Denosumab for bone diseases: translating bone biology into targeted therapy.

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Tsourdi, Elena; Rachner, Tilman D; Rauner, Martina; Hamann, Christine; Hofbauer, Lorenz C

2011-12-01

Signalling of receptor activator of nuclear factor-κB (RANK) ligand (RANKL) through RANK is a critical pathway to regulate the differentiation and activity of osteoclasts and, hence, a master regulator of bone resorption. Increased RANKL activity has been demonstrated in diseases characterised by excessive bone loss such as osteoporosis, rheumatoid arthritis and osteolytic bone metastases. The development and approval of denosumab, a fully MAB against RANKL, has heralded a new era in the treatment of bone diseases by providing a potent, targeted and reversible inhibitor of bone resorption. This article summarises the molecular and cellular biology of the RANKL/RANK system and critically reviews preclinical and clinical studies that have established denosumab as a promising novel therapy for metabolic and malignant bone diseases. We will discuss the potential indications for denosumab along with a critical review of safety and analyse its potential within the concert of established therapies.

Study partners should be required in preclinical Alzheimer's disease trials.

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Grill, Joshua D; Karlawish, Jason

2017-12-06

In an effort to intervene earlier in Alzheimer's disease (AD), clinical trials are testing promising candidate therapies in preclinical disease. Preclinical AD trial participants are cognitively normal, functionally independent, and autonomous decision-makers. Yet, like AD dementia trials, preclinical trials require dual enrollment of a participant and a knowledgeable informant, or study partner. The requirement of dyadic enrollment is a barrier to recruitment and may present unique ethical challenges. Despite these limitations, the requirement should continue. Study partners may be essential to ensure participant safety and wellbeing, including overcoming distress related to biomarker disclosure and minimizing risk for catastrophic reactions and suicide. The requirement may maximize participant retention and ensure data integrity, including that study partners are the source of data that will ultimately instruct whether a new treatment has a clinical benefit and meaningful impact on the population health burden associated with AD. Finally, study partners are needed to ensure the scientific and clinical value of trials. Preclinical AD will represent a new model of care, in which persons with no symptoms are informed of probable cognitive decline and eventual dementia. The rationale for early diagnosis in symptomatic AD is equally applicable in preclinical AD-to minimize risk, maximize quality of life, and ensure optimal planning and communication. Family members and other sources of support will likely be essential to the goals of this new model of care for preclinical AD patients and trials must instruct this clinical practice.

Microenvironmental influence on pre-clinical activity of polo-like kinase inhibition in multiple myeloma: implications for clinical translation.

Directory of Open Access Journals (Sweden)

Douglas W McMillin

Full Text Available Polo-like kinases (PLKs play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM. We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM and rapid (commitment to cell death <24 hrs in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM

A numerical study on stress distribution across the ankle joint: Effects of material distribution of bone, muscle force and ligaments.

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Mondal, Subrata; Ghosh, Rajesh

2017-09-01

The goal of this study is to develop a realistic three dimensional FE model of intact ankle joint. Three dimensional FE model of the intact ankle joint was developed using computed tomography data sets. The effect of muscle force, ligaments and proper material property distribution of bone on stress distribution across the intact ankle joint was studied separately. Present study indicates bone material property, ligaments and muscle force have influence on stress distribution across the ankle joint. Proper bone material, ligaments and muscle must be considered in the computational model for pre-clinical analysis of ankle prosthesis.

Gallium a unique anti-resorptive agent in bone: Preclinical studies on its mechanisms of action

International Nuclear Information System (INIS)

Bockman, R.; Adelman, R.; Donnelly, R.; Brody, L.; Warrell, R.; Jones, K.W.

1990-01-01

The discovery of gallium as a new and unique agent for the treatment of metabolic bone disorders was in part fortuitous. Gallium is an exciting new therapeutic agent for the treatment of pathologic states characterized by accelerated bone resorption. Compared to other therapeutic metal compounds containing platinum or germanium, gallium affects its antiresorptive action without any evidence of a cytotoxic effect on bone cells. Gallium is unique amongst all therapeutically available antiresorptive agents in that it favors bone formation. 18 refs., 1 fig

Animal models for bone tissue engineering and modelling disease

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Griffin, Michelle

2018-01-01

ABSTRACT Tissue engineering and its clinical application, regenerative medicine, are instructing multiple approaches to aid in replacing bone loss after defects caused by trauma or cancer. In such cases, bone formation can be guided by engineered biodegradable and nonbiodegradable scaffolds with clearly defined architectural and mechanical properties informed by evidence-based research. With the ever-increasing expansion of bone tissue engineering and the pioneering research conducted to date, preclinical models are becoming a necessity to allow the engineered products to be translated to the clinic. In addition to creating smart bone scaffolds to mitigate bone loss, the field of tissue engineering and regenerative medicine is exploring methods to treat primary and secondary bone malignancies by creating models that mimic the clinical disease manifestation. This Review gives an overview of the preclinical testing in animal models used to evaluate bone regeneration concepts. Immunosuppressed rodent models have shown to be successful in mimicking bone malignancy via the implantation of human-derived cancer cells, whereas large animal models, including pigs, sheep and goats, are being used to provide an insight into bone formation and the effectiveness of scaffolds in induced tibial or femoral defects, providing clinically relevant similarity to human cases. Despite the recent progress, the successful translation of bone regeneration concepts from the bench to the bedside is rooted in the efforts of different research groups to standardise and validate the preclinical models for bone tissue engineering approaches. PMID:29685995

Perspective: Recommendations for benchmarking pre-clinical studies of nanomedicines

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Dawidczyk, Charlene M.; Russell, Luisa M.; Searson, Peter C.

2015-01-01

Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small molecule drug therapy for cancer, and to achieve both therapeutic and diagnostic functions in the same platform. Pre-clinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of pre-clinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of pre-clinical trials and propose a protocol for benchmarking that we recommend be included in in vivo pre-clinical studies of drug delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. PMID:26249177

Quantification of osteolytic bone lesions in a preclinical rat trial

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Fränzle, Andrea; Bretschi, Maren; Bäuerle, Tobias; Giske, Kristina; Hillengass, Jens; Bendl, Rolf

2013-10-01

In breast cancer, most of the patients who died, have developed bone metastasis as disease progression. Bone metastases in case of breast cancer are mainly bone destructive (osteolytic). To understand pathogenesis and to analyse response to different treatments, animal models, in our case rats, are examined. For assessment of treatment response to bone remodelling therapies exact segmentations of osteolytic lesions are needed. Manual segmentations are not only time-consuming but lack in reproducibility. Computerized segmentation tools are essential. In this paper we present an approach for the computerized quantification of osteolytic lesion volumes using a comparison to a healthy reference model. The presented qualitative and quantitative evaluation of the reconstructed bone volumes show, that the automatically segmented lesion volumes complete missing bone in a reasonable way.

Selection of unrelated donors for bone marrow transplantation studied in rhesus monkeys

International Nuclear Information System (INIS)

Wagemaker, G.; Bekkum, D.W. van

Graft versus Host disease (GvHD) remains to be a severe limitation to a more general application of bone marrow transplantation. Clinically acceptable results are restricted to those potential recipients for which a major histocompatibility complex (MHC) identical sibling donor is available. At an average family size of 2 to 3 siblings, the frequency of such donors is not more than approximately 30%. This pre-clinical study in rhesus monkeys is directed at the selection of donors for recipients which lack an MHC identical sibling. (Auth.)

USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE

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Langbaum, Jessica B.S.; Fleisher, Adam S.; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T.; Caselli, Richard J.; Tariot, Pierre N.; Reiman, Eric M.

2014-01-01

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID:23752908

Reproducibility of preclinical animal research improves with heterogeneity of study samples

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Vogt, Lucile; Sena, Emily S.; Würbel, Hanno

2018-01-01

Single-laboratory studies conducted under highly standardized conditions are the gold standard in preclinical animal research. Using simulations based on 440 preclinical studies across 13 different interventions in animal models of stroke, myocardial infarction, and breast cancer, we compared the accuracy of effect size estimates between single-laboratory and multi-laboratory study designs. Single-laboratory studies generally failed to predict effect size accurately, and larger sample sizes rendered effect size estimates even less accurate. By contrast, multi-laboratory designs including as few as 2 to 4 laboratories increased coverage probability by up to 42 percentage points without a need for larger sample sizes. These findings demonstrate that within-study standardization is a major cause of poor reproducibility. More representative study samples are required to improve the external validity and reproducibility of preclinical animal research and to prevent wasting animals and resources for inconclusive research. PMID:29470495

The impact of weakly bound ⁸⁹Zr on preclinical studies: Non-specific accumulation in solid tumors and aspergillus infection

DEFF Research Database (Denmark)

Severin, Gregory; Jørgensen, Jesper T.; Wiehr, Stefan

2015-01-01

free or weakly bound 89Zr released in circulation. 89Zr oxalate had the desired characteristics, and was injected into mice bearing FaDu and HT29 solid tumor xenografts, and mice infected in the lungs with the mold Aspergillus fumigatus, as well as in healthy controls (naïve). PET/CT and PET/MR imaging...... followed to quantify the distribution of the radionuclide in the disease models. Results 89Zr oxalate was found to have a plasma half-life of 5.1 ± 2.3 h, accumulating mainly in the bones of all animals. Both tumor types accumulated 89Zr on the order of 2-4% ID/cm3, which is comparable to EPR...... in the disease sites in the present study, we recommend control experiments mapping the biodistribution of free 89Zr in any preclinical study employing 89Zr where bone uptake is observed. Aqueous 89Zr oxalate appears to be a suitable compound for such studies. This is especially relevant in studies where...

Tissue Engineering of the Urethra: A Systematic Review and Meta-analysis of Preclinical and Clinical Studies.

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Versteegden, Luuk R M; de Jonge, Paul K J D; IntHout, Joanna; van Kuppevelt, Toin H; Oosterwijk, Egbert; Feitz, Wout F J; de Vries, Rob B M; Daamen, Willeke F

2017-10-01

Urethra repair by tissue engineering has been extensively studied in laboratory animals and patients, but is not routinely used in clinical practice. To systematically investigate preclinical and clinical evidence of the efficacy of tissue engineering for urethra repair in order to stimulate translation of preclinical studies to the clinic. A systematic search strategy was applied in PubMed and EMBASE. Studies were independently screened for relevance by two reviewers, resulting in 80 preclinical and 23 clinical studies of which 63 and 13 were selected for meta-analysis to assess side effects, functionality, and study completion. Analyses for preclinical and clinical studies were performed separately. Full circumferential and inlay procedures were assessed independently. Evaluated parameters included seeding of cells and type of biomaterial. Meta-analysis revealed that cell seeding significantly reduced the probability of encountering side effects in preclinical studies. Remarkably though, cells were only sparsely used in the clinic (4/23 studies) and showed no significant reduction of side effects. ln 21 out of 23 clinical studies, decellularized templates were used, while in preclinical studies other biomaterials showed promising outcomes as well. No direct comparison to current clinical practice could be made due to the limited number of randomized controlled studies. Due to a lack of controlled (pre)clinical studies, the efficacy of tissue engineering for urethra repair could not be determined. Meta-analysis outcome measures were similar to current treatment options described in literature. Surprisingly, it appeared that favorable preclinical results, that is inclusion of cells, were not translated to the clinic. Improved (pre)clinical study designs may enhance clinical translation. We reviewed all available literature on urethral tissue engineering to assess the efficacy in preclinical and clinical studies. We show that improvements to (pre)clinical study

Preclinical and clinical safety studies on DNA vaccines.

NARCIS (Netherlands)

Schalk, Johanna A C; Mooi, Frits R; Berbers, Guy A M; Aerts, Leon A G J M van; Ovelgönne, Hans; Kimman, Tjeerd G

2007-01-01

DNA vaccines are based on the transfer of genetic material, encoding an antigen, to the cells of the vaccine recipient. Despite high expectations of DNA vaccines as a result of promising preclinical data their clinical utility remains unproven. However, much data is gathered in preclinical and

Bone pain

DEFF Research Database (Denmark)

Frost, Charlotte Ørsted; Hansen, Rikke Rie; Heegaard, Anne-Marie

2016-01-01

Skeletal conditions are common causes of chronic pain and there is an unmet medical need for improved treatment options. Bone pain is currently managed with disease modifying agents and/or analgesics depending on the condition. Disease modifying agents affect the underlying pathophysiology...... of the disease and reduce as a secondary effect bone pain. Antiresorptive and anabolic agents, such as bisphosphonates and intermittent parathyroid hormone (1-34), respectively, have proven effective as pain relieving agents. Cathepsin K inhibitors and anti-sclerostin antibodies hold, due to their disease...... modifying effects, promise of a pain relieving effect. NSAIDs and opioids are widely employed in the treatment of bone pain. However, recent preclinical findings demonstrating a unique neuronal innervation of bone tissue and sprouting of sensory nerve fibers open for new treatment possibilities....

Automated assessment of bone changes in cross-sectional micro-CT studies of murine experimental osteoarthritis.

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Das Neves Borges, Patricia; Vincent, Tonia L; Marenzana, Massimo

2017-01-01

The degradation of articular cartilage, which characterises osteoarthritis (OA), is usually paired with excessive bone remodelling, including subchondral bone sclerosis, cysts, and osteophyte formation. Experimental models of OA are widely used to investigate pathogenesis, yet few validated methodologies for assessing periarticular bone morphology exist and quantitative measurements are limited by manual segmentation of micro-CT scans. The aim of this work was to chart the temporal changes in periarticular bone in murine OA by novel, automated micro-CT methods. OA was induced by destabilisation of the medial meniscus (DMM) in 10-week old male mice and disease assessed cross-sectionally from 1- to 20-weeks post-surgery. A novel approach was developed to automatically segment subchondral bone compartments into plate and trabecular bone in micro-CT scans of tibial epiphyses. Osteophyte volume, as assessed by shape differences using 3D image registration, and by measuring total epiphyseal volume was performed. Significant linear and volumetric structural modifications in subchondral bone compartments and osteophytes were measured from 4-weeks post-surgery and showed progressive changes at all time points; by 20 weeks, medial subchondral bone plate thickness increased by 160±19.5 μm and the medial osteophyte grew by 0.124±0.028 μm3. Excellent agreement was found when automated measurements were compared with manual assessments. Our automated methods for assessing bone changes in murine periarticular bone are rapid, quantitative, and highly accurate, and promise to be a useful tool in future preclinical studies of OA progression and treatment. The current approaches were developed specifically for cross-sectional micro-CT studies but could be applied to longitudinal studies.

Automated assessment of bone changes in cross-sectional micro-CT studies of murine experimental osteoarthritis.

Directory of Open Access Journals (Sweden)

Patricia Das Neves Borges

Full Text Available The degradation of articular cartilage, which characterises osteoarthritis (OA, is usually paired with excessive bone remodelling, including subchondral bone sclerosis, cysts, and osteophyte formation. Experimental models of OA are widely used to investigate pathogenesis, yet few validated methodologies for assessing periarticular bone morphology exist and quantitative measurements are limited by manual segmentation of micro-CT scans. The aim of this work was to chart the temporal changes in periarticular bone in murine OA by novel, automated micro-CT methods.OA was induced by destabilisation of the medial meniscus (DMM in 10-week old male mice and disease assessed cross-sectionally from 1- to 20-weeks post-surgery. A novel approach was developed to automatically segment subchondral bone compartments into plate and trabecular bone in micro-CT scans of tibial epiphyses. Osteophyte volume, as assessed by shape differences using 3D image registration, and by measuring total epiphyseal volume was performed.Significant linear and volumetric structural modifications in subchondral bone compartments and osteophytes were measured from 4-weeks post-surgery and showed progressive changes at all time points; by 20 weeks, medial subchondral bone plate thickness increased by 160±19.5 μm and the medial osteophyte grew by 0.124±0.028 μm3. Excellent agreement was found when automated measurements were compared with manual assessments.Our automated methods for assessing bone changes in murine periarticular bone are rapid, quantitative, and highly accurate, and promise to be a useful tool in future preclinical studies of OA progression and treatment. The current approaches were developed specifically for cross-sectional micro-CT studies but could be applied to longitudinal studies.

Early reversal cells in adult human bone remodeling

DEFF Research Database (Denmark)

Abdelgawad, Mohamed Essameldin; Delaissé, Jean-Marie; Hinge, Maja

2016-01-01

The mechanism coupling bone resorption and formation is a burning question that remains incompletely answered through the current investigations on osteoclasts and osteoblasts. An attractive hypothesis is that the reversal cells are likely mediators of this coupling. Their nature is a big matter...... of debate. The present study performed on human cancellous bone is the first one combining in situ hybridization and immunohistochemistry to demonstrate their osteoblastic nature. It shows that the Runx2 and CD56 immunoreactive reversal cells appear to take up TRAcP released by neighboring osteoclasts....... Earlier preclinical studies indicate that reversal cells degrade the organic matrix left behind by the osteoclasts and that this degradation is crucial for the initiation of the subsequent bone formation. To our knowledge, this study is the first addressing these catabolic activities in adult human bone...

Doxorubicin-mediated bone loss in breast cancer bone metastases is driven by an interplay between oxidative stress and induction of TGFβ.

Directory of Open Access Journals (Sweden)

Tapasi Rana

Full Text Available Breast cancer patients, who are already at increased risk of developing bone metastases and osteolytic bone damage, are often treated with doxorubicin. Unfortunately, doxorubicin has been reported to induce damage to bone. Moreover, we have previously reported that doxorubicin treatment increases circulating levels of TGFβ in murine pre-clinical models. TGFβ has been implicated in promoting osteolytic bone damage, a consequence of increased osteoclast-mediated resorption and suppression of osteoblast differentiation. Therefore, we hypothesized that in a preclinical breast cancer bone metastasis model, administration of doxorubicin would accelerate bone loss in a TGFβ-mediated manner. Administration of doxorubicin to 4T1 tumor-bearing mice produced an eightfold increase in osteolytic lesion areas compared untreated tumor-bearing mice (P = 0.002 and an almost 50% decrease in trabecular bone volume expressed in BV/TV (P = 0.0005, both of which were rescued by anti-TGFβ antibody (1D11. Doxorubicin, which is a known inducer of oxidative stress, decreased osteoblast survival and differentiation, which was rescued by N-acetyl cysteine (NAC. Furthermore, doxorubicin treatment decreased Cu-ZnSOD (SOD1 expression and enzyme activity in vitro, and treatment with anti-TGFβ antibody was able to rescue both. In conclusion, a combination therapy using doxorubicin and anti-TGFβ antibody might be beneficial for preventing therapy-related bone loss in cancer patients.

Effects of gastric inhibitory polypeptide, glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonists on Bone Cell Metabolism.

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Hansen, Morten S S; Tencerova, Michaela; Frølich, Jacob; Kassem, Moustapha; Frost, Morten

2018-01-01

The relationship between gut and skeleton is increasingly recognized as part of the integrated physiology of the whole organism. The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the intestine in response to nutrient intake and exhibit several physiological functions including regulation of islet hormone secretion and glucose levels. A number of GLP-1 receptor agonists (GLP-1RAs) are currently used in treatment of type 2 diabetes and obesity. However, GIP and GLP-1 cognate receptors are widely expressed suggesting that incretin hormones mediate effects beyond control of glucose homeostasis, and reports on associations between incretin hormones and bone metabolism have emerged. The aim of this MiniReview was to provide an overview of current knowledge regarding the in vivo and in vitro effects of GIP and GLP-1 on bone metabolism. We identified a total of 30 pre-clinical and clinical investigations of the effects of GIP, GLP-1 and GLP-1RAs on bone turnover markers, bone mineral density (BMD), bone microarchitecture and fracture risk. Studies conducted in cell cultures and rodents demonstrated that GIP and GLP-1 play a role in regulating skeletal homeostasis, with pre-clinical data suggesting that GIP inhibits bone resorption whereas GLP-1 may promote bone formation and enhance bone material properties. These effects are not corroborated by clinical studies. While there is evidence of effects of GIP and GLP-1 on bone metabolism in pre-clinical investigations, clinical trials are needed to clarify whether similar effects are present and clinically relevant in humans. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Guided Bone Regeneration in Long-Bone Defects with a Structural Hydroxyapatite Graft and Collagen Membrane

Science.gov (United States)

2013-01-01

Original Articles Guided Bone Regeneration in Long-Bone Defects with a Structural Hydroxyapatite Graft and Collagen Membrane Teja Guda, PhD,1,2 John...Joint Surg Br 90-B, 1617, 2008. 6. Carlo Reis, E.C., Borges AaPB, Araujo, M.V.F., Mendes, V.C., Guan, L., and Davies, J.E. Periodontal regeneration...Regeneration of periodontal tissues: combinations of barrier membranes and grafting materials–biological foundation and preclinical evi- dence: a

Concise Review: Mesenchymal Stem (Stromal) Cells: Biology and Preclinical Evidence for Therapeutic Potential for Organ Dysfunction Following Trauma or Sepsis.

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Matthay, Michael A; Pati, Shibani; Lee, Jae-Woo

2017-02-01

Several experimental studies have provided evidence that bone-marrow derived mesenchymal stem (stromal) cells (MSC) may be effective in treating critically ill surgical patients who develop traumatic brain injury, acute renal failure, or the acute respiratory distress syndrome. There is also preclinical evidence that MSC may be effective in treating sepsis-induced organ failure, including evidence that MSC have antimicrobial properties. This review considers preclinical studies with direct relevance to organ failure following trauma, sepsis or major infections that apply to critically ill patients. Progress has been made in understanding the mechanisms of benefit, including MSC release of paracrine factors, transfer of mitochondria, and elaboration of exosomes and microvesicles. Regardless of how well they are designed, preclinical studies have limitations in modeling the complexity of clinical syndromes, especially in patients who are critically ill. In order to facilitate translation of the preclinical studies of MSC to critically ill patients, there will need to be more standardization regarding MSC production with a focus on culture methods and cell characterization. Finally, well designed clinical trials will be needed in critically ill patient to assess safety and efficacy. Stem Cells 2017;35:316-324. © 2016 AlphaMed Press.

A review of targeted therapies evaluated by the Pediatric Preclinical Testing Program for osteosarcoma

Directory of Open Access Journals (Sweden)

Valerie eSampson

2013-05-01

Full Text Available Osteosarcoma, the most common malignant bone tumor of childhood, is a high grade primary bone sarcoma that occurs mostly in adolescence. Standard treatment consists of surgery in combination with multi-agent chemotherapy regimens. The development and approval of imatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL in children and the fully human monoclonal antibody, anti-GD2, as part of an immune therapy for high-risk neuroblastoma patients have established the precedent for use of targeted inhibitors along with standard chemotherapy backbones. However, few targeted agents tested have achieved traditional clinical end points for osteosarcoma. Many biological agents demonstrating anti-tumor responses in preclinical and early phase clinical testing have failed to reach response thresholds to justify randomized trials with large numbers of patients. The development of targeted therapies for pediatric cancer remains a significant challenge. To aid in the prioritization of new agents for clinical testing, the Pediatric Preclinical Testing Program (PPTP has developed reliable and robust preclinical pediatric cancer models to rapidly screen agents for activity in multiple childhood cancers and establish pharmacological parameters and effective drug concentrations for clinical trials. In this article, we examine a range of standard and novel agents that have been evaluated by the PPTP, and we discuss the preclinical and clinical development of these for the treatment of osteosarcoma. We further demonstrate that committed resources for hypothesis-driven drug discovery and development are needed to yield clinical successes in the search for new therapies for this pediatric disease.

Study on 41Ca-AMS for diagnosis and assessment of cancer bone metastasis in rats

International Nuclear Information System (INIS)

Shen, Hongtao; Pang, Fangfang; Jiang, Shan; He, Ming; Dong, Kejun; Dou, Liang; Pang, Yijun; Yang, Xianlin; Ruan, Xiangdong; Liu, Manjun; Xia, Chunbo

2015-01-01

The annual incidence of new cancer patients in China is about 2 million, 30–40% of which will end up with bone metastasis. Profound study on the preclinical model and early diagnosis of cancer bone metastasis in rats are very significant for the drug development, better understanding and treatment of bone metastases. In order to monitor the process of bone metabolism and early detection of bone metastasis of cancer cells, a technique of 41 Ca isotope tracer combined with AMS has been developed and applied in the study on the bone metastasis of cancer cells by rat model. In this work, 3-month-old female Sprague–Dawley (SD) rats were randomly divided into different groups, and tumor cells injected respectively into the tail vein, femoral artery, femoral cavity and the thigh muscle to establish the rat models for bone metastases. The most appropriate model, i.e., the thigh muscle group, was finally adopted in our real metastases experiment. Each rat in this group was intramuscularly (i.m.) injected with 250 μl CaCl 2 solution (containing 1.4 mg Ca and 5nCi 41 Ca). About 40 days later, the rat mammary gland carcinoma cells (Walker 256) were injected into these rats following the established protocol. After bone metastasis, medicine interventions were performed. The sequential urine and blood samples were collected and analyzed for 41 Ca (by AMS) and N-terminal telopeptide (Ntx), respectively. Bone Mineral Density (BMD) values in the femur and the tibia were measured by CT scan. The results of 41 Ca/Ca in longitudinal urinary samples can sensitively reveal the skeletal perturbations caused by bone metastasis of rats, suggests that 41 Ca might be similarly developed for human use and improve clinical management through the assessment of the curative effect and non-invasive detection of the earliest stages of cancer growth in bone.

An in vitro 3D bone metastasis model by using a human bone tissue culture and human sex-related cancer cells.

Science.gov (United States)

Salamanna, Francesca; Borsari, Veronica; Brogini, Silvia; Giavaresi, Gianluca; Parrilli, Annapaola; Cepollaro, Simona; Cadossi, Matteo; Martini, Lucia; Mazzotti, Antonio; Fini, Milena

2016-11-22

One of the main limitations, when studying cancer-bone metastasis, is the complex nature of the native bone environment and the lack of reliable, simple, inexpensive models that closely mimic the biological processes occurring in patients and allowing the correct translation of results. To enhance the understanding of the mechanisms underlying human bone metastases and in order to find new therapies, we developed an in vitro three-dimensional (3D) cancer-bone metastasis model by culturing human breast or prostate cancer cells with human bone tissue isolated from female and male patients, respectively. Bone tissue discarded from total hip replacement surgery was cultured in a rolling apparatus system in a normoxic or hypoxic environment. Gene expression profile, protein levels, histological, immunohistochemical and four-dimensional (4D) micro-CT analyses showed a noticeable specificity of breast and prostate cancer cells for bone colonization and ingrowth, thus highlighting the species-specific and sex-specific osteotropism and the need to widen the current knowledge on cancer-bone metastasis spread in human bone tissues. The results of this study support the application of this model in preclinical studies on bone metastases and also follow the 3R principles, the guiding principles, aimed at replacing/reducing/refining (3R) animal use and their suffering for scientific purposes.

Preliminary study for small animal preclinical hadrontherapy facility

Energy Technology Data Exchange (ETDEWEB)

Russo, G. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Pisciotta, P., E-mail: pietro.pisciotta@ibfm.cnr.it [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy); Cirrone, G.A.P.; Romano, F. [National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy); Cammarata, F.; Marchese, V.; Forte, G.I.; Lamia, D.; Minafra, L.; Bravatá, V. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Acquaviva, R. [University of Catania, Catania (Italy); Gilardi, M.C. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Cuttone, G. [National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy)

2017-02-21

Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

Preliminary study for small animal preclinical hadrontherapy facility

Science.gov (United States)

Russo, G.; Pisciotta, P.; Cirrone, G. A. P.; Romano, F.; Cammarata, F.; Marchese, V.; Forte, G. I.; Lamia, D.; Minafra, L.; Bravatá, V.; Acquaviva, R.; Gilardi, M. C.; Cuttone, G.

2017-02-01

Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

Preliminary study for small animal preclinical hadrontherapy facility

International Nuclear Information System (INIS)

Russo, G.; Pisciotta, P.; Cirrone, G.A.P.; Romano, F.; Cammarata, F.; Marchese, V.; Forte, G.I.; Lamia, D.; Minafra, L.; Bravatá, V.; Acquaviva, R.; Gilardi, M.C.; Cuttone, G.

2017-01-01

Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

Scaffold-cell bone engineering in a validated preclinical animal model: precursors vs differentiated cell source.

Science.gov (United States)

Berner, A; Henkel, J; Woodruff, M A; Saifzadeh, S; Kirby, G; Zaiss, S; Gohlke, J; Reichert, J C; Nerlich, M; Schuetz, M A; Hutmacher, D W

2017-07-01

The properties of osteoblasts (OBs) isolated from the axial skeleton (tOBs) differ from OBs of the orofacial skeleton (mOBs) due to the different embryological origins of the bones. The aim of the study was to assess and compare the regenerative potential of allogenic bone marrow-derived mesenchymal progenitor cells with allogenic tOBs and allogenic mOBs in combination with a mPCL-TCP scaffold in critical-sized segmental bone defects in sheep tibiae. After 6 months, the tibiae were explanted and underwent biomechanical testing, micro-computed tomography (microCT) and histological and immunohistochemical analyses. Allogenic MPCs demonstrated a trend towards a better outcome in biomechanical testing and the mean values of newly formed bone. Biomechanical, microCT and histological analysis showed no significant differences in the bone regeneration potential of tOBs and mOBs in our in vitro study, as well as in the bone regeneration potential of different cell types in vivo. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

The development of neural stimulators: a review of preclinical safety and efficacy studies.

