect of osteoporosis treatments on bone healing is an interesting possibility and merits further clinical research.

Restoration of prostaglandin E2-producing splenic macrophages in sup 89 Sr-treated mice with bone marrow from Corynebacterium parvum primed donors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shibata, Y.

1989-05-01

Administration of Corynebacterium parvum (CP), 56 mg/kg ip to CBA/J mice effected the induction of prostaglandin E2 (PGE2) producing macrophages (M phi) in the bone marrow and the spleen. Maximal release of PGE2 from M phi cultured in vitro with calcium ionophore A23187 for 2 h was reached by marrow M phi removed on 5 days after CP (450 ng/mg cell protein), and by splenic M phi 9 days after CP (400 ng/mg). Neither M phi population, however, yielded more than 6.0 ng/mg leukotriene C4. To assess ontogenic relationships mice were depleted of bone marrow and blood monocytes by ivmore » injection of the bone-seeking isotope, 89Sr. CP was given at several points before or after bone marrow cell depletion. PGE2 production by splenic M phi harvested on day 9 after CP was profoundly impaired when CP was administered either concurrently with or 3 days after 89Sr. When CP was administered 1, 3, 5, and 7 days before 89Sr, however, the induction of PGE2-producing M phi in the spleen was unaffected. To determine whether bone marrow cells from CP-injected donors can restore PGE2-producing splenic M phi (PGSM) in 89Sr-mice, recipient mice which had and had not received CP 3 days after 89Sr were transfused with 5 x 10(6) syngeneic bone marrow cells from donor mice prepared at varying intervals after CP administration. The results clearly indicate the capacity of bone marrow cells harvested on either day 1 or 2 following CP to restore PGSM in CP-primed, but not unprimed, recipients.« less

Studies on focal alveolar bone healing with technetium (Tc)-99m labeled methylene diphosphonate and gold-collimated cadmium telluride probe

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsuchimochi, M.; Hosain, F.; Engelke, W.

1991-01-01

The benefit of using a collimator for a miniaturized cadmium telluride probe was evaluated by monitoring the bone-healing processes for 13 weeks after the induction of small iatrogenic alveolar bone lesions in one side of the mandible in beagles. Technetium (Tc)-99m labeled methylene diphosphonate (200 to 300 MBq, 5.1 to 8.1 mCi, in a solution of 0.5 to 1 ml, intravenously) was used as a bone-seeking radiopharmaceutical. The radioactivity over the bone lesion (L) and the contralateral normal site (C) in the mandible were measured between 1.5 and 2 hours after injection of the tracer, and the activity ratio L/Cmore » served as an index of relative bone uptake. A study of six dogs revealed that the healing response to a hemispheric bone defect of 2 mm diameter in the cortical bone could not be detected by an uncollimated probe, and in a repeated study in two dogs the use of a gold collimator (5 mm in diameter, 5 mm in length) did not increase the L/C ratio significantly. A second study in six dogs with 5 mm lesions showed that although systematic trends in the time courses of the L/C ratio obtained both with and without the collimator could be demonstrated, the L/C ratio of collimated versus uncollimated measurements was significantly (p less than 0.005) increased. In three of the latter six dogs, abscesses developed after 9 weeks, leading to a second increase (p less than 0.05) of the L/C ratio with collimation compared with the noninflammation group; without collimation no significant (p greater than 0.15) difference between the two groups could be demonstrated.« less

Stepwise verification of bone regeneration using recombinant human bone morphogenetic protein-2 in rat fibula model

PubMed Central

2017-01-01

Objectives The purpose of this study was to introduce our three experiments on bone morphogenetic protein (BMP) and its carriers performed using the critical sized segmental defect (CSD) model in rat fibula and to investigate development of animal models and carriers for more effective bone regeneration. Materials and Methods For the experiments, 14, 16, and 24 rats with CSDs on both fibulae were used in Experiments 1, 2, and 3, respectively. BMP-2 with absorbable collagen sponge (ACS) (Experiments 1 and 2), autoclaved autogenous bone (AAB) and fibrin glue (FG) (Experiment 3), and xenogenic bone (Experiment 2) were used in the experimental groups. Radiographic and histomorphological evaluations were performed during the follow-up period of each experiment. Results Significant new bone formation was commonly observed in all experimental groups using BMP-2 compared to control and xenograft (porcine bone) groups. Although there was some difference based on BMP carrier, regenerated bone volume was typically reduced by remodeling after initially forming excessive bone. Conclusion BMP-2 demonstrates excellent ability for bone regeneration because of its osteoinductivity, but efficacy can be significantly different depending on its delivery system. ACS and FG showed relatively good bone regeneration capacity, satisfying the essential conditions of localization and release-control when used as BMP carriers. AAB could not provide release-control as a BMP carrier, but its space-maintenance role was remarkable. Carriers and scaffolds that can provide sufficient support to the BMP/carrier complex are necessary for large bone defects, and AAB is thought to be able to act as an effective scaffold. The CSD model of rat fibula is simple and useful for initial estimate of bone regeneration by agents including BMPs. PMID:29333367

Tumor resistance to vascular disrupting agents: mechanisms, imaging, and solutions

PubMed Central

Liang, Wenjie; Ni, Yicheng; Chen, Feng

2016-01-01

The emergence of vascular disrupting agents (VDAs) is a significant advance in the treatment of solid tumors. VDAs induce rapid and selective shutdown of tumor blood flow resulting in massive necrosis. However, a viable marginal tumor rim always remains after VDA treatment and is a major cause of recurrence. In this review, we discuss the mechanisms involved in the resistance of solid tumors to VDAs. Hypoxia, tumor-associated macrophages, and bone marrow-derived circulating endothelial progenitor cells all may contribute to resistance. Resistance can be monitored using magnetic resonance imaging markers. The various solutions proposed to manage tumor resistance to VDAs emphasize combining these agents with other approaches including antiangiogenic agents, chemotherapy, radiotherapy, radioimmunotherapy, and sequential dual-targeting internal radiotherapy. PMID:26812886

Bone Accumulation by Leopards in the Late Pleistocene in the Moncayo Massif (Zaragoza, NE Spain)

PubMed Central

Sauqué, Víctor; Rabal-Garcés, Raquel; Sola-Almagro, Cristina; Cuenca-Bescós, Gloria

2014-01-01

Eating habits of Panthera pardus are well known. When there are caves in its territory, prey accumulates inside them. This helps to prevent its kill from being stolen by other predators like hyenas. Although the leopard is an accumulator of bones in caves, few studies have been conducted on existing lairs. There are, however, examples of fossil vertebrate sites whose main collecting agent is the leopard. During the Late Pleistocene, the leopard was a common carnivore in European faunal associations. Here we present a new locality of Quaternary mammals with a scarce human presence, the cave of Los Rincones (province of Zaragoza, Spain); we show the leopard to be the main accumulator of the bones in the cave, while there are no interactions between humans and leopards. For this purpose, a taphonomic analysis is performed on different bone-layers of the cave. PMID:24642667

Management of osteoporosis in the aging male: Focus on zoledronic acid

PubMed Central

Piper, Paul K; Gruntmanis, Ugis

2009-01-01

Osteoporosis in the aging male remains an important yet under-recognized and undertreated disease. Current US estimates indicate that over 14 million men have osteoporosis or low bone mass, and men suffer approximately 500,000 osteoporotic fractures each year. Men experience fewer osteoporotic fractures than women but have higher mortality after fracture. Bisphosphonates are potent antiresorptive agents that inhibit osteoclast activity, suppress in vivo markers of bone turnover, increase bone mineral density, decrease fractures, and improve survival in men with osteoporosis. Intravenous zoledronic acid may be a preferable alternative to oral bisphosphonate therapy in patients with cognitive dysfunction, the inability to sit upright, or significant gastrointestinal pathology. Zoledronic acid (Reclast) is approved in the US as an annual 5 mg intravenous infusion to treat osteoporosis in men. The zoledronic acid (Zometa) 4 mg intravenous dose has been studied in the prevention of bone loss associated with androgen deprivation therapy. PMID:19750231

Management of osteoporosis in the aging male: focus on zoledronic acid.

PubMed

Piper, Paul K; Gruntmanis, Ugis

2009-01-01

Osteoporosis in the aging male remains an important yet under-recognized and undertreated disease. Current US estimates indicate that over 14 million men have osteoporosis or low bone mass, and men suffer approximately 500,000 osteoporotic fractures each year. Men experience fewer osteoporotic fractures than women but have higher mortality after fracture. Bisphosphonates are potent antiresorptive agents that inhibit osteoclast activity, suppress in vivo markers of bone turnover, increase bone mineral density, decrease fractures, and improve survival in men with osteoporosis. Intravenous zoledronic acid may be a preferable alternative to oral bisphosphonate therapy in patients with cognitive dysfunction, the inability to sit upright, or significant gastrointestinal pathology. Zoledronic acid (Reclast) is approved in the US as an annual 5 mg intravenous infusion to treat osteoporosis in men. The zoledronic acid (Zometa) 4 mg intravenous dose has been studied in the prevention of bone loss associated with androgen deprivation therapy.

Current Status of Research on Osteoporosis after Solid Organ Transplantation: Pathogenesis and Management

PubMed Central

2015-01-01

Improved survival following organ transplantation has brought to the forefront some long-term complications, among which osteoporosis and associated fractures are the major ones that adversely affect the quality of life in recipients. The pathogenesis of osteoporosis in transplant recipients is complex and multifactorial which may be related to increased bone resorption, decreased bone formation, or both. Studies have shown that the preexisting underlying metabolic bone disorders and the use of immunosuppressive agents are the major risk factors for osteoporosis and fractures after organ transplantation. And rapid bone loss usually occurs in the first 6–12 months with a significant increase in fracture risk. This paper will provide an updated review on the possible pathogenesis of posttransplant osteoporosis and fractures, the natural history, and the current prevention and treatment strategies concerning different types of organ transplantation. PMID:26649301

EBV, HCMV, HHV6, and HHV7 Screening in Bone Marrow Samples from Children with Acute Lymphoblastic Leukemia

PubMed Central

Morales-Sánchez, A.; Pompa-Mera, E. N.; Fajardo-Gutiérrez, A.; Alvarez-Rodríguez, F. J.; Bekker-Méndez, V. C.; Flores-Chapa, J. de Diego; Flores-Lujano, J.; Jiménez-Hernández, E.; Peñaloza-González, J. G.; Rodríguez-Zepeda, M. C.; Torres-Nava, J. R.; Velázquez-Aviña, M. M.; Amador-Sánchez, R.; Alvarado-Ibarra, M.; Reyes-Zepeda, N.; Espinosa-Elizondo, R. M.; Pérez-Saldivar, M. L.; Núñez-Enríquez, J. C.; Mejía-Aranguré, J. M.; Fuentes-Pananá, E. M.

2014-01-01

Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood worldwide and Mexico has reported one of the highest incidence rates. An infectious etiology has been suggested and supported by epidemiological evidences; however, the identity of the involved agent(s) is not known. We considered that early transmitted lymphotropic herpes viruses were good candidates, since transforming mechanisms have been described for them and some are already associated with human cancers. In this study we interrogated the direct role of EBV, HCMV, HHV6, and HHV7 human herpes viruses in childhood ALL. Viral genomes were screened in 70 bone marrow samples from ALL patients through standard and a more sensitive nested PCR. Positive samples were detected only by nested PCR indicating a low level of infection. Our result argues that viral genomes were not present in all leukemic cells, and, hence, infection most likely was not part of the initial genetic lesions leading to ALL. The high statistical power of the study suggested that these agents are not involved in the genesis of ALL in Mexican children. Additional analysis showed that detected infections or coinfections were not associated with prognosis. PMID:25309913

EBV, HCMV, HHV6, and HHV7 screening in bone marrow samples from children with acute lymphoblastic leukemia.

PubMed

Morales-Sánchez, A; Pompa-Mera, E N; Fajardo-Gutiérrez, A; Alvarez-Rodríguez, F J; Bekker-Méndez, V C; Flores-Chapa, J de Diego; Flores-Lujano, J; Jiménez-Hernández, E; Peñaloza-González, J G; Rodríguez-Zepeda, M C; Torres-Nava, J R; Velázquez-Aviña, M M; Amador-Sánchez, R; Alvarado-Ibarra, M; Reyes-Zepeda, N; Espinosa-Elizondo, R M; Pérez-Saldivar, M L; Núñez-Enríquez, J C; Mejía-Aranguré, J M; Fuentes-Pananá, E M

2014-01-01

Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood worldwide and Mexico has reported one of the highest incidence rates. An infectious etiology has been suggested and supported by epidemiological evidences; however, the identity of the involved agent(s) is not known. We considered that early transmitted lymphotropic herpes viruses were good candidates, since transforming mechanisms have been described for them and some are already associated with human cancers. In this study we interrogated the direct role of EBV, HCMV, HHV6, and HHV7 human herpes viruses in childhood ALL. Viral genomes were screened in 70 bone marrow samples from ALL patients through standard and a more sensitive nested PCR. Positive samples were detected only by nested PCR indicating a low level of infection. Our result argues that viral genomes were not present in all leukemic cells, and, hence, infection most likely was not part of the initial genetic lesions leading to ALL. The high statistical power of the study suggested that these agents are not involved in the genesis of ALL in Mexican children. Additional analysis showed that detected infections or coinfections were not associated with prognosis.

Calculating Hematopoietic-Mode-Lethality Risk Avoidance Associated with Radionuclide Decorporation Countermeasures Related to a Radiological Terrorism Incident

PubMed Central

Scott, Bobby R.

2009-01-01

This paper provides theoretical health-risk-assessment tools that are designed to facilitate planning for and managing radiological terrorism incidents that involve ingestion exposure to bone-seeking radionuclides (e.g., radiostrontium nuclides). The focus is on evaluating lethality risk avoidance (RAV; i.e., the decrease in risk) that is associated with radionuclide decorporation countermeasures employed to remove ingested bone-seeking beta and/or gamma-emitting radionuclides from the body. To illustrate the application of tools presented, hypothetical radiostrontium decorporation scenarios were considered that involved evaluating the hematopoietic-mode-lethality RAV. For evaluating the efficacy of specific decorporation countermeasures, the lethality risk avoidance proportion (RAP; which is the RAV divided by the total lethality risk in the absence of protective countermeasures) is introduced. The lethality RAP is expected to be a useful tool for designing optimal radionuclide decorporation schemes and for identifying green, yellow and red dose-rate zones. For the green zone, essentially all of the lethality risk is expected to be avoided (RAP = 1) as a consequence of the radionuclide decorporation scheme used. For the yellow zone, some but not all of the lethality risk is expected to be avoided. For the red zone, none of the lethality risk (which equals 1) is expected to be avoided. PMID:20011652

Traumatic fracture in a healthy man: benign or pathologic?