Science.gov (United States)

Shepherd, Robert K; Villalobos, Joel; Burns, Owen; Nayagam, David

2018-05-14

Given the rapid expansion of the field of neural stimulation and the rigorous regulatory approval requirements required before these devices can be applied clinically, it is important that there is clarity around conducting preclinical safety and efficacy studies required for the development of this technology. The present review examines basic design principles associated with the development of a safe neural stimulator and describes the suite of preclinical safety studies that need to be considered when taking a device to clinical trial. Neural stimulators are active implantable devices that provide therapeutic intervention, sensory feedback or improved motor control via electrical stimulation of neural or neuro-muscular tissue in response to trauma or disease. Because of their complexity, regulatory bodies classify these devices in the highest risk category (Class III), and they are therefore required to go through a rigorous regulatory approval process before progressing to market. The successful development of these devices is achieved through close collaboration across disciplines including engineers, scientists and a surgical/clinical team, and the adherence to clear design principles. Preclinical studies form one of several key components in the development pathway from concept to product release of neural stimulators. Importantly, these studies provide iterative feedback in order to optimise the final design of the device. Key components of any preclinical evaluation include: in vitro studies that are focussed on device reliability and include accelerated testing under highly controlled environments; in vivo studies using animal models of the disease or injury in order to assess safety and, given an appropriate animal model, the efficacy of the technology under both passive and electrically active conditions; and human cadaver and ex vivo studies designed to ensure the device's form factor conforms to human anatomy, to optimise the surgical approach and to

Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling

Directory of Open Access Journals (Sweden)

Fabrizio Accardi

2015-01-01

Full Text Available Multiple myeloma (MM is characterized by a high capacity to induce alterations in the bone remodeling process. The increase in osteoclastogenesis and the suppression of osteoblast formation are both involved in the pathophysiology of the bone lesions in MM. The proteasome inhibitor (PI bortezomib is the first drug designed and approved for the treatment of MM patients by targeting the proteasome. However, recently novel PIs have been developed to overcome bortezomib resistance. Interestingly, several preclinical data indicate that the proteasome complex is involved in both osteoclast and osteoblast formation. It is also evident that bortezomib either inhibits osteoclast differentiation induced by the receptor activator of nuclear factor kappa B (NF-κB ligand (RANKL or stimulates the osteoblast differentiation. Similarly, the new PIs including carfilzomib and ixazomib can inhibit bone resorption and stimulate the osteoblast differentiation. In a clinical setting, PIs restore the abnormal bone remodeling by normalizing the levels of bone turnover markers. In addition, a bone anabolic effect was described in responding MM patients treated with PIs, as demonstrated by the increase in the osteoblast number. This review summarizes the preclinical and clinical evidence on the effects of bortezomib and other new PIs on myeloma bone disease.

Spontaneous bone metastases in a preclinical orthotopic model of invasive lobular carcinoma; the effect of pharmacological targeting TGFβ receptor I kinase.

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Buijs, Jeroen T; Matula, Kasia M; Cheung, Henry; Kruithof-de Julio, Marianna; van der Mark, Maaike H; Snoeks, Thomas J; Cohen, Ron; Corver, Willem E; Mohammad, Khalid S; Jonkers, Jos; Guise, Theresa A; van der Pluijm, Gabri

2015-04-01

Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the most frequently occurring histological subtypes of breast cancer, accounting for 80-90% and 10-15% of the total cases, respectively. At the time of diagnosis and surgical resection of the primary tumour, most patients do not have clinical signs of metastases, but bone micrometastases may already be present. Our aim was to develop a novel preclinical ILC model of spontaneous bone micrometastasis. We used murine invasive lobular breast carcinoma cells (KEP) that were generated by targeted deletion of E-cadherin and p53 in a conditional K14cre;Cdh1((F/F));Trp53((F/F)) mouse model of de novo mammary tumour formation. After surgical resection of the growing orthotopically implanted KEP cells, distant metastases were formed. In contrast to other orthotopic breast cancer models, KEP cells readily formed skeletal metastases with minimal lung involvement. Continuous treatment with SD-208 (60 mg/kg per day), an orally available TGFβ receptor I kinase inhibitor, increased the tumour growth at the primary site and increased the number of distant metastases. Furthermore, when SD-208 treatment was started after surgical resection of the orthotopic tumour, increased bone colonisation was also observed (versus vehicle). Both our in vitro and in vivo data show that SD-208 treatment reduced TGFβ signalling, inhibited apoptosis, and increased proliferation. In conclusion, we have demonstrated that orthotopic implantation of murine ILC cells represent a new breast cancer model of minimal residual disease in vivo, which comprises key steps of the metastatic cascade. The cancer cells are sensitive to the anti-tumour effects of TGFβ. Our in vivo model is ideally suited for functional studies and evaluation of new pharmacological intervention strategies that may target one or more steps along the metastatic cascade of events. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on

Preclinical experimental stress studies: protocols, assessment and comparison.

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Bali, Anjana; Jaggi, Amteshwar Singh

2015-01-05

Stress is a state of threatened homeostasis during which a variety of adaptive processes are activated to produce physiological and behavioral changes. Preclinical models are pivotal for understanding these physiological or pathophysiological changes in the body in response to stress. Furthermore, these models are also important for the development of novel pharmacological agents for stress management. The well described preclinical stress models include immobilization, restraint, electric foot shock and social isolation stress. Stress assessment in animals is done at the behavioral level using open field, social interaction, hole board test; at the biochemical level by measuring plasma corticosterone and ACTH; at the physiological level by measuring food intake, body weight, adrenal gland weight and gastric ulceration. Furthermore the comparison between different stressors including electric foot shock, immobilization and cold stressor is described in terms of intensity, hormonal release, protein changes in brain, adaptation and sleep pattern. This present review describes these preclinical stress protocols, and stress assessment at different levels. Copyright © 2014 Elsevier B.V. All rights reserved.

In vivo quantification of bone-fluorine by delayed neutron activation analysis: a pilot study of hand-bone-fluorine levels in a Canadian population

International Nuclear Information System (INIS)

Chamberlain, Mike; Gräfe, James L; Aslam; Byun, Soo-Hyun; Chettle, David R; Egden, Lesley M; Webber, Colin E; McNeill, Fiona E

2012-01-01

Humans can be exposed to fluorine (F) through their diet, occupation, environment and oral dental care products. Fluorine, at proper dosages, is believed to have positive effects by reducing the incidence of dental caries, but fluorine toxicity can occur when people are exposed to excessive quantities of fluorine. In this paper we present the results of a small pilot in vivo study on 33 participants living in Southwestern Ontario, Canada. The mean age of participants was 45 ± 18 years with a range of 20–87 years. The observed calcium normalized hand-bone-fluorine concentrations in this small pilot study ranged from 1.1 to 8.8 mg F/g Ca. Every person measured in this study had levels of fluorine in bone above the detection limit of the system. The average fluorine concentration in bone was found to be 3.5 ± 0.4 mg F/g Ca. No difference was observed in average concentration for men and women. In addition, a significant correlation (r 2 = 0.55, p < 0.001) was observed between hand-bone-fluorine content and age. The amount of fluorine was found to increase at a rate of 0.084 ± 0.014 mg F/g Ca per year. There was no significant difference observed in this small group of subjects between the accumulation rates in men and women. To the best of our knowledge, this is the first time data from in vivo measurement of fluorine content in humans by neutron activation analysis have been presented. The data determined by this technique were found to be consistent with results from ex vivo studies from other countries. We suggest that the data demonstrate that this low risk non-invasive diagnostic technique will permit the routine assessment of bone-fluorine content with potential application in the study of clinical bone-related diseases. This small study demonstrated that people in Southern Ontario are exposed to fluoride in measureable quantities, and that fluoride can be seen to accumulate in bone with age. However, all volunteers were found to have levels below those

Mesenchymal stem cells from cortical bone demonstrate increased clonal incidence, potency, and developmental capacity compared to their bone marrow–derived counterparts

Directory of Open Access Journals (Sweden)

Daniel Blashki

2016-08-01

Full Text Available In this study, we show that matrix dense cortical bone is the more potent compartment of bone than bone marrow as a stromal source for mesenchymal stem cells as isolated from adult rats. Lineage-depleted cortical bone-mesenchymal stem cells demonstrated >150-fold enrichment of colony forming unit–fibroblasts per cell incidence. compared to lineage-depleted bone marrow-mesenchymal stem cells, corresponding to a 70-fold increase in absolute recovered colony forming unit–fibroblasts. The composite phenotype Lin−/CD45−/CD31−/VLA-1+/Thy-1+ enriched for clonogenic mesenchymal stem cells solely from cortical bone–derived cells from which 70% of clones spontaneously differentiated into all lineages of bone, cartilage, and adipose. Both populations generated vascularized bone tissue within subcutaneous implanted collagen scaffolds; however, cortical bone–derived cells formed significantly more osteoid than bone marrow counterparts, quantified by histology. The data demonstrate that our isolation protocol identifies and validates mesenchymal stem cells with superior clonal, proliferative, and developmental potential from cortical bone compared to the bone marrow niche although marrow persists as the typical source for mesenchymal stem cells both in the literature and current pre-clinical therapies.

Osseointegration in osteoporotic-like condition: A systematic review of preclinical studies.

Science.gov (United States)

Dereka, X; Calciolari, E; Donos, N; Mardas, N

2018-05-30

Osteoporosis is one of the most common skeletal disorders affecting a significant percentage of people worldwide. Research data suggested that systemic diseases such as osteoporosis could act as risk factors for osseointegration, jeopardizing the healing process and thus the predictability of dental implant success on compromised patients. It is well accepted that preclinical studies in animal models reproducing the osteoporotic condition are one of the most important stages in the research of new biomaterials and therapeutic modalities. The aim of this systematic review was to investigate whether osteoporosis compromises dental implant osseointegration in experimental osteoporotic-like conditions. A 3-stage systematic literature research was conducted in MEDLINE via OVID and EMBASE up to and including March 2017. Experimental studies reporting on dental implant osseointegration on different osteoporotic animal models were assessed. The studies had to report on the percentage of bone-to-implant contact (%BIC) as the primary outcome. ARRIVE guidelines for reporting on animal research were applied to evaluate the methodological quality and risk of bias of the studies. Fifty-seven studies met the inclusion criteria and were assessed qualitatively. The most adopted animal model was the rat. A variability of %BIC values was observed, ranging from 30% to 99% and from 26% to 94% for the healthy and osteoporotic group, respectively. The great majority (47) of the included studies concluded that estrogen deficiency significantly affects BIC values, 9 studies stated that it was not possible to observe statistical differences in BIC between ovariectomized and healthy groups and 1 study did not provide a comparison between the healthy and osteoporotic group. Owing to the great heterogeneity in implant surface, study design, observation time-points, site of implant placement and reported outcomes, a meta-analysis could not be performed. An overall high risk of bias was observed

The effect of learning styles and study behavior on success of preclinical students in pharmacology.

Science.gov (United States)

Asci, Halil; Kulac, Esin; Sezik, Mekin; Cankara, F Nihan; Cicek, Ekrem

2016-01-01

To evaluate the effect of learning styles and study behaviors on preclinical medical students' pharmacology exam scores in a non-Western setting. Grasha-Reichmann Student Learning Study Scale and a modified Study Behavior Inventory were used to assess learning styles and study behaviors of preclinical medical students (n = 87). Logistic regression models were used to evaluate the independent effect of gender, age, learning style, and study behavior on pharmacology success. Collaborative (40%) and competitive (27%) dominant learning styles were frequent in the cohort. The most common study behavior subcategories were study reading (40%) and general study habits (38%). Adequate listening and note-taking skills were associated with pharmacology success, whereas students with adequate writing skills had lower exam scores. These effects were independent of gender. Preclinical medical students' study behaviors are independent predictive factors for short-term pharmacology success.

In vivo quantification of bone-fluorine by delayed neutron activation analysis: a pilot study of hand-bone-fluorine levels in a Canadian population.

Science.gov (United States)

Chamberlain, Mike; Gräfe, James L; Aslam; Byun, Soo-Hyun; Chettle, David R; Egden, Lesley M; Webber, Colin E; McNeill, Fiona E

2012-03-01

Humans can be exposed to fluorine (F) through their diet, occupation, environment and oral dental care products. Fluorine, at proper dosages, is believed to have positive effects by reducing the incidence of dental caries, but fluorine toxicity can occur when people are exposed to excessive quantities of fluorine. In this paper we present the results of a small pilot in vivo study on 33 participants living in Southwestern Ontario, Canada. The mean age of participants was 45 ± 18 years with a range of 20-87 years. The observed calcium normalized hand-bone-fluorine concentrations in this small pilot study ranged from 1.1 to 8.8 mg F/g Ca. Every person measured in this study had levels of fluorine in bone above the detection limit of the system. The average fluorine concentration in bone was found to be 3.5 ± 0.4 mg F/g Ca. No difference was observed in average concentration for men and women. In addition, a significant correlation (r(2) = 0.55, p fluorine content and age. The amount of fluorine was found to increase at a rate of 0.084 ± 0.014 mg F/g Ca per year. There was no significant difference observed in this small group of subjects between the accumulation rates in men and women. To the best of our knowledge, this is the first time data from in vivo measurement of fluorine content in humans by neutron activation analysis have been presented. The data determined by this technique were found to be consistent with results from ex vivo studies from other countries. We suggest that the data demonstrate that this low risk non-invasive diagnostic technique will permit the routine assessment of bone-fluorine content with potential application in the study of clinical bone-related diseases. This small study demonstrated that people in Southern Ontario are exposed to fluoride in measureable quantities, and that fluoride can be seen to accumulate in bone with age. However, all volunteers were found to have levels below those expected with clinical fluorosis, and only

Study on {sup 41}Ca-AMS for diagnosis and assessment of cancer bone metastasis in rats

Energy Technology Data Exchange (ETDEWEB)

Shen, Hongtao; Pang, Fangfang [College of Physics and Technology, Guangxi Normal University, Guilin 541004 (China); China Institute of Atomic Energy, P.O. Box 275-50, Beijing 102413 (China); Jiang, Shan; He, Ming; Dong, Kejun; Dou, Liang [China Institute of Atomic Energy, P.O. Box 275-50, Beijing 102413 (China); Pang, Yijun [College of Physics and Technology, Guangxi Normal University, Guilin 541004 (China); China Institute of Atomic Energy, P.O. Box 275-50, Beijing 102413 (China); Yang, Xianlin [College of Physics and Technology, Guangxi Normal University, Guilin 541004 (China); Ruan, Xiangdong [College of Physics, Guangxi University, Nanning 530004 (China); Liu, Manjun; Xia, Chunbo [Guiin Medical University, Guilin 541004 (China)

2015-10-15

The annual incidence of new cancer patients in China is about 2 million, 30–40% of which will end up with bone metastasis. Profound study on the preclinical model and early diagnosis of cancer bone metastasis in rats are very significant for the drug development, better understanding and treatment of bone metastases. In order to monitor the process of bone metabolism and early detection of bone metastasis of cancer cells, a technique of {sup 41}Ca isotope tracer combined with AMS has been developed and applied in the study on the bone metastasis of cancer cells by rat model. In this work, 3-month-old female Sprague–Dawley (SD) rats were randomly divided into different groups, and tumor cells injected respectively into the tail vein, femoral artery, femoral cavity and the thigh muscle to establish the rat models for bone metastases. The most appropriate model, i.e., the thigh muscle group, was finally adopted in our real metastases experiment. Each rat in this group was intramuscularly (i.m.) injected with 250 μl CaCl{sub 2} solution (containing 1.4 mg Ca and 5nCi {sup 41}Ca). About 40 days later, the rat mammary gland carcinoma cells (Walker 256) were injected into these rats following the established protocol. After bone metastasis, medicine interventions were performed. The sequential urine and blood samples were collected and analyzed for {sup 41}Ca (by AMS) and N-terminal telopeptide (Ntx), respectively. Bone Mineral Density (BMD) values in the femur and the tibia were measured by CT scan. The results of {sup 41}Ca/Ca in longitudinal urinary samples can sensitively reveal the skeletal perturbations caused by bone metastasis of rats, suggests that {sup 41}Ca might be similarly developed for human use and improve clinical management through the assessment of the curative effect and non-invasive detection of the earliest stages of cancer growth in bone.

A methodology for the investigation of toughness and crack propagation in mouse bone.

Science.gov (United States)

Carriero, Alessandra; Zimmermann, Elizabeth A; Shefelbine, Sandra J; Ritchie, Robert O

2014-11-01

Bone fracture is a health concern for those with aged bone and brittle bone diseases. Mouse bone is widely used as a model of human bone, especially to investigate preclinical treatment strategies. However, little is known about the mechanisms of mouse bone fracture and its similarities and differences from fracture in human bone. In this work we present a methodology to investigate the fracture toughness during crack initiation and crack propagation for mouse bone. Mouse femora were dissected, polished on their periosteal surface, notched on the posterior surface at their mid-diaphysis, and tested in three-point bending under displacement control at a rate of 0.1mm/min using an in situ loading stage within an environmental scanning electron microscope. We obtained high-resolution real-time imaging of the crack initiation and propagation in mouse bone. From the images we can measure the crack extension at each step of the crack growth and calculate the toughness of the bone (in terms of stress intensity factor (K) and work to fracture (Wf)) as a function of stable crack length (Δa), thus generating a resistance curve for the mouse bone. The technique presented here provides insight into the evolution of microdamage and the toughening mechanisms that resist crack propagation, which are essential for preclinical development of treatments to enhance bone quality and combat fracture risk. Copyright © 2014 Elsevier Ltd. All rights reserved.

Challenges for Preclinical Investigations of Human Biofield Modalities

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Gronowicz, Gloria; Bengston, William

2015-01-01

Preclinical models for studying the effects of the human biofield have great potential to advance our understanding of human biofield modalities, which include external qigong, Johrei, Reiki, therapeutic touch, healing touch, polarity therapy, pranic healing, and other practices. A short history of Western biofield studies using preclinical models is presented and demonstrates numerous and consistent examples of human biofields significantly affecting biological systems both in vitro and in vivo. Methodological issues arising from these studies and practical solutions in experimental design are presented. Important questions still left unanswered with preclinical models include variable reproducibility, dosing, intentionality of the practitioner, best preclinical systems, and mechanisms. Input from the biofield practitioners in the experimental design is critical to improving experimental outcomes; however, the development of standard criteria for uniformity of practice and for inclusion of multiple practitioners is needed. Research in human biofield studies involving preclinical models promises a better understanding of the mechanisms underlying the efficacy of biofield therapies and will be important in guiding clinical protocols and integrating treatments with conventional medical therapies. PMID:26665042

Evaluation of autogenous PRGF+β-TCP with or without a collagen membrane on bone formation and implant osseointegration in large size bone defects. A preclinical in vivo study.

Science.gov (United States)

Batas, Leonidas; Stavropoulos, Andreas; Papadimitriou, Serafim; Nyengaard, Jens R; Konstantinidis, Antonios

2016-08-01

The aim of this study was to evaluate whether the adjunctive use of a collagen membrane enhances bone formation and implant osseointegration in non-contained defects grafted with chair-side prepared autologous platelet-rich growth factor (PRGF) adsorbed on a β-TCP particulate carrier. Large box-type defects (10 × 6 mm; W × D) were prepared in the edentulated and completely healed mandibles of six Beagles dogs. An implant with moderately rough surface was placed in the center of each defect leaving the coronal 6 mm of the implant not covered with bone. The remaining defect space was then filled out with chair-side prepared autologous PRGF adsorbed on β-TCP particles and either covered with a collagen membrane (PRGF/β-TCP+CM) (6 defects) or left without a membrane (PRGF/β-TCP) (5 defects). Histology 4 months post-op showed new lamellar and woven bone formation encompassing almost entirely the defect and limited residual β-TCP particles. Extent of osseointegration of the previously exposed portion of the implants varied, but in general was limited. Within the defect, new mineralized bone (%) averaged 43.2 ± 9.86 vs. 39.9 ± 13.7 in the PRGF/β-TCP+CM and PRGF/β-TCP group (P = 0.22) and relative mineralized bone-to-implant contact (%) averaged 26.2 ± 16.45 vs. 35.91 ± 24.45, respectively (P = 0.5). First, bone-to-implant contact from the implant top was 4.1 ± 1.5 and 3.2 ± 2.3 (P = 0.9), in the PRGF/β-TCP+CM and PRGF/β-TCP group, respectively. Implantation of chair-side prepared autologous PRGF adsorbed on a β-TCP carrier in non-contained peri-implant defects resulted in large amounts of bone regeneration, but osseointegration was limited. Provisions for GBR with a collagen membrane did not significantly enhance bone regeneration or implant osseointegration. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Standard Operating Procedures (SOPs) for Evaluating the Heart in Preclinical Studies of Duchenne Muscular Dystrophy.

Science.gov (United States)

Duan, Dongsheng; Rafael-Fortney, Jill A; Blain, Alison; Kass, David A; McNally, Elizabeth M; Metzger, Joseph M; Spurney, Christopher F; Kinnett, Kathi

2016-02-01

A recent working group meeting focused on contemporary cardiac issues in Duchenne muscular dystrophy (DMD) was hosted by the National Heart, Lung, and Blood Institute in collaboration with the Parent Project Muscular Dystrophy. An outcome of this meeting was to provide freely available detailed protocols for preclinical animal studies. The goal of these protocols is to improve the quality and reproducibility of cardiac preclinical studies aimed at developing new therapeutics for the prevention and treatment of DMD cardiomyopathy.

Where Do Bone-Targeted Agents RANK in Breast Cancer Treatment?

Directory of Open Access Journals (Sweden)

Roger von Moos

2013-08-01

Full Text Available Breast cancer cells preferentially metastasise to the skeleton, owing, in part, to the fertile environment provided by bone. Increased bone turnover releases growth factors that promote tumour cell growth. In turn, tumour cells release factors that stimulate further bone turnover, resulting in a vicious cycle of metastasis growth and bone destruction. The RANK-RANK ligand (RANKL pathway plays a key role in this cycle, and inhibition of RANKL using the fully-human monoclonal antibody denosumab, has demonstrated efficacy in delaying skeletal complications associated with bone metastases in three phase 3 trials. Preclinical studies suggest that the RANKL pathway also plays a role in breast cancer tumourigenesis and migration to bone. In a subgroup analysis of the negative Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE trial, the bisphosphonate zoledronic acid showed potential for improving survival in patients who were postmenopausal; however, a prospective study in this patient population is required to validate this observation. Ongoing trials are examining whether adjuvant blockade of the RANKL pathway using denosumab can prevent disease recurrence in patients with high-risk breast cancer. These are building on analogous studies that have shown that denosumab improves bone metastasis-free survival in prostate cancer and suggested that it confers an overall survival benefit in non-small-cell lung cancer.

Cartilage Repair With Autologous Bone Marrow Mesenchymal Stem Cell Transplantation: Review of Preclinical and Clinical Studies.

Science.gov (United States)

Yamasaki, Shinya; Mera, Hisashi; Itokazu, Maki; Hashimoto, Yusuke; Wakitani, Shigeyuki

2014-10-01

Clinical trials of various procedures, including bone marrow stimulation, mosaicplasty, and autologous chondrocyte implantation, have been explored to treat articular cartilage defects. However, all of them have some demerits. We focused on autologous culture-expanded bone marrow mesenchymal stem cells (BMSC), which can proliferate without losing their capacity for differentiation. First, we transplanted BMSC into the defective articular cartilage of rabbit and succeeded in regenerating osteochondral tissue. We then applied this transplantation in humans. Our previous reports showed that treatment with BMSC relieves the clinical symptoms of chondral defects in the knee and elbow joint. We investigated the efficacy of BMSC for osteoarthritic knee treated with high tibial osteotomy, by comparing 12 BMSC-transplanted patients with 12 cell-free patients. At 16-month follow-up, although the difference in clinical improvement between both groups was not significant, the arthroscopic and histological grading score was better in the cell-transplanted group. At the over 10-year follow-up, Hospital for Special Surgery knee scores improved to 76 and 73 in the BMSC-transplanted and cell-free groups, respectively, which were better than preoperative scores. Additionally, neither tumors nor infections were observed in all patients, and in the clinical study, we have never observed hypertrophy of repaired tissue, thereby guaranteeing the clinical safety of this therapy. Although we have never observed calcification above the tidemark in rabbit model and human histologically, the repair cartilage was not completely hyaline cartilage. To elucidate the optimum conditions for cell therapy, other stem cells, culture conditions, growth factors, and gene transfection methods should be explored.

Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas.

Science.gov (United States)

Sangiolo, Dario; Mesiano, Giulia; Gammaitoni, Loretta; Leuci, Valeria; Todorovic, Maja; Giraudo, Lidia; Cammarata, Cristina; Dell'Aglio, Carmine; D'Ambrosio, Lorenzo; Pisacane, Alberto; Sarotto, Ivana; Miano, Sara; Ferrero, Ivana; Carnevale-Schianca, Fabrizio; Pignochino, Ymera; Sassi, Francesco; Bertotti, Andrea; Piacibello, Wanda; Fagioli, Franca; Aglietta, Massimo; Grignani, Giovanni

2014-01-01

Unresectable metastatic bone sarcoma and soft-tissue sarcomas (STS) are incurable due to the inability to eradicate chemoresistant cancer stem-like cells (sCSC) that are likely responsible for relapses and drug resistance. In this study, we investigated the preclinical activity of patient-derived cytokine-induced killer (CIK) cells against autologous bone sarcoma and STS, including against putative sCSCs. Tumor killing was evaluated both in vitro and within an immunodeficient mouse model of autologous sarcoma. To identify putative sCSCs, autologous bone sarcoma and STS cells were engineered with a CSC detector vector encoding eGFP under the control of the human promoter for OCT4, a stem cell gene activated in putative sCSCs. Using CIK cells expanded from 21 patients, we found that CIK cells efficiently killed allogeneic and autologous sarcoma cells in vitro. Intravenous infusion of CIK cells delayed autologous tumor growth in immunodeficient mice. Further in vivo analyses established that CIK cells could infiltrate tumors and that tumor growth inhibition occurred without an enrichment of sCSCs relative to control-treated animals. These results provide preclinical proof-of-concept for an effective strategy to attack autologous sarcomas, including putative sCSCs, supporting the clinical development of CIK cells as a novel class of immunotherapy for use in settings of untreatable metastatic disease.

Factors influencing the approaches to studying of preclinical and clinical students and postgraduate trainees

Directory of Open Access Journals (Sweden)

Samarasekera Dharmabandu N

2011-05-01

Full Text Available Abstract Background Students can be classified into three categories depending on their approaches to studying; namely, deep approach (DA, strategic approach (SA and surface apathetic or superficial approach (SAA. The aim of this study was to identify factors affecting the approaches to studying among Sri Lankan medical undergraduates and post graduate trainees and to analyze the change in the pattern of study skills with time and experience. Method Pre-clinical and clinical students of the Faculty of Medicine, University of Colombo and postgraduate trainees in Surgery at the National Hospital of Sri Lanka were invited to complete the Approaches and Study Skills Inventory for Students (ASSIST questionnaire. Results A total of 187 pre clinical (M: F = 96:91, 124 clinical (M: F = 61:63 and 53 post graduate trainees (M: F = 50:3 participated in the study. Approaches of male and female students were similar. SA was significantly affected by age among the preclinical students (p = 0.01, but not in other groups. Among pre-clinical students, males preferred a teacher who supported understanding (p = 0.04 but females preferred a passive transmission of information (p Conclusion Different factors affect the approach to studying in different groups but these explain only a small fraction of the variance observed.

Spinal Cord Tolerance in the Age of Spinal Radiosurgery: Lessons From Preclinical Studies

International Nuclear Information System (INIS)

Medin, Paul M.; Boike, Thomas P.

2011-01-01

Clinical implementation of spinal radiosurgery has increased rapidly in recent years, but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970s. The influences of field length, dose rate, inhomogeneous dose distributions, and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in preclinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small- and large-animal models. Extensive investigation of inhomogeneous dose distributions in the rat has demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Preclinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose-volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data are sparse, but results from guinea pig, rat, and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials.

Systemic therapy of bone metastases

International Nuclear Information System (INIS)

Skripekova, A.

2012-01-01

Complications of bone metastases can seriously influence quality of life of the patients including of their independence in activities of daily living. Bisfosfonates are reducing skeletal morbidity in solid tumors and in multiple myeloma by 30 - 50% (1). They are not only used in active antineoplastic therapy in the prevention of skeletal complications by bone metastases but they are also significantly useful in prevention of the decrease of osseous mass by hormonal manipulation. Preclinical and in part clinical data suppose that there is some role of bisfosfonates in prevention of formation of metastases by early cancer. Denosumab is fully humanized antibody against RANKL (receptor activator of nuclear factor κ-B ligand) which is very important in pathogenesis of bone resorption induced by osteoclasts. In this work we discuss about pathological mechanisms of bone resorption in multiple myeloma and solid tumors, we resume data from randomized clinical trials and we focus on the application of anti resorption therapy in clinical practice. (author)

A reversal phase arrest uncoupling the bone formation and resorption contributes to the bone loss in glucocorticoid treated ovariectomised aged sheep

DEFF Research Database (Denmark)

Andreasen, Christina Møller; Ding, Ming; Overgaard, Søren

2015-01-01

Large animals as sheep are often used as models for human osteoporosis. Our aim was therefore to determine how glucocorticoid treatment of ovariectomised sheep affects the cancellous bone, determining the cellular events within the bone remodelling process that contributes to their bone loss...... in postmenopausal women with glucocorticoid-induced osteoporosis. This supports the relevance of the sheep model to the pathophysiology of glucocorticoid-induced osteoporosis in postmenopausal women, making it a relevant preclinical model for orthopaedic implant and biomaterial research........ Twenty female sheep were assigned for two groups; an untreated control group and an ovariectomised group treated with glucocorticoids (0.6mg/kg/day, 5 times weekly) for 7months. At 7months the glucocorticoid-treated ovariectomised sheep showed a significant change in the bone microstructure revealed...

No preclinical rationale for IGF1R directed therapy in chondrosarcoma of bone

NARCIS (Netherlands)

Peterse, E.F.P.; Cleven, A.H.G.; Jong, de Y.; Briaire-de, Bruijn I.; Fletcher, J.A.; Danen, E.H.J.; Cleton, A.M.; Bov'ee, J.V.M.G.

2016-01-01

Background Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of the role of the IGF pathway in chondrosarcoma to determine if it can be a target for therapy, which was

Sequential changes in bone marrow architecture during continuous low dose gamma irradiation

International Nuclear Information System (INIS)

Seed, T.M.; Chubb, G.T.; Tolle, D.V.

1981-01-01

Beagles continuously exposed to low daily doses (10 R) of whole-body 60 Co ν-radiation are prone to develop either early occurring aplasstic anemia or late occurring myeloproliferative disorders. In this study, we have examined by a combination of light microscopy and scanning and transmission electron microscopy the sequential changes in the morphology of biopsied rib bone marrow of continuously irradiated dogs that developed either aplastic anemia, myelofibrosis, or myelogenous leukemia. Characteristic modifications of key elements of marrow architecture have been observed during preclinical and clinical phases of these hemopathological conditions. These architectural changes during preclinical phases appear to be related to the pathological progression to each of the radiation-induced hemopathological end points

Computational bone remodelling simulations and comparisons with DEXA results.

Science.gov (United States)

Turner, A W L; Gillies, R M; Sekel, R; Morris, P; Bruce, W; Walsh, W R

2005-07-01

Femoral periprosthetic bone loss following total hip replacement is often associated with stress shielding. Extensive bone resorption may lead to implant or bone failure and complicate revision surgery. In this study, an existing strain-adaptive bone remodelling theory was modified and combined with anatomic three-dimensional finite element models to predict alterations in periprosthetic apparent density. The theory incorporated an equivalent strain stimulus and joint and muscle forces from 45% of the gait cycle. Remodelling was simulated for three femoral components with different design philosophies: cobalt-chrome alloy, two-thirds proximally coated; titanium alloy, one-third proximally coated; and a composite of cobalt-chrome surrounded by polyaryletherketone, fully coated. Theoretical bone density changes correlated significantly with clinical densitometry measurements (DEXA) after 2 years across the Gruen zones (R2>0.67, p<0.02), with average differences of less than 5.4%. The results suggest that a large proportion of adaptive bone remodelling changes seen clinically with these implants may be explained by a consistent theory incorporating a purely mechanical stimulus. This theory could be applied to pre-clinical testing of new implants, investigation of design modifications, and patient-specific implant selection.