PubMed

Nora, Elizabeth H; Kennel, Kurt A; Christian, Rose C

2006-01-01

To describe the challenge of determining the correct diagnosis in a healthy adult male patient with a recent femoral fracture and a history of multiple bone fractures. We present clinical, radiologic, laboratory, and histopathologic details in a patient with a history of recurrent fractures associated with minimal trauma. Moreover, the various types of osteopetrosis are reviewed. A 34-year-old African American man was in his usual state of good health when he fell hard on concrete. Immediately after the fall, he was able to bear weight, although pain prompted him to seek medical care. Besides a personal history of multiple fractures, he had no other medical problems. He had never smoked, denied illicit drug use, and had no family history of bone disorders or recurrent fractures. Findings on physical examination were unremarkable. Radiography disclosed an incomplete femoral fracture and osteosclerosis. Bone survey revealed diffuse, symmetric osteosclerosis of both the axial and the appendicular skeleton. The long bones showed areas of almost complete obliteration of the medullary canal, along with prominent hyperostosis. Additionally, a "bone-within-bone" appearance to the thickened endosteum was noted. A bone scan demonstrated numerous areas of symmetric radiotracer uptake. Laboratory analyses were unremarkable, including a complete blood cell count, electrolytes, serum protein electrophoresis, thyrotropin, and parathyroid hormone. Total alkaline phosphatase was mildly elevated at 162 U/L (normal range, 35 to 130). Seven needles were broken during attempts to perform a bone biopsy. Histologic examination showed normal bone marrow with "woven" bone and areas of primary spongiosa within mature osteoid. Autosomal dominant osteopetrosis type 2 was diagnosed on the basis of his clinical presentation and the radiologic and pathologic findings. The preliminary diagnosis for this patient's condition was Paget's disease, and determining the correct diagnosis of osteopetosis prevented the administration of inappropriate therapy. In addition, this case report reminds the clinician that genetic disease may manifest in adulthood.

Decision Facilitator for Launch Operations using Intelligent Agents

NASA Technical Reports Server (NTRS)

Thirumalainambi, Rajkumar; Bardina, Jorge

2005-01-01

Launch operations require millions of micro-decisions which contribute to the macro decision of 'Go/No-Go' for a launch. Knowledge workers"(such as managers and technical professionals) need information in a timely precise manner as it can greatly affect mission success. The intelligent agent (web search agent) uses the words of a hypertext markup language document which is connected through the internet. The intelligent agent's actions are to determine if its goal of seeking a website containing a specified target (e.g., keyword or phrase), has been met. There are few parameters that should be defined for the keyword search like "Go" and "No-Go". Instead of visiting launch and range decision making servers individually, the decision facilitator constantly connects to all servers, accumulating decisions so the final decision can be decided in a timely manner. The facilitator agent uses the singleton design pattern, which ensures that only a single instance of the facilitator agent exists at one time. Negotiations could proceed between many agents resulting in a final decision. This paper describes details of intelligent agents and their interaction to derive an unified decision support system.

Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice

PubMed Central

Walker, Emma C.; McGregor, Narelle E.; Poulton, Ingrid J.; Solano, Melissa; Pompolo, Sueli; Fernandes, Tania J.; Constable, Matthew J.; Nicholson, Geoff C.; Zhang, Jian-Guo; Nicola, Nicos A.; Gillespie, Matthew T.; Martin, T. John; Sims, Natalie A.

2010-01-01

Effective osteoporosis therapy requires agents that increase the amount and/or quality of bone. Any modification of osteoclast-mediated bone resorption by disease or drug treatment, however, elicits a parallel change in osteoblast-mediated bone formation because the processes are tightly coupled. Anabolic approaches now focus on uncoupling osteoblast action from osteoclast formation, for example, by inhibiting sclerostin, an inhibitor of bone formation that does not influence osteoclast differentiation. Here, we report that oncostatin M (OSM) is produced by osteoblasts and osteocytes in mouse bone and that it has distinct effects when acting through 2 different receptors, OSM receptor (OSMR) and leukemia inhibitory factor receptor (LIFR). Specifically, mouse OSM (mOSM) inhibited sclerostin production in a stromal cell line and in primary murine osteoblast cultures by acting through LIFR. In contrast, when acting through OSMR, mOSM stimulated RANKL production and osteoclast formation. A key role for OSMR in bone turnover was confirmed by the osteopetrotic phenotype of mice lacking OSMR. Furthermore, in contrast to the accepted model, in which mOSM acts only through OSMR, mOSM inhibited sclerostin expression in Osmr–/– osteoblasts and enhanced bone formation in vivo. These data reveal what we believe to be a novel pathway by which bone formation can be stimulated independently of bone resorption and provide new insights into OSMR and LIFR signaling that are relevant to other medical conditions, including cardiovascular and neurodegenerative diseases and cancer. PMID:20051625

The effect of N-acetylcysteine on mechanical fatigue resistance of antibiotic-loaded bone cement.

PubMed

Sukur, Erhan; Akar, Abdulhalim; Topcu, Huseyin Nevzat; Cicekli, Ozgur; Kochai, Alauddin; Turker, Mehmet

2018-05-31

This biomechanical study evaluates the effect of N-acetylcysteine alone and in combination with the most commonly used antibiotic-loaded bone cement mixtures. We mixed eight bone cement mixture groups including combinations of N-acetylcysteine, gentamicin, teicoplanin, and vancomycin and applied a four-point bending test individually to each sample on days 1 and 15 using an MTS Acumen test device. The result was less than 50 MPa-the limit declared by the ISO (International Standards Organization)-in only the "gentamicin + bone cement + N-acetylcysteine" group. Mechanical fatigue resistance of the bone cement decreased significantly with the addition of N-acetylcysteine both on day 1 and day 15 (p <  0.001). With the addition of N-acetylcysteine into the "gentamicin + bone cement" and "vancomycin + bone cement" mixtures, a significant decrease in mechanical fatigue resistance was observed both on day 1 and day 15 (p <  0.001). In contrast, with the addition of N-acetylcysteine into the "teicoplanin + bone cement" mixture, no significant difference in mechanical fatigue resistance was observed on days 1 and 15 (p = 0.093, p = 0.356). Preliminary results indicate that adding N-acetylcysteine to teicoplanin-loaded bone cement does not significantly affect the cement's mechanical resistance, potentially leading to a new avenue for preventing and treating peri-prosthetic joint infection. N-acetylcysteine may, therefore, be considered as an alternative agent to be added to antibiotic-loaded bone cement mixtures used in the prevention of peri-prosthetic joint infection.

The Identification of Proteoglycans and Glycosaminoglycans in Archaeological Human Bones and Teeth

PubMed Central

Coulson-Thomas, Yvette M.; Coulson-Thomas, Vivien J.; Norton, Andrew L.; Gesteira, Tarsis F.; Cavalheiro, Renan P.; Meneghetti, Maria Cecília Z.; Martins, João R.; Dixon, Ronald A.; Nader, Helena B.

2015-01-01

Bone tissue is mineralized dense connective tissue consisting mainly of a mineral component (hydroxyapatite) and an organic matrix comprised of collagens, non-collagenous proteins and proteoglycans (PGs). Extracellular matrix proteins and PGs bind tightly to hydroxyapatite which would protect these molecules from the destructive effects of temperature and chemical agents after death. DNA and proteins have been successfully extracted from archaeological skeletons from which valuable information has been obtained; however, to date neither PGs nor glycosaminoglycan (GAG) chains have been studied in archaeological skeletons. PGs and GAGs play a major role in bone morphogenesis, homeostasis and degenerative bone disease. The ability to isolate and characterize PG and GAG content from archaeological skeletons would unveil valuable paleontological information. We therefore optimized methods for the extraction of both PGs and GAGs from archaeological human skeletons. PGs and GAGs were successfully extracted from both archaeological human bones and teeth, and characterized by their electrophoretic mobility in agarose gel, degradation by specific enzymes and HPLC. The GAG populations isolated were chondroitin sulfate (CS) and hyaluronic acid (HA). In addition, a CSPG was detected. The localization of CS, HA, three small leucine rich PGs (biglycan, decorin and fibromodulin) and glypican was analyzed in archaeological human bone slices. Staining patterns were different for juvenile and adult bones, whilst adolescent bones had a similar staining pattern to adult bones. The finding that significant quantities of PGs and GAGs persist in archaeological bones and teeth opens novel venues for the field of Paleontology. PMID:26107959

Formononetin, a methoxy isoflavone, enhances bone regeneration in a mouse model of cortical bone defect.

PubMed

Singh, Krishna Bhan; Dixit, Manisha; Dev, Kapil; Maurya, Rakesh; Singh, Divya

2017-06-01

The bone regeneration and healing effect of formononetin was evaluated in a cortical bone defect model that predominantly heals by intramembranous ossification. For this study, female Balb/c mice were ovariectomised (OVx) and a drill-hole injury was generated in the midfemoral bones of all animals. Treatment with formononetin commenced the day after and continued for 21 d. Parathyroid hormone (PTH1-34) was used as a reference standard. Animals were killed at days 10 and 21. Femur bones were collected at the injury site for histomorphometry studies using microcomputed tomography (μCT) and confocal microscopy. RNA and protein were harvested from the region surrounding the drill-hole injury. For immunohistochemistry, 5 µm sections of decalcified femur bone adjoining the drill-hole site were cut. μCT analysis showed that formononetin promoted bone healing at days 10 and 21 and the healing effect observed was significantly better than in Ovx mice and equal to PTH treatment in many aspects. Formononetin also significantly enhanced bone regeneration as assessed by calcein-labelling studies. In addition, formononetin enhanced the expression of osteogenic markers at the injury site in a manner similar to PTH. Formononetin treatment also led to predominant runt-related transcription factor 2 and osteocalcin localisation at the injury site. These results support the potential of formononetin to be a bone-healing agent and are suggestive of its promising role in the fracture-repair process.

Chemical terrorism for the intensivist.

PubMed

Chalela, Julio A; Burnett, Thomas

2012-05-01

The use of chemical agents for terrorist attacks or military warfare is a major concern at the present time. Chemical agents can cause significant morbidity, are relatively inexpensive, and are easy to store and use. Weaponization of chemical agents is only limited by the physicochemical properties of some agents. Recent incidents involving toxic industrial chemicals and chemical terrorist attacks indicate that critical care services are frequently utilized. For obvious reasons, the critical care literature on chemical terrorism is scarce. This article reviews the clinical aspects of diagnosing and treating victims of chemical terrorism while emphasizing the critical care management. The intensivist needs to be familiar with the chemical agents that could be used in a terrorist attack. The military classification divides agents into lung agents, blood agents, vesicants, and nerve agents. Supportive critical care is the cornerstone of treatment for most casualties, and dramatic recovery can occur in many cases. Specific antidotes are available for some agents, but even without the antidote, aggressive intensive care support can lead to favorable outcome in many cases. Critical care and emergency services can be overwhelmed by a terrorist attack as many exposed but not ill will seek care.

32 CFR 552.57 - Authorization to solicit.

Code of Federal Regulations, 2010 CFR

2010-07-01

... specific appointment must be made with the individual and must be conducted in family quarters or in other..., whether the agent is employed by a reputable firm. (b) Certain companies seeking solicitation privileges on military installations may arrange personal demonstrations of their products at social gatherings...

Yeast-incorporated gallium attenuates glucocorticoid-induced bone loss in rats by inhibition of bone resorption.

PubMed

Ren, Zhaozhou; Yang, Liqing; Xue, Feng; Meng, Qingjie; Wang, Kejia; Wu, Xian; Ji, Chao; Jiang, Teng; Liu, Da; Zhou, Long; Zhang, Jing; Fu, Qin

2013-06-01

Glucocorticoids (GC) are potent anti-inflammatory agents and widely used for the treatment of many immune-mediated and inflammatory diseases, whereas GC-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis and significantly increases the patients' morbidity and mortality. GIOP is characterized as diminished osteogenesis and accelerated bone resorption. Yeast-incorporated gallium (YG) as an organic compound not only reduces elements-associated toxicity, but also maintains its therapeutic effect on improving bone loss or promoting fracture healing in ovariectomized female rats. The aim of this study was to examine whether YG could prevent GC-induced bone loss. Five-month-old male Sprague-Dawley rats were randomly divided into three groups (n = 6): two groups were administered dexamethasone (0.1 mg/kg/day) or vehicle (PBS) subcutaneously for 5 weeks; one other group was received dexamethasone subcutaneously and YG (120 μg/kg/day) orally. Trabecular bone microarchitectural parameters, bone mineral density (BMD), bone strength, body weight, and serum biochemical markers of bone resorption and formation were examined. Compared to the GC alone group, treatment with YG not only prevented microarchitectural deterioration of trabecular bone volume relative to tissue volume, trabecular number, and trabecular separation, but also significantly improved BMD, mechanical strength, and body weight in GC-treated rats. Moreover, YG decreased tartrate-resistant acid phosphatase 5b level but failed to change alkaline phosphatase level in GC-treated rats. This is the first study to show that YG prominently attenuates bone loss and microarchitectural deterioration and inhibits the increased bone resorption in GIOP. It implies that YG might be an alternative therapy for prevention of GC-induced bone loss in humans.

Process for the manufacture of 117Sn diethylenetriaminepentaacetic acids

DOEpatents

Srivastava, Suresh C.; Li, Zizhong; Meinken, George

2003-01-01

Novel methods are provided for the manufacture of .sup.117m Sn(Sn.sup.4+) DTPA. The method allows the use of DTPA, a toxic chelating agent, in an approximately 1:1 ratio to .sup.117m Sn(Sn.sup.4+) via either aqueous conditions, or using various organic solvents, such as methylene chloride. A pharmaceutical composition manufactured by the novel method is also provided, as well as methods for treatment of bone tumors and pain associated with bone cancer using the pharmaceutical composition of the invention.