Stem Cells for Cartilage Repair: Preclinical Studies and Insights in Translational Animal Models and Outcome Measures

Directory of Open Access Journals (Sweden)

Melissa Lo Monaco

2018-01-01

Full Text Available Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs or induced pluripotent stem cells (iPSCs have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair.

Stem Cells for Cartilage Repair: Preclinical Studies and Insights in Translational Animal Models and Outcome Measures.

Science.gov (United States)

Lo Monaco, Melissa; Merckx, Greet; Ratajczak, Jessica; Gervois, Pascal; Hilkens, Petra; Clegg, Peter; Bronckaers, Annelies; Vandeweerd, Jean-Michel; Lambrichts, Ivo

2018-01-01

Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair.

A Bone-Implant Interaction Mouse Model for Evaluating Molecular Mechanism of Biomaterials/Bone Interaction.

Science.gov (United States)

Liu, Wenlong; Dan, Xiuli; Wang, Ting; Lu, William W; Pan, Haobo

2016-11-01

The development of an optimal animal model that could provide fast assessments of the interaction between bone and orthopedic implants is essential for both preclinical and theoretical researches in the design of novel biomaterials. Compared with other animal models, mice have superiority in accessing the well-developed transgenic modification techniques (e.g., cell tracing, knockoff, knockin, and so on), which serve as powerful tools in studying molecular mechanisms. In this study, we introduced the establishment of a mouse model, which was specifically tailored for the assessment of bone-implant interaction in a load-bearing bone marrow microenvironment and could potentially allow the molecular mechanism study of biomaterials by using transgenic technologies. The detailed microsurgery procedures for developing a bone defect (Φ = 0.8 mm) at the metaphysis region of the mouse femur were recorded. According to our results, the osteoconductive and osseointegrative properties of a well-studied 45S5 bioactive glass were confirmed by utilizing our mouse model, verifying the reliability of this model. The feasibility and reliability of the present model were further checked by using other materials as objects of study. Furthermore, our results indicated that this animal model provided a more homogeneous tissue-implant interacting surface than the rat at the early stage of implantation and this is quite meaningful for conducting quantitative analysis. The availability of transgenic techniques to mechanism study of biomaterials was further testified by establishing our model on Nestin-GFP transgenic mice. Intriguingly, the distribution of Nestin + cells was demonstrated to be recruited to the surface of 45S5 glass as early as 3 days postsurgery, indicating that Nestin + lineage stem cells may participate in the subsequent regeneration process. In summary, the bone-implant interaction mouse model could serve as a potential candidate to evaluate the early stage tissue

Ex vivo expansion of bone marrow stromal cells by platelet-rich plasma: a promising strategy in maxillo-facial surgery.

Science.gov (United States)

Oliva, A; Passaro, I; Di Pasquale, R; Di Feo, A; Criscuolo, M; Zappia, V; Della Ragione, F; D'Amato, S; Annunziata, M; Guida, L

2005-01-01

The aim of our study is to evaluate in vitro the response of bone marrow stromal cells (BMSCs) to platelet-rich plasma (PRP), in order to clarify the potential role of their combined use in a preclinical phase preceding BMSCs transplantation for bone repair and regeneration procedures. The incubation of BMSCs with PRP promoted a remarkable, dose- and time- dependent, growth stimulation, that was paralleled to a strong increase in the quantity of type I collagen and to a significant decrease in the activity of the early osteoblastic differentiation marker, alkaline phosphatase (AP). Once PRP was removed and osteogenic inducers were added, AP returned to levels comparable to the control, while the late phenotypic markers, osteocalcin and matrix calcification, were enhanced to higher levels than in controls. Our data demonstrate that PRP induces a remarkable ex vivo enrichment of BMSCs maintaining their differentiative potential. Thus PRP represents a valid preclinical tool for obtaining an effective, rapid and safe ex vivo expansion of BMSCs prior to their clinical utilization in bone engineering.

Melatonin and breast cancer: Evidences from preclinical and human studies.

Science.gov (United States)

Kubatka, Peter; Zubor, Pavol; Busselberg, Dietrich; Kwon, Taeg Kyu; Adamek, Mariusz; Petrovic, Daniel; Opatrilova, Radka; Gazdikova, Katarina; Caprnda, Martin; Rodrigo, Luis; Danko, Jan; Kruzliak, Peter

2018-02-01

The breast cancer affects women with high mortality and morbidity worldwide. The risk is highest in the most developed world but also is markedly rising in the developing countries. It is well documented that melatonin has a significant anti-tumor activities demonstrated on various cancer types in a plethora of preclinical studies. In breast cancer, melatonin is capable to disrupt estrogen-dependent cell signaling, resulting in a reduction of estrogen-stimulated cells, moreover, it's obvious neuro-immunomodulatory effect in organism was described. Several prospective studies have demonstrated the inverse correlation between melatonin metabolites and the risk of breast cancer. This correlation was confirmed by observational studies that found lower melatonin levels in breast cancer patients. Moreover, clinical studies have showed that circadian disruption of melatonin synthesis, specifically night shift work, is linked to increased breast cancer risk. In this regard, proper light/dark exposure with more selective use of light at night along with oral supplementation of melatonin may have benefits for high-risk women. The results of current preclinical studies, the mechanism of action, and clinical efficacy of melatonin in breast cancer are reviewed in this paper. Melatonin alone or in combined administration seems to be appropriate drug for the treatment of early stages of breast cancer with documented low toxicity over a wide range of doses. These and other issues are also discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of multi-deficiencies-diet on bone parameters of peripheral bone in ovariectomized mature rat.

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Thaqif El Khassawna

Full Text Available Many postmenopausal women have vitamin D and calcium deficiency. Therefore, vitamin D and calcium supplementation is recommended for all patients with osteopenia and osteoporosis. We used an experimental rat model to test the hypothesis that induction of osteoporosis is more efficiently achieved in peripheral bone through combining ovariectomy with a unique multi-deficiencies diet (vitamin D depletion and deficient calcium, vitamin K and phosphorus. 14-week-old Sprague-Dawley rats served as controls to examine the initial bone status. 11 rats were bilaterally ovariectomized (OVX and fed with multi-deficiencies diet. Three months later the treated group and the Sham group (n = 8 were euthanized. Bone biomechanical competence of the diaphyseal bone was examined on both, tibia and femur. Image analysis was performed on tibia via µCT, and on femur via histological analysis. Lower torsional stiffness indicated inferior mechanical competence of the tibia in 3 month OVX+Diet. Proximal metaphyseal region of the tibia showed a diminished bone tissue portion to total tissue in the µCT despite the increased total area as evaluated in both µCT and histology. Cortical bone showed higher porosity and smaller cross sectional thickness of the tibial diaphysis in the OVX+Diet rats. A lower ALP positive area and elevated serum level of RANKL exhibited the unbalanced cellular interaction in bone remodeling in the OVX+Diet rat after 3 month of treatment. Interestingly, more adipose tissue area in bone marrow indicated an effect of bone loss similar to that observed in osteoporotic patients. Nonetheless, the presence of osteoid and elevated serum level of PTH, BGP and Opn suggest the development of osteomalacia rather than an osteoporosis. As the treatment and fracture management of both osteoporotic and osteomalacia patients are clinically overlapping, this study provides a preclinical animal model to be utilized in local supplementation of minerals, drugs

Effects of multi-deficiencies-diet on bone parameters of peripheral bone in ovariectomized mature rat.

Science.gov (United States)

El Khassawna, Thaqif; Böcker, Wolfgang; Govindarajan, Parameswari; Schliefke, Nathalie; Hürter, Britta; Kampschulte, Marian; Schlewitz, Gudrun; Alt, Volker; Lips, Katrin Susanne; Faulenbach, Miriam; Möllmann, Henriette; Zahner, Daniel; Dürselen, Lutz; Ignatius, Anita; Bauer, Natali; Wenisch, Sabine; Langheinrich, Alexander Claus; Schnettler, Reinhard; Heiss, Christian

2013-01-01

Many postmenopausal women have vitamin D and calcium deficiency. Therefore, vitamin D and calcium supplementation is recommended for all patients with osteopenia and osteoporosis. We used an experimental rat model to test the hypothesis that induction of osteoporosis is more efficiently achieved in peripheral bone through combining ovariectomy with a unique multi-deficiencies diet (vitamin D depletion and deficient calcium, vitamin K and phosphorus). 14-week-old Sprague-Dawley rats served as controls to examine the initial bone status. 11 rats were bilaterally ovariectomized (OVX) and fed with multi-deficiencies diet. Three months later the treated group and the Sham group (n = 8) were euthanized. Bone biomechanical competence of the diaphyseal bone was examined on both, tibia and femur. Image analysis was performed on tibia via µCT, and on femur via histological analysis. Lower torsional stiffness indicated inferior mechanical competence of the tibia in 3 month OVX+Diet. Proximal metaphyseal region of the tibia showed a diminished bone tissue portion to total tissue in the µCT despite the increased total area as evaluated in both µCT and histology. Cortical bone showed higher porosity and smaller cross sectional thickness of the tibial diaphysis in the OVX+Diet rats. A lower ALP positive area and elevated serum level of RANKL exhibited the unbalanced cellular interaction in bone remodeling in the OVX+Diet rat after 3 month of treatment. Interestingly, more adipose tissue area in bone marrow indicated an effect of bone loss similar to that observed in osteoporotic patients. Nonetheless, the presence of osteoid and elevated serum level of PTH, BGP and Opn suggest the development of osteomalacia rather than an osteoporosis. As the treatment and fracture management of both osteoporotic and osteomalacia patients are clinically overlapping, this study provides a preclinical animal model to be utilized in local supplementation of minerals, drugs and growth factors

Preclinical evaluation of intravenously administered 111In-and 90Y-labeled B72.3 immunoconjugate (GYK-DTPA) in beagle dogs

International Nuclear Information System (INIS)

Quadri, S.M.; Vriesendorp, H.M.; Yi Shao; Blum, J.E.; Leichner, P.K.; Williams, J.R.

1993-01-01

B72.3, a monoclonal antibody with reactivity against human adenocarcinomas was obtained from the Cytogen Corporation in the form of an immunoconjugate coupled with linker-chelator GYK-DTPA by using proprietary carbohydrate directed site specific chemistry. The immunoconjugate was radiolabeled with indium-111 or yttrium-90. A preclinical analysis was performed in 10 normal beagle dogs. The pharmacokinetics of intravenously administered indium- and yttrium-labeled immunoconjugates were compared serially in blood, bone marrow and urine samples. Compared to 90 Y less of the 111 In label ended up in urine and more was found in blood and bone marrow. Indium-labeled B72.3 GYK-DTPA had relatively higher uptake in most glandular tissues than 111 In-labeled antiferritin immunoconjugate. Bone marrow toxicity was the dose limiting side effect after intravenous infusion of 90 Y-labeled B72.3 GYK-DTPA. Toxicity was also observed in the liver but not in other organ systems. Recently other investigators obtained similar results with these immunoconjugates in human patients. A preclinical pharmacokinetic analysis of radioimmunoconjugates in beagle dogs provided useful information regarding bone marrow toxicity, liver toxicity and in vivo instability of the immunoconjugate. Data suggest that for future trials in human patients, a more stable chelated immunoconjugate for yttrium is needed to achieve less liver uptake and a better correlation with the 111 In-labeled product than the 90 Y-labeled B72.3 GYK-DTPA used in this investigation. (Author)

Preclinical studies of dendrimer prodrugs.

Science.gov (United States)

Kojima, Chie

2015-01-01

Dendrimers are synthetic macromolecules with well-defined structures bearing a wide variety of functional groups on their periphery. These groups can be used to conjugate bioactive molecules such as drugs, ligands and imaging agents. Dendrimer prodrugs can be used to improve the water solubility and pharmacokinetic properties of the corresponding free drugs. This article summarizes preclinical studies pertaining to the use of drug-dendrimer conjugates as dendrimer prodrugs for the treatments of various diseases, including cancer and inflammatory diseases. A wide range of anticancer drugs have been conjugated to dendrimers via biodegradable linkers. The side effects of the parent drugs can be markedly reduced using dendrimer prodrugs, with some drugs showing improved efficacy. Anti-inflammatory agents have also been conjugated to dendrimers and used to treat a number of inflammatory diseases. Drug-dendrimer conjugates are preferable to drug-dendrimer complexes, where the use of degradable linkers is critical to the release of the drug. Polyethylene glycol and/or ligands can be added to a dendrimer prodrug, which is useful for the targeting of affected tissues. Imaging probes can also be incorporated into dendrimer prodrugs for the simultaneous delivery of therapeutic and diagnostic agents as 'theranostics.'

Bone turnover markers in sheep and goat: A review of the scientific literature

Directory of Open Access Journals (Sweden)

JOSÉ A. CAMASSA

Full Text Available ABSTRACT Bone turnover markers (BTMs are product of bone cell activity and are generally divided in bone formation and bone resorption markers. The purpose of this review was to structure the available information on the use of BTMs in studies on small ruminants, especially for monitoring their variations related to diet, exercise, gestation and metabolic lactation state, circadian and seasonal variations, and also during skeletal growth. Pre-clinical and translational studies using BTMs with sheep and goats as animal models in orthopaedic research studies to help in the evaluation of the fracture healing process and osteoporosis research are also described in this review. The available information from the reviewed studies was systematically organized in order to highlight the most promising BTMs in small ruminant research, as well as provide a wide view of the use of sheep and goat as animal models in orthopaedic research, type of markers and commercial assay kits with cross-reactivity in sheep and goat, method of sample and storage of serum and urine for bone turnover markers determination and the usefulness and limitations of bone turnover markers in the different studies, therefore an effective tool for researchers that seek answers to different questions while using BTMs in small ruminants.

The fabrication of bioresorbable implants for bone defects replacement using computer tomogram and 3D printing

Science.gov (United States)

Kuznetsov, P. G.; Tverdokhlebov, S. I.; Goreninskii, S. I.; Bolbasov, E. N.; Popkov, A. V.; Kulbakin, D. E.; Grigoryev, E. G.; Cherdyntseva, N. V.; Choinzonov, E. L.

2017-09-01

The present work demonstrates the possibility of production of personalized implants from bioresorbable polymers designed for replacement of bone defects. The stages of creating a personalized implant are described, which include the obtaining of 3D model from a computer tomogram, development of the model with respect to shape of bone fitment bore using Autodesk Meshmixer software, and 3D printing process from bioresorbable polymers. The results of bioresorbable polymer scaffolds implantation in pre-clinical tests on laboratory animals are shown. The biological properties of new bioresorbable polymers based on poly(lactic acid) were studied during their subcutaneous, intramuscular, bone and intraosseous implantation in laboratory animals. In all cases, there was a lack of a fibrous capsule formation around the bioresorbable polymer over time. Also, during the performed study, conclusions were made on osteogenesis intensity depending on the initial state of bone tissue.

Evaluation of cell binding peptide (p15) with silk fibre enhanced hydroxyappatite bone substitute for posterolateral spinal fusion in sheep

DEFF Research Database (Denmark)

Axelsen, M.; Jespersen, Stig; Overgaard, Søren

2015-01-01

Background: Spinal fusion is indicated in the surgical management of various spinal disorders. To ensure stabile fusion, bone graft materials are essential. Traditionally allo- or autograft has been used, but both are associated with limitations. Synthetic bone graft materials that reassemble today......: In this study, we compared fusion rates between silk fibre enhanced anorganic bovine derived hydroxyapatite matrix (ABM) with and without P15 peptide coating in uninstrumented PLF in a preclinical setting. Study design: Randomised prospective study in sheep. Method/materials: Twelve Tex/got sheep underwent open...

A phase II clinical trial does not show that high dose simvastatin has beneficial effect on markers of bone turnover in multiple myeloma

DEFF Research Database (Denmark)

Søndergaard, Teis Esben; Pedersen, PT; Levin Andersen, Thomas

2008-01-01

Several studies have evaluated the impact of low dose statin (20-80 mg/day) on bone metabolism with inconclusive results despite promising data of preclinical studies. In this study, we investigated the effect of high dose simvastatin (HD-Sim) on biochemical markers of bone turnover and disease...... acid phosphatase, TRACP); (ii) bone resorption (collagen fragments CTX and NTX); (iii) bone formation (osteocalcin and aminoterminal propeptide of type I collagen PINP); (iv) cholesterol; (v) regulators of bone metabolism [osteoprotegerin (OPG) and Dickkopf-1 (DKK-1)] and (vi) disease activity...... (monoclonal proteins or free light chains in serum). TRACP activity in serum and levels of collagen fragments (NTX) in urine increased for all patients temporarily during the 7 days of treatment with HD-Sim indicating that osteoclasts may have been stimulated rather than inhibited. The other markers of bone...

The Devil Is in the Details: Incomplete Reporting in Preclinical Animal Research.

Science.gov (United States)

Avey, Marc T; Moher, David; Sullivan, Katrina J; Fergusson, Dean; Griffin, Gilly; Grimshaw, Jeremy M; Hutton, Brian; Lalu, Manoj M; Macleod, Malcolm; Marshall, John; Mei, Shirley H J; Rudnicki, Michael; Stewart, Duncan J; Turgeon, Alexis F; McIntyre, Lauralyn

2016-01-01

Incomplete reporting of study methods and results has become a focal point for failures in the reproducibility and translation of findings from preclinical research. Here we demonstrate that incomplete reporting of preclinical research is not limited to a few elements of research design, but rather is a broader problem that extends to the reporting of the methods and results. We evaluated 47 preclinical research studies from a systematic review of acute lung injury that use mesenchymal stem cells (MSCs) as a treatment. We operationalized the ARRIVE (Animal Research: Reporting of In Vivo Experiments) reporting guidelines for pre-clinical studies into 109 discrete reporting sub-items and extracted 5,123 data elements. Overall, studies reported less than half (47%) of all sub-items (median 51 items; range 37-64). Across all studies, the Methods Section reported less than half (45%) and the Results Section reported less than a third (29%). There was no association between journal impact factor and completeness of reporting, which suggests that incomplete reporting of preclinical research occurs across all journals regardless of their perceived prestige. Incomplete reporting of methods and results will impede attempts to replicate research findings and maximize the value of preclinical studies.

Zoledronic acid use in patients with bone metastases from renal cell carcinoma or bladder cancer.

Science.gov (United States)

Saad, Fred; Eastham, James A

2010-06-01

Approximately 30% of patients with renal cell carcinoma (RCC) and 40% of patients with bladder cancer develop bone metastases that can disrupt normal bone homeostasis and place patients at risk for potentially life-limiting skeletal-related events (SREs). In the absence of bone-directed therapies, patients with RCC may experience up to four SREs per year. In patients with bone metastases from RCC or bladder cancer, zoledronic acid (ZOL) significantly reduced the risk of SREs compared with placebo. In addition to its bone-protective effects, preclinical and early clinical evidence indicates that ZOL prevents tumor progression. For example, retrospective subset analysis in patients with RCC indicated that ZOL extended time to disease progression and demonstrated a trend toward improved overall survival compared with placebo. Additionally, a study in patients with bone metastases from bladder cancer demonstrated that ZOL improved 1-year overall survival compared with placebo. Bone metastases place a heavy burden on patients with RCC or bladder cancer, and early, continuous treatment with ZOL may provide anticancer benefits in addition to important patient quality of life. 2010. Published by Elsevier Inc.

Modeling the Western Diet for Preclinical Investigations.

Science.gov (United States)

Hintze, Korry J; Benninghoff, Abby D; Cho, Clara E; Ward, Robert E

2018-05-01

Rodent models have been invaluable for biomedical research. Preclinical investigations with rodents allow researchers to investigate diseases by using study designs that are not suitable for human subjects. The primary criticism of preclinical animal models is that results are not always translatable to humans. Some of this lack of translation is due to inherent differences between species. However, rodent models have been refined over time, and translatability to humans has improved. Transgenic animals have greatly aided our understanding of interactions between genes and disease and have narrowed the translation gap between humans and model animals. Despite the technological innovations of animal models through advances in genetics, relatively little attention has been given to animal diets. Namely, developing diets that replicate what humans eat will help make animal models more relevant to human populations. This review focuses on commonly used rodent diets that are used to emulate the Western dietary pattern in preclinical studies of obesity and type 2 diabetes, nonalcoholic liver disease, maternal nutrition, and colorectal cancer.

The Devil Is in the Details: Incomplete Reporting in Preclinical Animal Research.

Directory of Open Access Journals (Sweden)

Marc T Avey

Full Text Available Incomplete reporting of study methods and results has become a focal point for failures in the reproducibility and translation of findings from preclinical research. Here we demonstrate that incomplete reporting of preclinical research is not limited to a few elements of research design, but rather is a broader problem that extends to the reporting of the methods and results. We evaluated 47 preclinical research studies from a systematic review of acute lung injury that use mesenchymal stem cells (MSCs as a treatment. We operationalized the ARRIVE (Animal Research: Reporting of In Vivo Experiments reporting guidelines for pre-clinical studies into 109 discrete reporting sub-items and extracted 5,123 data elements. Overall, studies reported less than half (47% of all sub-items (median 51 items; range 37-64. Across all studies, the Methods Section reported less than half (45% and the Results Section reported less than a third (29%. There was no association between journal impact factor and completeness of reporting, which suggests that incomplete reporting of preclinical research occurs across all journals regardless of their perceived prestige. Incomplete reporting of methods and results will impede attempts to replicate research findings and maximize the value of preclinical studies.

Examination performances of German and international medical students in the preclinical studying-term--a descriptive study.

Science.gov (United States)

Huhn, D; Resch, F; Duelli, R; Möltner, A; Huber, J; Karimian Jazi, K; Amr, A; Eckart, W; Herzog, W; Nikendei, C

2014-01-01

Medical students with a migration background face several specific problems during their studies. International surveys show first indications that this group of students performs worse in written, oral or practical exams. However, so far, nothing is known about the performance of international students in written pre-clinical tests as well as in pre-clinical State Examinations for German-speaking countries. A descriptive, retrospective analysis of the exam performances of medical students in the pre-clinical part of their studies was conducted at the Faculty of Medicine of Heidelberg in for the year 2012. Performance in written tests of the final exams in the second (N=276), third (N=292) and fourth semester (N=285) were compared between German students, students from EU countries and students from non-EU countries. Same comparison was drawn for the performance in the oral exam of the First State Examination in the period from 2009 - 2012 (N=1137). German students performed significantly better than students with a non-EU migration background both in all written exams and in the oral State Examination (all pstudents with an EU migration background was significantly better than that of students with a non-EU background in the written exam at the end of the third and fourth semester (pstudents completed the oral exam of the First State Examination significantly earlier than students with a non-EU migration background (students with a country of origin outside of the European Union has to be seen as a high-risk group among students with a migration background. For this group, there is an urgent need for early support to prepare for written and oral examinations.

Bioengineered Temporomandibular Joint Disk Implants: Study Protocol for a Two-Phase Exploratory Randomized Preclinical Pilot Trial in 18 Black Merino Sheep (TEMPOJIMS)

Science.gov (United States)

Monje, Florencio Gil; González-García, Raúl; Little, Christopher B; Mónico, Lisete; Pinho, Mário; Santos, Fábio Abade; Carrapiço, Belmira; Gonçalves, Sandra Cavaco; Morouço, Pedro; Alves, Nuno; Moura, Carla; Wang, Yadong; Jeffries, Eric; Gao, Jin; Sousa, Rita; Neto, Lia Lucas; Caldeira, Daniel; Salvado, Francisco

2017-01-01

Background Preclinical trials are essential to test efficacious options to substitute the temporomandibular joint (TMJ) disk. The contemporary absence of an ideal treatment for patients with severe TMJ disorders can be related to difficulties concerning the appropriate study design to conduct preclinical trials in the TMJ field. These difficulties can be associated with the use of heterogeneous animal models, the use of the contralateral TMJ as control, the absence of rigorous randomized controlled preclinical trials with blinded outcomes assessors, and difficulties involving multidisciplinary teams. Objective This study aims to develop a new, reproducible, and effective study design for preclinical research in the TMJ domain, obtaining rigorous data related to (1) identify the impact of bilateral discectomy in black Merino sheep, (2) identify the impact of bilateral discopexy in black Merino sheep, and (3) identify the impact of three different bioengineering TMJ discs in black Merino sheep. Methods A two-phase exploratory randomized controlled preclinical trial with blinded outcomes is proposed. In the first phase, nine sheep are randomized into three different surgical bilateral procedures: bilateral discectomy, bilateral discopexy, and sham surgery. In the second phase, nine sheep are randomized to bilaterally test three different TMJ bioengineering disk implants. The primary outcome is the histological gradation of TMJ. Secondary outcomes are imaging changes, absolute masticatory time, ruminant time per cycle, ruminant kinetics, ruminant area, and sheep weight. Results Previous preclinical studies in this field have used the contralateral unoperated side as a control, different animal models ranging from mice to a canine model, with nonrandomized, nonblinded and uncontrolled study designs and limited outcomes measures. The main goal of this exploratory preclinical protocol is to set a new standard for future preclinical trials in oromaxillofacial surgery

Harmonization in preclinical epilepsy research: A joint AES/ILAE translational initiative.

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Galanopoulou, Aristea S; French, Jacqueline A; O'Brien, Terence; Simonato, Michele

2017-11-01

Among the priority next steps outlined during the first translational epilepsy research workshop in London, United Kingdom (2012), jointly organized by the American Epilepsy Society (AES) and the International League Against Epilepsy (ILAE), are the harmonization of research practices used in preclinical studies and the development of infrastructure that facilitates multicenter preclinical studies. The AES/ILAE Translational Task Force of the ILAE has been pursuing initiatives that advance these goals. In this supplement, we present the first reports of the working groups of the Task Force that aim to improve practices of performing rodent video-electroencephalography (vEEG) studies in experimental controls, generate systematic reviews of preclinical research data, and develop preclinical common data elements (CDEs) for epilepsy research in animals. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Biological basis of sex differences in drug abuse: preclinical and clinical studies.

Science.gov (United States)

Lynch, Wendy J; Roth, Megan E; Carroll, Marilyn E

2002-11-01

The recent focus on drug abuse in women has brought attention to numerous differences between women and men. In this review, we discuss both preclinical and clinical findings of sex differences in drug abuse as well as mechanisms that may underlie these differences. Recent evidence suggests that the progression to dependence and abuse may differ between women and men; thus, different prevention and treatment strategies may be required. Similar sex differences in drug sensitivity and self-administration have been reported in laboratory animal studies. Females appear to be more vulnerable than males to the reinforcing effects of psychostimulants, opiates, and nicotine during many phases of the addiction process (e.g. acquisition, maintenance, dysregulation-escalation, relapse). Male and female animals differ in their behavioral, neurological, and pharmacological responses to drugs. Although the role of sex in the mechanisms of drug action remains unclear, preclinical and clinical studies indicate that ovarian hormones, particularly estrogen, play a role in producing sex differences in drug abuse. Future research is necessary to provide information on how to design more effective drug abuse treatment programs and resources that are sex specific.

The basics of preclinical drug development for neurodegenerative disease indications.

Science.gov (United States)

Steinmetz, Karen L; Spack, Edward G

2009-06-12

Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

Pomegranate Peel Extract Prevents Bone Loss in a Preclinical Model of Osteoporosis and Stimulates Osteoblastic Differentiation in Vitro

Directory of Open Access Journals (Sweden)

Mélanie Spilmont

2015-11-01

Full Text Available The nutritional benefits of pomegranate have attracted great scientific interest. The pomegranate, including the pomegranate peel, has been used worldwide for many years as a fruit with medicinal activity, mostly antioxidant properties. Among chronic diseases, osteoporosis, which is associated with bone remodelling impairment leading to progressive bone loss, could eventually benefit from antioxidant compounds because of the involvement of oxidative stress in the pathogenesis of osteopenia. In this study, with in vivo and ex vivo experiments, we investigated whether the consumption of pomegranate peel extract (PGPE could limit the process of osteopenia. We demonstrated that in ovariectomized (OVX C57BL/6J mice, PGPE consumption was able to significantly prevent the decrease in bone mineral density (−31.9%; p < 0.001 vs. OVX mice and bone microarchitecture impairment. Moreover, the exposure of RAW264.7 cells to serum harvested from mice that had been given a PGPE-enriched diet elicited reduced osteoclast differentiation and bone resorption, as shown by the inhibition of the major osteoclast markers. In addition, PGPE appeared to substantially stimulate osteoblastic MC3T3-E1 alkaline phosphatase (ALP activity at day 7, mineralization at day 21 and the transcription level of osteogenic markers. PGPE may be effective in preventing the bone loss associated with ovariectomy in mice, and offers a promising alternative for the nutritional management of this disease.

Pomegranate Peel Extract Prevents Bone Loss in a Preclinical Model of Osteoporosis and Stimulates Osteoblastic Differentiation in Vitro.

Science.gov (United States)

Spilmont, Mélanie; Léotoing, Laurent; Davicco, Marie-Jeanne; Lebecque, Patrice; Miot-Noirault, Elisabeth; Pilet, Paul; Rios, Laurent; Wittrant, Yohann; Coxam, Véronique

2015-11-11

The nutritional benefits of pomegranate have attracted great scientific interest. The pomegranate, including the pomegranate peel, has been used worldwide for many years as a fruit with medicinal activity, mostly antioxidant properties. Among chronic diseases, osteoporosis, which is associated with bone remodelling impairment leading to progressive bone loss, could eventually benefit from antioxidant compounds because of the involvement of oxidative stress in the pathogenesis of osteopenia. In this study, with in vivo and ex vivo experiments, we investigated whether the consumption of pomegranate peel extract (PGPE) could limit the process of osteopenia. We demonstrated that in ovariectomized (OVX) C57BL/6J mice, PGPE consumption was able to significantly prevent the decrease in bone mineral density (-31.9%; p < 0.001 vs. OVX mice) and bone microarchitecture impairment. Moreover, the exposure of RAW264.7 cells to serum harvested from mice that had been given a PGPE-enriched diet elicited reduced osteoclast differentiation and bone resorption, as shown by the inhibition of the major osteoclast markers. In addition, PGPE appeared to substantially stimulate osteoblastic MC3T3-E1 alkaline phosphatase (ALP) activity at day 7, mineralization at day 21 and the transcription level of osteogenic markers. PGPE may be effective in preventing the bone loss associated with ovariectomy in mice, and offers a promising alternative for the nutritional management of this disease.

Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments.

Directory of Open Access Journals (Sweden)

Valerie C Henderson

Full Text Available The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external or programmatic research activity they primarily address.We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria--most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation.By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice. Please see later in the article for the Editors' Summary.

Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments.

Science.gov (United States)

Henderson, Valerie C; Kimmelman, Jonathan; Fergusson, Dean; Grimshaw, Jeremy M; Hackam, Dan G

2013-01-01

The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address. We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria--most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation. By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice. Please see later in the article for the Editors' Summary.

Comparative biomechanical study between fresh frozen bone and fresh frozen pasteurized bone process

International Nuclear Information System (INIS)

Ferdiansyah Abdurrahman

1999-01-01

To observe the biomechanical properties difference between fresh frozen bone and fresh frozen pasteurized bone process Thirty eight femurs bones taken from 6 years old primate.(macaca fascicularis) from Primate Nursery Center LIPI Bogor, 20 bones were 6 cm cut for bending test and 18 remains were 3 cm cut for compression test. All bones were frozen and then divided into two groups for each biomechanical study. First group (I 0 bones for bending test and 9 bones for compression test) were undergone fresh frozen procession only. The second group with the same amount was undergone fresh frozen and pasteurized on 60 degree C for three hours. Bending test was done until the bones were broken on control group and pasteurized group and the result was compared, the same procedure was done for compression test. The study was done in room temperature. The biomechanical test result was analyzed by two independent T tests. The bending test control group has ( mean 0.097 N / mm sup 2 (SD = 0.007) and the pasteurized group ( mean 0. I 0 1 N / mm sup 2 (SD = 0.0 1 3), there was no significant difference (p 0.399). The compression test control group has ( = mean 0.71 N / mm sup 2 (SD=0.128)where as the pasteurized group has(mean 0.50N/mm sup 2 (SD=0.111),there was significant difference (p =0.004) From the result biomechanical study on bending test, there was no significant difference of bone strength, whereas on compression test the fresh frozen with pasteurized bone group is 125% stronger than control group. The result of this study will be very useful for reconstruction bone allograft

A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies: important issues and lessons relevant to the design of future clinical research.

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Disma, Nicola; Mondardini, Maria C; Terrando, Niccolò; Absalom, Anthony R; Bilotta, Federico

2016-01-01

Preclinical evidence suggests that anesthetic agents harm the developing brain thereby causing long-term neurocognitive impairments. It is not clear if these findings apply to humans, and retrospective epidemiological studies thus far have failed to show definitive evidence that anesthetic agents are harmful to the developing human brain. The aim of this systematic review was to summarize the preclinical studies published over the past decade, with a focus on methodological issues, to facilitate the comparison between different preclinical studies and inform better design of future trials. The literature search identified 941 articles related to the topic of neurotoxicity. As the primary aim of this systematic review was to compare methodologies applied in animal studies to inform future trials, we excluded a priori all articles focused on putative mechanism of neurotoxicity and the neuroprotective agents. Forty-seven preclinical studies were finally included in this review. Methods used in these studies were highly heterogeneous-animals were exposed to anesthetic agents at different developmental stages, in various doses and in various combinations with other drugs, and overall showed diverse toxicity profiles. Physiological monitoring and maintenance of physiological homeostasis was variable and the use of cognitive tests was generally limited to assessment of specific brain areas, with restricted translational relevance to humans. Comparison between studies is thus complicated by this heterogeneous methodology and the relevance of the combined body of literature to humans remains uncertain. Future preclinical studies should use better standardized methodologies to facilitate transferability of findings from preclinical into clinical science. © 2015 John Wiley & Sons Ltd.

Thymoquinone as a Potential Adjuvant Therapy for Cancer Treatment: Evidence from Preclinical Studies

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A.G.M. Mostofa

2017-06-01

Full Text Available Thymoquinone (TQ, the main bioactive component of Nigella sativa, has been found to exhibit anticancer effects in numerous preclinical studies. Due to its multitargeting nature, TQ interferes in a wide range of tumorigenic processes and counteracts carcinogenesis, malignant growth, invasion, migration, and angiogenesis. Moreover, TQ can specifically sensitize tumor cells toward conventional cancer treatments (e.g., radiotherapy, chemotherapy, and immunotherapy and simultaneously minimize therapy-associated toxic effects in normal cells. In this review, we summarized the adjuvant potential of TQ as observed in various in vitro and in vivo animal models and discussed the pharmacological properties of TQ to rationalize its supplementary role in potentiating the efficacy of standard therapeutic modalities namely surgery, radiotherapy, chemotherapy, and immunotherapy. Altogether, we suggest further comprehensive evaluation of TQ in preclinical and clinical levels to delineate its implied utility as a novel complementary adjuvant therapy for cancer treatment.

Three dimensional mapping of strontium in bone by dual energy K-edge subtraction imaging

International Nuclear Information System (INIS)

Cooper, D M L; Chapman, L D; Carter, Y; Zhouping, W; Wu, Y; Panahifar, A; Duke, M J M; Doschak, M; Britz, H M; Bewer, B

2012-01-01

The bones of many terrestrial vertebrates, including humans, are continually altered through an internal process of turnover known as remodeling. This process plays a central role in bone adaptation and disease. The uptake of fluorescent tetracyclines within bone mineral is widely exploited as a means of tracking new tissue formation. While investigation of bone microarchitecture has undergone a dimensional shift from 2D to 3D in recent years, we lack a 3D equivalent to fluorescent labeling. In the current study we demonstrate the ability of synchrotron radiation dual energy K-edge subtraction (KES) imaging to map the 3D distribution of elemental strontium within rat vertebral samples. This approach has great potential for ex vivo analysis of preclinical models and human tissue samples. KES also represents a powerful tool for investigating the pharmokinetics of strontium-based drugs recently approved in many countries around the globe for the treatment of osteoporosis. (paper)

SU-C-303-03: Dosimetric Model of the Beagle Needed for Pre-Clinical Testing of Radiopharmaceuticals

Energy Technology Data Exchange (ETDEWEB)

Shang, M; Sands, M; Bolch, W [University of Florida, Gainesville, FL (United States)

2015-06-15

Purpose: Large animal models, most popularly beagles, have been crucial surrogates to humans in determining radiation safety levels of radiopharmaceuticals. This study aims to develop a detailed beagle phantom to accurately approximate organ absorbed doses for therapy nuclear medicine preclinical studies. Methods: A 3D NURBS model was created subordinate to a whole body CT of an adult beagle. Bones were harvested and CT imaged to offer macroscopic skeletal detail. Samples of trabecular spongiosa were cored and imaged to offer microscopic skeletal detail for bone trabeculae and marrow volume fractions. Results: Organ masses in the model are typical of an adult beagle. Trends in volume fractions for skeletal dosimetry are fundamentally similar to those found in existing models of other canine species. Conclusion: This work warrants its use in further investigations of radiation transport calculation for electron and photon dosimetry. This model accurately represents the anatomy of a beagle, and can be directly translated into a useable geometry for a voxel-based Monte Carlo radiation transport program such as MCNP6. Work supported by a grant from the Hyundai Hope on Wheels Foundation for Pediatric Cancer Research.

Engraftment of Prevascularized, Tissue Engineered Constructs in a Novel Rabbit Segmental Bone Defect Model

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Alexandre Kaempfen

2015-06-01

Full Text Available The gold standard treatment of large segmental bone defects is autologous bone transfer, which suffers from low availability and additional morbidity. Tissue engineered bone able to engraft orthotopically and a suitable animal model for pre-clinical testing are direly needed. This study aimed to evaluate engraftment of tissue-engineered bone with different prevascularization strategies in a novel segmental defect model in the rabbit humerus. Decellularized bone matrix (Tutobone seeded with bone marrow mesenchymal stromal cells was used directly orthotopically or combined with a vessel and inserted immediately (1-step or only after six weeks of subcutaneous “incubation” (2-step. After 12 weeks, histological and radiological assessment was performed. Variable callus formation was observed. No bone formation or remodeling of the graft through TRAP positive osteoclasts could be detected. Instead, a variable amount of necrotic tissue formed. Although necrotic area correlated significantly with amount of vessels and the 2-step strategy had significantly more vessels than the 1-step strategy, no significant reduction of necrotic area was found. In conclusion, the animal model developed here represents a highly challenging situation, for which a suitable engineered bone graft with better prevascularization, better resorbability and higher osteogenicity has yet to be developed.

Examination performances of German and international medical students in the preclinical studying-term – A descriptive study

Science.gov (United States)

Huhn, D.; Resch, F.; Duelli, R.; Möltner, A.; Huber, J.; Karimian Jazi, K.; Amr, A.; Eckart, W.; Herzog, W.; Nikendei, C.

2014-01-01

Introduction: Medical students with a migration background face several specific problems during their studies. International surveys show first indications that this group of students performs worse in written, oral or practical exams. However, so far, nothing is known about the performance of international students in written pre-clinical tests as well as in pre-clinical State Examinations for German-speaking countries. Method: A descriptive, retrospective analysis of the exam performances of medical students in the pre-clinical part of their studies was conducted at the Faculty of Medicine of Heidelberg in for the year 2012. Performance in written tests of the final exams in the second (N=276), third (N=292) and fourth semester (N=285) were compared between German students, students from EU countries and students from non-EU countries. Same comparison was drawn for the performance in the oral exam of the First State Examination in the period from 2009 - 2012 (N=1137). Results: German students performed significantly better than students with a non-EU migration background both in all written exams and in the oral State Examination (all pstudents with an EU migration background was significantly better than that of students with a non-EU background in the written exam at the end of the third and fourth semester (pstudents completed the oral exam of the First State Examination significantly earlier than students with a non-EU migration background (students with a country of origin outside of the European Union has to be seen as a high-risk group among students with a migration background. For this group, there is an urgent need for early support to prepare for written and oral examinations. PMID:25228931

The basics of preclinical drug development for neurodegenerative disease indications

Directory of Open Access Journals (Sweden)

Spack Edward G

2009-06-01

Full Text Available Abstract Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s. Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Science.gov (United States)

Shen, Jia; James, Aaron W.; Zhang, Xinli; Pang, Shen; Zara, Janette N.; Asatrian, Greg; Chiang, Michael; Lee, Min; Khadarian, Kevork; Nguyen, Alan; Lee, Kevin S.; Siu, Ronald K.; Tetradis, Sotirios; Ting, Kang; Soo, Chia

2017-01-01

The differentiation factor NEL-like molecule-1 (NELL-1) has been reported as osteoinductive in multiple in vivo preclinical models. Bone morphogenetic protein (BMP)-2 is used clinically for skeletal repair, but in vivo administration can induce abnormal, adipose-filled, poor-quality bone. We demonstrate that NELL-1 combined with BMP2 significantly optimizes osteogenesis in a rodent femoral segmental defect model by minimizing the formation of BMP2-induced adipose-filled cystlike bone. In vitro studies using the mouse bone marrow stromal cell line M2-10B4 and human primary bone marrow stromal cells have confirmed that NELL-1 enhances BMP2-induced osteogenesis and inhibits BMP2-induced adipogenesis. Importantly, the ability of NELL-1 to direct BMP2-treated cells toward osteogenesis and away from adipogenesis requires intact canonical Wnt signaling. Overall, these studies establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis. The novel abilities of NELL-1 to stimulate Wnt signaling and to repress adipogenesis may highlight new treatment approaches for bone loss in osteoporosis. PMID:26772960

Plasma-sprayed titanium coating to polyetheretherketone improves the bone-implant interface.

Science.gov (United States)

Walsh, William R; Bertollo, Nicky; Christou, Chrisopher; Schaffner, Dominik; Mobbs, Ralph J

2015-05-01

Rapid and stable fixation at the bone-implant interface would be regarded as one of the primary goals to achieve clinical efficacy, regardless of the surgical site. Although mechanical and physical properties of polyetheretherketone (PEEK) provide advantages for implant devices, the hydrophobic nature and the lack of direct bone contact remains a limitation. To examine the effects of a plasma-sprayed titanium coated PEEK on the mechanical and histologic properties at the bone-implant interface. A preclinical laboratory study. Polyetheretherketone and plasma-sprayed titanium coated PEEK implants (Ti-bond; Spinal Elements, Carlsbad, CA, USA) were placed in a line-to-line manner in cortical bone and in a press-fit manner in cancellous bone of adult sheep using an established ovine model. Shear strength was assessed in the cortical sites at 4 and 12 weeks, whereas histology was performed in cortical and cancellous sites at both time points. The titanium coating dramatically improved the shear strength at the bone-implant interface at 4 weeks and continued to improve with time compared with PEEK. Direct bone ongrowth in cancellous and cortical sites can be achieved using a plasma-sprayed titanium coating on PEEK. Direct bone to implant bonding can be achieved on PEEK in spite of its hydrophobic nature using a plasma-sprayed titanium coating. The plasma-sprayed titanium coating improved mechanical properties in the cortical sites and the histology in cortical and cancellous sites. Copyright © 2015 Elsevier Inc. All rights reserved.

Spectroscopic analysis of bones for forensic studies

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Tofanelli, Mirko [Applied and Laser Spectroscopy Laboratory, Institute of Chemistry of Organometallic Compounds, Research Area of CNR, Via G. Moruzzi, 1, 56124 Pisa (Italy); Pardini, Lorenzo [Institut für Physik und IRIS Adlershof, Humboldt-Universität zu Berlin, Zum Großen Windkanal 6, 12489 Berlin (Germany); Borrini, Matteo [Research Centre in Evolutionary Anthropology and Palaeoecology, School of Natural Sciences and Psychology, Liverpool John Moores University, Byrom Street, Liverpool (United Kingdom); Bartoli, Fulvio; Bacci, Alessandra [Department of Biology, University of Pisa, Via A. Volta, 4, 56126 Pisa (Italy); D’Ulivo, Alessandro; Pitzalis, Emanuela; Mascherpa, Marco Carlo; Legnaioli, Stefano; Lorenzetti, Giulia; Pagnotta, Stefano [Applied and Laser Spectroscopy Laboratory, Institute of Chemistry of Organometallic Compounds, Research Area of CNR, Via G. Moruzzi, 1, 56124 Pisa (Italy); Holanda Cavalcanti, Gildo de [Instituto de Fìsica, Universidade Federal Fluminense, Av. Gal. Milton Tavares de Souza, s/no Campus da Praia Vermelha, CEP 24210-346, Niterói, Rio de Janeiro (Brazil); Lezzerini, Marco [Department of Earth Sciences, University of Pisa, Via Santa Maria, 53, 56126 Pisa (Italy); Palleschi, Vincenzo, E-mail: vincenzo.palleschi@cnr.it [Applied and Laser Spectroscopy Laboratory, Institute of Chemistry of Organometallic Compounds, Research Area of CNR, Via G. Moruzzi, 1, 56124 Pisa (Italy)

2014-09-01

The elemental analysis of human bones can give information about the dietary habits of the deceased, especially in the last years of their lives, which can be useful for forensic studies. The most important requirement that must be satisfied for this kind of analysis is that the concentrations of analyzed elements are the same as ante mortem. In this work, a set of bones was analyzed using Laser-Induced Breakdown Spectroscopy (LIBS) and validated using Inductively Coupled Plasma–Optical Emission Spectroscopy (ICP-OES), in order to compare those two techniques and to investigate the effect of possible alterations in the elemental concentrations' proportion resulting from the treatment usually applied for preparing the bones for traditional forensic analysis. The possibility that elemental concentrations' changes would occur after accidental or intentional burning of the bones was also studied. - Highlights: • The LIBS analysis of (animal) bones is presented, to establish its feasibility for forensic studies. • Untreated bones and bones subjected to high temperatures (boiled, burned) were analyzed. • A simple calibration, using a single reference sample, gave reasonable quantitative results. • The comparison of the results demonstrates that LIBS analysis can provide nutritional information. • The nutritional information obtained are the same on untreated, boiled and burned bones.

Spectroscopic analysis of bones for forensic studies

International Nuclear Information System (INIS)

Tofanelli, Mirko; Pardini, Lorenzo; Borrini, Matteo; Bartoli, Fulvio; Bacci, Alessandra; D’Ulivo, Alessandro; Pitzalis, Emanuela; Mascherpa, Marco Carlo; Legnaioli, Stefano; Lorenzetti, Giulia; Pagnotta, Stefano; Holanda Cavalcanti, Gildo de; Lezzerini, Marco; Palleschi, Vincenzo

2014-01-01

The elemental analysis of human bones can give information about the dietary habits of the deceased, especially in the last years of their lives, which can be useful for forensic studies. The most important requirement that must be satisfied for this kind of analysis is that the concentrations of analyzed elements are the same as ante mortem. In this work, a set of bones was analyzed using Laser-Induced Breakdown Spectroscopy (LIBS) and validated using Inductively Coupled Plasma–Optical Emission Spectroscopy (ICP-OES), in order to compare those two techniques and to investigate the effect of possible alterations in the elemental concentrations' proportion resulting from the treatment usually applied for preparing the bones for traditional forensic analysis. The possibility that elemental concentrations' changes would occur after accidental or intentional burning of the bones was also studied. - Highlights: • The LIBS analysis of (animal) bones is presented, to establish its feasibility for forensic studies. • Untreated bones and bones subjected to high temperatures (boiled, burned) were analyzed. • A simple calibration, using a single reference sample, gave reasonable quantitative results. • The comparison of the results demonstrates that LIBS analysis can provide nutritional information. • The nutritional information obtained are the same on untreated, boiled and burned bones

Piroxicam treatment augments bone abnormalities in interleukin-10 knockout mice.

Science.gov (United States)

Holgersen, Kristine; Dobie, Ross; Farquharson, Colin; vanʼt Hof, Rob; Ahmed, Syed Faisal; Hansen, Axel Kornerup; Holm, Thomas L

2015-02-01

Osteoporosis and fractures are common complications of inflammatory bowel disease. The pathogenesis is multifactorial and has been partly attributed to intestinal inflammation. The aim of this study was to evaluate bone status and assess the association between bone loss and gut inflammation in an experimental colitis model. Colitis was induced in interleukin-10 knockout mice (PAC IL-10 k.o.) by peroral administration of piroxicam for 12 days. The degree of colitis was assessed by clinical, macroscopic, and microscopic evaluation. Trabecular and cortical bone microarchitecture of tibia were determined using micro-computed tomography. Moreover, the serum levels of bone formation and bone resorption biomarkers were measured, and inflammatory protein profiling was performed on colons. PAC IL-10 k.o. mice developed severe colitis, characterized by hyperplasia and focal transmural inflammation, which was consistent with Crohn's disease-like pathology. The gut inflammation was accompanied by a 14% and 12% reduction in trabecular thickness relative to piroxicam-treated wild type and untreated wild type mice, respectively (P < 0.001). The trabecular bone structure was also changed in PAC IL-10 k.o. mice, whereas no differences in cortical bone geometry were observed. The trabecular thickness was inversely correlated with serum levels of CTX (r = -0.93, P = 0.006). Moreover, numerous inflammatory mediators, including RANKL and osteoprotegerin, were significantly increased in the colon of PAC IL-10 k.o. mice. PAC IL-10 k.o. mice develop bone loss and changed trabecular structure, as a result of increased bone resorption. Thus, the PAC IL-10 k.o. model could be a useful experimental model in preclinical research of inflammatory bowel disease-associated bone loss.

Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies.

Science.gov (United States)

Sarris, Jerome; McIntyre, Erica; Camfield, David A

2013-03-01

Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. This article (part 1) reviews herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In part 2, we review herbal medicines for which there have been clinical investigations for anxiolytic activity. An open-ended, language-restricted (English) search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) using specific search criteria to identify herbal medicines that have been investigated for anxiolytic activity. This search of the literature revealed 1,525 papers, from which 53 herbal medicines were included in the full review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed in part 2), with another 32 having solely preclinical studies (reviewed here in part 1). Preclinical evidence of anxiolytic activity (without human clinical trials) was found for Albizia julibrissin, Sonchus oleraceus, Uncaria rhynchophylla, Stachys lavandulifolia, Cecropia glazioui, Magnolia spp., Eschscholzia californica, Erythrina spp., Annona spp., Rubus brasiliensis, Apocynum venetum, Nauclea latifolia, Equisetum arvense, Tilia spp., Securidaca longepedunculata, Achillea millefolium, Leea indica, Juncus effusus, Coriandrum sativum, Eurycoma longifolia, Turnera diffusa, Euphorbia hirta, Justicia spp., Crocus sativus, Aloysia polystachya, Albies pindrow, Casimiroa edulis, Davilla rugosa, Gastrodia elata, Sphaerathus indicus, Zizyphus jujuba and Panax ginseng. Common mechanisms of action for the majority of botanicals reviewed primarily involve GABA, either via direct receptor binding or ionic channel or cell membrane modulation; GABA transaminase

Resistance vs resilience to Alzheimer disease: Clarifying terminology for preclinical studies.

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Arenaza-Urquijo, Eider M; Vemuri, Prashanthi

2018-04-10

Preventing or delaying Alzheimer disease (AD) through lifestyle interventions will come from a better understanding of the mechanistic underpinnings of (1) why a significant proportion of elderly remain cognitively normal with AD pathologies (ADP), i.e., amyloid or tau; and (2) why some elderly individuals do not have significant ADP. In the last decades, concepts such as brain reserve, cognitive reserve, and more recently brain maintenance have been proposed along with more general notions such as (neuro)protection and compensation. It is currently unclear how to effectively apply these concepts in the new field of preclinical AD specifically separating the 2 distinct mechanisms of coping with pathology vs avoiding pathology. We propose a simplistic conceptual framework that builds on existing concepts using the nomenclature of resistance in the context of avoiding pathology, i.e., remaining cognitively normal without significant ADP, and resilience in the context of coping with pathology, i.e., remaining cognitively normal despite significant ADP. In the context of preclinical AD studies, we (1) define these concepts and provide recommendations (and common scenarios) for their use; (2) discuss how to employ this terminology in the context of investigating mechanisms and factors; (3) highlight the complementarity and clarity they provide to existing concepts; and (4) discuss different study designs and methodologies. The application of the proposed framework for framing hypotheses, study design, and interpretation of results and mechanisms can provide a consistent framework and nomenclature for researchers to reach consensus on identifying factors that may prevent ADP or delay the onset of cognitive impairment. © 2018 American Academy of Neurology.

Extracurricular activities associated with stress and burnout in preclinical medical students

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Jawad Fares

2016-09-01

Full Text Available This study aims to assess the prevalence of stress and burnout among preclinical medical students in a private university in Beirut, Lebanon, and evaluate the association between extracurricular involvement and stress and burnout relief in preclinical medical students. A cross-sectional survey was conducted on a random sample of 165 preclinical medical students. Distress level was measured using the 12-item General Health Questionnaire (GHQ-12 while that of burnout was measured through the Maslach Burnout Inventory-Student Survey (MBI-SS. The MBI-SS assesses three interrelated dimensions: emotional exhaustion, cynicism, and academic efficacy. Extracurricular activities were divided into four categories: physical exercise, music, reading, and social activities. All selected participants responded. A substantial proportion of preclinical medical students suffered from stress (62% and burnout (75%. Bivariate and multivariate regression analyses revealed that being a female or a 1st year medical student correlated with higher stress and burnout. Music-related activities were correlated with lower burnout. Social activities or living with parents were associated with lower academic efficacy. The high stress and burnout levels call for action. Addressing the studying conditions and attending to the psychological wellbeing of preclinical medical students are recommendations made in the study.

Extracurricular activities associated with stress and burnout in preclinical medical students.

Science.gov (United States)

Fares, Jawad; Saadeddin, Zein; Al Tabosh, Hayat; Aridi, Hussam; El Mouhayyar, Christopher; Koleilat, Mohamad Karim; Chaaya, Monique; El Asmar, Khalil

2016-09-01

This study aims to assess the prevalence of stress and burnout among preclinical medical students in a private university in Beirut, Lebanon, and evaluate the association between extracurricular involvement and stress and burnout relief in preclinical medical students. A cross-sectional survey was conducted on a random sample of 165 preclinical medical students. Distress level was measured using the 12-item General Health Questionnaire (GHQ-12) while that of burnout was measured through the Maslach Burnout Inventory-Student Survey (MBI-SS). The MBI-SS assesses three interrelated dimensions: emotional exhaustion, cynicism, and academic efficacy. Extracurricular activities were divided into four categories: physical exercise, music, reading, and social activities. All selected participants responded. A substantial proportion of preclinical medical students suffered from stress (62%) and burnout (75%). Bivariate and multivariate regression analyses revealed that being a female or a 1st year medical student correlated with higher stress and burnout. Music-related activities were correlated with lower burnout. Social activities or living with parents were associated with lower academic efficacy. The high stress and burnout levels call for action. Addressing the studying conditions and attending to the psychological wellbeing of preclinical medical students are recommendations made in the study. Copyright © 2015 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.

Serum bone alkaline phosphatase and calcaneus bone density predict fractures: a prospective study.

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Ross, P D; Kress, B C; Parson, R E; Wasnich, R D; Armour, K A; Mizrahi, I A

2000-01-01

The aim of this study was to assess the ability of serum bone-specific alkaline phosphatase (bone ALP), creatinine-corrected urinary collagen crosslinks (CTx) and calcaneus bone mineral density (BMD) to identify postmenopausal women who have an increased risk of osteoporotic fractures. Calcaneus BMD and biochemical markers of bone turnover (serum bone ALP and urinary CTx) were measured in 512 community-dwelling postmenopausal women (mean age at baseline 69 years) participating in the Hawaii Osteoporosis Study. New spine and nonspine fractures subsequent to the BMD and biochemical bone markers measurements were recorded over an average of 2.7 years. Lateral spinal radiographs were used to identify spine fractures. Nonspine fractures were identified by self-report at the time of each examination. During the 2.7-year follow-up, at least one osteoporotic fracture occurred in 55 (10.7%) of the 512 women. Mean baseline serum bone ALP and urinary CTx were significantly higher among women who experienced an osteoporotic fracture compared with those women who did not fracture. In separate age-adjusted logistic regression models, serum bone ALP, urinary CTx and calcaneus BMD were each significantly associated with new fractures (odds ratios of 1.53, 1.54 and 1.61 per SD, respectively). Multiple variable logistic regression analysis identified BMD and serum bone ALP as significant predictors of fracture (p = 0.002 and 0.017, respectively). The results from this investigation indicate that increased bone turnover is significantly associated with an increased risk of osteoporotic fracture in postmenopausal women. This association is similar in magnitude and independent of that observed for BMD.

Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases

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Louise A. Mesentier-Louro

2016-01-01

Full Text Available Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized.

Impact of diet restriction in the management of diabetes: evidences from preclinical studies.

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Krishan, Pawan; Bedi, Onkar; Rani, Monika

2018-03-01

The inappropriate dietary habits lead to the onset of age-related pathologies which include diabetes and cardiovascular ailments. Dietary restriction and nutritional therapy play an important role in the prevention of these chronic ailments. Preclinical research provides a basis for the therapeutic exploration of new dietary interventions for the clinical trials to potentiate the scientific management of diabetes and its related complications which further help in translating these nutritional improvements from bench to bedside. Within the same context, numerous therapeutically proved preclinical dietary interventions like high-fiber diet, caloric restriction, soy isoflavone-containing diets, etc., have shown the promising results for the management of diabetes and the associated complications. The focus of the present review is to highlight the various preclinical evidences of diet restriction for the management of diabetes and which will be helpful for enlightening the new ideas of nutritional therapy for future research exploration. In addition, some potential approaches are also discussed which are associated with various nutritional interventions to combat progressive diabetes and the associated disorders. Graphical abstract ᅟ.

The Economics of Reproducibility in Preclinical Research.

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Leonard P Freedman

2015-06-01

Full Text Available Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B/year spent on preclinical research that is not reproducible-in the United States alone. We outline a framework for solutions and a plan for long-term improvements in reproducibility rates that will help to accelerate the discovery of life-saving therapies and cures.

Learning style preferences: A study of pre-clinical medical students in Barbados

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OJEH, NKEMCHO; SOBERS-GRANNUM, NATASHA; GAUR, UMA; UDUPA, ALAYA; MAJUMDER, MD.ANWARUL AZIM

2017-01-01

Introduction: Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students’ learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compar...

Insights From Pre-Clinical and Clinical Studies on the Role of Innate Inflammation in Atherosclerosis Regression

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Karishma Rahman

2018-05-01

Full Text Available Atherosclerosis, the underlying cause of coronary artery (CAD and other cardiovascular diseases, is initiated by macrophage-mediated immune responses to lipoprotein and cholesterol accumulation in artery walls, which result in the formation of plaques. Unlike at other sites of inflammation, the immune response becomes maladaptive and inflammation fails to resolve. The most common treatment for reducing the risk from atherosclerosis is low density lipoprotein cholesterol (LDL-C lowering. Studies have shown, however, that while significant lowering of LDL-C reduces the risk of heart attacks to some degree, there is still residual risk for the majority of the population. We and others have observed “residual inflammatory risk” of atherosclerosis after plasma cholesterol lowering in pre-clinical studies, and that this phenomenon is clinically relevant has been dramatically reinforced by the recent Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS trial. This review will summarize the role of the innate immune system, specifically macrophages, in atherosclerosis progression and regression, as well as the pre-clinical and clinical models that have provided significant insights into molecular pathways involved in the resolution of plaque inflammation and plaque regression. Partnered with clinical studies that can be envisioned in the post-CANTOS period, including progress in developing targeted plaque therapies, we expect that pre-clinical studies advancing on the path summarized in this review, already revealing key mechanisms, will continue to be essential contributors to achieve the goals of dampening plaque inflammation and inducing its resolution in order to maximize the therapeutic benefits of conventional risk factor modifications, such as LDL-C lowering.

Exploratory study of factors related to educational scores of first preclinical year medical students.

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Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarayut

2014-03-01

The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students. Questionnaires were sent out to all first preclinical year medical students, with 79.8% being returned (245/307 questionnaires). Positive correlations were revealed between the premedical year grade point average (pre-MD GPA) and anatomy, physiology, and biochemistry scores (R = 0.664, 0.521, and 0.653, respectively, P student satisfaction with anatomy, the percentage of expected reading, monthly earnings, reading after class and near exam time, and duration of sleeping periods near exam time (R = 0.773, R(2) = 0.598, P student satisfaction with biochemistry, and exam performance expectations (R = 0.794, R(2) = 0.630, P satisfaction.