The Johns Hopkins RTR Consortium: A Collaborative Approach to Advance Translational Science and Standardize Clinical Monitoring of Restorative Transplantation - Immunomodulation and Tolerance Induction after VCA using Biologic Agent (cTLA4-Ig) and Donor Bone Marrow Cells

DTIC Science & Technology

2014-10-01

group, Pig 22227, was due to a gastrointestinal bleed , related to either infectious gastroenteritis/colitis or stress ulcer formation. The third... upper extremity transplantation. Delays in progress and incomplete groups will be discussed in detail in Section 5 – Changes/Problems. Table 1...Implemented successfully first clinical protocol for upper extremity transplantation using donor bone marrow cell therapies and tacrolimus

Utilizing time-lapse micro-CT-correlated bisphosphonate binding kinetics and soft tissue-derived input functions to differentiate site-specific changes in bone metabolism in vivo.

PubMed

Tower, R J; Campbell, G M; Müller, M; Glüer, C C; Tiwari, S

2015-05-01

The turnover of bone is a tightly regulated process between bone formation and resorption to ensure skeletal homeostasis. This process differs between bone types, with trabecular bone often associated with higher turnover than cortical bone. Analyses of bone by micro-computed tomography (micro-CT) reveal changes in structure and mineral content, but are limited in the study of metabolic activity at a single time point, while analyses of serum markers can reveal changes in bone metabolism, but cannot delineate the origin of any aberrant findings. To obtain a site-specific assessment of bone metabolic status, bisphosphonate binding kinetics were utilized. Using a fluorescently-labeled bisphosphonate, we show that early binding kinetics monitored in vivo using fluorescent molecular tomography (FMT) can monitor changes in bone metabolism in response to bone loss, stimulated by ovariectomy (OVX), or bone gain, resulting from treatment with the anabolic bone agent parathyroid hormone (PTH), and is capable of distinguishing different, metabolically distinct skeletal sites. Using time-lapse micro-CT, longitudinal bone turnover was quantified. The spine showed a significantly greater percent resorbing volume and surface in response to OVX, while mice treated with PTH showed significantly greater resorbing volume per bone surface in the spine and significantly greater forming surfaces in the knee. Correlation studies between binding kinetics and micro-CT suggest that forming surfaces, as assessed by time-lapse micro-CT, are preferentially reflected in the rate constant values while forming and resorbing bone volumes primarily affect plateau values. Additionally, we developed a blood pool correction method which now allows for quantitative multi-compartment analyses to be conducted using FMT. These results further expand our understanding of bisphosphonate binding and the use of bisphosphonate binding kinetics as a tool to monitor site-specific changes in bone metabolism in vivo. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Bounded extremum seeking for angular velocity actuated control of nonholonomic unicycle

DOE PAGES

Scheinker, Alexander

2016-08-17

Here, we study control of the angular-velocity actuated nonholonomic unicycle, via a simple, bounded extremum seeking controller which is robust to external disturbances and measurement noise. The vehicle performs source seeking despite not having any position information about itself or the source, able only to sense a noise corrupted scalar value whose extremum coincides with the unknown source location. In order to control the angular velocity, rather than the angular heading directly, a controller is developed such that the closed loop system exhibits multiple time scales and requires an analysis approach expanding the previous work of Kurzweil, Jarnik, Sussmann, andmore » Liu, utilizing weak limits. We provide analytic proof of stability and demonstrate how this simple scheme can be extended to include position-independent source seeking, tracking, and collision avoidance of groups on autonomous vehicles in GPS-denied environments, based only on a measure of distance to an obstacle, which is an especially important feature for an autonomous agent.« less

The Osteogenesis Effect and Underlying Mechanisms of Local Delivery of gAPN in Extraction Sockets of Beagle Dogs

PubMed Central

Hu, Hongcheng; Pu, Yinfei; Lu, Songhe; Zhang, Kuo; Guo, Yuan; Lu, Hui; Li, Deli; Li, Xuefen; Li, Zichen; Wu, Yuwei; Tang, Zhihui

2015-01-01

A plastic and biodegradable bone substitute consists of poly (l-lactic-co-glycolic) acid and 30 wt % β-tricalcium phosphate has been previously fabricated, but its osteogenic capability required further improvement. We investigated the use of globular adiponectin (gAPN) as an anabolic agent for tissue-engineered bone using this scaffold. A qualitative analysis of the bone regeneration process was carried out using μCT and histological analysis 12 weeks after implantation. CBCT (Cone Beam Computed Tomography) superimposition was used to characterise the effect of the different treatments on bone formation. In this study, we also explored adiponectin’s (APN) influence on primary cultured human jaw bone marrow mesenchymal stem cells gene expressions involved in the osteogenesis. We found that composite scaffolds loaded with gAPN or bone morphogenetic protein 2 (BMP2) exhibited significantly increased bone formation and mineralisation following 12 weeks in the extraction sockets of beagle dogs, as well as enhanced expression of osteogenic markers. In vitro investigation revealed that APN also promoted osteoblast differentiation of primary cultured human jaw bone marrow mesenchymal stem cells (h-JBMMSCs), accompanied by increased activity of alkaline phosphatase, greater mineralisation, and production of the osteoblast-differentiated genes osteocalcin, bone sialoprotein and collagen type I, which was reversed by APPL1 siRNA. Therefore, the composite scaffold loaded with APN exhibited superior activity for guided bone regeneration compared with blank control or Bio-Oss® (a commercially available product). The composite scaffold with APN has significant potential for clinical applications in bone tissue engineering. PMID:26492241

Dynamic iterative beam hardening correction (DIBHC) in myocardial perfusion imaging using contrast-enhanced computed tomography.

PubMed

Stenner, Philip; Schmidt, Bernhard; Allmendinger, Thomas; Flohr, Thomas; Kachelrie, Marc

2010-06-01

In cardiac perfusion examinations with computed tomography (CT) large concentrations of iodine in the ventricle and in the descending aorta cause beam hardening artifacts that can lead to incorrect perfusion parameters. The aim of this study is to reduce these artifacts by performing an iterative correction and by accounting for the 3 materials soft tissue, bone, and iodine. Beam hardening corrections are either implemented as simple precorrections which cannot account for higher order beam hardening effects, or as iterative approaches that are based on segmenting the original image into material distribution images. Conventional segmentation algorithms fail to clearly distinguish between iodine and bone. Our new algorithm, DIBHC, calculates the time-dependent iodine distribution by analyzing the voxel changes of a cardiac perfusion examination (typically N approximately 15 electrocardiogram-correlated scans distributed over a total scan time up to T approximately 30 s). These voxel dynamics are due to changes in contrast agent. This prior information allows to precisely distinguish between bone and iodine and is key to DIBHC where each iteration consists of a multimaterial (soft tissue, bone, iodine) polychromatic forward projection, a raw data comparison and a filtered backprojection. Simulations with a semi-anthropomorphic dynamic phantom and clinical scans using a dual source CT scanner with 2 x 128 slices, a tube voltage of 100 kV, a tube current of 180 mAs, and a rotation time of 0.28 seconds have been carried out. The uncorrected images suffer from beam hardening artifacts that appear as dark bands connecting large concentrations of iodine in the ventricle, aorta, and bony structures. The CT-values of the affected tissue are usually underestimated by roughly 20 HU although deviations of up to 61 HU have been observed. For a quantitative evaluation circular regions of interest have been analyzed. After application of DIBHC the mean values obtained deviate by only 1 HU for the simulations and the corrected values show an increase of up to 61 HU for the measurements. One iteration of DIBHC greatly reduces the beam hardening artifacts induced by the contrast agent dynamics (and those due to bone) now allowing for an improved assessment of contrast agent uptake in the myocardium which is essential for determining myocardial perfusion.

Outcomes of matched sibling donor bone marrow transplantation in children using single-agent calcineurin inhibitors as prophylaxis for graft versus host disease.

PubMed

Elgarten, Caitlin W; Arnold, Danielle E; Bunin, Nancy J; Seif, Alix E

2018-01-01

Optimal graft versus host disease (GVHD) prophylaxis prevents severe manifestations without excess immunosuppression. Standard prophylaxis includes a calcineurin inhibitor (CNI) with low-dose methotrexate. However, single-agent CNI may be sufficient prophylaxis for a defined group of patients. Single-agent CNI has been used for GVHD prophylaxis for human leukocyte antigen (HLA)-matched sibling donor (MSD) bone marrow transplants (BMTs) in young patients at the Children's Hospital of Philadelphia for over 20 years. Here, we describe outcomes using this prophylactic strategy in a recent cohort. We performed a single-institution chart review and retrospective analysis of consecutive children undergoing MSD BMT who received single-agent CNI for GVHD prophylaxis between January 2002 and December 2014. Fifty-two children with a median age of 6.1 years (interquartile range [IQR] 2.5-8.3) and donor age of 6 years (IQR 3-10), with malignant and nonmalignant diseases (n = 35 and 17, respectively) were evaluated. Forty-three (82.6%) received oral prophylaxis with single-agent tacrolimus after initial intravenous therapy. Rates of GVHD were consistent with reported rates on dual prophylaxis: the overall incidence of grades 2-4 acute GVHD was 25.5%, grades 3-4 GVHD 9.8%, and chronic GVHD 10.4%. The cumulative incidence of relapse among children with malignancy was 20% at a median of 237 days (IQR 194-318) post-transplant. Two-year overall survival was 82.7% (95% confidence interval [CI]: 69.4-90.6%) and event-free survival was 78.9% (95% CI: 65.1-87.7%). No patient experienced graft failure. Single-agent CNI is a safe, effective approach to GVHD prophylaxis in young patients undergoing HLA-identical sibling BMT. Additionally, single-agent oral tacrolimus is a reasonable alternative to cyclosporine in this population. © 2017 Wiley Periodicals, Inc.

Human stem cell osteoblastogenesis mediated by novel glycogen synthase kinase 3 inhibitors induces bone formation and a unique bone turnover biomarker profile in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gilmour, Peter S., E-mail: Peter.Gilmour@astrazeneca.com; O'Shea, Patrick J.; Fagura, Malbinder

Wnt activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism in rodents making GSK-3 a potential therapeutic target for osteoporotic and osteolytic metastatic bone disease. To understand the wnt pathway related to human disease translation, the ability of 3 potent inhibitors of GSK-3 (AZD2858, AR79, AZ13282107) to 1) drive osteoblast differentiation and mineralisation using human adipose-derived stem cells (hADSC) in vitro; and 2) stimulate rat bone formation in vivo was investigated. Bone anabolism/resorption was determined using clinically relevant serum biomarkers as indicators of bone turnover and bone formation assessed in femurs by histopathology and pQCT/μCT imaging. GSK-3 inhibitorsmore » caused β-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. AZD2858 produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28 days exposure in rats. After 7 days, AZD2858, AR79 or AZ13282107 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. This biomarker profile was differentiated from anabolic agent PTH{sub 1–34} or the anti-resorptive Alendronate-induced changes. Increased bone formation in cortical and cancellous bone as assessed by femur histopathology supported biomarker changes. 14 day AR79 treatment increased bone mineral density and trabecular thickness, and decreased trabecular number and connectivity assessed by pQCT/μCT. GSK-3 inhibition caused hADSC osteoblastogenesis and mineralisation in vitro. Increased femur bone mass associated with changes in bone turnover biomarkers confirmed in vivo bone formation and indicated uncoupling of bone formation and resorption. - Highlights: • Wnt modulation with 3 novel GSK-3 inhibitors alters bone growth. • Human stem cell osteoblastogenesis and mineralisation produced by GSK-3 inhibition. • In rats, 3 GSK-3 inhibitors produced a unique serum bone turnover biomarker profile. • Enhanced bone formation was seen within 7 to 14 days of compound treatment in rats.« less

Distributed Nash Equilibrium Seeking for Generalized Convex Games with Shared Constraints

NASA Astrophysics Data System (ADS)

Sun, Chao; Hu, Guoqiang

2018-05-01

In this paper, we deal with the problem of finding a Nash equilibrium for a generalized convex game. Each player is associated with a convex cost function and multiple shared constraints. Supposing that each player can exchange information with its neighbors via a connected undirected graph, the objective of this paper is to design a Nash equilibrium seeking law such that each agent minimizes its objective function in a distributed way. Consensus and singular perturbation theories are used to prove the stability of the system. A numerical example is given to show the effectiveness of the proposed algorithms.

Clinical Features and Risk Factors of Skeletal-Related Events in Genitourinary Cancer Patients with Bone Metastasis: A Retrospective Analysis of Prostate Cancer, Renal Cell Carcinoma, and Urothelial Carcinoma.

PubMed

Owari, Takuya; Miyake, Makito; Nakai, Yasushi; Morizawa, Yosuke; Itami, Yoshitaka; Hori, Shunta; Anai, Satoshi; Tanaka, Nobumichi; Fujimoto, Kiyohide

2018-06-06

The objective of the present study was to report the incidence of skeletal-related events (SREs) and identify risk factors for SREs in patients with genitourinary cancer with newly diagnosed bone metastasis. This retrospective study included 180 patients with bone metastasis from prostate cancer (PCa; n = 111), renal cell carcinoma (RCC; n = 43), and urothelial carcinoma (UC; n = 26). Clinical factors at the time of diagnosis of bone metastasis were evaluated with Cox proportional hazards regression analysis to identify independent risk factors for SREs. During follow-up, 29 (26%) patients with PCa, 30 (70%) with RCC, and 15 (58%) with UC developed SREs. Treatment with bone-modifying agents (BMAs) before the development of SREs and within 6 months from the diagnosis of bone metastasis significantly delayed the time to first SRE as compared to nonuse of BMAs. Multivariate analysis identified type of primary cancer (PCa vs. RCC, PCa vs. UC), performance status, and bone pain as significant independent predictive risk factors for SREs. Treatment with BMAs significantly delayed the development of first SREs. The identified predictors of SREs might be useful to select patients who would benefit most from early treatment with BMAs. © 2018 S. Karger AG, Basel.

Lions as Bone Accumulators? Paleontological and Ecological Implications of a Modern Bone Assemblage from Olduvai Gorge.

PubMed

Arriaza, Mari Carmen; Domínguez-Rodrigo, Manuel; Yravedra, José; Baquedano, Enrique

2016-01-01

Analytic models have been developed to reconstruct early hominin behaviour, especially their subsistence patterns, revealed mainly through taphonomic analyses of archaeofaunal assemblages. Taphonomic research is used to discern which agents (carnivores, humans or both) generate the bone assemblages recovered at archaeological sites. Taphonomic frameworks developed during the last decades show that the only large-sized carnivores in African biomes able to create bone assemblages are leopards and hyenas. A carnivore-made bone assemblage located in the short-grassland ecological unit of the Serengeti (within Olduvai Gorge) was studied. Taphonomic analyses of this assemblage including skeletal part representation, bone density, breakage patterns and anatomical distribution of tooth marks, along with an ecological approach to the prey selection made by large carnivores of the Serengeti, were carried out. The results show that this bone assemblage may be the first lion-accumulated assemblage documented, although other carnivores (namely spotted hyenas) may have also intervened through postdepositional ravaging. This first faunal assemblage potentially created by lions constitutes a new framework for neotaphonomic studies. Since lions may accumulate carcasses under exceptional circumstances, such as those documented at the site reported here, this finding may have important consequences for interpretations of early archaeological and paleontological sites, which provide key information about human evolution.

MicroRNA Functions in Osteogenesis and Dysfunctions in Osteoporosis

PubMed Central

van Wijnen, Andre J.; van de Peppel, Jeroen; van Leeuwen, Johannes P.; Lian, Jane B.; Stein, Gary S.; Westendorf, Jennifer J.; Oursler, Merry-Jo; Sampen, Hee-Jeong Im; Taipaleenmaki, Hanna; Hesse, Eric; Riester, Scott; Kakar, Sanjeev

2013-01-01

MicroRNAs (miRNAs) are critical post-transcriptional regulators of gene expression that control osteoblast mediated bone formation and osteoclast-related bone remodelling. Deregulation of miRNA mediated mechanisms is emerging as an important pathological factor in bone degeneration (e.g., osteoporosis) and other bone-related diseases. MiRNAs are intriguing regulatory molecules that are networked with cell signaling pathways and intricate transcriptional programs through ingenuous circuits with remarkably simple logic. This overview examines key principles by which miRNAs control differentiation of osteoblasts as they evolve from mesenchymal stromal cells during osteogenesis, or of osteoclasts as they originate from monocytic precursors in the hematopoietic lineage during osteoclastogenesis. Of particular note are miRNAs that are temporally up-regulated during osteoblastogenesis (e.g., miR-218) or osteoclastogenesis (e.g., miR-148a). Each miRNA stimulates differentiation by suppressing inhibitory signalling pathways (‘double-negative’ regulation). The excitement surrounding miRNAs in bone biology stems from the prominent effects that individual miRNAs can have on biological transitions during differentiation of skeletal cells and correlations of miRNA dysfunction with bone diseases. MiRNAs have significant clinical potential which is reflected by their versatility as disease-specific biomarkers and their promise as therapeutic agents to ameliorate or reverse bone tissue degeneration. PMID:23605904

Lions as Bone Accumulators? Paleontological and Ecological Implications of a Modern Bone Assemblage from Olduvai Gorge

PubMed Central

Arriaza, Mari Carmen; Domínguez-Rodrigo, Manuel; Yravedra, José; Baquedano, Enrique

2016-01-01

Analytic models have been developed to reconstruct early hominin behaviour, especially their subsistence patterns, revealed mainly through taphonomic analyses of archaeofaunal assemblages. Taphonomic research is used to discern which agents (carnivores, humans or both) generate the bone assemblages recovered at archaeological sites. Taphonomic frameworks developed during the last decades show that the only large-sized carnivores in African biomes able to create bone assemblages are leopards and hyenas. A carnivore-made bone assemblage located in the short-grassland ecological unit of the Serengeti (within Olduvai Gorge) was studied. Taphonomic analyses of this assemblage including skeletal part representation, bone density, breakage patterns and anatomical distribution of tooth marks, along with an ecological approach to the prey selection made by large carnivores of the Serengeti, were carried out. The results show that this bone assemblage may be the first lion-accumulated assemblage documented, although other carnivores (namely spotted hyenas) may have also intervened through postdepositional ravaging. This first faunal assemblage potentially created by lions constitutes a new framework for neotaphonomic studies. Since lions may accumulate carcasses under exceptional circumstances, such as those documented at the site reported here, this finding may have important consequences for interpretations of early archaeological and paleontological sites, which provide key information about human evolution. PMID:27144649

N-AC-l-Leu-PEI-mediated miR-34a delivery improves osteogenic differentiation under orthodontic force.

PubMed

Yu, Wenwen; Zheng, Yi; Yang, Zhujun; Fei, Hongbo; Wang, Yang; Hou, Xu; Sun, Xinhua; Shen, Yuqin

2017-12-15

Rare therapeutic genes or agents are reported to control orthodontic bone remodeling. MicroRNAs have recently been associated with bone metabolism. Here, we report the in vitro and in vivo effects of miR-34a on osteogenic differentiation under orthodontic force using an N -acetyl-L-leucine-modified polyethylenimine ( N -Ac-l-Leu-PEI) carrier. N -Ac-l-Leu-PEI exhibited low cytotoxicity and high miR-34a transfection efficiency in rat bone mineral stem cells and local alveolar bone tissue. After transfection, miR-34a enhanced the osteogenic differentiation of Runx2 and ColI , Runx2 and ColI protein levels, and early osteogenesis function under orthodontic strain in vitro . MiR-34a also enhanced alveolar bone remodeling under orthodontic force in vivo , as evidenced by elevated gene and protein expression, upregulated indices of alveolar bone anabolism, and diminished tooth movement. We determined that the mechanism miR-34a in osteogenesis under orthodontic force may be associated with GSK-3β. These results suggested that miR-34a delivered by N -Ac-l-Leu-PEI could be a potential therapeutic target for orthodontic treatment.

The distribution of 99mTc-EHDP in the tissues of the dog and its application in the assessment of fracture healing.

PubMed

Hughes, S

1977-07-01

Technetium-labelled ethane hydroxydiphosphonate (99mTc-EHDP) is a commonly used bone-scanning agent. After injection it leaves the circulation to enter bone and to be cleared by the kidney. The transcapillary exchange of 99mTc-EHDP in bone was examined and found to be low. The capillary movement was compared with that of sucrose, a freely diffusible substance, and it was found that the permeability ratio of 99mTc-EHDP to 14C-sucrose was similar to the diffusion coefficient ratio, suggesting that 99mTc-EHDP passes through the capillaries by the process of passive diffusion. The renal clearance of 99mTc-EHDP was 24 ml/min and was unaffected by the action of parathyroid hormone. After a fracture the bone blood flow increases, although the transcapillary extraction of 99mTc-EHDP does not change. This is because there is an increase, from recruitment and dilatation of capillaries, in the surface area available for exchange. Therefore the increased isotopic activity seen on a bone scan after a fracture is primarily related to an increase in bone blood supply from capillary enhancement within the cortex.

Nutlin-3 Treatment Spares Cisplatin-Induced Inhibition of Bone Healing While Maintaining Osteosarcoma Toxicity

PubMed Central

Stine, Kimo C.; Wahl, Elizabeth C.; Liu, Lichu; Skinner, Robert A.; VanderSchilden, Jaclyn; Bunn, Robert C.; Montgomery, Corey O.; Aronson, James; Becton, David L.; Nicholas, Richard W.; Swearingen, Christopher J.; Suva, Larry J.; Lumpkin, Charles K.

2017-01-01

The majority of Osteosarcoma (OS) patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. These protocols include distraction osteogenesis (DO), which is characterized by direct new bone formation. Cisplatin (CDP) is extensively used for OS chemotherapy and recent studies, using a mouse DO model, have demonstrated that CDP has profound negative effects on bone repair. Recent oncological therapeutic strategies are based on the use of standard cytotoxic drugs plus an assortment of biologic agents. Here we demonstrate that the previously reported CDP-associated inhibition of bone repair can be modulated by the administration of a small molecule p53 inducer (nutlin-3). The effects of nutlin-3 on CDP osteotoxicity were studied using both pre- and post-operative treatment models. In both cases the addition of nutlin-3, bracketing CDP exposure, demonstrated robust and significant bone sparing activity (p < 0.01–0.001). In addition the combination of nutlin-3 and CDP induced equivalent OS tumor killing in a xenograft model. Collectively, these results demonstrate that the induction of p53 peri-operatively protects bone healing from the toxic effects of CDP, while maintaining OS toxicity. PMID:26867804

Cross-talk of MicroRNA and hydrogen sulfide: A novel therapeutic approach for bone diseases.

PubMed

Zhai, Yuankun; Tyagi, Suresh C; Tyagi, Neetu

2017-08-01

Bone homeostasis requires a balance between the bone formation of osteoblasts and bone resorption of osteoclasts to maintain ideal bone mass and bone quality. An imbalance in bone remodeling processes results in bone metabolic disorders such as osteoporosis. Hydrogen sulfide (H 2 S), a gasotransmitter, has attracted the focus of many researchers due to its multiple physiological functions. It has been implicated in anti-inflammatory, vasodilatory, angiogenic, cytoprotective, anti-oxidative and anti-apoptotic mechanisms. H 2 S has also been shown to exert osteoprotective activity through its anti-inflammatory and anti-oxidative effects. However, the underlying molecular mechanisms by which H 2 S mitigates bone diseases are not completely understood. Experimental evidence suggests that H 2 S may regulate signaling pathways by directly influencing a gene in the cascade or interacting with some other gasotransmitter (carbon monoxide or nitric oxide) or both. MicroRNAs (miRNAs) are short non-coding RNAs which regulate gene expression by targeting, binding and suppressing mRNAs; thus controlling cell fate. Certainly, bone remodeling is also regulated by miRNAs expression and has been reported in many studies. MicroRNAs also regulate H 2 S biosynthesis. The inter-regulation of microRNAs and H 2 S opens a new possibility for exploring the H 2 S-microRNA crosstalk in bone diseases. However, the relationship between miRNAs, bone development, and H 2 S is still not well explained. This review focuses on miRNAs and their roles in regulating bone remodeling and possible mechanisms behind H 2 S mediated bone loss inhibition, H 2 S-miRNAs crosstalk in relation to the pathophysiology of bone remodeling, and future perspectives for miRNA-H 2 S as a therapeutic agent for bone diseases. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Tocotrienol supplementation in postmenopausal osteoporosis: evidence from a laboratory study.

PubMed

Muhammad, Norliza; Luke, Douglas Alwyn; Shuid, Ahmad Nazrun; Mohamed, Norazlina; Soelaiman, Ima Nirwana

2013-10-01

Accelerated bone loss that occurs in postmenopausal women has been linked to oxidative stress and increased free radicals. We propose the use of antioxidants to prevent and reverse postmenopausal osteoporosis. This study aimed to examine the effects of tocotrienol, a vitamin E analog, on bone loss due to estrogen deficiency. Our previous study showed that tocotrienol increased the trabecular bone volume and trabecular number in ovariectomized rats. In the current study, we investigated the effects of tocotrienol supplementation on various biochemical parameters in a postmenopausal osteoporosis rat model. A total of 32 female Wistar rats were randomly divided into four groups. The baseline group was sacrificed at the start of the study, and another group was sham operated. The remaining rats were ovariectomized and either given olive oil as a vehicle or treated with tocotrienol at a dose of 60 mg/kg body weight. After four weeks of treatment, blood was withdrawn for the measurement of interleukin-1 (IL1) and interleukin-6 (IL6) (bone resorbing cytokines), serum osteocalcin (a bone formation marker) and pyridinoline (a bone resorption marker). Tocotrienol supplementation in ovariectomized rats significantly reduced the levels of osteocalcin, IL1 and IL6. However, it did not alter the serum pyridinoline level. Tocotrienol prevented osteoporotic bone loss by reducing the high bone turnover rate associated with estrogen deficiency. Therefore, tocotrienol has the potential to be used as an anti-osteoporotic agent in postmenopausal women.

Osteoporosis: the current status of mesenchymal stem cell-based therapy.

PubMed

Phetfong, Jitrada; Sanvoranart, Tanwarat; Nartprayut, Kuneerat; Nimsanor, Natakarn; Seenprachawong, Kanokwan; Prachayasittikul, Virapong; Supokawej, Aungkura

2016-01-01

Osteoporosis, or bone loss, is a progressive, systemic skeletal disease that affects millions of people worldwide. Osteoporosis is generally age related, and it is underdiagnosed because it remains asymptomatic for several years until the development of fractures that confine daily life activities, particularly in elderly people. Most patients with osteoporotic fractures become bedridden and are in a life-threatening state. The consequences of fracture can be devastating, leading to substantial morbidity and mortality of the patients. The normal physiologic process of bone remodeling involves a balance between bone resorption and bone formation during early adulthood. In osteoporosis, this process becomes imbalanced, resulting in gradual losses of bone mass and density due to enhanced bone resorption and/or inadequate bone formation. Several growth factors underlying age-related osteoporosis and their signaling pathways have been identified, such as osteoprotegerin (OPG)/receptor activator of nuclear factor B (RANK)/RANK ligand (RANKL), bone morphogenetic protein (BMP), wingless-type MMTV integration site family (Wnt) proteins and signaling through parathyroid hormone receptors. In addition, the pathogenesis of osteoporosis has been connected to genetics. The current treatment of osteoporosis predominantly consists of antiresorptive and anabolic agents; however, the serious adverse effects of using these drugs are of concern. Cell-based replacement therapy via the use of mesenchymal stem cells (MSCs) may become one of the strategies for osteoporosis treatment in the future.

7 CFR 205.401 - Application for certification.

Code of Federal Regulations, 2010 CFR

2010-01-01

... PROVISIONS NATIONAL ORGANIC PROGRAM Certification § 205.401 Application for certification. A person seeking... certification to a certifying agent. The application must include the following information: (a) An organic... 7 Agriculture 3 2010-01-01 2010-01-01 false Application for certification. 205.401 Section 205.401...