Alveolar bone healing in rats: micro-CT, immunohistochemical and molecular analysis

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Jaqueline Suemi HASSUMI

2018-06-01

Full Text Available Abstract Alveolar bone healing after upper incisor extraction in rats is a classical model of preclinical studies. The underlying morphometric, cellular and molecular mechanism, however, remains imprecise in a unique study. Objectives The aim of this study was therefore to characterize the alveolar bone healing after upper incisor extraction in rats by micro computed tomographic (Micro-CT, immunohistochemical and real-time polymerase chain reaction (RT-PCR analysis. Material and Methods Thirty animals (Rattus norvegicus, Albinus Wistar were divided into three groups after upper incisors extraction at 7, 14, and 28 days. Micro-CT was evaluated based on the morphometric parameters. Subsequently, the histological analyses and immunostaining of osteoprotegerin (OPG, receptor activator of nuclear kappa B ligand (RANKL and tartrate resistant acid phosphate (TRAP was performed. In addition, RT-PCR analyses of OPG, RANKL, the runt-related transcription factor 2 (RUNX2, osteocalcin (OC, osteopontin (OPN, osterix (OST and receptor activator of nuclear kappa B (RANK were performed to determine the expression of these proteins in the alveolar bone healing. Results Micro-CT: The morphometric parameters of bone volume and trabecular thickness progressively increased over time. Consequently, a gradual decrease in trabecular separation, trabecular space and total bone porosity was observed. Immunohistochemical: There were no differences statistically significant between the positive labeling for OPG, RANKL and TRAP in the different periods. RT-PCR: At 28 days, there was a significant increase in OPG expression, while RANKL expression and the RANKL/OPG ratio both decreased over time. Conclusion Micro-CT showed the newly formed bone had favorable morphometric characteristics of quality and quantity. Beyond the RUNX2, OC, OPN, OST, and RANK proteins expressed in the alveolar bone healing, OPG and RANKL activity showed to be essential for activation of basic

Histological study on the new bone formation of the implanted bone allograft in sheep

International Nuclear Information System (INIS)

Li Youchen; Sun Guiying; Shi Zhancheng

1999-01-01

The purpose of this study is to compare the formation of new bone in the implanted frozen irradiated bone allograft with the fresh bone autograft. The work on animal model included resection and implantation of sheep's tibial diaphysis and intramedullary nail fixation, with total number 20. Tibias were harvested at 6, 12, and 24 months after operation. Sheep were fed with tetracycline I week before bone harvesting. Bones were examined with usual and fluorescence microscopes. The results showed that the progress of graft incorporation in allografts were generally similar to that of autografts. Capillaries penetration and callus formation extended from the host end to surround the host-graft junction in 6 months. Incorporation of new bone was nearly completed in 12 months; then the speed of new bone formation was decreased, and the implanted bone graft was almost completely substituted with non-nal bone structure in 24 months

New mechanisms and targets in the treatment of bone fragility.

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Martin, T John; Seeman, Ego

2007-01-01

Bone modelling and remodelling are cell-mediated processes responsible for the construction and reconstruction of the skeleton throughout life. These processes are chiefly mediated by locally generated cytokines and growth factors that regulate the differentiation, activation, work and life span of osteoblasts and osteoclasts, the cells that co-ordinate the volumes of bone resorbed and formed. In this way, the material composition and structural design of bone is regulated in accordance with its loading requirements. Abnormalities in this regulatory system compromise the material and structural determinants of bone strength producing bone fragility. Understanding the intercellular control processes that regulate bone modelling and remodelling is essential in planning therapeutic approaches to prevention and treatment of bone fragility. A great deal has been learnt in the last decade. Clinical trials carried out exclusively with drugs that inhibit bone resorption have identified the importance of reducing the rate of bone remodelling and so the progression of bone fragility to achieved fracture reductions of approx. 50%. These trials have also identified limitations that should be placed upon interpretation of bone mineral density changes in relation to treatment. New resorption inhibitors are being developed, based on mechanisms of action that are different from existing drugs. Some of these might offer resorption inhibition without reducing bone formation. More recent research has provided the first effective anabolic therapy for bone reconstruction. Daily injections of PTH (parathyroid hormone)-(1-34) have been shown in preclinical studies and in a large clinical trial to increase bone tissue mass and reduce the risk of fractures. The action of PTH differs from that of the resorption inhibitors, but whether it is more effective in fracture reduction is not known. Understanding the cellular and molecular mechanisms of PTH action, particularly its interactions with

Preclinical Testing of an Oncolytic Parvovirus: Standard Protoparvovirus H-1PV Efficiently Induces Osteosarcoma Cell Lysis In Vitro

OpenAIRE

Carsten Geiss; Zoltán Kis; Barbara Leuchs; Monika Frank-Stöhr; Jörg R. Schlehofer; Jean Rommelaere; Christiane Dinsart; Jeannine Lacroix

2017-01-01

Osteosarcoma is the most frequent malignant disease of the bone. On the basis of early clinical experience in the 1960s with H-1 protoparvovirus (H-1PV) in osteosarcoma patients, this effective oncolytic virus was selected for systematic preclinical testing on various osteosarcoma cell cultures. A panel of five human osteosarcoma cell lines (CAL 72, H-OS, MG-63, SaOS-2, U-2OS) was tested. Virus oncoselectivity was confirmed by infecting non-malignant human neonatal fibroblasts and osteoblasts...

Radiographic evaluation of bone adaptation adjacent to percutaneous osseointegrated prostheses in a sheep model.

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Jeyapalina, Sujee; Beck, James Peter; Bachus, Kent N; Chalayon, Ornusa; Bloebaum, Roy D

2014-10-01

Percutaneous osseointegrated prostheses (POPs) are being investigated as an alternative to conventional socket suspension and require a radiographic followup in translational studies to confirm that design objectives are being met. In this 12-month animal study, we determined (1) radiographic signs of osseointegration and (2) radiographic signs of periprosthetic bone hypertrophy and resorption (adaptation) and (3) confirmed them with the histologic evidence of host bone osseointegration and adaptation around a novel, distally porous-coated titanium POP with a collar. A POP device was designed to fit the right metacarpal bone of sheep. Amputation and implantation surgeries (n = 14) were performed, and plane-film radiographs were collected quarterly for 12 months. Radiographs were assessed for osseointegration (fixation) and bone adaptation (resorption and hypertrophy). The cortical wall and medullary canal widths were used to compute the cortical index and expressed as a percentage. Based on the cortical index changes and histologic evaluations, bone adaptation was quantified. Radiographic data showed signs of osseointegration including those with incomplete seating against the collar attachment. Cortical index data indicated distal cortical wall thinning if the collar was not seated distally. When implants were bound proximally, bone resorbed distally and the diaphyseal cortex hypertrophied. Histopathologic evidence and cortical index measurements confirmed the radiographic indications of adaptation and osseointegration. Distal bone loading, through collar attachment and porous coating, limited the distal bone resorption. Serial radiographic studies, in either animal models or preclinical trials for new POP devices, will help to determine which designs are likely to be safe over time and avoid implant failures.

Standards and Methodological Rigor in Pulmonary Arterial Hypertension Preclinical and Translational Research.

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Provencher, Steeve; Archer, Stephen L; Ramirez, F Daniel; Hibbert, Benjamin; Paulin, Roxane; Boucherat, Olivier; Lacasse, Yves; Bonnet, Sébastien

2018-03-30

Despite advances in our understanding of the pathophysiology and the management of pulmonary arterial hypertension (PAH), significant therapeutic gaps remain for this devastating disease. Yet, few innovative therapies beyond the traditional pathways of endothelial dysfunction have reached clinical trial phases in PAH. Although there are inherent limitations of the currently available models of PAH, the leaky pipeline of innovative therapies relates, in part, to flawed preclinical research methodology, including lack of rigour in trial design, incomplete invasive hemodynamic assessment, and lack of careful translational studies that replicate randomized controlled trials in humans with attention to adverse effects and benefits. Rigorous methodology should include the use of prespecified eligibility criteria, sample sizes that permit valid statistical analysis, randomization, blinded assessment of standardized outcomes, and transparent reporting of results. Better design and implementation of preclinical studies can minimize inherent flaws in the models of PAH, reduce the risk of bias, and enhance external validity and our ability to distinguish truly promising therapies form many false-positive or overstated leads. Ideally, preclinical studies should use advanced imaging, study several preclinical pulmonary hypertension models, or correlate rodent and human findings and consider the fate of the right ventricle, which is the major determinant of prognosis in human PAH. Although these principles are widely endorsed, empirical evidence suggests that such rigor is often lacking in pulmonary hypertension preclinical research. The present article discusses the pitfalls in the design of preclinical pulmonary hypertension trials and discusses opportunities to create preclinical trials with improved predictive value in guiding early-phase drug development in patients with PAH, which will need support not only from researchers, peer reviewers, and editors but also from

Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models.

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Benito, Juliana; Ramirez, Marc S; Millward, Niki Zacharias; Velez, Juliana; Harutyunyan, Karine G; Lu, Hongbo; Shi, Yue-Xi; Matre, Polina; Jacamo, Rodrigo; Ma, Helen; Konoplev, Sergej; McQueen, Teresa; Volgin, Andrei; Protopopova, Marina; Mu, Hong; Lee, Jaehyuk; Bhattacharya, Pratip K; Marszalek, Joseph R; Davis, R Eric; Bankson, James A; Cortes, Jorge E; Hart, Charles P; Andreeff, Michael; Konopleva, Marina

2016-04-01

To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models. Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models. Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a "hypoxia index" compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells. These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. ©2015 American Association for Cancer Research.

Alveolar Ridge Augmentation with Three-Dimensional Printed Hydroxyapatite Devices: A Preclinical Study.

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Fiorellini, Joseph P; Norton, Michael R; Luan, Kevin WanXin; Kim, David Minjoon; Wada, Kei; Sarmiento, Hector L

2018-02-14

The objective of this study was to evaluate the effectiveness of precise three-dimensional hydroxyapatite printed micro- and macrochannel devices for alveolar ridge augmentation in a canine model. All grafts induced minimal inflammatory and fibrotic reactions. Examination of undecalcified sections revealed that both types of grafts demonstrated bone ingrowth. The majority of the bone growth into the block graft was into the channels, though a portion grew directly into the construct in the form of small bony spicules. In conclusion, bone ingrowth was readily demonstrated in the middle of the implanted printed devices.

Growth/differentiation factor-5: pre-clinical and clinical evaluations of periodontal regeneration and alveolar augmentation--review.

Science.gov (United States)

Lee, Jaebum; Wikesjö, Ulf M E

2014-08-01

Growth/differentiation factor-5 (GDF-5) plays critical roles in mesenchymal cell differentiation and stimulates human periodontal ligament cell proliferation. Potentially, GDF-5 may also play roles in wound healing including periodontal regeneration and alveolar augmentation. The objective of this review was to provide up-to-date information from pre-clinical/clinical studies evaluating GDF-5 for these indications. A comprehensive search using PubMed and Google search engines was conducted to identify reports on GDF-5 applied to periodontal and alveolar indications. Two reviewers independently screened the titles and abstracts from a total of 479 reports. Full-length articles of 17 pre-clinical and four clinical studies were selected and reviewed. Canine-, porcine- and non-human primate-based models as well as human clinical trials were used in the evaluation of GDF-5 in support of periodontal regeneration and alveolar augmentation. An absorbable collagen sponge (ACS), β-tricalcium phosphate (β-TCP) and a poly(lactic-co-glycolic) acid (PLGA) were evaluated as candidate carriers for GDF-5 using various dose and healing intervals demonstrating significantly enhanced periodontal regeneration/alveolar augmentation including cementum, periodontal ligament and alveolar bone with limited, if any, adverse effects. Growth/differentiation factor-5 supports periodontal regeneration/alveolar augmentation without aberrant healing events documented in qualified pre-clinical models and clinical pilot studies. In perspective, GDF-5 appears a promising technology for periodontal regeneration/alveolar augmentation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A study of 23 unicameral bone cysts of the calcaneus: open chip allogeneic bone graft versus percutaneous injection of bone powder with autogenous bone marrow.

Science.gov (United States)

Park, Il-Hyung; Micic, Ivan Dragoljub; Jeon, In-Ho

2008-02-01

The treatment of unicameral bone cyst varies from percutaneous needle biopsy, aspiration and local injection of steroid, autologous bone marrow, or demineralized bone matrix to curettage and open bone-grafting. The purpose of this study was to compare the results of open chip allogeneic bone graft versus percutaneous injection of demineralized bone powder with autogenous bone marrow in management of calcaneal cysts. Twenty-three calcaneal unicameral cysts in 20 patients were treated. Lyophilized irradiated chip allogeneic bone (CAB) and autogenous bone marrow were used for treatment of 13 cysts in 11 patients, and 10 cysts in 9 patients were treated with percutaneous injection of irradiated allogeneic demineralized bone powder (DBP) and autogenous bone marrow. There were 11 males and 9 female patients with mean age of 17 years. The patients were followed for an average of 49.4 months. Complete healing was achieved in 9 cysts treated with chip allogeneic bone and in 5 cysts treated with powdered bone. Four cysts treated with CAB and 3 cysts treated with DBP healed with a defect. Two cysts treated with powdered bone and autogenous bone marrow were classified as persistent. No infections or pathological fractures were observed during the followup period. Percutaneous injection of a mixture of allogeneic bone powder with autogenous bone marrow is a minimal invasive method and could be an effective alternative in the treatment of unicameral calcaneal bone cysts. The postoperative morbidity was low, the hospital stay was brief, and patient's comfort for unrestricted activity was enhanced.

Rigor or mortis: best practices for preclinical research in neuroscience.

Science.gov (United States)

Steward, Oswald; Balice-Gordon, Rita

2014-11-05

Numerous recent reports document a lack of reproducibility of preclinical studies, raising concerns about potential lack of rigor. Examples of lack of rigor have been extensively documented and proposals for practices to improve rigor are appearing. Here, we discuss some of the details and implications of previously proposed best practices and consider some new ones, focusing on preclinical studies relevant to human neurological and psychiatric disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Study of bone metastasis of cervical carcinoma by bone scintigraphy

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Okamura, Shinsuke; Okamoto, Yoshiaki; Maeda, Takayoshi; Sano, Takashi; Ueki, Minoru; Sugimoto, Osamu; Sakata, Tsunehiko; Yamasaki, Kouichi; Akagi, Hiroaki

1985-04-01

In carrying out bone scintigraphy in 224 cases over the 5 years from June, 1978 to May, 1983 as a part of the post-treatment management of cervical carcinoma. Bone metastases were seen in 12.5% (28 cases) of the subjects, about 6% of the total post-treatment cases of cervical carcinoma in the corresponding period (466 cases). Bone metastases were seen in 9.3% (16/172) of post-operative cases, compared with 23.1% (12/52) of non-operative cases. Bone metastases were not seen in clinical stages Ia through IIa (49 cases) but were seen in IIb or higher stages. Bone metastasis rates by histological type, according to WHO classification, were 12.8% (26/203) in squamous cell carcinoma, 5.9% (1/17) in adenocarcinoma, and 25% (1/4) in adenosquamous carcinoma. Among the squamous cell carcinoma cases, small cell non-keratinizing type had the highest bone metastasis rate. Of 172 post-operative cases, 20.8% (11/53) of those with lymph node metastasis exhibited bone metastasis, higher than the 4.2% (5/119) in cases without lymph node metastasis. As to CPL classification, bone metastasis was seen more often in L type (18.8%) than C(0.0%) or P types (6.6%). Our risk classification of 168 cases demonstrated that bone metastasis was not seen in risk I group (74 cases), but was seen in 6.7% (1/17) of risk II group and in 19.0% (15/79) of risk III group. Twenty-eight cases with bone metastasis included 11 cases with local recurrence, 8 with pulmonary metastases, 4 with hepatic metastases and 4 with Virchow's lymphnode metastases. The 28 bone metastasis cases included 10 cases with multiple bone metastases and 5 with only a single bone metastasis. Most bone metastases were seen in the lumbar vertebrae and the pelvic bone. Post-operative cases had more distant metastases than non-operative cases. On diagnosis of bone metastases and 17 of the 28 patients had pain, 6 of the remaining 11 patients developing pain thereafter. (J.P.N.).

Interaction between tumor cell surface receptor RAGE and proteinase 3 mediates prostate cancer metastasis to bone

Science.gov (United States)

Kolonin, Mikhail G.; Sergeeva, Anna; Staquicini, Daniela I.; Smith, Tracey L.; Tarleton, Christy A.; Molldrem, Jeffrey J.; Sidman, Richard L.; Marchiò, Serena; Pasqualini, Renata; Arap, Wadih

2017-01-01

Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE-PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a non-proteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short time frame. Our findings demonstrate how RAGE-PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention. PMID:28428279

Imaging of alkaline phosphatase activity in bone tissue.

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Terence P Gade

Full Text Available The purpose of this study was to develop a paradigm for quantitative molecular imaging of bone cell activity. We hypothesized the feasibility of non-invasive imaging of the osteoblast enzyme alkaline phosphatase (ALP using a small imaging molecule in combination with (19Flourine magnetic resonance spectroscopic imaging ((19FMRSI. 6, 8-difluoro-4-methylumbelliferyl phosphate (DiFMUP, a fluorinated ALP substrate that is activatable to a fluorescent hydrolysis product was utilized as a prototype small imaging molecule. The molecular structure of DiFMUP includes two Fluorine atoms adjacent to a phosphate group allowing it and its hydrolysis product to be distinguished using (19Fluorine magnetic resonance spectroscopy ((19FMRS and (19FMRSI. ALP-mediated hydrolysis of DiFMUP was tested on osteoblastic cells and bone tissue, using serial measurements of fluorescence activity. Extracellular activation of DiFMUP on ALP-positive mouse bone precursor cells was observed. Concurringly, DiFMUP was also activated on bone derived from rat tibia. Marked inhibition of the cell and tissue activation of DiFMUP was detected after the addition of the ALP inhibitor levamisole. (19FMRS and (19FMRSI were applied for the non-invasive measurement of DiFMUP hydrolysis. (19FMRS revealed a two-peak spectrum representing DiFMUP with an associated chemical shift for the hydrolysis product. Activation of DiFMUP by ALP yielded a characteristic pharmacokinetic profile, which was quantifiable using non-localized (19FMRS and enabled the development of a pharmacokinetic model of ALP activity. Application of (19FMRSI facilitated anatomically accurate, non-invasive imaging of ALP concentration and activity in rat bone. Thus, (19FMRSI represents a promising approach for the quantitative imaging of bone cell activity during bone formation with potential for both preclinical and clinical applications.

Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus

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Sam Illingworth

2017-06-01

Full Text Available Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev. As enadenotucirev does not replicate in animal cells, a panel of primary human cells was used to evaluate enadenotucirev replication selectivity in vitro, demonstrating that virus genome levels were >100-fold lower in normal cells relative to tumor cells. Acute intravenous tolerability in mice was used to assess virus particle-mediated toxicology and effects on innate immunity. These studies showed that particle toxicity could be ameliorated by dose fractionation, using an initial dose of virus to condition the host such that cytokine responses to subsequent doses were significantly attenuated. This, in turn, supported the initiation of a phase I intravenous clinical trial with a starting dose of 1 × 1010 virus particles given on days 1, 3, and 5.

Horizontal Bone Reconstruction on sites with different amounts of native bone: a retrospective study

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André Antonio Pelegrine

2018-04-01

Full Text Available Abstract: The lack of guidelines for bone augmentation procedures might compromise decision making in implantology. The objective of this study was to perform a retrospective study to verify the outcomes of horizontal bone reconstruction in implant dentistry with different types of materials and amounts of native bone in the recipient bed to allow for a new guideline for horizontal bone reconstruction. One hundred preoperative CT scans were retrospectively evaluated and categorized in accordance to horizontal bone defects as presence (Group P or absence (Group A of cancellous bone in the recipient bed. Different approaches were used to treat the edentulous ridge and the outcomes were defined either as satisfactory or unsatisfactory regarding the possibility of implant placement. The percentage distribution of the patients according to the presence or absence of cancellous bone was 92% for Group P and 8% for Group A. In Group P, 98% of the patients had satisfactory outcomes, and the use of autografts had 100% of satisfactory outcomes in this group. In Group A, 37.5% of the patients had satisfactory outcomes, and the use of autografts also yielded 100% of satisfactory outcomes. The use of allografts and xenografts in Group A had 0% and 33.3% of satisfactory outcomes, respectively. Therefore, it seems reasonable to speculate that the presence of cancellous bone might be predictive and predictable when the decision includes bone substitutes. In cases of absence of cancellous bone in the recipient bed, the use of a vitalized graft seems to be mandatory.

Radioisotopic studies of bone diseases

International Nuclear Information System (INIS)

Ell, P.J.

1976-01-01

Consideration is given to the study of bone diseases. The most used radionuclides in the skeletal investigation are analysed and a table of radiopharmaceuticals of localization in the skeleton is showed. Emphasis is given to the use of Strontium 85 and 87m, fluorine 18 and technetium 99m. The phosphate compounds labelled with Technetium 99m are studied in detail and the structures of these organic and inorganic compounds are given. A table with values of the blood clearance of those compounds is presented. The skeletal distribution of the phosphate compounds-sup(99m)Tc, as well as the abnormal scintigraphy of skeleton by means of them, are analysed. Referring to bone diseases, the benign and malignant ones are studied: a table is given of bone diseases with positive imaging to the skeleton scintigraphy in the former case and the main applications of this scintigraphy in the latter one. Emphasis is given, in all the cases, to the clinical applications of the method, with recommendations in each one. Scintigraphic imagings are presented referring to each item studied [pt

Tissue Engineering of the Urethra: A Systematic Review and Meta-analysis of Preclinical and Clinical Studies

NARCIS (Netherlands)

Versteegden, L.R.; Jonge, P. de; Hout, J. in't; Kuppevelt, T.H. van; Oosterwijk, E.; Feitz, W.F.J.; Vries, R.B.M. de; Daamen, W.F.

2017-01-01

CONTEXT: Urethra repair by tissue engineering has been extensively studied in laboratory animals and patients, but is not routinely used in clinical practice. OBJECTIVE: To systematically investigate preclinical and clinical evidence of the efficacy of tissue engineering for urethra repair in order

Characterization of novel preclinical dose distributions for micro irradiator

International Nuclear Information System (INIS)

Kodra, J; Miles, D; Yoon, S W; Kirsch, D G; Oldham, M

2017-01-01

This work explores and demonstrates the feasibility of utilizing new 3D printing techniques to implement advanced micro radiation therapy for pre-clinical small animal studies. 3D printed blocks and compensators were designed and printed from a strong x-ray attenuating material at sub-millimeter resolution. These techniques enable a powerful range of new preclinical treatment capabilities including grid therapy, lattice therapy, and IMRT treatment. At small scales, verification of these treatments is exceptionally challenging, and high resolution 3D dosimetry (0.5mm 3 ) is an essential capability to characterize and verify these capabilities, Here, investigate the 2D and 3D dosimetry of several novel pre-clinical treatments using a combination of EBT film and Presage/optical-CT 3D dosimetry in rodent-morphic dosimeters. (paper)

Characterization of novel preclinical dose distributions for micro irradiator

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Kodra, J.; Miles, D.; Yoon, S. W.; Kirsch, D. G.; Oldham, M.

2017-05-01

This work explores and demonstrates the feasibility of utilizing new 3D printing techniques to implement advanced micro radiation therapy for pre-clinical small animal studies. 3D printed blocks and compensators were designed and printed from a strong x-ray attenuating material at sub-millimeter resolution. These techniques enable a powerful range of new preclinical treatment capabilities including grid therapy, lattice therapy, and IMRT treatment. At small scales, verification of these treatments is exceptionally challenging, and high resolution 3D dosimetry (0.5mm3) is an essential capability to characterize and verify these capabilities, Here, investigate the 2D and 3D dosimetry of several novel pre-clinical treatments using a combination of EBT film and Presage/optical-CT 3D dosimetry in rodent-morphic dosimeters.

Preclinical models in radiation oncology

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Kahn Jenna

2012-12-01

Full Text Available Abstract As the incidence of cancer continues to rise, the use of radiotherapy has emerged as a leading treatment modality. Preclinical models in radiation oncology are essential tools for cancer research and therapeutics. Various model systems have been used to test radiation therapy, including in vitro cell culture assays as well as in vivo ectopic and orthotopic xenograft models. This review aims to describe such models, their advantages and disadvantages, particularly as they have been employed in the discovery of molecular targets for tumor radiosensitization. Ultimately, any model system must be judged by its utility in developing more effective cancer therapies, which is in turn dependent on its ability to simulate the biology of tumors as they exist in situ. Although every model has its limitations, each has played a significant role in preclinical testing. Continued advances in preclinical models will allow for the identification and application of targets for radiation in the clinic.

In question: the scientific value of preclinical safety pharmacology and toxicology studies with cell-based therapies

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Christiane Broichhausen

2014-01-01

Full Text Available A new cell-based medicinal product containing human regulatory macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with regulatory macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.

Chronological study for solitary bone metastasis in the sternum from breast cancer with bone scintigraphy

International Nuclear Information System (INIS)

Miyoshi, Hidenao; Otsuka, Nobuaki; Sone, Teruki; Nagai, Kiyohisa; Tamada, Tsutomu; Mimura, Hiroaki; Yanagimoto, Shinichi; Tomomitsu, Tatsushi; Fukunaga, Masao

1999-01-01

Since breast cancer is frequently associated with bone metastasis, bone scintigraphies have been performed to determine pre-operative staging and to survey postoperative bone metastasis. The sternum, in particular, is a site at which is difficult to differentiate between benign bone disease and bone metastasis, because of varied uptake and wide individual variations. In this study, chronological bone images were scintigraphied in six cases with solitary sternal metastasis and three cases with benign bone disease including two fracture cases and one arthritis case. On bone scintigrams in which solitary sternal metastasis appeared, increased uptake was found in five cases, and photon deficiency was observed in one case. During follow-up scintigraphies, abnormal accumulations, such as hot spots and cold lesions, increased in the bone metastasis while abnormal uptake disappeared or was unchanged in the benign bone disease cases. On CT, four cases showed osteolytic change, and one exhibited osteosclerotic change. These findings indicate that sternal metastasis usually shows osteolytic change, even if a hot lesion is recognized on bone scintigraphy. In solitary sternal metastasis, for which early diagnosis is difficult, both an integrated diagnosis using other imaging techniques and chronological bone scintigraphy are important. (author)

Stress, Burnout and Coping Strategies in Preclinical Medical Students

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Fares, Jawad; Al Tabosh, Hayat; Saadeddin, Zein; El Mouhayyar, Christopher; Aridi, Hussam

2016-01-01

It is acknowledged that physicians do not seek the same expert aid for themselves as they would offer their patients. In their preclinical years, medical students appear to espouse comparable behavior. To many, medicine is described as a never-ending path that places the student under heavy stress and burnout from the beginning, leaving him/her vulnerable and with insufficient coping methods. Hence, the objective of this study is to 1) explore the prevalence of stress and burnout among preclinical medical students, and 2) propose solutions to decrease stress and burnout and improve medical education in the preclinical years. A detailed scholarly research strategy using Google Scholar, Scopus, Embase, MEDLINE and PubMed was implemented to highlight key themes that are relevant to preclinical medical students’ stress and burnout. Stress varied among different samples of medical students and ranged between 20.9% and 90%. Conversely, burnout ranged between 27% and 75%. Methods that help in reducing the incidence of stress and burnout by promoting strategies that focus on personal engagement, extracurricular activities, positive reinterpretation and expression of emotion, student-led mentorship programs, evaluation systems, career counseling and life coaching should be adopted. PMID:27042604

Stress, Burnout and Coping Strategies in Preclinical Medical Students.

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Fares, Jawad; Al Tabosh, Hayat; Saadeddin, Zein; El Mouhayyar, Christopher; Aridi, Hussam

2016-02-01

It is acknowledged that physicians do not seek the same expert aid for themselves as they would offer their patients. In their preclinical years, medical students appear to espouse comparable behavior. To many, medicine is described as a never-ending path that places the student under heavy stress and burnout from the beginning, leaving him/her vulnerable and with insufficient coping methods. Hence, the objective of this study is to 1) explore the prevalence of stress and burnout among preclinical medical students, and 2) propose solutions to decrease stress and burnout and improve medical education in the preclinical years. A detailed scholarly research strategy using Google Scholar, Scopus, Embase, MEDLINE and PubMed was implemented to highlight key themes that are relevant to preclinical medical students' stress and burnout. Stress varied among different samples of medical students and ranged between 20.9% and 90%. Conversely, burnout ranged between 27% and 75%. Methods that help in reducing the incidence of stress and burnout by promoting strategies that focus on personal engagement, extracurricular activities, positive reinterpretation and expression of emotion, student-led mentorship programs, evaluation systems, career counseling and life coaching should be adopted.

Use of platelet lysate for bone regeneration - are we ready for clinical translation?

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Altaie, Ala; Owston, Heather; Jones, Elena

2016-02-26

Current techniques to improve bone regeneration following trauma or tumour resection involve the use of autograft bone or its substitutes supplemented with osteoinductive growth factors and/or osteogenic cells such as mesenchymal stem cells (MSCs). Although MSCs are most commonly grown in media containing fetal calf serum, human platelet lysate (PL) offers an effective alternative. Bone marrow - derived MSCs grown in PL-containing media display faster proliferation whilst maintaining good osteogenic differentiation capacity. Limited pre-clinical investigations using PL-expanded MSCs seeded onto osteoconductive scaffolds indicate good potential of such constructs to repair bone in vivo. In an alternative approach, nude PL-coated scaffolds without seeded MSCs have been proposed as novel regenerative medicine devices. Even though methods to coat scaffolds with PL vary, in vitro studies suggest that PL allows for MSC adhesion, migration and differentiation inside these scaffolds. Increased new bone formation and vascularisation in comparison to uncoated scaffolds have also been observed in vivo. This review outlines the state-of-the-art research in the field of PL for ex vivo MSC expansion and in vivo bone regeneration. To minimise inconsistency between the studies, further work is required towards standardisation of PL preparation in terms of the starting material, platelet concentration, leukocyte depletion, and the method of platelet lysis. PL quality control procedures and its "potency" assessment are urgently needed, which could include measurements of key growth and attachment factors important for MSC maintenance and differentiation. Furthermore, different PL formulations could be tailor-made for specific bone repair indications. Such measures would undoubtedly speed up clinical translation of PL-based treatments for bone regeneration.

Good Laboratory Practice Preclinical Safety Studies for GSK2696273 (MLV Vector-Based Ex Vivo Gene Therapy for Adenosine Deaminase Deficiency Severe Combined Immunodeficiency) in NSG Mice.