77 FR 8884 - Draft Guidance for Industry on Quality Considerations in Demonstrating Biosimilarity to a...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-15

... information (e.g., characterization, adventitious agent safety, process controls, and specifications) for the... Manufacturing Process Assessment of Physiochemical Properties Functional Activities Receptor Binding and... 351(k) application. FDA will also seek OMB approval for this information collection. In addition, this...

Uncertainty in a spatial evacuation model

NASA Astrophysics Data System (ADS)

Mohd Ibrahim, Azhar; Venkat, Ibrahim; Wilde, Philippe De

2017-08-01

Pedestrian movements in crowd motion can be perceived in terms of agents who basically exhibit patient or impatient behavior. We model crowd motion subject to exit congestion under uncertainty conditions in a continuous space and compare the proposed model via simulations with the classical social force model. During a typical emergency evacuation scenario, agents might not be able to perceive with certainty the strategies of opponents (other agents) owing to the dynamic changes entailed by the neighborhood of opponents. In such uncertain scenarios, agents will try to update their strategy based on their own rules or their intrinsic behavior. We study risk seeking, risk averse and risk neutral behaviors of such agents via certain game theory notions. We found that risk averse agents tend to achieve faster evacuation time whenever the time delay in conflicts appears to be longer. The results of our simulations also comply with previous work and conform to the fact that evacuation time of agents becomes shorter once mutual cooperation among agents is achieved. Although the impatient strategy appears to be the rational strategy that might lead to faster evacuation times, our study scientifically shows that the more the agents are impatient, the slower is the egress time.

Bioinorganic Activity of Technetium Radiopharmaceuticals.

ERIC Educational Resources Information Center

Pinkerton, Thomas C.; And Others

1985-01-01

Technetium radiopharmaceuticals are diagnostic imaging agents used in the field of nuclear medicine to visualize tissues, anatomical structures, and metabolic disorders. Bioavailability of technetium complexes, thyroid imaging, brain imaging, kidney imaging, imaging liver function, bone imaging, and heart imaging are the major areas discussed. (JN)

The fatigue behavior of an amorphous brittle composite material

NASA Astrophysics Data System (ADS)

Kumar, Brijesh

The use of poly methyl methacrylate (PMMA) based bone cement as a grouting agent for the in-vivo fixation of orthopaedic implants has been in practice for nearly fifty years. Fatigue failure of the bone cement has been identified as the primary cause of cement failure. Implant loosening due to the failure of the cement is one of the major reasons necessitating revision surgery. The need for a more fatigue resistant bone cement is well documented in the literature. One method of producing a more fatigue resistant bone cement is to reinforce it with short fibers. The fundamental purpose of this work was to investigate the possible improvement of the fatigue characteristics of bone cement provided by the following two types of fiber reinforcements: short flexible Polyethylene Terephalate (PET) fibers and stiff milled carbon fibers. It has been shown that the reinforcement of the bone cement with fibers provides substantial improvement of the fracture toughness of the bone cement. In this investigation the impact of fiber reinforcement on the fatigue properties of the bone cement was studied. The effects of the fiber reinforcement on the fatigue life of bone cement has been determined experimentally. Since fatigue characteristics are known to have considerable scatter, a methodology was developed to analyze the experimental data in a statistically rigorous manner. The effect of the fiber reinforcement on bone cement was also analyzed using a theoretical approach and by conducting extensive Scanning Electron Microscopy (SEM) of the fractured surfaces. The results of this study indicate that fiber reinforcement improves the fatigue life of bone cement at a very high level of reliability. This could potentially lead to a more fatigue tolerant bone cement, which would delay the need for revision surgery due to implant loosening.

Study of tissue engineered bone nodules by Fourier transform infrared spectroscopy.

PubMed

Aydin, Halil Murat; Hu, Bin; Suso, Josep Sulé; El Haj, Alicia; Yang, Ying

2011-02-21

The key criteria for assessing the success of bone tissue engineering are the quality and quantity of the produced minerals within the cultured constructs. The accumulation of calcium ions and inorganic phosphates in culture medium serves as nucleating agents for the formation of hydroxyapatite, which is the main inorganic component of bone. Bone nodule formation is one of the hallmarks of mineralization in such cell cultures. In this study, we developed a new two-step procedure to accelerate bone formation in which mouse bone cell aggregates were produced first on various chemically treated non-adhesive substrates. After this step, the bone cells' growth and mineralization were followed in conventional culture plates. The number and size of cell aggregates were studied with light microscopy. The minerals' formation in the form of nodules produced by the cell aggregates and the bone crystal quality were studied with Fourier Transform Infrared (FTIR) spectroscopy. The FTIR spectra of the ash specimens (mineral phase only) from thermal gravimetric analysis (TGA) provided valuable information of the quality of the minerals. The υ(4) PO(4) region (550-650 cm(-1)), which reveals apatitic and non-apatitic HPO(4) or PO(4) environments, and phosphate region (910-1180 cm(-1)) were examined for the minerals produced in the form of nodules. The peak position and intensity of the spectra demonstrate that the quality of the bone produced by cell aggregates, especially from the bigger ones, which were formed on Plunoric treated substrates, exhibit a composition more similar to that of native bone. This work establishes a new protocol for high quality bone formation and characterization, with the potential to be applied to bone tissue engineering.

Radiation induced fracture of the scapula

DOE Office of Scientific and Technical Information (OSTI.GOV)

Riggs, J.H. III; Schultz, G.D.; Hanes, S.A.

A case of radiation induced osteonecrosis resulting in a fracture of the scapula in a 76-yr-old female patient with a history of breast carcinoma is presented. Diagnostic imaging, laboratory recommendations and clinical findings are discussed along with an algorithm for the safe management of patients with a history of cancer and musculoskeletal complaints. This case demonstrates the necessity of a thorough investigation of musculoskeletal complaints in patients with previous bone-seeking carcinomas.

Accumulation of rare earth elements in human bone within the lifespan.

PubMed

Zaichick, Sofia; Zaichick, Vladimir; Karandashev, Vasilii; Nosenko, Sergey

2011-02-01

For the first time, the contents of rare earth elements (REEs) in a rib bone of a healthy human were determined. The mean value of the contents of Ce, Dy, Er, Gd, La, Nd, Pr, Sm, Tb, and Yb (10 elements out of 17 total REEs), as well as the upper limit of means for Ho, Lu, Tm, and Y (4 elements) were measured in the rib bone tissue of 38 females and 42 males (15 to 55 years old) using inductively coupled plasma mass spectrometry (ICP-MS). We found age-related accumulation of REEs in the bone tissue of healthy individuals who lived in a non-industrial region. It was calculated that during a lifespan the content of REEs in a skeleton of non-industrial region residents may increase by one to two orders of magnitude. Using our results as indicative normal values and published data we estimated relative Gd accumulation in the bone tissue of patients according to magnetic resonance imaging with contrast agent and La accumulation in the bone tissue of patients receiving hemodialysis after treatment with lanthanum carbonate as a phosphate binder. It was shown that after such procedures contents of Gd and La in the bone tissue of patients are two to three orders of magnitude higher than normal levels. In our opinion, REEs incorporation may affect bone quality and health similar to other potentially toxic trace metals. The impact of elevated REEs content on bone physiology, biochemistry and morphology requires further investigation.

Bone cell-independent benefits of raloxifene on the skeleton: A novel mechanism for improving bone material properties

PubMed Central

Gallant, Maxime A.; Brown, Drew M.; Hammond, Max; Wallace, Joseph M.; Du, Jiang; Deymier-Black, Alix C.; Almer, Jonathan D.; Stock, Stuart R.; Allen, Matthew R.; Burr, David B.

2014-01-01

Raloxifene is an FDA approved agent used to treat bone loss and decrease fracture risk. In clinical trials and animal studies, raloxifene reduces fracture risk and improves bone mechanical properties, but the mechanisms of action remain unclear because these benefits occur largely independent of changes to bone mass. Using a novel experimental approach, machined bone beams, both from mature male canine and human male donors, were depleted of living cells and then exposed to raloxifene ex vivo. Our data show that ex vivo exposure of non-viable bone to raloxifene improves intrinsic toughness, both in canine and human cortical bone beams tested by 4-point bending. These effects are cell-independent and appear to be mediated by an increase in matrix bound water, assessed using basic gravimetric weighing and sophisticated ultrashort echo time magnetic resonance imaging. The hydroxyl groups (−OH) on raloxifene were shown to be important in both the water and toughness increases. Wide and small angle x-ray scattering patterns during 4-pt bending show that raloxifene alters the transfer of load between the collagen matrix and the mineral crystals, placing lower strains on the mineral, and allowing greater overall deformation prior to failure. Collectively, these findings provide a possible mechanistic explanation for the therapeutic effect of raloxifene and more importantly identify a cell-independent mechanism that can be utilized for novel pharmacological approaches for enhancing bone strength. PMID:24468719

Men's health-seeking behaviours regarding bone health after a fragility fracture: a secondary analysis of qualitative data.

PubMed

Sale, J E M; Ashe, M C; Beaton, D; Bogoch, E; Frankel, L

2016-10-01

In our qualitative study, men with fragility fractures described their spouses as playing an integral role in their health behaviours. Men also described taking risks, preferring not to dwell on the meaning of the fracture and/or their bone health. Communication strategies specific to men about bone health should be developed. We examined men's experiences and behaviours regarding bone health after a fragility fracture. We conducted a secondary analysis of five qualitative studies. In each primary study, male and female participants were interviewed for 1-2 h and asked to describe recommendations they had received for bone health and what they were doing about those recommendations. Maintaining the phenomenological approach of the primary studies, the transcripts of all male participants were re-analyzed to highlight experiences and behaviours particular to men. Twenty-two men (50-88 years old) were identified. Sixteen lived with a wife, male partner, or family member and the remaining participants lived alone. Participants had sustained hip fractures (n = 7), wrist fractures (n = 5), vertebral fractures (n = 2) and fractures at other locations (n = 8). Fourteen were taking antiresorptive medication at the time of the interview. In general, men with a wife/female partner described these women as playing an integral role in their health behaviours, such as removing tripping hazards and organizing their medication regimen. While participants described giving up activities due to their bone health, they also described taking risks such as drinking too much alcohol and climbing ladders or deliberately refusing to adhere to bone health recommendations. Finally, men did not dwell on the meaning of the fracture and/or their bone health. Behaviours consistent with those shown in other studies on men were described by our sample. We recommend that future research address these findings in more detail so that communication strategies specific to men about bone health be developed.

From Here to Autonomicity: Self-Managing Agents and the Biological Metaphors that Inspire Them

NASA Technical Reports Server (NTRS)

Sterritt, Roy; Hinchey, Mike

2005-01-01

We seek inspiration for self-managing systems from (obviously, pre-existing) biological mechanisms. Autonomic Computing (AC), a self-managing systems initiative based on the biological metaphor of the autonomic nervous system, is increasingly gaining momentum as the way forward for integrating and designing reliable systems, while agent technologies have been identified as a key enabler for engineering autonomicity in systems. This paper looks at other biological metaphors such as reflex and healing, heart- beat monitors, pulse monitors and apoptosis for assisting in the realization of autonomicity.

Physicians with MBA degrees: change agents for healthcare improvement.

PubMed

Lazarus, Arthur

2010-01-01

Increasingly, physicians gravitating toward the fields of quality improvement and healthcare management are seeking MBA degrees to supplement their medical training. Approximately half of all U.S. medical schools offer combined MD-MBA degrees, and numerous executive MBA programs exist for physicians in practice. Physicians who enter management are considered change agents for healthcare improvement, yet they receive little support and encouragement from their medical teachers and practicing colleagues. This situation can be rectified by placing greater value on the role of business-trained physicians and subsidizing their tuition for business school.

The inhibition of RANK-ligand in the management of postmenopausal osteoporosis and related fractures: the role of denosumab.

PubMed

Capozzi, Anna; Lello, Stefano; Pontecorvi, Alfredo

2014-06-01

There is great interest in new treatments of osteoporosis owing to general ageing of population and increased risk for fragility fractures in the elderly. Current therapies show a good efficacy in improving bone quality and bone density, but, in spite of a certain reduction in fracture rate, according to each treatment, the problem of osteoporotic fractures is yet far from to be solved. Moreover, some treatments may produce different side effects. Denosumab (Dmab), a receptor activator of nuclear factor kappa-B ligand (RANKL)-inhibitor, is an agent recently introduced in clinical practice for treatment of osteoporosis of postmenopausal women. Dmab has improved bone mineral density and prevented new vertebral and non-vertebral fractures with a similar efficacy in comparison with alendronate. Many clinical studies showed Dmab produces also significant improvement versus placebo in bone quality as indicated by decreasing markers of bone turnover. Patients using Dmab reported less risk of AFF (Atypical Femoral Fractures) and ONJ (Osteonecrosis of the Jaw) with an increased number of cellulitis. Here, we review articles using Dmab for female post-menopausal osteoporosis.

A novel route in bone tissue engineering: magnetic biomimetic scaffolds.