Science.gov (United States)

Carriglio, Nicola; Klapwijk, Jan; Hernandez, Raisa Jofra; Vezzoli, Michela; Chanut, Franck; Lowe, Rhiannon; Draghici, Elena; Nord, Melanie; Albertini, Paola; Cristofori, Patrizia; Richards, Jane; Staton, Hazel; Appleby, Jonathan; Aiuti, Alessandro; Sauer, Aisha V

2017-03-01

GSK2696273 (autologous CD34+ cells transduced with retroviral vector that encodes for the human adenosine deaminase [ADA] enzyme) is a gamma-retroviral ex vivo gene therapy of bone marrow-derived CD34+ cells for the treatment of adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID). ADA-SCID is a severe monogenic disease characterized by immunologic and nonimmunologic symptoms. Bone-marrow transplant from a matched related donor is the treatment of choice, but it is available for only a small proportion of patients. Ex vivo gene therapy of patient bone-marrow CD34+ cells is an alternative treatment. In order to prepare for a marketing authorization application in the European Union, preclinical safety studies in mice were requested by the European Medicines Agency (EMA). A pilot study and a main biodistribution study were performed according to Good Laboratory Practice (GLP) at the San Raffaele Telethon Institute for Gene Therapy test facility. In the main study, human umbilical cord blood (UCB)-derived CD34+ cells were transduced with gamma-retroviral vector used in the production of GSK2696273. Groups of 10 male and 10 female NOD-SCID gamma (NSG) mice were injected intravenously with a single dose of transduced- or mock-transduced UCB CD34+ cells, and they were observed for 4 months. Engraftment and multilineage differentiation of blood cells was observed in the majority of animals in both groups. There was no significant difference in the level of chimerism between the two groups. In the gene therapy group, vector was detectable in lymphohemopoietic and nonlymphohemopoietic tissues, consistent with the presence of gene-modified human hematopoietic donor cells. Given the absence of relevant safety concerns in the data, the nonclinical studies and the clinical experience with GSK2696273 supported a successful application for market authorization in the European Union for the treatment of ADA-SCID patients, for whom no suitable human leukocyte

Rotary powered device for bone marrow aspiration and biopsy yields excellent specimens quickly and efficiently.

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Swords, Ronan T; Kelly, Kevin R; Cohen, Stephen C; Miller, Larry J; Philbeck, Thomas E; Hacker, Sander O; Spadaccini, Cathy J; Giles, Francis J; Brenner, Andrew J

2010-06-01

Recently, a new FDA-cleared battery powered bone marrow biopsy system was developed to allow operators access to the bone marrow space quickly and efficiently. A pre-clinical evaluation of the device (OnControl, Vidacare Corporation, San Antonio, TX, USA) on anesthetized pigs was conducted, in addition to a clinical evaluation in hematology clinic patients requiring a bone marrow biopsy. Twenty-six samples were collected from the swine model. No cellular artifact or thermal damage was reported in any of the samples obtained. For the clinical evaluation of the device, 16 patients were recruited. Mean time from needle contact with skin to needle removal was 38.5 +/- 13.94 seconds. No complications were reported. In this study, the manual and powered samples were equivalent in specimen quality. In the patients evaluated, the device was safe, easy to use and the mean procedural time was significantly faster than previously reported with a manual technique.

Assessing agreement between preclinical magnetic resonance imaging and histology: An evaluation of their image qualities and quantitative results

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Elschner, Cindy; Korn, Paula; Hauptstock, Maria; Schulz, Matthias C.; Range, Ursula; Jünger, Diana; Scheler, Ulrich

2017-01-01

One consequence of demographic change is the increasing demand for biocompatible materials for use in implants and prostheses. This is accompanied by a growing number of experimental animals because the interactions between new biomaterials and its host tissue have to be investigated. To evaluate novel materials and engineered tissues the use of non-destructive imaging modalities have been identified as a strategic priority. This provides the opportunity for studying interactions repeatedly with individual animals, along with the advantages of reduced biological variability and decreased number of laboratory animals. However, histological techniques are still the golden standard in preclinical biomaterial research. The present article demonstrates a detailed method comparison between histology and magnetic resonance imaging. This includes the presentation of their image qualities as well as the detailed statistical analysis for assessing agreement between quantitative measures. Exemplarily, the bony ingrowth of tissue engineered bone substitutes for treatment of a cleft-like maxillary bone defect has been evaluated. By using a graphical concordance analysis the mean difference between MRI results and histomorphometrical measures has been examined. The analysis revealed a slightly but significant bias in the case of the bone volume (biasHisto−MRI:Bone volume=2.40 %, p<0.005) and a clearly significant deviation for the remaining defect width (biasHisto−MRI:Defect width=−6.73 %, p≪0.005). But the study although showed a considerable effect of the analyzed section position to the quantitative result. It could be proven, that the bias of the data sets was less originated due to the imaging modalities, but mainly on the evaluation of different slice positions. The article demonstrated that method comparisons not always need the use of an independent animal study, additionally. PMID:28666026

A study of bone metastasis of cervical carcinoma by bone scintigraphy

International Nuclear Information System (INIS)

Okamura, Shinsuke; Okamoto, Yoshiaki; Maeda, Takayoshi; Sano, Takashi; Ueki, Minoru; Sugimoto, Osamu; Sakata, Tsunehiko; Yamasaki, Kouichi; Akagi, Hiroaki

1985-01-01

In carrying out bone scintigraphy in 224 cases over the 5 years from June, 1978 to May, 1983 as a part of the post-treatment management of cervical carcinoma. Bone metastases were seen in 12.5% (28 cases) of the subjects, about 6% of the total post-treatment cases of cervical carcinoma in the corresponding period (466 cases). Bone metastases were seen in 9.3% (16/172) of post-operative cases, compared with 23.1% (12/52) of non-operative cases. Bone metastases were not seen in clinical stages Ia through IIa (49 cases) but were seen in IIb or higher stages. Bone metastasis rates by histological type, according to WHO classification, were 12.8% (26/203) in squamous cell carcinoma, 5.9% (1/17) in adenocarcinoma, and 25% (1/4) in adenosquamous carcinoma. Among the squamous cell carcinoma cases, small cell non-keratinizing type had the highest bone metastasis rate (p<0.05). Of 172 post-operative cases, 20.8% (11/53) of those with lymphnode metastasis exhibited bone metastasis, higher than the 4.2% (5/119) in cases without lymphnode metastasis. As to CPL classification, bone metastasis was seen more often in L type (18.8%) than C(0.0%) or P types (6.6%). Our risk classification of 168 cases demonstrated that bone metastasis was not seen in risk I group (74 cases), but was seen in 6.7% (1/17) of risk II group and in 19.0% (15/79) of risk III group. Twenty-eight cases with bone metastasis included 11 cases with local recurrence, 8 with pulmonary metastases, 4 with hepatic metastases and 4 with Virchow's lymphnode metastases. The 28 bone metastasis cases included 10 cases with multiple bone metastases and 5 with only a single bone metastasis. Most bone metastases were seen in the lumbar vertebrae and the pelvic bone. Post-operative cases had more distant metastases than non-operative cases. On diagnosis of bone metastases and 17 of the 28 patients had pain, 6 of the remaining 11 patients developing pain thereafter. (J.P.N.)

[Impact of microdose clinical trials in the preclinical stage].

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Kim, Soonih

2014-01-01

A microdose clinical trial may be useful as a safe early-phase exploratory study using doses as low as 100 μg or less for determination of the disposition of a candidate compound in humans in a short period of time. This may increase confidence in candidate compounds, especially those for which it is difficult to predict disposition based on the results of in vitro or preclinical studies. In this study, we examined microdose trials performed in the preclinical stage for two first-in-class compounds with a new mechanism of action. These compounds showed species difference in first pass metabolism in the digestive tract and liver, causing uncertainty in prediction of disposition in humans. For this reason, first-in-human microdose clinical trials were performed. The results showed that the two compounds had effective blood concentrations after oral administration at a dose of 100 mg qd. Administration of an extremely small dose of one (14)C-labeled compound permitted identification of major metabolites. No toxic metabolites were detected. The preclinical toxic dose was determined based on prediction of blood exposure at the estimated maximum clinical dose. For the other candidate compound, the findings of the microdose trial indicated a high bioavailability after oral administration and low hepatic clearance after intravenous administration. These results suggested only a small risk of a change in disposition in patients with hepatic disorder. The data obtained for the two compounds suggest that microdose clinical trials can be useful for improving the process of candidate selection in the preclinical stage.

Polymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studies.

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Mandal, Abhirup; Bisht, Rohit; Rupenthal, Ilva D; Mitra, Ashim K

2017-02-28

Effective intraocular drug delivery poses a major challenge due to the presence of various elimination mechanisms and physiological barriers that result in low ocular bioavailability after topical application. Over the past decades, polymeric micelles have emerged as one of the most promising drug delivery platforms for the management of ocular diseases affecting the anterior (dry eye syndrome) and posterior (age-related macular degeneration, diabetic retinopathy and glaucoma) segments of the eye. Promising preclinical efficacy results from both in-vitro and in-vivo animal studies have led to their steady progression through clinical trials. The mucoadhesive nature of these polymeric micelles results in enhanced contact with the ocular surface while their small size allows better tissue penetration. Most importantly, being highly water soluble, these polymeric micelles generate clear aqueous solutions which allows easy application in the form of eye drops without any vision interference. Enhanced stability, larger cargo capacity, non-toxicity, ease of surface modification and controlled drug release are additional advantages with polymeric micelles. Finally, simple and cost effective fabrication techniques render their industrial acceptance relatively high. This review summarizes structural frameworks, methods of preparation, physicochemical properties, patented inventions and recent advances of these micelles as effective carriers for ocular drug delivery highlighting their performance in preclinical studies. Copyright © 2017 Elsevier B.V. All rights reserved.

The effects of surgicel and bone wax hemostatic agents on bone healing: An experimental study

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Nasser Nooh

2014-01-01

Full Text Available Background: The biological effects of hemostatic agends on the physiological healing process need to be tested. The aim of this study was to assess the effects of oxidized cellulose (surgicel and bone wax on bone healing in goats′ feet. Materials and Methods: Three congruent circular bone defects were created on the lateral aspects of the right and left metacarpal bones of ten goats. One defect was left unfilled and acted as a control; the remaining two defects were filled with bone wax and surgicel respectively. The 10 animals were divided into two groups of 5 animals each, to be sacrificed at the 3rd and 5th week postoperatively. Histological analysis assessing quality of bone formed and micro-computed tomography (MCT measuring the quantities of bone volume (BV and bone density (BD were performed. The results of MCT analysis pertaining to BV and BD were statistically analyzed using two-way analysis of variance (ANOVA and posthoc least significant difference tests. Results: Histological analysis at 3 weeks showed granulation tissue with new bone formation in the control defects, active bone formation only at the borders for surgicel filled defects and fibrous encapsulation with foreign body reaction in the bone wax filled defects. At 5 weeks, the control and surgicel filled defects showed greater bone formation; however the control defects had the greatest amount of new bone. Bone wax filled defects showed very little bone formation. The two-way ANOVA for MCT results showed significant differences for BV and BD between the different hemostatic agents during the two examination periods. Conclusion: Surgicel has superiority over bone wax in terms of osseous healing. Bone wax significantly hinders osteogenesis and induces inflammation.

Platelet-rich plasma: why intra-articular? A systematic review of preclinical studies and clinical evidence on PRP for joint degeneration.

Science.gov (United States)

Filardo, G; Kon, E; Roffi, A; Di Matteo, B; Merli, M L; Marcacci, M

2015-09-01

The aim of this review was to analyze the available evidence on the clinical application of this biological approach for the injective treatment of cartilage lesions and joint degeneration, together with preclinical studies to support the rationale for the use of platelet concentrates, to shed some light and give indications on what to treat and what to expect from intra-articular injections of platelet-rich plasma (PRP). All in vitro, in vivo preclinical and clinical studies on PRP injective treatment in the English language concerning the effect of PRP on cartilage, synovial tissue, menisci, and mesenchymal stem cells were considered. A systematic review on the PubMed database was performed using the following words: (platelet-rich plasma or PRP or platelet concentrate or platelet lysate or platelet supernatant) and (cartilage or chondrocytes or synoviocytes or menisci or mesenchymal stem cells). Fifty-nine articles met the inclusion criteria: 26 were in vitro, 9 were in vivo, 2 were both in vivo and in vitro, and 22 were clinical studies. The analysis showed an increasing number of published studies over time. Preclinical evidence supports the use of PRP injections that might promote a favourable environment for joint tissues healing. Only a few high-quality clinical trials have been published, which showed a clinical improvement limited over time and mainly documented in younger patients not affected by advanced knee degeneration. Besides the limits and sometimes controversial findings, the preclinical literature shows an overall support toward this PRP application. An intra-articular injection does not just target cartilage; instead, PRP might influence the entire joint environment, leading to a short-term clinical improvement. Many biological variables might influence the clinical outcome and have to be studied to optimize PRP injective treatment of cartilage degeneration and osteoarthritis.

Bone Mineral Density Is Positively Related to Carotid Intima-Media Thickness: Findings From a Population-Based Study in Adolescents and Premenopausal Women.

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Frysz, Monika; Deere, Kevin; Lawlor, Debbie A; Benfield, Li; Tobias, Jon H; Gregson, Celia L

2016-12-01

Osteoporosis and cardiovascular disease (CVD) are both common causes of morbidity and mortality. Previous studies, mainly of people older than 60 years, suggest a relationship between these conditions. Our aim was to determine the association between bone characteristics and CVD markers in younger and middle-aged individuals. Women (n = 3366) and their adolescent offspring (n = 4368) from the UK population-based cohort study, Avon Longitudinal Study of Parents and Children (ALSPAC), were investigated. We measured total body (TB) and hip bone mineral density (BMD), TB bone area (BA) and bone mineral content (BMC) by dual-energy X-ray absorptiometry (DXA), and carotid intima-media thickness (cIMT) by high-resolution ultrasound. Arterial distensibility was calculated as the difference between systolic and diastolic arterial diameters. Linear regression determined associations between bone exposures and cIMT (in adolescents) and both cIMT and arterial distensibility (in women), generating partial correlation coefficients. Mean (SD) age of women was 48 (4.2) years, body mass index (BMI) was 26.2 (5.0) kg/m 2 , and 71% were premenopausal. In confounder-adjusted analyses (age, height, lean mass, fat mass, menopause, smoking, estrogen replacement, calcium/vitamin D supplementation, and education) TB and hip BMD were both positively associated with cIMT (0.071 [0.030, 0.112], p = 0.001; 0.063 [0.025, 0.101], p = 0.001, respectively). Femoral neck BMD and TB BMD, BMC, and BA were positively associated with arterial distensibility. Mean (SD) age of adolescents was 17 (0.4) years, BMI was 23 (4.1) kg/m 2 , and 44.5% were male. Total hip and TB measurements were positively associated with cIMT, with similar magnitudes of association to those found in their mothers. In contrast to most published findings, we identified weak positive associations between BMD and cIMT in predominantly premenopausal women and their adolescent offspring. We found greater femoral neck

Rescuing loading induced bone formation at senescence.

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Sundar Srinivasan

2010-09-01

Full Text Available The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca(2+/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential.

Prospective study of bone metastasis from prostate cancer: comparison between large field diffusion-weighted imaging and bone scintigraphy

International Nuclear Information System (INIS)

Wang Xiaoying; Zhang Chunyan; Jiang Xuexiang

2009-01-01

Objective: To evaluate the large field diffusion weighted imaging (DWI) (from head vertex to lower leg) in detection of bone metastases from prostate cancer. Methods: One hundred and sixty- six consecutive patients who were suspected of prostate cancer received pelvic MRI and large field diffusion weighted imaging examination. Forty-nine of them underwent bone scintigraphy within one month of the examination of large field DWI. The images were double-blindly evaluated without the knowledge of the pathology result. Conventional MR T 1 and fat saturation T 2 weighted images were taken as standard for the diagnosis of bone metastasis. The sensitivity, specificity, and area under curve between large field DWI and bone scintigraphy were compared with McNemar test. Five patients with bone metastases exceeding 10 per patient were excluded in the lesion-by-lesion analysis. Results: Ten of the 49 patients were diagnosed as bone metastases. The diagnosis of bone metastasis were made in 15 patients by large field DWI and in 17 patients by bone scintigraphy. With patient number as study units (n=49), the diagnostic sensitivity of bone metastases with large field DWI and bone metastases were both 100% (10/10), and specificity were 87.2% (34/39) vs. 82.1% (32/39), respectively. ROC study showed the area under curve (AUC) of large field DWI and bone scintigraphy were 0.936 vs. 0.910, respectively. Totally 68 abnormal foci were identified from large field DWI and/or bone scintigraphy in 44 patients (while 5 patients with bone metastases exceeding 10 foci per patient were excluded), 20 of them were diagnosed as foci of bone metastasis. The diagnosis of bone metastases was made in 23 foci by large field DWI and in 34 by bone scintigraphy. With lesion numbers as study units (n=68), the diagnostic sensitivity of large field DWI and bone scintigraphy were both 90.0% (18/20), and specificity were 89.6% (43/48) vs. 66.7% (32/48), respectively. ROC study showed the area under curve of

A radiographic study of solitary bone cysts

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Kim, Kyung Rak; Hwang, Eui Hwan; Lee, Sang Rae [Dept. of Oral and Maxillofacial Radiology, Division of Dentistry, Kyung Hee University, Seoul (Korea, Republic of)

1994-02-15

The aim of this study was to evaluate the clinical, radiographic and histopathologic features of 23 cases of solitary bone cyst by means of the analysis of radiographs and biopsy specimens in 23 persons visited the Department of Oral and Maxillofacial Radiology, School of Dentistry, Kyung Hee University and Chunbuk National University. The obtained results were as follows; 1. The incidence of solitary bone cyst was almost equal in males (52.2%) and in females(42.8%) and the prevalent age of the solitary bone cyst were the second decade (47.8%) and the third decade (21.7%). 2. In the signs and symptoms of solitary bone cyst, pain or tenderness revealed in 17.4%, swelling revealed in 13.0%, pain and swelling revealed in 21.7%, paresthesia revealed in 4.4% and 43.5% were a symptom and the tooth vitality involved in the solitary bone cyst, 76.5% were posterior and 23.5% were either positive or negative. 3. In the location of the solitary bone cyst, 47.8% present posterior region, 21.7% present anterior region, 21.6% present anterior and posterior region, 4.4% present condylar process area. 4. In the hyperostotic border of the solitary bone cyst, 47.8% were seen entirely, 21.8% were seen partially, and 30.4% were not seen. 5. In the change of tooth, 59.1% were loss of the alveolar lamina dura, 13.6% were root resorption 4.55% were tooth displacement, 4.55% were root resorption and tooth displacement. 6. In the change of cortical bone of the solitary bone cyst, 39.1% were intact and 60.9% were thinning and expansion of cortical bone. 7. In the histopathologic findings of 9 cases, 33.3% were thin connective tissue wall, 11.1% were thickened myxo-fibromatous wall, 55.6% were thickened myxofibromatous wall with dysplastic bone formation.

A radiographic study of solitary bone cysts

International Nuclear Information System (INIS)

Kim, Kyung Rak; Hwang, Eui Hwan; Lee, Sang Rae

1994-01-01

The aim of this study was to evaluate the clinical, radiographic and histopathologic features of 23 cases of solitary bone cyst by means of the analysis of radiographs and biopsy specimens in 23 persons visited the Department of Oral and Maxillofacial Radiology, School of Dentistry, Kyung Hee University and Chunbuk National University. The obtained results were as follows; 1. The incidence of solitary bone cyst was almost equal in males (52.2%) and in females(42.8%) and the prevalent age of the solitary bone cyst were the second decade (47.8%) and the third decade (21.7%). 2. In the signs and symptoms of solitary bone cyst, pain or tenderness revealed in 17.4%, swelling revealed in 13.0%, pain and swelling revealed in 21.7%, paresthesia revealed in 4.4% and 43.5% were a symptom and the tooth vitality involved in the solitary bone cyst, 76.5% were posterior and 23.5% were either positive or negative. 3. In the location of the solitary bone cyst, 47.8% present posterior region, 21.7% present anterior region, 21.6% present anterior and posterior region, 4.4% present condylar process area. 4. In the hyperostotic border of the solitary bone cyst, 47.8% were seen entirely, 21.8% were seen partially, and 30.4% were not seen. 5. In the change of tooth, 59.1% were loss of the alveolar lamina dura, 13.6% were root resorption 4.55% were tooth displacement, 4.55% were root resorption and tooth displacement. 6. In the change of cortical bone of the solitary bone cyst, 39.1% were intact and 60.9% were thinning and expansion of cortical bone. 7. In the histopathologic findings of 9 cases, 33.3% were thin connective tissue wall, 11.1% were thickened myxo-fibromatous wall, 55.6% were thickened myxofibromatous wall with dysplastic bone formation.

A quantitative analysis of statistical power identifies obesity end points for improved in vivo preclinical study design.

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Selimkhanov, J; Thompson, W C; Guo, J; Hall, K D; Musante, C J

2017-08-01

The design of well-powered in vivo preclinical studies is a key element in building the knowledge of disease physiology for the purpose of identifying and effectively testing potential antiobesity drug targets. However, as a result of the complexity of the obese phenotype, there is limited understanding of the variability within and between study animals of macroscopic end points such as food intake and body composition. This, combined with limitations inherent in the measurement of certain end points, presents challenges to study design that can have significant consequences for an antiobesity program. Here, we analyze a large, longitudinal study of mouse food intake and body composition during diet perturbation to quantify the variability and interaction of the key metabolic end points. To demonstrate how conclusions can change as a function of study size, we show that a simulated preclinical study properly powered for one end point may lead to false conclusions based on secondary end points. We then propose the guidelines for end point selection and study size estimation under different conditions to facilitate proper power calculation for a more successful in vivo study design.

Roentgenologic study of sesamoid bones

International Nuclear Information System (INIS)

Lee, Son Young; Park, Byung Hwan; Kim, Dong Hyuk

1980-01-01

A radiological study on sesamoid bones of hands and feet was done in Korea adults who visited the Capital Armed Forces General Hospital Of Korea during last 10 months from Jan. 1, to Oct, 30, 1970. The incidence of presence or absence of sesamoid bones in each possible site and shape and partition were studied in 250 males and 200 females. The results are follow: 1. In hands, two sesamoids are present at metacarpophalangel joint of thumb in all and one at metacarpophalangeal joint of little finger in half, metacarpophalangeal joint of index, interphalangeal joint of thumb. Metacarpophalangeal joint of ring finger were other sites, in order of frequency. 2. In feet, two sesamoid are present at metacarpophalangeal joint of great toe in all, but the incidence at other sites are much lower comparison to hands and the sites are interphalangeal joint of great toe, metacarpophalangeal joint of 5th toe, metacarpophalangeal joint of 2nd toe, and metacarpophalangeal joint of 4th toe in order frequency. 3. In comparison with sexes, the incidence is a little greater in female at every site. 4. In general, the partition line of sesamoid bone is transverse, and fracture line of sesamoid is longitudinal. 5. In comparison with Europeans, the incidence of sesamoid bone at interphalangeal joint of thumb and great toe is about half, and at other sites, except metacaso phalangeal joint of thumb abd great toe, the incidence was smaller in each site.

Preclinical Data on Efficacy of 10 Drug-Radiation Combinations: Evaluations, Concerns, and Recommendations

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Helen B. Stone

2016-02-01

Full Text Available BACKGROUND: Clinical testing of new therapeutic interventions requires comprehensive, high-quality preclinical data. Concerns regarding quality of preclinical data have been raised in recent reports. This report examines the data on the interaction of 10 drugs with radiation and provides recommendations for improving the quality, reproducibility, and utility of future studies. The drugs were AZD6244, bortezomib, 17-DMAG, erlotinib, gefitinib, lapatinib, oxaliplatin/Lipoxal, sunitinib (Pfizer, Corporate headquarters, New York, NY, thalidomide, and vorinostat. METHODS: In vitro and in vivo data were tabulated from 125 published papers, including methods, radiation and drug doses, schedules of administration, assays, measures of interaction, presentation and interpretation of data, dosimetry, and conclusions. RESULTS: In many instances, the studies contained inadequate or unclear information that would hamper efforts to replicate or intercompare the studies, and that weakened the evidence for designing and conducting clinical trials. The published reports on these drugs showed mixed results on enhancement of radiation response, except for sunitinib, which was ineffective. CONCLUSIONS: There is a need for improved experimental design, execution, and reporting of preclinical testing of agents that are candidates for clinical use in combination with radiation. A checklist is provided for authors and reviewers to ensure that preclinical studies of drug-radiation combinations meet standards of design, execution, and interpretation, and report necessary information to ensure high quality and reproducibility of studies. Improved design, execution, common measures of enhancement, and consistent interpretation of preclinical studies of drug-radiation interactions will provide rational guidance for prioritizing drugs for clinical radiotherapy trials and for the design of such trials.

Preclinical electrogastrography in experimental pigs

Science.gov (United States)

Květina, Jaroslav; Varayil, Jithinraj Edakkanambeth; Ali, Shahzad Marghoob; Kuneš, Martin; Bureš, Jan; Tachecí, Ilja; Rejchrt, Stanislav; Kopáčová, Marcela

2010-01-01

Surface electrogastrography (EGG) is a non-invasive means of recording gastric myoelectric activity or slow waves from cutaneous leads placed over the stomach. This paper provides a comprehensive review of preclinical EGG. Our group recently set up and worked out the methods for EGG in experimental pigs. We gained our initial experience in the use of EGG in assessment of porcine gastric myoelectric activity after volume challenge and after intragastric administration of itopride and erythromycin. The mean dominant frequency in pigs is comparable with that found in humans. EGG in experimental pigs is feasible. Experimental EGG is an important basis for further preclinical projects in pharmacology and toxicology. PMID:21217873

Pre-Clinical Medical Students' Exposure to and Attitudes Toward Pharmaceutical Industry Marketing.

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Fein, Eric H; Vermillion, Michelle L; Uijtdehaage, Sebastian H J

2007-12-01

Background - Recent studies have examined the exposures and attitudes of physicians and third- and fourth-year medical students toward pharmaceutical industry marketing, but fewer studies have addressed these topics among pre-clinical medical students. Thus, the purpose of this study was to assess pre-clinical students' level of exposure to the pharmaceutical industry and their attitudes toward marketing. Method - First and second-year medical students at UCLA completed a 40-item survey based on previous studies. Results - Over three quarters of pre-clinical students (78.5% or 226 of 288) responded to the survey. Exposure to pharmaceutical industry marketing started very early in medical school. Most second-year students (77%) had received gifts including drug samples after three semesters. Most felt that this would not affect their future prescribing behavior. Conclusions - These findings and findings from related studies, coupled with the students' desire to learn more about the issue, suggest that an early educational intervention addressing this topic may be warranted in American medical schools.

Value of shared preclinical safety studies - The eTOX database.

Science.gov (United States)

Briggs, Katharine; Barber, Chris; Cases, Montserrat; Marc, Philippe; Steger-Hartmann, Thomas

2015-01-01

A first analysis of a database of shared preclinical safety data for 1214 small molecule drugs and drug candidates extracted from 3970 reports donated by thirteen pharmaceutical companies for the eTOX project (www.etoxproject.eu) is presented. Species, duration of exposure and administration route data were analysed to assess if large enough subsets of homogenous data are available for building in silico predictive models. Prevalence of treatment related effects for the different types of findings recorded were analysed. The eTOX ontology was used to determine the most common treatment-related clinical chemistry and histopathology findings reported in the database. The data were then mined to evaluate sensitivity of established in vivo biomarkers for liver toxicity risk assessment. The value of the database to inform other drug development projects during early drug development is illustrated by a case study.

Advanced Pre-clinical Research Approaches and Models to Studying Pediatric Anesthetic Neurotoxicity

Directory of Open Access Journals (Sweden)

Cheng eWang

2012-10-01

Full Text Available Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cell and nonhuman primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents. This review discusses the potential application of some sophisticaled research approaches, e.g., calcium imaging, in stem cell-derived in vitro models, especially human embryonic neural stem cells, along with their capacity for proliferation and their potential for differentiation, to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents. Also, this review attempts to discuss several advantages for using the developing rhesus monkey models (in vivo, when combined with dynamic molecular imaging approaches, in addressing critical issues related to the topic of pediatric sedation/anesthesia. These include the relationships between anesthetic-induced neurotoxicity, dose response, time-course and developmental stage at time of exposure (in vivo studies, serving to provide the most expeditious platform toward decreasing the uncertainty in extrapolating pre-clinical data to the human condition.

Sex differences in the vulnerability to drug abuse: a review of preclinical studies.

Science.gov (United States)

Roth, Megan E; Cosgrove, Kelly P; Carroll, Marilyn E

2004-10-01

Clinical and preclinical findings indicate that males and females differ on several aspects of drug reinforcement. Females are more vulnerable than males during transition periods of drug use that are characteristic of drug addiction and relapse. Females are also more sensitive than males to the reinforcing effects of stimulants. It has been suggested that ovarian hormones contribute to the mechanisms of action underlying these sex differences. This review examines the preclinical literature on sex differences and ovarian hormonal influences on drug self-administration in animals. It summarizes the findings on the effects of these variables during different phases of drug addiction. Possible differences in the mechanisms of action of drugs of abuse due to interactions with sex differences or ovarian hormonal factors are considered. The animal literature on sex differences in drug abuse treatment effectiveness is also discussed.

Biomechanical testing of isolated bones: holographic study

Science.gov (United States)

Silvennoinen, Raimo; Nygren, Kaarlo; Karna, Markku

1992-08-01

Holographic nondestructive testing (HNDT) is used to investigate the complex structures of bones of various shapes and sizes subjected to forces. Three antlered deer skulls of different species were investigated and significant species-specific differences were observed. The HNDT method was also used to verify the advanced healing of an osteosynthetized sheep jawbone. Radioulnar bones of a normal and an orphaned moose calf were subjected to a bending test. The undernourished calf showed torsio displacement combined with the bending of the bone, which was not seen in the normal calf. The effects of the masticatory forces on the moose skull surface were studied by simulating masseter muscle contractions with jawbones in occlusion. The fringe patterns showed fast-moving bone surfaces on the naso- maxillo-lacrimal region.

Computer stress study of bone with computed tomography

International Nuclear Information System (INIS)

Linden, M.J.; Marom, S.A.; Linden, C.N.