PubMed

Bock, N; Riminucci, A; Dionigi, C; Russo, A; Tampieri, A; Landi, E; Goranov, V A; Marcacci, M; Dediu, V

2010-03-01

In recent years, interest in tissue engineering and its solutions has increased considerably. In particular, scaffolds have become fundamental tools in bone graft substitution and are used in combination with a variety of bio-agents. However, a long-standing problem in the use of these conventional scaffolds lies in the impossibility of re-loading the scaffold with the bio-agents after implantation. This work introduces the magnetic scaffold as a conceptually new solution. The magnetic scaffold is able, via magnetic driving, to attract and take up in vivo growth factors, stem cells or other bio-agents bound to magnetic particles. The authors succeeded in developing a simple and inexpensive technique able to transform standard commercial scaffolds made of hydroxyapatite and collagen in magnetic scaffolds. This innovative process involves dip-coating of the scaffolds in aqueous ferrofluids containing iron oxide nanoparticles coated with various biopolymers. After dip-coating, the nanoparticles are integrated into the structure of the scaffolds, providing the latter with magnetization values as high as 15 emu g(-)(1) at 10 kOe. These values are suitable for generating magnetic gradients, enabling magnetic guiding in the vicinity and inside the scaffold. The magnetic scaffolds do not suffer from any structural damage during the process, maintaining their specific porosity and shape. Moreover, they do not release magnetic particles under a constant flow of simulated body fluids over a period of 8 days. Finally, preliminary studies indicate the ability of the magnetic scaffolds to support adhesion and proliferation of human bone marrow stem cells in vitro. Hence, this new type of scaffold is a valuable candidate for tissue engineering applications, featuring a novel magnetic guiding option. Copyright 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

When felids and hominins ruled at Olduvai Gorge: A machine learning analysis of the skeletal profiles of the non-anthropogenic Bed I sites

NASA Astrophysics Data System (ADS)

Arriaza, Mari Carmen; Domínguez-Rodrigo, Manuel

2016-05-01

In the past twenty years, skeletal part profiles, which are prone to equifinality, have not occupied a prominent role in the interpretation of early Pleistocene sites on Africa. Alternatively, taphonomic studies on bone surface modifications and bone breakage patterns, have provided heuristic interpretations of some of the best preserved archaeological record of this period; namely, the Olduvai Bed I sites. The most recent and comprehensive taphonomic study of these sites (Domínguez-Rodrigo et al., 2007a) showed that FLK Zinj was an anthropogenic assemblage in which hominins acquired carcasses via primary access. That study also showed that the other sites were palimpsests with minimal or no intervention by hominins. The FLK N, FLK NN and DK sequence seemed to be dominated by single-agent (mostly, felid) or multiple-agent (mostly, felid-hyenid) processes. The present study re-analyzes the Bed I sites focusing on skeletal part profiles. Machine learning methods, which incorporate complex algorithms, are powerful predictive and classification methods and have the potential to better extract information from skeletal part representation than past approaches. Here, multiple algorithms (via decision trees, neural networks, random forests and support vector machines) are combined to produce a solid interpretation of bone accumulation agency at the Olduvai Bed I sites. This new approach virtually coincides with previous taphonomic interpretations on a site by site basis and shows that felids were dominant accumulating agents over hyenas during Bed I times. The recent discovery of possibly a modern lion-accumulated assemblage at Olduvai Gorge (Arriaza et al., submitted) provides a very timely analog for this interpretation.

Seeing through Musculoskeletal Tissues: Improving In Situ Imaging of Bone and the Lacunar Canalicular System through Optical Clearing

PubMed Central

Berke, Ian M.; Miola, Joseph P.; David, Michael A.; Smith, Melanie K.; Price, Christopher

2016-01-01

In situ, cells of the musculoskeletal system reside within complex and often interconnected 3-D environments. Key to better understanding how 3-D tissue and cellular environments regulate musculoskeletal physiology, homeostasis, and health is the use of robust methodologies for directly visualizing cell-cell and cell-matrix architecture in situ. However, the use of standard optical imaging techniques is often of limited utility in deep imaging of intact musculoskeletal tissues due to the highly scattering nature of biological tissues. Drawing inspiration from recent developments in the deep-tissue imaging field, we describe the application of immersion based optical clearing techniques, which utilize the principle of refractive index (RI) matching between the clearing/mounting media and tissue under observation, to improve the deep, in situ imaging of musculoskeletal tissues. To date, few optical clearing techniques have been applied specifically to musculoskeletal tissues, and a systematic comparison of the clearing ability of optical clearing agents in musculoskeletal tissues has yet to be fully demonstrated. In this study we tested the ability of eight different aqueous and non-aqueous clearing agents, with RIs ranging from 1.45 to 1.56, to optically clear murine knee joints and cortical bone. We demonstrated and quantified the ability of these optical clearing agents to clear musculoskeletal tissues and improve both macro- and micro-scale imaging of musculoskeletal tissue across several imaging modalities (stereomicroscopy, spectroscopy, and one-, and two-photon confocal microscopy) and investigational techniques (dynamic bone labeling and en bloc tissue staining). Based upon these findings we believe that optical clearing, in combination with advanced imaging techniques, has the potential to complement classical musculoskeletal analysis techniques; opening the door for improved in situ investigation and quantification of musculoskeletal tissues. PMID:26930293

Seeing through Musculoskeletal Tissues: Improving In Situ Imaging of Bone and the Lacunar Canalicular System through Optical Clearing.

PubMed

Berke, Ian M; Miola, Joseph P; David, Michael A; Smith, Melanie K; Price, Christopher

2016-01-01

In situ, cells of the musculoskeletal system reside within complex and often interconnected 3-D environments. Key to better understanding how 3-D tissue and cellular environments regulate musculoskeletal physiology, homeostasis, and health is the use of robust methodologies for directly visualizing cell-cell and cell-matrix architecture in situ. However, the use of standard optical imaging techniques is often of limited utility in deep imaging of intact musculoskeletal tissues due to the highly scattering nature of biological tissues. Drawing inspiration from recent developments in the deep-tissue imaging field, we describe the application of immersion based optical clearing techniques, which utilize the principle of refractive index (RI) matching between the clearing/mounting media and tissue under observation, to improve the deep, in situ imaging of musculoskeletal tissues. To date, few optical clearing techniques have been applied specifically to musculoskeletal tissues, and a systematic comparison of the clearing ability of optical clearing agents in musculoskeletal tissues has yet to be fully demonstrated. In this study we tested the ability of eight different aqueous and non-aqueous clearing agents, with RIs ranging from 1.45 to 1.56, to optically clear murine knee joints and cortical bone. We demonstrated and quantified the ability of these optical clearing agents to clear musculoskeletal tissues and improve both macro- and micro-scale imaging of musculoskeletal tissue across several imaging modalities (stereomicroscopy, spectroscopy, and one-, and two-photon confocal microscopy) and investigational techniques (dynamic bone labeling and en bloc tissue staining). Based upon these findings we believe that optical clearing, in combination with advanced imaging techniques, has the potential to complement classical musculoskeletal analysis techniques; opening the door for improved in situ investigation and quantification of musculoskeletal tissues.

Epigallocatechin-3-gallate (EGCG) as a pro-osteogenic agent to enhance osteogenic differentiation of mesenchymal stem cells from human bone marrow: an in vitro study.

PubMed

Jin, Pan; Wu, Huayu; Xu, Guojie; Zheng, Li; Zhao, Jinmin

2014-05-01

The proliferation and osteogenic capacity of mesenchymal stem cells (MSCs) needs to be improved for their use in cell-based therapy for osteoporosis. (-)-Epigallocatechin-3-gallate (EGCG), one of the green tea catechins, has been widely investigated in studies of osteoblasts and osteoclasts. However, no consensus on its role as an osteogenic inducer has been reached, possibly because of the various types of cell lines examined and the range of concentrations of EGCG used. In this study, the osteogenic effects of EGCG are studied in primary human bone-marrow-derived MSCs (hBMSCs) by detecting cell proliferation, alkaline phosphatase (ALP) activity and the expression of relevant osteogenic markers. Our results show that EGCG has a strong stimulatory effect on hBMSCs developing towards the osteogenic lineage, especially at a concentration of 5 μM, as evidenced by an increased ALP activity, the up-regulated expression of osteogenic genes and the formation of bone-like nodules. Further exploration has indicated that EGCG directes osteogenic differentiation via the continuous up-regulation of Runx2. The underlying mechanism might involve EGCG affects on osteogenic differentiation through the modulation of bone morphogenetic protein-2 expression. EGCG has also been found to promote the proliferation of hBMSCs in a dose-dependent manner. This might be associated with its antioxidative effect leading to favorable amounts of reactive oxygen species in the cellular environment. Our study thus indicates that EGCG can be used as a pro-osteogenic agent for the stem-cell-based therapy of osteoporosis.

Bone scintigraphy of the aged patient. 1. /sup 99m/Tc-polyphosphate bone scintigraphy (in Japanese)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamamoto, M.; Chiba, K.; Tanno, M.

Application and evaluation of a new bone-seeking radiopharmaceuticai, / sup 99m/Tc-polyphosphate are reported. Analysis of the image by digital color display data analyzer (Phosdac) was performed. The subjects of the study were cases at Tokyo Metropolitan Geriatric Hospital ranging from 63 to 85 years old with several kinds of bone diseases. Polyphosphate kits (Diagnostic Isotopes, Inc.) were used to prepare /sup 99m/Tc, and a Rho/gamma HP gamma-camera was used for scintigraphy. The images obtained were analyzed by Phosdac to obtain clear image of the bone system. In the final preparation, presence of approximately 30% of free /sup 99m/Tc was noticedmore » by paper chromatography. /sup 99m/Tc- polyphosphate was cleared from the blood with a half time of about 60 min. Urinary excretion proved to be 40 to 60% within 24 hrs. The bone system was visualized rather clearly with high accumulation of the label in the diseased region in spite of the fact that geriatric cases had marked general osteoporotic tendencies. In some cases, ribs were clearly visualized, and different information from that of x-ray was obtained by scanning images. Data processing by Phosdac increased diagnostic accuracy by enhancing the difference of the density of the image as well as eliminating the background caused by free /sup 99m/TcO/sub 4/. In conclusion, /sup 99m/Tc-polyphosphate was proved to be useful for bone scanning in geriatric cases. A digital color display data analyzer was successfully applied for the processing of the original data. (auth)« less

Evaluation and modification of off-host flea collection techniques used in northwest Uganda: laboratory and field studies.

PubMed

Borchert, Jeff N; Eisen, Rebecca J; Holmes, Jennifer L; Atiku, Linda A; Mpanga, Joseph T; Brown, Heidi E; Graham, Christine B; Babi, Nackson; Montenieri, John A; Enscore, Russell E; Gage, Kenneth L

2012-01-01

Quantifying the abundance of host-seeking fleas is critical for assessing risk of human exposure to flea-borne disease agents, including Yersinia pestis, the etiological agent of plague. Yet, reliable measures of the efficacy of existing host-seeking flea collection methods are lacking. In this study, we compare the efficacy of passive and active methods for the collection of host-seeking fleas in both the laboratory and human habitations in a plague-endemic region of northwest Uganda. In the laboratory, lighted "Kilonzo" flea traps modified with either blinking lights, the creation of shadows or the generation of carbon dioxide were less efficient at collecting Xenopsylla cheopis Rothchild and Ctenocephalides felis Bouché fleas than an active collection method using white cotton socks or cotton flannel. Passive collection using Kilonzo light traps in the laboratory collected significantly more X. cheopis than C. felis and active collection, using white socks and flannel, collected significantly more C. felis than X. cheopis. In field studies conducted in Uganda, Kilonzo traps using a flashlight were similar in their collection efficacy to Kilonzo traps using kerosene lamps. However, in contrast to laboratory studies, Kilonzo flea traps using flashlights collected a greater number of fleas than swabbing. Within human habitations in Uganda, Kilonzo traps were especially useful for collecting C. felis, the dominant species found in human habitations in this area.

Bone Mineral 31P and Matrix-Bound Water Densities Measured by Solid-State 1H and 31P MRI

PubMed Central

Seifert, Alan C.; Li, Cheng; Rajapakse, Chamith S.; Bashoor- Zadeh, Mahdieh; Bhagat, Yusuf A.; Wright, Alexander C.; Zemel, Babette S.; Zavaliangos, Antonios; Wehrli, Felix W.

2014-01-01

Bone is a composite material consisting of mineral and hydrated collagen fractions. MRI of bone is challenging due to extremely short transverse relaxation times, but solid-state imaging sequences exist that can acquire the short-lived signal from bone tissue. Previous work to quantify bone density via MRI used powerful experimental scanners. This work seeks to establish the feasibility of MRI-based measurement on clinical scanners of bone mineral and collagen-bound water densities, the latter as a surrogate of matrix density, and to examine the associations of these parameters with porosity and donors’ age. Mineral and matrix-bound water images of reference phantoms and cortical bone from 16 human donors, ages 27-97 years, were acquired by zero-echo-time 31P and 1H MRI on whole body 7T and 3T scanners, respectively. Images were corrected for relaxation and RF inhomogeneity to obtain density maps. Cortical porosity was measured by micro-CT, and apparent mineral density by pQCT. MRI-derived densities were compared to x-ray-based measurements by least-squares regression. Mean bone mineral 31P density was 6.74±1.22 mol/L (corresponding to 1129±204 mg/cc mineral), and mean bound water 1H density was 31.3±4.2 mol/L (corresponding to 28.3±3.7 %v/v). Both 31P and bound water (BW) densities were correlated negatively with porosity (31P: R2 = 0.32, p < 0.005; BW: R2 = 0.63, p < 0.0005) and age (31P: R2 = 0.39, p < 0.05; BW: R2 = 0.70, p < 0.0001), and positively with pQCT density (31P: R2 = 0.46, p < 0.05; BW: R2 = 0.50, p < 0.005). In contrast, the bone mineralization ratio (expressed here as the ratio of 31P density to bound water density), which is proportional to true bone mineralization, was found to be uncorrelated with porosity, age, or pQCT density. This work establishes the feasibility of image-based quantification of bone mineral and bound water densities using clinical hardware. PMID:24846186

Mechanisms of "kidney governing bones" theory in traditional Chinese medicine.

PubMed

Ju, Dahong; Liu, Meijie; Zhao, Hongyan; Wang, Jun

2014-09-01

Studies conducted by our group on the mechanism of "kidney governing bones" theory in traditional Chinese medicine (TCM) are reviewed in this paper. Conclusions can be summarized as follows. (1) Neuroendocrine-immune network (NIN)-osteoclast regulatory pathway OPG-RANKL-RANK is one of the mechanisms of "kidney governing bones." Although kidney-reinforcing therapy is regarded as one of the holistic regulatory mechanisms of the body, characteristic holistic regulation in TCM can be reflected through nonselective regulation of the NIN during kidney reinforcement therapy, which can be used to treat osteoporosis through microadjustments in the microenvironment of the bone marrow. (2) Marrow exhaustion in TCM, which is the state wherein lipocytes in the bone marrow increase whereas other cells decrease, serves as the pathogenesis of osteoporosis brought about by failure of the "kidney governing bones." (3) The kidney in TCM can be regarded as a complex system comprising multiple functional units in the body, including the unit "governing bones." Kidney deficiency refers to a deficiency in only one or more units of the kidney system and not the whole system itself, which explains the kidney-reinforcing effect of many herbs; some herbs can treat osteoporosis, but some cannot. Although both classified as kidney-reinforcing agents, the former can resolve failure of the "kidney governing bones" unit while the latter regulates the failure of other units in the kidney system. Despite the current understanding on "kidney governing bones" theory, the mechanism of "kidney governing bones" remains complicated and unresolved. Thus, further studies in this area are warranted.