1986-01-01

A computer processing tool has been developed which, together with a finite element program, determines the stress-deformation pattern in a long bone, utilizing Computed Tomography (CT) data files for the geometry and radiographic density information. The geometry, together with mechanical properties and boundary conditions: loads and displacements, comprise the input of the Finite element (FE) computer program. The output of the program is the stresses and deformations in the bone. The processor is capable of developing an accurate three-dimensional finite element model from a scanned human long bone due to the CT high pixel resolution and the local mechanical properties determined from the radiographic densities of the scanned bone. The processor, together with the finite element program, serves first as an analysis tool towards improved understanding of bone function and remodelling. In this first stage, actual long bones may be scanned and analyzed under applied loads and displacements, determined from existing gait analyses. The stress-deformation patterns thus obtained may be used for studying the biomechanical behavior of particular long bones such as bones with implants and with osteoporosis. As a second stage, this processor may serve as a diagnostic tool for analyzing the biomechanical response of a specific patient's long long bone under applied loading by utilizing a CT data file of the specific bone as an input to the processor with the FE program

Influence of demineralized bone matrix's embryonic origin on bone formation: an experimental study in rats.

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Stavropoulos, Andreas; Kostopoulos, Lambros; Mardas, Nicolaos; Karring, Thorkild

2003-01-01

There are results suggesting that differences regarding bone-inducing potential, in terms of amount and/or rate of bone formation, exist between demineralized bone matrices (DBMs) of different embryonic origins. The aim of the present study was to examine whether the embryonic origin of DBM affects bone formation when used as an adjunct to guided tissue regeneration (GTR). Endomembranous (EM) and endochondral (ECH) DBMs were produced from calvarial and long bones of rats, respectively. Prior to the study the osteoinductive properties of the DBMs were confirmed in six rats following intramuscular implantation. Following surgical exposure of the mandibular ramus, a rigid hemispheric Teflon capsule loosely packed with a standardized quantity of DBM was placed with its open part facing the lateral surface of the ramus in both sides of the jaw in 30 rats. In one side of the jaw, chosen at random, the capsule was filled with EM-DBM, whereas in the other side ECH-DBM was used. Groups of 10 animals were sacrificed after healing periods of 1, 2, and 4 months, and undecalcified sections of the capsules were produced and subjected to histologic analysis and computer-assisted planimetric measurements. During the experiment increasing amounts of newly formed bone were observed inside the capsules in both sides of the animals' jaws. Limited bone formation was observed in the 1- and 2-month specimens, but after 4 months of healing, the newly formed bone in the ECH-DBM grafted sides occupied 59.1% (range 45.6-74.7%) of the area created by the capsule versus 46.9% (range 23.0-64.0%) in the EM-DBM grafted sides (p =.01). It is concluded that the embryonic origin of DBM influences bone formation by GTR and that ECH-DBM is superior to EM-DBM.

Celecoxib does not significantly delay bone healing in a rat femoral osteotomy model: a bone histomorphometry study

Directory of Open Access Journals (Sweden)

Iwamoto J

2011-12-01

Full Text Available Jun Iwamoto1, Azusa Seki2, Yoshihiro Sato3, Hideo Matsumoto11Institute for Integrated Sports Medicine, Keio University School of Medicine, Tokyo, Japan; 2Hamri Co, Ltd, Tokyo, Japan; 3Department of Neurology, Mitate Hospital, Fukuoka, JapanBackground and objective: The objective of the present study was to determine whether celecoxib, a cyclo-oxygenase-2 inhibitor, would delay bone healing in a rat femoral osteotomy model by examining bone histomorphometry parameters.Methods: Twenty-one 6-week-old female Sprague-Dawley rats underwent a unilateral osteotomy of the femoral diaphysis followed by intramedullary wire fixation; the rats were then divided into three groups: the vehicle administration group (control, n = 8, the vitamin K2 administration (menatetrenone 30 mg/kg orally, five times a week group (positive control, n = 5, and the celecoxib administration (4 mg/kg orally, five times a week group (n = 8. After 6 weeks of treatment, the wires were removed, and a bone histomorphometric analysis was performed on the bone tissue inside the callus. The lamellar area relative to the bone area was significantly higher and the total area and woven area relative to the bone area were significantly lower in the vitamin K2 group than in the vehicle group. However, none of the structural parameters, such as the callus and bone area relative to the total area, lamellar and woven areas relative to the bone area, or the formative and resorptive parameters such as osteoclast surface, number of osteoclasts, osteoblast surface, osteoid surface, eroded surface, and bone formation rate per bone surface differed significantly between the vehicle and celecoxib groups.Conclusion: The present study implies that celecoxib may not significantly delay bone healing in a rat femoral osteotomy model based on the results of a bone histomorphometric analysis.Keywords: femoral osteotomy, bone healing, callus, rat, celecoxib

No preclinical rationale for IGF1R directed therapy in chondrosarcoma of bone.

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Peterse, Elisabeth F P; Cleven, Arjen H G; De Jong, Yvonne; Briaire-de Bruijn, Inge; Fletcher, Jonathan A; Danen, Erik H J; Cleton-Jansen, Anne-Marie; Bovée, Judith V M G

2016-07-14

Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of the role of the IGF pathway in chondrosarcoma to determine if it can be a target for therapy, which was therefore explored in this study. Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot. The effect of activation and inhibition of IGF1R signalling on downstream targets was assessed by western blot. Ten chondrosarcoma cell lines were treated with OSI-906 (IGF1R and IR dual inhibitor) after which cell proliferation and migration were determined by a viability assay and the xCELLigence system, respectively. In addition, four chondrosarcoma cell lines were treated with a combination of doxorubicin and OSI-906. By immunohistochemistry, IGF1R expression levels were determined in tissue microarrays of 187 cartilage tumours and ten paraffin embedded cell lines. Mediators of IGF1R signalling are heterogeneously expressed and phosphorylated IRS1 was detected in 67 % of the tested chondrosarcoma cell lines, suggesting that IGF1R signalling is active in a subset of chondrosarcoma cell lines. In the cell lines with phosphorylated IRS1, inhibition of IGF1R signalling decreased phosphorylated Akt levels and increased IGF1R expression, but it did not influence MAPK or S6 activity. In line with these findings, treatment with IGF1R/IR inhibitors did not impact proliferation or migration in any of the chondrosarcoma cell lines, even upon stimulation with IGF1. Although synergistic effects of IGF1R/IR inhibition with doxorubicin are described for other cancers, our results demonstrate that this was not the case for chondrosarcoma. In addition, we found minimal IGF1R expression in primary tumours in contrast to the high expression detected in chondrosarcoma cell lines, even if both were derived from the

Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease.

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Ng, Kok Pin; Pascoal, Tharick A; Mathotaarachchi, Sulantha; Chung, Chang-Oh; Benedet, Andréa L; Shin, Monica; Kang, Min Su; Li, Xiaofeng; Ba, Maowen; Kandiah, Nagaendran; Rosa-Neto, Pedro; Gauthier, Serge

2017-05-09

To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD). We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [ 18 F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [ 18 F]fluorodeoxyglucose (FDG) PET. Individuals with preclinical AD with higher NPI scores had higher [ 18 F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction. The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

[Study on preparation and physicochemical properties of surface modified sintered bone].

Science.gov (United States)

Li, Jingfeng; Zheng, Qixin; Guo, Xiaodong

2012-06-01

The aim of this study is to investigate a new method for preparing a biomimetic bone material-surface modified sintered bovine cancellous bone, and to improve its bioactivity as a tissue engineering bone. The prepared sintered bovine cancellous bones with the same size were randomly divided into two groups, immersing in 1 and 1. 5 times simulated body fluid (SBF), respectively. The three time periods of soak time were 7, 14, and 21 days. After sintered bone was dried, the surface morphology of sintered bone and surface mineralization composition were observed under scanning electron microscopy (SEM). By comparing the effect of surface modification of sintered bone materials, we chose the most ideal material and studied its pore size, the rate of the porosity, the compress and bend intensity. And then the material and the sintered bone material without surface modification were compared. The study indicated that sintered bone material immersed in SBF (1.5 times) for 14 days showed the best effect of surface modification, retaining the original physico-chemical properties of sintered bone.

Resveratrol: A review of preclinical studies for human cancer prevention

International Nuclear Information System (INIS)

Athar, Mohammad; Back, Jung Ho; Tang Xiuwei; Kim, Kwang Ho; Kopelovich, Levy; Bickers, David R.; Kim, Arianna L.

2007-01-01

The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations

Bone histomorphometric study of young rats following oestrogen ...

African Journals Online (AJOL)

Osteoporosis is a global problem which results in increased fractures risk. The reports from earlier studies were inconsistent with the aging factor as well as the time which is needed to induce bone loss post-ovariectomy. This study aimed to determine the short-term effects of estrogen deficiency on bone structural ...

Bone marker gene expression in calvarial bones: different bone microenvironments.

Science.gov (United States)

Al-Amer, Osama

2017-12-01

In calvarial mice, mesenchymal stem cells (MSCs) differentiate into osteoprogenitor cells and then differentiate into osteoblasts that differentiate into osteocytes, which become embedded within the bone matrix. In this case, the cells participating in bone formation include MSCs, osteoprogenitor cells, osteoblasts and osteocytes. The calvariae of C57BL/KaLwRijHsD mice consist of the following five bones: two frontal bones, two parietal bones and one interparietal bone. This study aimed to analyse some bone marker genes and bone related genes to determine whether these calvarial bones have different bone microenvironments. C57BL/KaLwRijHsD calvariae were carefully excised from five male mice that were 4-6 weeks of age. Frontal, parietal, and interparietal bones were dissected to determine the bone microenvironment in calvariae. Haematoxylin and eosin staining was used to determine the morphology of different calvarial bones under microscopy. TaqMan was used to analyse the relative expression of Runx2, OC, OSX, RANK, RANKL, OPG, N-cadherin, E-cadherin, FGF2 and FGFR1 genes in different parts of the calvariae. Histological analysis demonstrated different bone marrow (BM) areas between the different parts of the calvariae. The data show that parietal bones have the smallest BM area compared to frontal and interparietal bones. TaqMan data show a significant increase in the expression level of Runx2, OC, OSX, RANKL, OPG, FGF2 and FGFR1 genes in the parietal bones compared with the frontal and interparietal bones of calvariae. This study provides evidence that different calvarial bones, frontal, parietal and interparietal, contain different bone microenvironments.

Material model of pelvic bone based on modal analysis: a study on the composite bone.

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Henyš, Petr; Čapek, Lukáš

2017-02-01

Digital models based on finite element (FE) analysis are widely used in orthopaedics to predict the stress or strain in the bone due to bone-implant interaction. The usability of the model depends strongly on the bone material description. The material model that is most commonly used is based on a constant Young's modulus or on the apparent density of bone obtained from computer tomography (CT) data. The Young's modulus of bone is described in many experimental works with large variations in the results. The concept of measuring and validating the material model of the pelvic bone based on modal analysis is introduced in this pilot study. The modal frequencies, damping, and shapes of the composite bone were measured precisely by an impact hammer at 239 points. An FE model was built using the data pertaining to the geometry and apparent density obtained from the CT of the composite bone. The isotropic homogeneous Young's modulus and Poisson's ratio of the cortical and trabecular bone were estimated from the optimisation procedure including Gaussian statistical properties. The performance of the updated model was investigated through the sensitivity analysis of the natural frequencies with respect to the material parameters. The maximal error between the numerical and experimental natural frequencies of the bone reached 1.74 % in the first modal shape. Finally, the optimised parameters were matched with the data sheets of the composite bone. The maximal difference between the calibrated material properties and that obtained from the data sheet was 34 %. The optimisation scheme of the FE model based on the modal analysis data provides extremely useful calibration of the FE models with the uncertainty bounds and without the influence of the boundary conditions.

Fixation of tibial plateau fractures with synthetic bone graft versus natural bone graft: a comparison study.

LENUS (Irish Health Repository)

Ong, J C Y

2012-06-01

The goal of this study was to determine differences in fracture stability and functional outcome between synthetic bone graft and natural bone graft with internal fixation of tibia plateau metaphyseal defects.

Can evaluation of a dental procedure at the outset of learning predict later performance at the preclinical level? A pilot study.

LENUS (Irish Health Repository)

Polyzois, Ioannis

2011-05-01

The purpose of this study was to examine the effectiveness of conventional pre-clinical training in dentistry and to determine if evaluation of a dental procedure at the beginning of dental training can be a predictor for future performance. A group of second year dental students with no previous experience in operative dentistry were asked to prepare a conventional class I cavity on a lower first molar typodont. Their first preparation was carried out after an introductory lecture and a demonstration and their second at the end of conventional training. The prepared typodonts were coded and blindly scored for the traditional assessment criteria of outline form, retention form, smoothness, cavity depth and cavity margin angulation. Once the codes were broken, a paired t-test was used to compare the difference between the means of before and after scores (P<0.0001) and a Pearson\\'s linear correlation to test the association (r=0.4). From the results of this study, we could conclude that conventional preclinical training results in a significant improvement in the manual skills of the dental students and that the dental procedure used had only a limited predictive value for later performance at the preclinical level.

Skeletal scintigraphy and quantitative tracer studies in metabolic bone disease

Science.gov (United States)

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

Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

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Abbate, Carlo; Trimarchi, Pietro Davide; Inglese, Silvia; Viti, Niccolò; Cantatore, Alessandra; De Agostini, Lisa; Pirri, Federico; Marino, Lorenza; Bagarolo, Renzo

2014-01-01

Objective. We describe a case of dementia with Lewy bodies (DLB) that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI-) DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS). The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder. PMID:24868122

NCI Pediatric Preclinical Testing Consortium

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NCI has awarded grants to five research teams to participate in its Pediatric Preclinical Testing Consortium, which is intended to help to prioritize which agents to pursue in pediatric clinical trials.

Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research

DEFF Research Database (Denmark)

Shane, Elizabeth; Burr, David; Ebeling, Peter R

2010-01-01

Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent...... published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete...

No preclinical rationale for IGF1R directed therapy in chondrosarcoma of bone

International Nuclear Information System (INIS)

Peterse, Elisabeth F. P.; Cleven, Arjen H. G.; De Jong, Yvonne; Briaire-de Bruijn, Inge; Fletcher, Jonathan A.; Danen, Erik H. J.; Cleton-Jansen, Anne-Marie; Bovée, Judith V. M. G.

2016-01-01

Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of the role of the IGF pathway in chondrosarcoma to determine if it can be a target for therapy, which was therefore explored in this study. Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot. The effect of activation and inhibition of IGF1R signalling on downstream targets was assessed by western blot. Ten chondrosarcoma cell lines were treated with OSI-906 (IGF1R and IR dual inhibitor) after which cell proliferation and migration were determined by a viability assay and the xCELLigence system, respectively. In addition, four chondrosarcoma cell lines were treated with a combination of doxorubicin and OSI-906. By immunohistochemistry, IGF1R expression levels were determined in tissue microarrays of 187 cartilage tumours and ten paraffin embedded cell lines. Mediators of IGF1R signalling are heterogeneously expressed and phosphorylated IRS1 was detected in 67 % of the tested chondrosarcoma cell lines, suggesting that IGF1R signalling is active in a subset of chondrosarcoma cell lines. In the cell lines with phosphorylated IRS1, inhibition of IGF1R signalling decreased phosphorylated Akt levels and increased IGF1R expression, but it did not influence MAPK or S6 activity. In line with these findings, treatment with IGF1R/IR inhibitors did not impact proliferation or migration in any of the chondrosarcoma cell lines, even upon stimulation with IGF1. Although synergistic effects of IGF1R/IR inhibition with doxorubicin are described for other cancers, our results demonstrate that this was not the case for chondrosarcoma. In addition, we found minimal IGF1R expression in primary tumours in contrast to the high expression detected in chondrosarcoma cell lines, even if both were derived from the

Assessment of the knowledge and attitudes regarding HIV/AIDS among pre-clinical medical students in Israel

Science.gov (United States)

2014-01-01

Background Today’s medical students are the future physicians of people living with HIV/AIDS (PLWHA). It is therefore essential that medical students possess the appropriate knowledge and attitudes regarding PLWHA. This study aims to evaluate knowledge and attitudes of pre-clinical Israeli medical students and to assess whether their knowledge and attitudes change throughout their pre-clinical studies. Methods A cross-sectional study was conducted among all pre-clinical medical students from the four medical schools in Israel during the academic year of 2010/2011 (a total of 1,470 students). A self-administered questionnaire was distributed. The questionnaire sought student responses pertaining to knowledge of HIV transmission and non-transmission routes, basic knowledge of HIV/AIDS treatment and attitudes towards HIV/AIDS. Results The study’s response rate was 62.24 percent. Knowledge among pre-clinical medical students was generally high and showed a statistically significant improvement as students progressed through their pre-clinical studies. However, there were some misconceptions, mostly regarding HIV transmission via breastfeeding and knowledge of HIV prevention after exposure to the virus. Students’ attitudes were found to include stigmatizing notions. Furthermore, the majority of medical students correlated HIV with shame and fear. In addition, students’ attitudes toward HIV testing and providing confidential medical information were contradictory to health laws, protocols and guidelines. Overall, no positive changes in students’ attitudes were observed during the pre-clinical years of medical school. Conclusion The knowledge of pre-clinical medical students in Israel is generally high, although there are some knowledge inadequacies that require more emphasis in the curricula of the medical schools. Contrary to HIV-related knowledge, medical students’ attitudes are unaffected by their progression through medical school. Therefore, medical

[Classification of results of studying blood plasma with laser correlation spectroscopy based on semiotics of preclinical and clinical states].

Science.gov (United States)

Ternovoĭ, K S; Kryzhanovskiĭ, G N; Musiĭchuk, Iu I; Noskin, L A; Klopov, N V; Noskin, V A; Starodub, N F

1998-01-01

The usage of laser correlation spectroscopy for verification of preclinical and clinical states is substantiated. Developed "semiotic" classifier for solving the problems of preclinical and clinical states is presented. The substantiation of biological algorithms as well as the mathematical support and software for the proposed classifier for the data of laser correlation spectroscopy of blood plasma are presented.

Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study

OpenAIRE

Feng, Yuan; Zhou, Jihong; Li, Zhanhua; Jiang, Ying; Zhou, Ying

2016-01-01

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis act...

The role of radiolabelled compounds in preclinical drug development

International Nuclear Information System (INIS)

Hawkins, D.R.

1988-01-01

The role of radiolabelled compounds in the development of new drugs is discussed, with particular reference to their use in toxicological, metabolic and pharmacokinetic studies for the pre-clinical safety evaluation of new drugs. (U.K.)

Sequential changes in bone marrow architecture during continuous low dose gamma irradiation

International Nuclear Information System (INIS)

Seed, T.M.; Chubb, G.T.; Tolle, D.V.

1981-01-01

Beagles continuously exposed to low daily doses (10 R) of whole-body 60Co gamma-radiation are prone to develop either early occurring aplastic anemia or late occurring myeloproliferative disorders (Seed et al., 1977). In this study, we have examined by a combination of light microscopy and scanning and transmission electron microscopy the sequential changes in the morphology of biopsied rib bone marrow of continuously irradiated dogs that developed either aplastic anemia, myelofibrosis, or myelogenous leukemia. Characteristic modification of key elements of marrow architecture have been observed during preclinical and clinical phases of these hemopathological conditions. The more prominent of these changes include the following. (i) In developing aplastic anemia: severe vascular sinus and parenchymal cord compression, and focally degenerate endosteal surfaces. (ii) In developing myelofibrosis: hyperplasia of endosteal and reticular stomal elements. (iii) In developing leukemia: hypertrophy of reticular and endothelial elements in the initial restructuring of the stromal matrix and the subsequent aberrant hemopoietic repopulation of the initially depleted stromal matrix. These architectural changes during preclinical phases appear to be related to the pathological progression to each of the radiation-induced hemopathological end points

Rapid ex vivo imaging of PAIII prostate to bone tumor with SWIFT-MRI.

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Luhach, Ihor; Idiyatullin, Djaudat; Lynch, Conor C; Corum, Curt; Martinez, Gary V; Garwood, Michael; Gillies, Robert J

2014-09-01

The limiting factor for MRI of skeletal/mineralized tissue is fast transverse relaxation. A recent advancement in MRI technology, SWIFT (Sweep Imaging with Fourier Transform), is emerging as a new approach to overcome this difficulty. Among other techniques like UTE, ZTE, and WASPI, the application of SWIFT technology has the strong potential to impact preclinical and clinical imaging, particularly in the context of primary or metastatic bone cancers because it has the added advantage of imaging water in mineralized tissues of bone allowing MRI images to be obtained of tissues previously visible only with modalities such as computed tomography (CT). The goal of the current study is to examine the feasibility of SWIFT for the assessment of the prostate cancer induced changes in bone formation (osteogenesis) and destruction (osteolysis) in ex vivo specimens. A luciferase expressing prostate cancer cell line (PAIII) or saline control was inoculated directly into the tibia of 6-week-old immunocompromised male mice. Tumor growth was assessed weekly for 3 weeks before euthanasia and dissection of the tumor bearing and sham tibias. The ex vivo mouse tibia specimens were imaged with a 9.4 Tesla (T) and 7T MRI systems. SWIFT images are compared with traditional gradient-echo and spin-echo MRI images as well as CT and histological sections. SWIFT images with nominal resolution of 78 μm are obtained with the tumor and different bone structures identified. Prostate cancer induced changes in the bone microstructure are visible in SWIFT images, which is supported by spin-echo, high resolution CT and histological analysis. SWIFT MRI is capable of high-quality high-resolution ex vivo imaging of bone tumor and surrounding bone and soft tissues. Furthermore, SWIFT MRI shows promise for in vivo bone tumor imaging, with the added benefits of nonexposure to ionizing radiation, quietness, and speed. Copyright © 2013 Wiley Periodicals, Inc.

Midlife women, bone health, vegetables, herbs and fruit study. The Scarborough Fair study protocol

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Gunn Caroline A

2013-01-01

Full Text Available Abstract Background Bone loss is accelerated in middle aged women but increased fruit/vegetable intake positively affects bone health by provision of micronutrients essential for bone formation, buffer precursors which reduce acid load and phytochemicals affecting inflammation and oxidative stress. Animal studies demonstrated bone resorption inhibiting properties of specific vegetables, fruit and herbs a decade ago. Objective: To increase fruit/vegetable intake in post menopausal women to 9 servings/day using a food specific approach to significantly reduce dietary acid load and include specific vegetables, fruit and herbs with bone resorbing inhibiting properties to assess effect on bone turnover, metabolic and inflammatory markers. Methods/Design The Scarborough Fair Study is a randomised active comparator controlled multi centre trial. It aimed to increase fruit and vegetable intake in 100 post menopausal women from ≤ 5 servings/day to ≥ 9 servings/day for 3 months. The women in the dietary intervention were randomly assigned to one of the two arms of the study. Both groups consumed ≥ 9 servings/day of fruit/vegetables and selected herbs but the diet of each group emphasised different fruit/vegetables/herbs with one group (B selecting from a range of vegetables, fruit and culinary herbs with bone resorbing inhibiting properties. 50 women formed a negative control group (Group C usual diet. Primary outcome variables were plasma bone markers assessed at baseline, 6 weeks and 12 weeks. Secondary outcome variables were plasma inflammation and metabolic markers and urinary electrolytes (calcium, magnesium, potassium and sodium assessed at baseline and 12 weeks. Dietary intake and urine pH change also were outcome variables. The dietary change was calculated with 3 day diet diaries and a 24 hour recall. Intervention participants kept a twice weekly record of fruit, vegetable and herb intake and urine pH. Discussion This study will provide

Bone tissue engineering and regeneration: from discovery to the clinic--an overview.

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O'Keefe, Regis J; Mao, Jeremy

2011-12-01

A National Institutes of Health sponsored workshop "Bone Tissue Engineering and Regeneration: From Discovery to the Clinic" gathered thought leaders from medicine, science, and industry to determine the state of art in the field and to define the barriers to translating new technologies to novel therapies to treat bone defects. Tissue engineering holds enormous promise to improve human health through prevention of disease and the restoration of healthy tissue functions. Bone tissue engineering, similar to that for other tissues and organs, requires integration of multiple disciplines such as cell biology, stem cells, developmental and molecular biology, biomechanics, biomaterials science, and immunology and transplantation science. Although each of the research areas has undergone enormous advances in last decade, the translation to clinical care and the development of tissue engineering composites to replace human tissues has been limited. Bone, similar to other tissue and organs, has complex structure and functions and requires exquisite interactions between cells, matrices, biomechanical forces, and gene and protein regulatory factors for sustained function. The process of engineering bone, thus, requires a comprehensive approach with broad expertise. Although in vitro and preclinical animal studies have been pursued with a large and diverse collection of scaffolds, cells, and biomolecules, the field of bone tissue engineering remains fragmented up to the point that a clear translational roadmap has yet to emerge. Translation is particularly important for unmet clinical needs such as large segmental defects and medically compromised conditions such as tumor removal and infection sites. Collectively, manuscripts in this volume provide luminary examples toward identification of barriers and strategies for translation of fundamental discoveries into clinical therapeutics. © Mary Ann Liebert, Inc.

Bone Tissue Engineering and Regeneration: From Discovery to the Clinic—An Overview

Science.gov (United States)

2011-01-01

A National Institutes of Health sponsored workshop “Bone Tissue Engineering and Regeneration: From Discovery to the Clinic” gathered thought leaders from medicine, science, and industry to determine the state of art in the field and to define the barriers to translating new technologies to novel therapies to treat bone defects. Tissue engineering holds enormous promise to improve human health through prevention of disease and the restoration of healthy tissue functions. Bone tissue engineering, similar to that for other tissues and organs, requires integration of multiple disciplines such as cell biology, stem cells, developmental and molecular biology, biomechanics, biomaterials science, and immunology and transplantation science. Although each of the research areas has undergone enormous advances in last decade, the translation to clinical care and the development of tissue engineering composites to replace human tissues has been limited. Bone, similar to other tissue and organs, has complex structure and functions and requires exquisite interactions between cells, matrices, biomechanical forces, and gene and protein regulatory factors for sustained function. The process of engineering bone, thus, requires a comprehensive approach with broad expertise. Although in vitro and preclinical animal studies have been pursued with a large and diverse collection of scaffolds, cells, and biomolecules, the field of bone tissue engineering remains fragmented up to the point that a clear translational roadmap has yet to emerge. Translation is particularly important for unmet clinical needs such as large segmental defects and medically compromised conditions such as tumor removal and infection sites. Collectively, manuscripts in this volume provide luminary examples toward identification of barriers and strategies for translation of fundamental discoveries into clinical therapeutics. PMID:21902614

In vivo 3-dimensional photoacoustic imaging of the renal vasculature in preclinical rodent models

OpenAIRE

Ogunlade, O.; Connell, J. J.; Huang, J. L.; Zhang, E.; Lythgoe, M. F.; Long, D. A.; Beard, P.

2017-01-01

Non-invasive imaging of the kidney vasculature in preclinical murine models is important for studying renal development, diseases and evaluating new therapies, but is challenging to achieve using existing imaging modalities. Photoacoustic imaging is a promising new technique that is particularly well suited to visualising the vasculature and could provide an alternative to existing preclinical imaging methods for studying renal vascular anatomy and function. To investigate this, an all-optica...

Mexican medicinal plants with anxiolytic or antidepressant activity: Focus on preclinical research.

Science.gov (United States)

López-Rubalcava, Carolina; Estrada-Camarena, Erika

2016-06-20

Anxiety and depression are considered the most prevalent psychiatric disorders worldwide. In Mexico, the use of medicinal plants to alleviate the symptoms associated with these psychiatric disorders is increasing. However, there is little scientific evidence that validates the efficacy of these plants. This evidence needs to be critically revised, and further studied to provided scientific support for their use. To identify the plants that are used in Mexico for the treatment of disorders related to anxiety and depression, and to review the current preclinical and when available, clinical information of these plants. We searched in scientific databases (Pubmed, Web of Science, Scopus and other web sources such as "Biblioteca digital de la medicina tradicional Mexicana" ) for Mexican plants used for the treatment of anxiety and depression that have been analyzed in preclinical studies. Additional information was obtained from published books. For this review, we also consider those plants used in Mexican traditional medicine for the treatment of "nervios," "susto" or "espanto;" common terms that describe symptoms related to anxiety and depression disorders. The bibliographic search identified 49 plants used in Mexican traditional medicine for the treatment of disorders related to anxiety and depression. From all these plants, 59% were analyzed in preclinical research, and only 8% were tested in clinical studies; only a few of these studies tried to elucidate their mechanism of action. In general, it is proposed that the plant extracts interact with the GABAergic system. However, only part of these studies attempted to analyze other neurotransmitter systems. Finally, in some cases, drug-herbal interactions were reported. There is a large number of Mexican medicinal plants used as a treatment for anxiety and depression disorders. Although some of these plants have been studied in preclinical research, in most cases these studies are preliminary, and the understanding

Effects of laser photherapy on bone defects grafted with mineral trioxide aggregate, bone morphogenetic proteins, and guided bone regeneration: a Raman spectroscopic study.

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Pinheiro, Antonio L B; Aciole, Gilberth T S; Cangussú, Maria Cristina T; Pacheco, Marcos T T; Silveira, Landulfo

2010-12-15

We have used Raman analysis to assess bone healing on different models. Benefits on the isolated or combined use of mineral trioxide aggregate, bone morphogenetic proteins, guided bone regeneration and laser on bone repair have been reported, but not their combination. We studied peaks of hydroxyapatite and CH groups on defects grafted with MTA, treated or not with laser, BMPs, and GBR. Ninety rats were divided in 10 groups each, subdivided into three subgroups. Laser (λ850 nm) was applied at every other day for 2 weeks. Raman readings were taken at the surface of the defect. Statistical analysis (CHA) showed significant differences between all groups (p = 0.001) and between Group II and all other (p hydroxyapatite (CHA) that is indicative of greater calcification and resistance of the bone. We conclude that the association of the MTA with laser phototherapy (LPT) and/or not with GBR resulted in a better bone repair. The use of the MTA associated to IR LPT resulted in a more advanced and quality bone repair. Copyright © 2010 Wiley Periodicals, Inc.

BEYOND GLYCEMIC CONTROL IN DIABETES MELLITUS: EFFECTS OF INCRETIN-BASED THERAPY ON BONE METABOLISM

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ELENA eCECCARELLI

2013-06-01

Full Text Available Diabetes mellitus (DM and osteoporosis (OP are common disorders with a significant health burden, and an increase in fracture risk has been described both in type 1 (T1DM and in type 2 (T2DM diabetes. The pathogenic mechanisms of impaired skeletal strength in diabetes remain to be clarified in details and they are only in part reflected by a variation in bone mineral density (BMD. In T2DM, the occurrence of low bone turnover together with a decreased osteoblast activity and compromised bone quality has been shown. Of note, some antidiabetic drugs (e.g. tiazolidinediones, insulin may deeply affect bone metabolism. In addition, the recently introduced class of incretin-based drugs (i.e. GLP-1 receptor agonists and DPP-4 inhibitors is expected to exert potentially beneficial effects on bone health, possibly due to a bone anabolic activity of GLP-1, that can be either direct or indirect through the involvement of thyroid C cells.Here we will review the established as well as the putative effects of incretin hormones and of incretin-based drugs on bone metabolism, both in preclinical models and in man, taking into account that such therapeutic strategy may be effective not only to achieve a good glycemic control, but also to improve bone health in diabetic patients.