Bone-Targeting Radiopharmaceuticals for the Treatment of Bone-Metastatic Castration-Resistant Prostate Cancer: Exploring the Implications of New Data

PubMed Central

Saylor, Philip J.; Everly, Jason J.; Sartor, Oliver

2014-01-01

Background. Clinical features of patients with castration-resistant prostate cancer (CRPC) are characterized by a high incidence of bone metastases, which are associated with impairment of quality of life, pain, skeletal-related events (SREs), and a negative impact on prognosis. Advances in the understanding of cancer cell-bone stroma interactions and molecular mechanisms have recently permitted the development of new agents. Purpose. We review the merits, applications, and limitations of emerging data sets on bone-metastatic CRPC with a focus on radium-223, an α-emitting radiopharmaceutical, and its use in therapy for this disease. Methods. References for this review were identified through searches of PubMed and Medline databases, and only papers published in English were considered. Related links in the databases were reviewed, along with relevant published guidelines, recently published abstracts from major medical meetings, and transcripts from a recent round table of clinical investigators. Results. Prior to radium-223, available bone-targeted therapies demonstrated the ability to delay SREs and palliate bone pain in patients with metastatic CRPC but without evidence of improvement in overall survival (OS). In a randomized controlled phase III trial, radium-223 demonstrated the ability to improve OS and delay SREs in docetaxel-pretreated or docetaxel-unfit men with symptomatic bone-metastatic CRPC and was not associated with significantly more grade 3 or 4 adverse events than placebo. Conclusion. Radium-223 has a targeted effect on bone metastases in CRPC and has an important role in docetaxel-pretreated or docetaxel-unfit men with symptomatic bone-metastatic CRPC. PMID:25232039

Dietary phlorizin enhances osteoblastogenic bone formation through enhancing β-catenin activity via GSK-3β inhibition in a model of senile osteoporosis.

PubMed

Antika, Lucia Dwi; Lee, Eun-Jung; Kim, Yun-Ho; Kang, Min-Kyung; Park, Sin-Hye; Kim, Dong Yeon; Oh, Hyeongjoo; Choi, Yean-Jung; Kang, Young-Hee

2017-11-01

Osteoporosis is one of the most prevalent forms of age-related bone diseases. Increased bone loss with advancing age has become a grave public health concern. This study examined whether phlorizin and phloretin, dihydrochalcones in apple peels, inhibited senile osteoporosis through enhancing osteoblastogenic bone formation in cell-based and aged mouse models. Submicromolar phloretin and phlorizin markedly stimulated osteoblast differentiation of MC3T3-E1 cells with increased transcription of Runx2 and osteocalcin. Senescence-accelerated resistant mouse strain prone-6 (SAMP6) mice were orally supplemented with 10 mg/kg phlorizin and phloretin daily for 12 weeks. Male senescence-accelerated resistant mouse strain R1 mice were employed as a nonosteoporotic age-matched control. Oral administration of ploretin and phorizin boosted bone mineralization in all the bones of femur, tibia and vertebra of SAMP6. In particular, phlorizin reduced serum RANKL/OPG ratio and diminished TRAP-positive osteoclasts in trabecular bones of SAMP6. Additionally, treating phlorizin to SAMP6 inhibited the osteoporotic resorption in distal femoral bones through up-regulating expression of BMP-2 and collagen-1 and decreasing production of matrix-degrading cathepsin K and MMP-9. Finally, phlorizin and phloretin antagonized GSK-3β induction and β-catenin phosphorylation in osteoblasts and aged mouse bones. Therefore, phlorizin and phloretin were potential therapeutic agents encumbering senile osteoporosis through promoting bone-forming osteoblastogenesis via modulation of GSK-3β/β-catenin-dependent signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

Local delivery of a selective androgen receptor modulator failed as an anabolic agent in a rat bone marrow ablation model

PubMed Central

Aro, Hannu T; Kulkova, Julia; Moritz, Niko; Kähkönen, Esa; Mattila, Riina H

2015-01-01

Background and purpose — Selective androgen receptor modulators (SARMs) have been developed to have systemic anabolic effects on bones and muscles without the adverse effects of steroidal androgens. One unexplored therapeutic option is the targeted application of SARMs for the enhancement of local new bone formation. We evaluated the osteogenic efficacy of a locally released SARM (ORM-11984). Methods — ORM-11984 was mixed with a copolymer of L-lactide and ɛ-caprolactone (PLCL). An in vitro dissolution test confirmed the sustainable release of ORM-11984 from the matrix. A bone marrow ablation model was used in female Sprague-Dawley rats. Implants containing 10%, 30%, or 50% ORM-11984 by weight or pure PLCL were inserted into the medullary canal of the ablated tibia. At 6 and 12 weeks, the volume of intramedullary new bone and the perimeter of bone-implant contact were measured by micro-computed tomography and histomorphometry. Results — Contrary to our hypothesis, there was a negative correlation between the amount of new bone around the implant and the dose of ORM-11984. There was only a mild (and not statistically significant) enhancement of bone formation in ablated bones subjected to the lowest dose of the SARM (10%). Interpretation — This study suggests that intramedullary/endosteal osteogenesis had a negative, dose-dependent response to locally released SARM. This result highlights the complexity of androgenic effects on bones and also suggests that there are biological limits to the targeted local application of SARMs. PMID:26198725

Preparation and characterization of an iron oxide-hydroxyapatite nanocomposite for potential bone cancer therapy.

PubMed

Sneha, Murugesan; Sundaram, Nachiappan Meenakshi

2015-01-01

Recently, multifunctional magnetic nanostructures have been found to have potential applications in biomedical and tissue engineering. Iron oxide nanoparticles are biocompatible and have distinctive magnetic properties that allow their use in vivo for drug delivery and hyperthermia, and as T2 contrast agents for magnetic resonance imaging. Hydroxyapatite is used frequently due to its well-known biocompatibility, bioactivity, and lack of toxicity, so a combination of iron oxide and hydroxyapatite materials could be useful because hydroxyapatite has better bone-bonding ability. In this study, we prepared nanocomposites of iron oxide and hydroxyapatite and analyzed their physicochemical properties. The results suggest that these composites have superparamagnetic as well as biocompatible properties. This type of material architecture would be well suited for bone cancer therapy and other biomedical applications.

U.S. Officials Scrutinize Colleges' Deals with Lenders

ERIC Educational Resources Information Center

Field, Kelly

2007-01-01

In December 2005, purchasing agents at Florida International University issued a request for proposals seeking banks and student-loan companies for a list of "preferred lenders" that the university planned to give to prospective borrowers. The request alone was not unusual. Many colleges use competitive bidding to secure attractive terms…

7 CFR 205.504 - Evidence of expertise and ability.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 3 2013-01-01 2013-01-01 false Evidence of expertise and ability. 205.504 Section 205... expertise and ability. A private or governmental entity seeking accreditation as a certifying agent must... handling techniques; its ability to fully comply with and implement the organic certification program...

Prostaglandin E2 Prevents Ovariectomy-Induced Cancellous Bone Loss in Rats

NASA Technical Reports Server (NTRS)

Ke, Hua Zhu; Li, Mei; Jee, Webster S. S.

1992-01-01

The object of this study was to determine whether prostaglandin E2, (PGE2) can prevent ovariectomy induced cancellous bone loss. Thirty-five 3-month-old female Sprague-Dawley rats were divided into two groups. The rats in the first group were ovariectomized (OVX) while the others received sham operation (sham-OVX). The OVX group was further divided into three treatment groups. The daily doses for the three groups were 0,1 and 6 mg PGE2/kg for 90 days. Bone histomorphometric analyses were performed on double-fluorescent-labeled undecalcified proximal tibial metaphysis (PTM). We confirmed that OVX induces massive cancellous bone loss (-80%) and a higher bone turnover (+143%). The new findings from the present study demonstrate that bone loss due to ovarian hormone deficiency can be prevented by a low-dose (1 mg) daily administration of PGE2. Furthermore, a higher-dose (6 mg) daily administration of PGE2 not only prevents bone loss but also adds extra bone to the proximal tibial metaphyses. PGE, at the 1-mg dose level significantly increased trabecular bone area, trabecular width, trabecular node density, density of node to node, ratio of node to free end, and thus significantly decreased trabecular separation from OVX controls. At this dose level, these same parameters did not differ significantly from sham-OVX controls. However, at the 6-mg dose level PGE2, there were significant increases in trabecular bone area, trabecular width, trabecular node density, density of node to node, and ratio of node to free end, while there was significant decrease in trabecular separation from both OVX and sham-operated controls. The changes in indices of trabecular bone microanatomical structure indicated that PGE2 prevented bone loss as well as the disconnection of existing trabeculae. In summary, PGE2, administration to OVX rats decreased bone turnover and increased bone formation parameters resulting in a positive bone balance that prevented bone loss (in both lower and higher doses) and added extra bone to metaphyses of OVX rats (in higher dose). These findings support the strategy of the use of bone stimulation agents in the prevention of estrogen depletion bone loss (postmenopausal osteoporosis).

42 CFR 71.50 - Scope and definitions.

Code of Federal Regulations, 2014 CFR

2014-10-01

... importations of various animal hosts or vectors or other etiological agents from foreign countries into the... the following meanings: Animal product or Product means the hide, hair, skull, teeth, bones, claws, blood, tissue, or other biological samples from an animal, including trophies, mounts, rugs, or other...

42 CFR 71.50 - Scope and definitions.

Code of Federal Regulations, 2013 CFR

2013-10-01

... importations of various animal hosts or vectors or other etiological agents from foreign countries into the... the following meanings: Animal product or Product means the hide, hair, skull, teeth, bones, claws, blood, tissue, or other biological samples from an animal, including trophies, mounts, rugs, or other...

Gadolinium toxicity and treatment.

PubMed

Ramalho, Joana; Ramalho, Miguel; Jay, Michael; Burke, Lauren M; Semelka, Richard C

2016-12-01

Gadolinium based contrast agents (GBCAs) play an important role in the diagnostic evaluation of many patients. The safety of these agents has been once again questioned after gadolinium deposits were observed and measured in brain and bone of patients with normal renal function. This retention of gadolinium in the human body has been termed "gadolinium storage condition". The long-term and cumulative effects of retained gadolinium in the brain and elsewhere are not as yet understood. Recently, patients who report that they suffer from chronic symptoms secondary to gadolinium exposure and retention created gadolinium-toxicity on-line support groups. Their self-reported symptoms have recently been published. Bone and joint complaints, and skin changes were two of the most common complaints. This condition has been termed "gadolinium deposition disease". In this review we will address gadolinium toxicity disorders, from acute adverse reactions to GBCAs to gadolinium deposition disease, with special emphasis on the latter, as it is the most recently described and least known. Copyright © 2016 Elsevier Inc. All rights reserved.

International Myeloma Working Group Consensus Statement for the Management, Treatment, and Supportive Care of Patients With Myeloma Not Eligible for Standard Autologous Stem-Cell Transplantation

PubMed Central

Palumbo, Antonio; Rajkumar, S. Vincent; San Miguel, Jesus F.; Larocca, Alessandra; Niesvizky, Ruben; Morgan, Gareth; Landgren, Ola; Hajek, Roman; Einsele, Hermann; Anderson, Kenneth C.; Dimopoulos, Meletios A.; Richardson, Paul G.; Cavo, Michele; Spencer, Andrew; Stewart, A. Keith; Shimizu, Kazuyuki; Lonial, Sagar; Sonneveld, Pieter; Durie, Brian G.M.; Moreau, Philippe; Orlowski, Robert Z.

2014-01-01

Purpose To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. Methods A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. Results Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. Conclusion These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice. PMID:24419113

Clinical aspects of feline immunodeficiency and feline leukemia virus infection.

PubMed

Hartmann, Katrin

2011-10-15

Feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) are retroviruses with a global impact on the health of domestic cats. The two viruses differ in their potential to cause disease. FIV can cause an acquired immunodeficiency syndrome that increases the risk of developing opportunistic infections, neurological diseases, and tumors. In most naturally infected cats, however, FIV itself does not cause severe clinical signs, and FIV-infected cats may live many years without any health problems. FeLV is more pathogenic, and was long considered to be responsible for more clinical syndromes than any other agent in cats. FeLV can cause tumors (mainly lymphoma), bone marrow suppression syndromes (mainly anemia) and lead to secondary infectious diseases caused by suppressive effects of the virus on bone marrow and the immune system. Today, FeLV is less important as a deadly infectious agent as in the last 20 years prevalence has been decreasing in most countries. Copyright © 2011 Elsevier B.V. All rights reserved.

New Paradigms for Advanced Prostate Cancer

PubMed Central

Petrylak, Daniel P

2007-01-01

In men with metastatic hormone-refractory prostate cancer, androgen blockade produces dramatic and rapid declines in prostate-specific antigen (PSA), bone pain, and urinary tract obstruction. Nevertheless, there have been limited options with at best palliative results for patients who progress despite a castrate testosterone level. This paradigm changed in 2004 with the publication of 2 randomized clinical trials that demonstrated a 20% to 24% survival benefit for docetaxel-based therapy when compared to mitoxantrone and prednisone, data that supported US Food and Drug Administration approval of docetaxel-based therapy for the treatment of metastatic hormone-refractory prostate cancer. This article reviews the preliminary data and the timing and sequencing implications of ongoing clinical trials. Studies are evaluating the combination of docetaxel with agents that target bone, tumor vasculature, and the vitamin D receptor as well as second-line agents, such as satraplatin. The role of immune therapy is also evolving, and further studies will define the optimal timing of chemotherapy with immune therapy. PMID:17554403

Fabrication and performance of porous lithium sodium potassium niobate ceramic

NASA Astrophysics Data System (ADS)

Chen, Caifeng; Zhu, Yuan; Ji, Jun; Cai, Feixiang; Zhang, Youming; Zhang, Ningyi; Wang, Andong

2018-02-01

Porous lithium sodium potassium niobate (LNK) ceramic has excellent piezoelectric properties, chemical stability and great chemical compatibility. It has a good application potential in the field of biological bone substitute. In the paper, porous LNK ceramic was fabricated with egg albumen foaming agent by foaming method. Effects of preparation process of the porous LNK ceramic on density, phase structure, hole size and piezoelectric properties were researched and characterized. The results show that the influence factors of LNK solid content and foaming agent addition are closely relevant to properties of the porous LNK ceramic. When solid content is 65% and foaming agent addition is 30%, the porous LNK ceramic has uniform holes and the best piezoelectric properties.

Incidence of hypophosphatemia in advanced cancer patients: a recent report from a single institution.

PubMed

Yoshida, Taichi; Taguchi, Daiki; Fukuda, Koji; Shimazu, Kazuhiro; Inoue, Masahiro; Murata, Katsunori; Shibata, Hiroyuki

2017-04-01

Recent approval of molecular-targeted agents has contributed to improving the therapeutic outcomes of advanced cancer patients. However, they result in unusual adverse events that rarely occur with cytotoxic agents, such as hypertension, hypomagnesemia, and an acne-like rash. Although hypophosphatemia can be induced by various agents, some kinds of molecular-targeted agents are known to induce it. In addition, cancer survivors may be at a risk of hypophosphatemia. One hundred and seventy patients, who visited the Department of Clinical Oncology at Akita University from 1 April 2014 to 31 August 2016 were enrolled in this study after providing informed consent. Serum inorganic phosphorus levels were examined along with other routine clinical examinations. Correlation between the serum inorganic phosphorus level and other clinical data were also analyzed. Grade ≥2 severe hypophosphatemia (<2.5 mg/dL of phosphorus) was detected in 49.4% of patients, and grade ≥3 (<2.0 mg/dL of phosphorus) was observed in 22.9% patients. These results indicated that the presence of bone metastasis (p < 0.001), history of bone-modifying agents (p < 0.001) and molecular-targeted drugs (p = 0.001), and time from the date of the first visit to the date of minimum serum phosphorus level (p < 0.001) might correlate with hypophosphatemia. Multivariate logistic regression analysis showed that disease duration might be a risk factor (p = 0.0466). As hypophosphatemia can be induced by various factors in advanced cancer patients, the serum phosphorus level of cancer patients at risk should be cautiously examined.

Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease

PubMed Central

Nyman, Jeffry S.; Merkel, Alyssa R.; Uppuganti, Sasidhar; Nayak, Bijaya; Rowland, Barbara; Makowski, Alexander J.; Oyajobi, Babatunde O.; Sterling, Julie A.

2016-01-01

Multiplemyeloma (MM) patients frequently develop tumor-induced bone destruction, yet no therapy completely eliminates the tumor or fully reverses bone loss. Transforming growth factor-β (TGF-β) activity often contributes to tumor-induced bone disease, and pre-clinical studies have indicated that TGF-β inhibition improves bone volume and reduces tumor growth in bone metastatic breast cancer. We hypothesized that inhibition of TGF-β signaling also reduces tumor growth, increases bone volume, and improves vertebral body strength in MM-bearing mice. We treated myeloma tumor-bearing (immunocompetent KaLwRij and immunocompromised Rag2 −/−) mice with a TGF-β inhibitory (1D11) or control (13C4) antibody, with or without the anti-myeloma drug bortezomib, for 4 weeks after inoculation of murine 5TGM1 MM cells. TGF-β inhibition increased trabecular bone volume, improved trabecular architecture, increased tissue mineral density of the trabeculae as assessed by ex vivo micro-computed tomography, and was associated with significantly greater vertebral body strength in biomechanical compression tests. Serum monoclonal paraprotein titers and spleen weights showed that 1D11 monotherapy did not reduce overall MM tumor burden. Combination therapy with 1D11 and bortezomib increased vertebral body strength, reduced tumor burden, and reduced cortical lesions in the femoral metaphysis, although it did not significantly improve cortical bone strength in three-point bending tests of the mid-shaft femur. Overall, our data provides rationale for evaluating inhibition of TGF-β signaling in combination with existing anti-myeloma agents as a potential therapeutic strategy to improve outcomes in patients with myeloma bone disease. PMID:27423464

Effects of abaloparatide-SC (BA058) on bone histology and histomorphometry: The ACTIVE phase 3 trial.

PubMed

Moreira, Carolina A; Fitzpatrick, Lorraine A; Wang, Yamei; Recker, Robert R

2017-04-01

There are a number of effective treatments for osteoporosis but most are in the antiresorptive class of compounds. Abaloparatide-SC is a new osteoanabolic agent, which increased bone mineral density and lowered the risk of osteoporosis-related fractures in the phase 3 ACTIVE trial. The objective of this report is to describe the effects of abaloparatide-SC 80μg on bone histology and histomorphometry in iliac crest bone biopsies from this trial in which participants were randomized to receive blinded daily subcutaneous injections of placebo or abaloparatide-SC 80μg/d or open-label teriparatide 20μg/d for 18months. Iliac crest bone biopsies were obtained between 12 and 18months. Qualitative histological analysis of biopsies from abaloparatide-SC-treated patients revealed normal bone microarchitecture without evidence of adverse effects on mineralization or on the formation of normal lamellar bone. There were no bone marrow abnormalities, marrow fibrosis nor was there presence of excess osteoid or woven bone. There were few significant differences among the three treatment groups in a standard panel of static and dynamic histomorphometric indices. The mineral apposition rate was higher in the teriparatide-treated group than in the placebo-treated group. The eroded surface was lower in the abaloparatide-SC-treated group than in the placebo-treated group. Cortical porosity was higher in both the abaloparatide-SC- and the teriparatide-treated groups than in the placebo-treated group. We conclude that histological and histomorphometric analysis of iliac crest bone biopsies from subjects who were treated for up to 18months with abaloparatide-SC showed no evidence of concern for bone safety. ClinicalTrials.gov number NCT01343004. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease.

PubMed

Nyman, Jeffry S; Merkel, Alyssa R; Uppuganti, Sasidhar; Nayak, Bijaya; Rowland, Barbara; Makowski, Alexander J; Oyajobi, Babatunde O; Sterling, Julie A

2016-10-01

Multiple myeloma (MM) patients frequently develop tumor-induced bone destruction, yet no therapy completely eliminates the tumor or fully reverses bone loss. Transforming growth factor-β (TGF-β) activity often contributes to tumor-induced bone disease, and pre-clinical studies have indicated that TGF-β inhibition improves bone volume and reduces tumor growth in bone metastatic breast cancer. We hypothesized that inhibition of TGF-β signaling also reduces tumor growth, increases bone volume, and improves vertebral body strength in MM-bearing mice. We treated myeloma tumor-bearing (immunocompetent KaLwRij and immunocompromised Rag2-/-) mice with a TGF-β inhibitory (1D11) or control (13C4) antibody, with or without the anti-myeloma drug bortezomib, for 4weeks after inoculation of murine 5TGM1 MM cells. TGF-β inhibition increased trabecular bone volume, improved trabecular architecture, increased tissue mineral density of the trabeculae as assessed by ex vivo micro-computed tomography, and was associated with significantly greater vertebral body strength in biomechanical compression tests. Serum monoclonal paraprotein titers and spleen weights showed that 1D11 monotherapy did not reduce overall MM tumor burden. Combination therapy with 1D11 and bortezomib increased vertebral body strength, reduced tumor burden, and reduced cortical lesions in the femoral metaphysis, although it did not significantly improve cortical bone strength in three-point bending tests of the mid-shaft femur. Overall, our data provides rationale for evaluating inhibition of TGF-β signaling in combination with existing anti-myeloma agents as a potential therapeutic strategy to improve outcomes in patients with myeloma bone disease. Published by Elsevier Inc.

Inorganic materials for bone repair or replacement applications.

PubMed

Hertz, Audrey; Bruce, Ian J

2007-12-01

In recent years, excipient systems have been used increasingly in biomedicine in reconstructive and replacement surgery, as bone cements, drug-delivery vehicles and contrast agents. Particularly, interest has been growing in the development and application of controlled pore inorganic ceramic materials for use in bone-replacement and bone-repair roles and, in this context, attention has been focused on calcium-phosphate, bioactive glasses and SiO2- and TiO2-based materials. It has been shown that inorganic materials that most closely mimic bone structure and surface chemistry most closely function best in bone replacement/repair and, in particular, if a substance possesses a macroporous structure (pores and interconnections >100 microm diameter), then cell infiltration, bone growth and vascularization can all be promoted. The surface roughness and micro/mesoporosity of a material have also been observed to significantly influence its ability to promote apatite nucleation and cell attachment significantly. Pores (where present) can also be packed with pharmaceuticals and biomolecules (e.g., bone morphogenetic proteins [BMPs], which can stimulate bone formation). Finally, the most bio-efficient - in terms of collagen formation and apatite nucleation - materials are those that are able to provide soluble mineralizing species (Si, Ca, PO(4)) at their implant sites and/or are doped or have been surface-activated with specific functional groups. This article presents the context and latest advances in the field of bone-repair materials, especially with respect to the development of bioactive glasses and micro/mesoporous and macroporous inorganic scaffolds. It deals with the possible methods of preparing porous pure/doped or functionalized silicas or their composites, the studies that have been undertaken to evaluate their abilities to act as bone repair scaffolds and also presents future directions for work in that context.

The Chondrogenic Induction Potential for Bone Marrow-Derived Stem Cells between Autologous Platelet-Rich Plasma and Common Chondrogenic Induction Agents: A Preliminary Comparative Study.

PubMed

Wang, Shan-Zheng; Chang, Qing; Kong, Xiang-Fei; Wang, Chen

2015-01-01

The interests in platelet-rich plasma (PRP) and their application in stem cell therapy have contributed to a better understanding of the basic biology of the prochondrogenesis effect on bone marrow-derived stem cells (BMSCs). We aimed at comparing the effect of autologous PRP with common chondrogenic induction agents (CCIAs) on the chondrogenic differentiation of BMSCs. Rabbit BMSCs were isolated and characterized by flow cytometry and differentiated towards adipocytes and osteoblasts. The chondrogenic response of BMSCs to autologous PRP and CCIAs which included transforming growth factor-β1 (TGF-β1), dexamethasone (DEX), and vitamin C (Vc) was examined by cell pellet culture. The isolated BMSCs after two passages highly expressed CD29 and CD44 but minimally expressed CD45. The osteogenic and adipogenic differentiation potentials of the isolated BMSCs were also confirmed. Compared with common CCIAs, autologous PRP significantly upregulated the chondrogenic related gene expression, including Col-2, AGC, and Sox-9. Osteogenic related gene expression, including Col-1 and OCN, was not of statistical significance between these two groups. Thus, our data shows that, compared with common chondrogenic induction agents, autologous PRP can be more effective in promoting the chondrogenesis of BMSCs.

Validity of maternal report of care-seeking for childhood illness.

PubMed

Carter, Emily D; Ndhlovu, Micky; Munos, Melinda; Nkhama, Emmy; Katz, Joanne; Eisele, Thomas P

2018-06-01

Accurate data on care-seeking for child illness are needed to improve public health programs and reduce child mortality. The accuracy of maternal report of care-seeking for child illness as collected through household surveys has not been validated. A 2016 survey compared reported care-seeking against a gold-standard of health care provider documented care-seeking events among a random sample of mothers of children <5 years in Southern Province, Zambia. Enrolled children were assigned cards with unique barcodes. Seventy-five health care providers were given smartphones with a barcode reader and instructed to scan the cards of participating children seeking care at the source, generating an electronic record of the care-seeking event. Additionally, providers gave all caregivers accessing care for a child <5 years provider-specific tokens used to verify the point of care during the household survey. Reported care-seeking events were ascertained in each household using a questionnaire modeled off the Zambia Demographic and Health Survey (DHS) / Multiple Indicator Cluster Survey (MICS). The accuracy of maternal report of care-seeking behavior was estimated by comparing care-seeking events reported by mothers against provider-documented events. Data were collected on 384 children with fever, diarrhea, and/or symptoms of ARI in the preceding 2 weeks. Most children sought care from government facilities or community-based agents (CBAs). We found high sensitivity (Rural: 0.91, 95% confidence interval CI 0.84-0.95; Urban: 0.98, 95% CI 0.92-0.99) and reasonable specificity (Rural: 0.71, 95% CI 0.57-0.82; Urban: 0.76, 95% CI 0.62-0.85) of maternal report of care-seeking for child illness by type of provider. Maternal report of any care-seeking and seeking care from a skilled provider had slightly higher sensitivity and specificity. Seeking care from a traditional practitioner was associated with lower odds of accurately reporting the event, while seeking care from a government provider was associated with greater odds of accurate report. The measure resulted in a slight overestimation of true care-seeking behavior in the study population. Maternal report is a valid measure of care-seeking for child illness in settings with high utilization of public sector providers. The study findings were limited by the low diversity in care-seeking practices for child illness and the exclusion of shops.

Lessons Learned From the Children’s Environmental Exposure Research Study

PubMed Central

Resnik, David B.; Wing, Steven

2007-01-01

We examined 5 different ethical concerns about the Children’s Environmental Exposure Research Study and make some recommendations for future studies of exposure to hazardous environmental agents in the home. Researchers should seek community consultation and participation; make participants aware of all the risks associated with the research, including hazards discovered in the home and uncertainties about the risks of agents under investigation; and take steps to ensure that their studies will not have unfair representation of the poor or people of color. Researchers should also avoid even the appearance of a financial conflict of interest in studies that are likely to be controversial and make it clear to all parties that studies will not intentionally expose subjects to hazardous environmental agents. PMID:17267718

Lessons learned from the Children's Environmental Exposure Research Study.

PubMed

Resnik, David B; Wing, Steven

2007-03-01

We examined 5 different ethical concerns about the Children's Environmental Exposure Research Study and make some recommendations for future studies of exposure to hazardous environmental agents in the home. Researchers should seek community consultation and participation; make participants aware of all the risks associated with the research, including hazards discovered in the home and uncertainties about the risks of agents under investigation; and take steps to ensure that their studies will not have unfair representation of the poor or people of color. Researchers should also avoid even the appearance of a financial conflict of interest in studies that are likely to be controversial and make it clear to all parties that studies will not intentionally expose subjects to hazardous environmental agents.