Preclinical students’ experiences in early clerkships after skills training partly offered in primary health care centers: a qualitative study from Indonesia

Science.gov (United States)

2012-01-01

Background Students may encounter difficulties when they have to apply clinical skills trained in their pre-clinical studies in clerkships. Early clinical exposure in the pre-clinical phase has been recommended to reduce these transition problems. The aim of this study is to explore differences in students' experiences during the first clerkships between students exclusively trained in a skills laboratory and peers for whom part of their skills training was substituted by early clinical experiences (ECE). Methods Thirty pre-clinical students trained clinical skills exclusively in a skills laboratory; 30 peers received part of their skills training in PHC centers. Within half a year after commencing their clerkships all 60 students shared their experiences in focus group discussions (FGDs). Verbatim transcripts of FGDs were analyzed using Atlas-Ti software. Results Clerkship students who had participated in ECE in PHC centers felt better prepared to perform their clinical skills during the first clerkships than peers who had only practiced in a skills laboratory. ECE in PHC centers impacted positively in particular on students’ confidence, clinical reasoning, and interpersonal communication. Conclusion In the Indonesian setting ECE in PHC centers reduce difficulties commonly encountered by medical students in the first clerkships. PMID:22640419

Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

Directory of Open Access Journals (Sweden)

Carlo Abbate

2014-01-01

Full Text Available Objective. We describe a case of dementia with Lewy bodies (DLB that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI- DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS. The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder.

Subjective memory complaints in preclinical autosomal dominant Alzheimer disease.

Science.gov (United States)

Norton, Daniel J; Amariglio, Rebecca; Protas, Hillary; Chen, Kewei; Aguirre-Acevedo, Daniel C; Pulsifer, Brendan; Castrillon, Gabriel; Tirado, Victoria; Munoz, Claudia; Tariot, Pierre; Langbaum, Jessica B; Reiman, Eric M; Lopera, Francisco; Sperling, Reisa A; Quiroz, Yakeel T

2017-10-03

To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). We examined self-reported and study partner-based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. Self-reported SMC were greater in carriers than noncarriers ( p = 0.02). Study partner-based SMC did not differ between groups ( p = 0.21), but in carriers increased with age ( r = 0.66, p < 0.001) and decreased with hippocampal volume ( r = -0.35, p = 0.08). Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset. © 2017 American Academy of Neurology.

Preclinical evaluation of natural antioxidants for development of radioprotector

International Nuclear Information System (INIS)

Chaudhury, N.K.; Adhikary, J.S.; Mishra, K.

2014-01-01

Whole body gamma ray exposure is harmful to all organs and systems. Various health effects depend on the radiation dose and dose rate and nature of exposure. Natural antioxidants have desired properties for development of radioprotector. However poor bioavailability and relatively low efficacy require high dose for intended applications. Selection of appropriate antioxidant is an important step for undertaking detailed preclinical evaluation in recommended animal models. Our focus is on natural antioxidants for development of radioprotector. We have performed extensive studies on selection of antioxidants using standard assay methods and during the course of these studies we have modified a number of assays. A number of antioxidants were considered for screening of potential radioprotectors. The antioxidants studied are available commercially as chemically pure compound. The outcome was selection of sesamol, component of sesame oil. Toxicity studies were carried out using OECD 423 toxicity guideline and undertaken efficacy studies in C57BL/6 mice and compared with another antioxidant melatonin. Sesamol (250 mg/kg body weight) has shown survival about 76% which was comparable to 86% with melatonin at lethal radiation dose. Further evaluation studies have been performed using radiation doses at LD 50/30 and sub lethal range and the antioxidant dose was also lowered. Sesamol has increased antioxidant level in mice, lowered radiation induced damages in radiosensitive organs, facilitated recovery of haematopoietic and gastrointestinal systems. Sesamol also provided protection in germs cells. Bacterial translocation from GI in irradiated mice was also inhibited in the presence of sesamol. Chromosomal aberrations and micronuclei formation were lowered in bone marrow of mice and in human peripheral blood lymphocytes. Interestingly, both the antioxidants are from different origin but demonstrated similar trend in all measured parameters. Pharmacokinetic studies are in

Is medical students' moral orientation changeable after preclinical medical education?

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Lin, Chaou-Shune; Tsou, Kuo-Inn; Cho, Shu-Ling; Hsieh, Ming-Shium; Wu, Hsi-Chin; Lin, Chyi-Her

2012-03-01

Moral orientation can affect ethical decision-making. Very few studies have focused on whether medical education can change the moral orientation of the students. The purpose of the present study was to document the types of moral orientation exhibited by medical students, and to study if their moral orientation was changed after preclinical education. From 2007 to 2009, the Mojac scale was used to measure the moral orientation of Taiwan medical students. The students included 271 first-year and 109 third-year students. They were rated as a communitarian, dual, or libertarian group and followed for 2 years to monitor the changes in their Mojac scores. In both first and third-year students, the dual group after 2 years of preclinical medical education did not show any significant change. In the libertarian group, first and third-year students showed a statistically significant increase from a score of 99.4 and 101.3 to 103.0 and 105.7, respectively. In the communitarian group, first and third-year students showed a significant decline from 122.8 and 126.1 to 116.0 and 121.5, respectively. During the preclinical medical education years, students with communitarian orientation and libertarian orientation had changed in their moral orientation to become closer to dual orientation. These findings provide valuable hints to medical educators regarding bioethics education and the selection criteria of medical students for admission.

Use of Bone Marrow derived Stem Cells in patients with Cardiovascular Disorders

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Abraham S

2007-01-01

Full Text Available Patients with end stage heart failure have very few treatment options. The long waiting times for transplant and the complications associated with immunosuppression has led to the search for alternatives. Subsequent to the isolation and characterization of stem cells, tremendous advances have been made and the safety and feasibility of autologous bone marrow derived stem cells has been proven in preclinical studies. Clinical studies have also shown mobilized cells repair the infracted heart, improving function and survival. We have started a clinical study to evaluate the efficacy of bone marrow derived stem cells. Bone-marrow was aspirated from the right iliac crest and the stem cells were isolated by density gradient method and suspended according to the mode of delivery.From Jan 2007 till date 10 patients (8 adults, 2 children, age with end stage cardiovascular disorder of varied etiology (Ischemic left ventricular dysfunction - 6 patients, Primary pulmonary hypertension - 2 patients, Dilated cardiomyopathy -1 patient, Biventricular non-compaction -1 patient underwent stem cell therapy. All patients were evaluated and cardiac function was measured by using echocardiography and thallium scintigraphy. There were no procedure related complications. These patients are being regularly followed-up and one patient who has completed 6-month follow-up has shown improvement in perfusion as well as increase in ejection fraction of 10%. Stem cell therapy in patients with end-stage cardiovascular disorder might be a promising tool by means of angiogenesis and other paracrine mechanisms.

A Comparative Study of Bio artificial Bone Tissue Poly-L-lactic Acid/Polycaprolactone and PLLA Scaffolds Applied in Bone Regeneration

International Nuclear Information System (INIS)

Weng, W.; Song, Sh.; Cao, L.; Chen, X.; Cai, Y.; Li, H.; Zhou, Q.; Zhang, J.; Su, J.

2014-01-01

Bio artificial bone tissue engineering is an increasingly popular technique to repair bone defect caused by injury or disease. This study aimed to investigate the feasibility of PLLA/PCL (poly-L-lactic acid/polycaprolactone) by a comparison study of PLLA/PCL and PLLA scaffolds applied in bone regeneration. Thirty healthy mature New Zealand rabbits on which 15 mm distal ulna defect model had been established were selected and then were divided into three groups randomly: group A (repaired with PLLA scaffold), group B (repaired with PLLA/PCL scaffold), and group C (no scaffold) to evaluate the bone-remodeling ability of the implants. Micro-CT examination revealed the prime bone regeneration ability of group B in three groups. Bone mineral density of surgical site in group B was higher than group A but lower than group C. Meanwhile, the bone regeneration in both groups A and B proceeded with signs of inflammation for the initial fast degradation of scaffolds. As a whole, PLLA/PCL scaffolds in vivo initially degrade fast and were better suited to repair bone defect than PLLA in New Zealand rabbits. Furthermore, for the low mineral density of new bone and rapid degradation of the scaffolds, more researches were necessary to optimize the composite for bone regeneration.

Roentgen study of bone age in obese children

International Nuclear Information System (INIS)

Baldzhijski, A.; Totsev, N.; Petrova, Ch.

1991-01-01

The study included 100 children (50 boys and 50 girls) aged from 1 to 18 years with different degree of obesity, classified according to the scheme of Knyazev et al. The bone age was determined by a X-ray method including conventional X-ray study of the left hand at standard conditions. The H. Thiemann - I. Nittz Atlass (1986) was used as a test. It was established that the children with overweight had a change in the bone age which in most cases outstriped the calendar one. It was stated that the determination of the index 'bone age' remained to be a reliable method for studing the obesity effect on the growth and developing of the children' organism. 2 figs., 2 tabs., 12 refs

Combined preclinical magnetic particle imaging and magnetic resonance imaging. Initial results in mice

International Nuclear Information System (INIS)

Kaul, M.G.; Mummert, T.; Jung, C.; Raabe, N.; Ittrich, H.; Adam, G.; Heinen, U.; Reitmeier, A.

2015-01-01

Magnetic particle imaging (MPI) is a new radiologic imaging modality. For the first time, a commercial preclinical scanner is installed. The goal of this study was to establish a workflow between MPI and magnetic resonance imaging (MRI) scanners for a complete in vivo examination of a mouse and to generate the first co-registered in vivo MR-MP images. The in vivo examination of five mice were performed on a preclinical MPI scanner and a 7 Tesla preclinical MRI system. MRI measurements were used for anatomical referencing and validation of the injection of superparamagnetic iron oxide (SPIO) particles during a dynamic MPI scan. We extracted MPI data of the injection phase and co-registered it with MRI data. A workflow process for a combined in vivo MRI and MPI examination was established. A successful injection of ferucarbotran was proven in MPI and MRI. MR-MPI co-registration allocated the SPIOs in the inferior vena cava and the heart during and shortly after the injection. The acquisition of preclinical MPI and MRI data is feasible and allows the combined analysis of MR-MPI information.

Combined preclinical magnetic particle imaging and magnetic resonance imaging. Initial results in mice

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Kaul, M.G.; Mummert, T.; Jung, C.; Raabe, N.; Ittrich, H.; Adam, G. [University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Diagnostic and Interventional Radiology; Weber, O. [Philips Medical Systems DMC GmbH, Hamburg (Germany); Heinen, U. [Bruker BioSpin MRI GmbH, Ettlingen (Germany); Reitmeier, A. [Medical Center Hamburg-Eppendorf, Hamburg (Germany). Animal Facility; Knopp, T. [University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Diagnostic and Interventional Radiology; Hamburg University of Technology, Hamburg (Germany)

2015-05-15

Magnetic particle imaging (MPI) is a new radiologic imaging modality. For the first time, a commercial preclinical scanner is installed. The goal of this study was to establish a workflow between MPI and magnetic resonance imaging (MRI) scanners for a complete in vivo examination of a mouse and to generate the first co-registered in vivo MR-MP images. The in vivo examination of five mice were performed on a preclinical MPI scanner and a 7 Tesla preclinical MRI system. MRI measurements were used for anatomical referencing and validation of the injection of superparamagnetic iron oxide (SPIO) particles during a dynamic MPI scan. We extracted MPI data of the injection phase and co-registered it with MRI data. A workflow process for a combined in vivo MRI and MPI examination was established. A successful injection of ferucarbotran was proven in MPI and MRI. MR-MPI co-registration allocated the SPIOs in the inferior vena cava and the heart during and shortly after the injection. The acquisition of preclinical MPI and MRI data is feasible and allows the combined analysis of MR-MPI information.

New nano-hydroxyapatite in bone defect regeneration: A histological study in rats.

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Kubasiewicz-Ross, Paweł; Hadzik, Jakub; Seeliger, Julia; Kozak, Karol; Jurczyszyn, Kamil; Gerber, Hanna; Dominiak, Marzena; Kunert-Keil, Christiane

2017-09-01

Many types of bone substitute materials are available on the market. Researchers are refining new bone substitutes to make them comparable to autologous grafting materials in treatment of bone defects. The purpose of the study was to evaluate the osseoconductive potential and bone defect regeneration in rat calvaria bone defects treated with new synthetic nano-hydroxyapatite. The study was performed on 30 rats divided into 5 equal groups. New preproduction of experimental nano-hydroxyapatite material by NanoSynHap (Poznań, Poland) was tested and compared with commercially available materials. Five mm critical size defects were created and filled with the following bone grafting materials: 1) Geistlich Bio-Oss ® ; 2) nano-hydroxyapatite+β-TCP; 3) nano-hydroxyapatite; 4) nano-hydroxyapatite+collagen membrane. The last group served as controls without any augmentation. Bone samples from calvaria were harvested for histological and micro-ct evaluation after 8 weeks. New bone formation was observed in all groups. Histomorphometric analysis revealed an amount of regenerated bone between 34.2 and 44.4% in treated bone defects, whereas only 13.0% regenerated bone was found in controls. Interestingly, in group 3, no significant particles of the nano-HA material were found. In contrast, residual bone substitute material could be detected in all other test groups. Micro-CT study confirmed the results of the histological examinations. The new nano-hydroxyapatite provides comparable results to other grafts in the field of bone regeneration. Copyright © 2017 Elsevier GmbH. All rights reserved.

Decalcified allograft in repair of lytic lesions of bone: A study to evolve bone bank in developing countries

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Anil Kumar Gupta

2016-01-01

Full Text Available Background: The quest for ideal bone graft substitutes still haunts orthopedic researchers. The impetus for this search of newer bone substitutes is provided by mismatch between the demand and supply of autogenous bone grafts. Bone banking facilities such as deep frozen and freeze-dried allografts are not so widely available in most of the developing countries. To overcome the problem, we have used partially decalcified, ethanol preserved, and domestic refrigerator stored allografts which are economical and needs simple technology for procurement, preparation, and preservation. The aim of the study was to assess the radiological and functional outcome of the partially decalcified allograft (by weak hydrochloric acid in patients of benign lytic lesions of bone. Through this study, we have also tried to evolve, establish, and disseminate the concept of the bone bank. Materials and Methods: 42 cases of lytic lesions of bone who were treated by decalcified (by weak hydrochloric acid, ethanol preserved, allografts were included in this prospective study. The allograft was obtained from freshly amputated limbs or excised femoral heads during hip arthroplasties under strict aseptic conditions. The causes of lytic lesions were unicameral bone cyst ( n = 3, aneurysmal bone cyst ( n = 3, giant cell tumor ( n = 9, fibrous dysplasia ( n = 12, chondromyxoid fibroma, chondroma, nonossifying fibroma ( n = 1 each, tubercular osteomyelitis ( n = 7, and chronic pyogenic osteomyelitis ( n = 5. The cavity of the lesion was thoroughly curetted and compactly filled with matchstick sized allografts. Results: Quantitative assessment based on the criteria of Sethi et al. (1993 was done. There was complete assimilation in 27 cases, partial healing in 12 cases, and failure in 3 cases. Functional assessment was also done according to which there were 29 excellent results, 6 good, and 7 cases of failure (infection, recurrence, and nonunion of pathological fracture. We

Studies on the distribution of hematopoietic bone marrow by bone marrow scintigraphy, 3. The bone marrow scintigraphy with /sup 111/In-chloride

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Fujimori, K [Kyoto Univ. (Japan). Faculty of Medicine

1976-04-01

A study was made to determine wheter or not bone marrow scintigraphy with /sup 111/In chloride delineates the real distribution of hematopoietic cells. In a patient with acute myelogenous luekemia at the stage of complete remission, there was a significant incorporation of /sup 111/In into bone marrow cells (20 - 28% compared with 6% in the controls). Incorporation of /sup 111/In into peripheral blood cells was 0 at after 10 hours and 5% to 6% after 7 days. The plasma disappearance curve of /sup 111/In consisted of 2 exponential components, one with a half-life of 6.5 to 9.5 hours followed by a slow component with a half-life of 20 to 30 hours. 5 to 7% of the injected dose was excreted in the urine in 24 hours. The distribution of active marrow was investigated with bone marrow scintigraphy in various hematological disorders and the results were compared with those obtained with sup(99m)Tc sulfur colloid. The results obtained in this study suggest that /sup 111/In is incorporated into erythroid precursors, and that this property of /sup 111/In makes in an ideal bone marrow scanning agent for observation of real hematopoietic bone marrow distribution in blood disease.

Roles of Vitamins D and K, Nutrition, and Lifestyle in Low-Energy Bone Fractures in Children and Young Adults.

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Karpiński, Michał; Popko, Janusz; Maresz, Katarzyna; Badmaev, Vladimir; Stohs, Sidney J

2017-07-01

The research on skeletal system health in children and young adults, while recognizing the important role of calcium and vitamin D, goes beyond these nutritional standards. This review focuses on the role of vitamin K in combination with vitamin D and other factors in bone health. The current understanding is that maintaining bone health and prevention of low-energy fractures in any pediatric population includes nutritional factors combined with an active lifestyle. Calcium, vitamin D, and vitamin K supplementation contribute independently and collectively to bone health. The beneficial role of vitamin K, particularly vitamin K2 as menaquinone-7 (MK-7), in bone and cardiovascular health is reasonably well supported scientifically, with several preclinical, epidemiological, and clinical studies published over the last decade. Osteocalcin and matrix-Gla (glutamate-containing) protein (MGP) exemplify vitamin K-dependent proteins involved in building bone matrix and keeping calcium from accumulating in the arterial walls, respectively. An important part of the mechanism of vitamin K involves carboxylation and posttranslational activation of the family of vitamin K-dependent proteins, which prevent expression of pro-inflammatory factors and support improvement in bone mineral concentration, bone mineral density, and the quality of bone matrix. Understanding the combined approach to a healthy skeletal system in children and young adults, including the roles of vitamins D and K, calcium, healthy diet, and exercise, is particularly important in view of reports of subclinical insufficiency of vitamins D and K in otherwise healthy pediatric populations with low-energy bone fractures.

Learning style preferences: A study of pre-clinical medical students in Barbados

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OJEH, NKEMCHO; SOBERS-GRANNUM, NATASHA; GAUR, UMA; UDUPA, ALAYA; MAJUMDER, MD.ANWARUL AZIM

2017-01-01

Introduction: Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students’ learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. Methods: The VARK questionnaire was administered to pre-clinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. Results: The majority of the students were multimodal learners with no differences observed between males (59.5%) and females (60.0%), with tetramodal being the most common. Read/write (33.8%) followed by kinesthetic (32.5%) were the most common learning style preferences. The sensory modality preference for females was read/write (34.2%) and for males it was kinesthetic (40.5%). Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. Conclusion: The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might assist

Learning style preferences: A study of pre-clinical medical students in Barbados.

Science.gov (United States)

Ojeh, Nkemcho; Sobers-Grannum, Natasha; Gaur, Uma; Udupa, Alaya; Majumder, Md Anwarul Azim

2017-10-01

Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students' learning needs and support a conductive learning environment. The VARK [an acronym for visual (V), aural (A), read/write (R) and kinesthetic (K)] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. The VARK questionnaire was administered to pre-clinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. The majority of the students were multimodal learners with no differences observed between males (59.5%) and females (60.0%), with tetramodal being the most common. Read/write (33.8%) followed by kinesthetic (32.5%) were the most common learning style preferences. The sensory modality preference for females was read/write (34.2%) and for males it was kinesthetic (40.5%). Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might assist educators in designing blended teaching

Learning style preferences: A study of Pre-clinical Medical Students in Barbados

Directory of Open Access Journals (Sweden)

NKEMCHO OJEH

2017-10-01

Full Text Available Introduction: Educators need to be aware of different learning styles to effectively tailor instructional strategies and methods to cater to the students’ learning needs and support a conductive learning environment. The VARK [an acronym for visual (V, aural (A, read/write (R and kinesthetic (K] instrument is a useful model to assess learning styles. The aim of this study was to use the VARK questionnaire to determine the learning styles of pre-clinical medical students in order to compare the perceived and assessed learning style preferences, assess gender differences in learning style preferences, and determine whether any relationships exists between awareness of learning styles and academic grades, age, gender and learning modality. Methods: The VARK questionnaire was administered to preclinical students taking a variety of courses in the first three years of the undergraduate MB BS degree programme at the Faculty of Medical Sciences, The University of the West Indies, Cave Hill Campus, Barbados in 2014. Results: The majority of the students were multimodal learners with no differences observed between males (59.5% and females (60.0%, with tetramodal being the most common. Read/write (33.8% followed by kinesthetic (32.5% were the most common learning style preferences. The sensory modality preference for females was read/write (34.2% and for males it was kinesthetic (40.5%. Significant differences were observed between the perceived and assessed learning style preferences with a majority of visual and read/write learners correctly matching their perceived to their actual learning styles. Awareness of learning styles was associated with learning modality but not with academic performance, age or gender. Overall, 60.7% of high achievers used multimodal learning compared to 56.9% low achievers. Conclusion: The findings from this study indicated that the VARK tool was useful in gathering information about different learning styles, and might

Preclinical acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of ["1"8F]fluorocholine in mice

International Nuclear Information System (INIS)

Silveira, Marina B.; Ferreira, Soraya M.Z.M.D.; Nascimento, Leonardo T.C.; Costa, Flávia M.; Mendes, Bruno M.; Ferreira, Andrea V.; Malamut, Carlos; Silva, Juliana B.; Mamede, Marcelo

2016-01-01

["1"8F]Fluorocholine (["1"8F]FCH) has been proven to be effective in prostate cancer. Since ["1"8F]FCH is classified as a new radiopharmaceutical in Brazil, preclinical safety and efficacy data are required to support clinical trials and to obtain its approval. The aim of this work was to perform acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of ["1"8F]FCH. The results could support its use in nuclear medicine as an important piece of work for regulatory in Brazil. - Highlights: • Data demonstrated the high quality, safety and effectiveness of ["1"8F]FCH. • ["1"8F]FCH preclinical profile is in accordance with previously published. • Toxicity, distribution, kinetics and radiation dosimetry were well characterized. • The results are important for regulatory issues in Brazil and other countries.

Vertical ridge augmentation using an equine bone and collagen block infused with recombinant human platelet-derived growth factor-BB: a randomized single-masked histologic study in non-human primates.

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Nevins, Myron; Al Hezaimi, Khalid; Schupbach, Peter; Karimbux, Nadeem; Kim, David M

2012-07-01

This study tests the effectiveness of hydroxyapatite and collagen bone blocks of equine origin (eHAC), infused with recombinant human platelet-derived growth factor-BB (rhPDGF-BB), to augment localized posterior mandibular defects in non-human primates (Papio hamadryas). Bilateral critical-sized defects simulating severe atrophy were created at the time of the posterior teeth extraction. Test and control blocks (without growth factor) were randomly grafted into the respective sites in each non-human primate. All sites exhibited vertical ridge augmentation, with physiologic hard- and soft-tissue integration of the blocks when clinical and histologic examinations were done at 4 months after the vertical ridge augmentation procedure. There was a clear, although non-significant, tendency to increased regeneration in the test sites. As in the first two preclinical studies in this series using canines, experimental eHAC blocks infused with rhPDGF-BB proved to be a predictable and technically viable method to predictably regenerate bone and soft tissue in critical-sized defects. This investigation supplies additional evidence that eHAC blocks infused with rhPDGF-BB growth factor is a predictable and technically feasible option for vertical augmentation of severely resorbed ridges.

Study of tissue engineered bone nodules by Fourier transform infrared spectroscopy.

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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.

Identification of new epilepsy treatments: issues in preclinical methodology.

Science.gov (United States)

Galanopoulou, Aristea S; Buckmaster, Paul S; Staley, Kevin J; Moshé, Solomon L; Perucca, Emilio; Engel, Jerome; Löscher, Wolfgang; Noebels, Jeffrey L; Pitkänen, Asla; Stables, James; White, H Steve; O'Brien, Terence J; Simonato, Michele

2012-03-01

Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, that is, age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome, or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical antiepilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis, and comorbidities. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Contribution of micro-scanner in the preclinical study of hepatic and pancreatic cancer treatments in rat

International Nuclear Information System (INIS)

Youssef Azer Akladios, Cherif

2010-01-01

Animal experimentation is an unavoidable step in preclinical studies and relies on small animals. In vivo imaging constitutes a precious tool giving information on anatomy, biochemistry, physiology, genetic, pharmacology, while saving cell and tissue integrities of investigated animals. It opens wide the scientific perspective in the field of biological development, physiopathology of diseases, as well as in oncology, from early diagnosis to cancer treatment. This thesis had demonstrated the relevance of micro-scanner in the longitudinal follow up and the management of ortho-topic models of hepatic and pancreatic carcinoma in the rat. For both of these cancers, known to be very poorly or even non curable, there is an urgent need of research on the bases of their onco-genesis as of investigation of the resulting new therapeutic routes. The results of our thesis suggest a role for micro-CT in the preclinical evaluation of their emerging therapies. As far as animal experiment is concerned, in vivo micro-scanner imaging permits, beside a reduction in the number of experimental animals, to establish new (imaging) end-points allowing experiment ending before any sign of animal suffering. It fulfils the main requirements of animal experiment. (author) [fr

The interplay between academic performance and quality of life among preclinical students.

Science.gov (United States)

Shareef, Mohammad Abrar; AlAmodi, Abdulhadi A; Al-Khateeb, Abdulrahman A; Abudan, Zainab; Alkhani, Mohammed A; Zebian, Sanderlla I; Qannita, Ahmed S; Tabrizi, Mariam J

2015-10-31

The high academic performance of medical students greatly influences their professional competence in long term career. Meanwhile, medical students greatly demand procuring a good quality of life that can help them sustain their medical career. This study examines validity and reliability of the tool among preclinical students and testifies the influence of their scholastic performance along with gender and academic year on their quality of life. A cross sectional study was conducted by distributing World Health Organization Quality of Life, WHOQOL-BREF, survey among medical students of year one to three at Alfaisal University. For validity, item discriminate validity(IDV) and confirmatory factor analysis were measured and for reliability, Cronbach's α test and internal item consistency(IIC) were examined. The association of GPA, gender and academic year with all major domains was drawn using Pearson's correlation, independent samples t-test and one-way ANOVA, respectively. A total of 335 preclinical students have responded to this questionnaire. The construct has demonstrated an adequate validity and good reliability. The high academic performance of students positively correlated with physical (r = 0.23, p student scored higher than female peers in physical and psychological health. This study has identified a direct relationship between the academic performance of preclinical students and their quality of life. The WHOQOL-BREF is a valid and reliable tool among preclinical students and the positive direction of high academic performance with greater QOL suggests that academic achievers procure higher satisfaction and poor achievers need a special attention for the improvement of their quality of life.

Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

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Tanaka, Takuji [Cytopatholgy Division, Tohkai Cytopathology Institute, Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu 500-8285 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan)

2012-07-16

Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.

Occipital bone thickness: Implications on occipital-cervical fusion. A cadaveric study.

Science.gov (United States)

Zarghooni, Kourosh; Boese, Chrisoph K; Siewe, Jan; Röllinghoff, Marc; Eysel, Peer; Scheyerer, Max J

2016-12-01

The aim of this study was to create a map of the occipital bone using a cadaveric morphometric analysis. Twelve heads, from seven male and five female cadavers, were studied. The thickness of the occipital bone was measured with a digital vernier caliper within a coordinate system. The maximum thickness of the occipital bone could be measured at the external occipital protuberance (mean 15.4 mm; range 9-29.3 mm). All male individuals had higher bone thickness around this point. Further lateral a steady decrease of bone thickness could be observed. Same could be observed in craniocaudal direction. However, values above the superior nuchal line were on average thicker than below. The measurements demonstrated a great individual variability of bone thickness of the occipital bone. The results emphasize the role of preoperative planning for the feasibility of placement of an occipital screw. Copyright © 2016 Turkish Association of Orthopaedics and Traumatology. Production and hosting by Elsevier B.V. All rights reserved.

Super bone scans on bone scintigraphy in patients with metastatic bone tumor

International Nuclear Information System (INIS)

Morita, Koichi; Fukunaga, Masao; Otsuka, Nobuaki

1988-01-01

Eight patients with malignant tumor (3 with gastric cancer, 4 with prostatic cancer, 1 with transitional cell carcinoma), which showed diffusely increased uptake of 99m Tc labelled phosphorous compound in axial skeleton (''Super Bone Scan'') on bone scintigraphy were clinically studied. No relationship with its histological type of the tumor was recognized. All cases revealed extremely high serum ALP concentration, which might reflect increased osteoblastic activity. Furthermore, on bone roentgenograms all cases showed predominantly osteosclerotic change in the metastatic bones, while some did locally osteolytic change. In three cases with gastric cancer, although they had diffuse skeletal metastases, two had no evidence of liver metastases. Thus, it seemed that clinical study of patients with ''Super Bone Scan'' was interesting to evaluate the mechanism of accumulation of 99m Tc labelled phosphorous compound to bone and bone metabolism, and the pathophysiology in the pathway of bone metastases. (author)

Three-dimensional visualization and characterization of bone structure using reconstructed in-vitro μCT images: A pilot study for bone microarchitecture analysis

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Latief, Fourier Dzar Eljabbar, E-mail: fourier@fi.itb.ac.id [Physics of Earth and Complex Systems, Faculty of Mathematics and Natural Sciences, Institut Teknologi Bandung, Jl. Ganesha 10, Bandung 40132 (Indonesia); Dewi, Dyah Ekashanti Octorina [2Biomedical Engineering Research Division, School of Electrical Engineering and Informatics, Institut Teknologi Bandung, Jl. Ganesha 10, Bandung 40132 (Indonesia); Shari, Mohd Aliff Bin Mohd [Faculty of Electrical Engineering, Universiti Teknologi MARA Malaysia, 40000 Shah Alam, Selangor (Malaysia)

2014-03-24

Micro Computed Tomography (μCT) has been largely used to perform micrometer scale imaging of specimens, bone biopsies and small animals for the study of porous or cavity-containing objects. One of its favored applications is for assessing structural properties of bone. In this research, we perform a pilot study to visualize and characterize bone structure of a chicken bone thigh, as well as to delineate its cortical and trabecular bone regions. We utilize an In-Vitro μCT scanner Skyscan 1173 to acquire a three dimensional image data of a chicken bone thigh. The thigh was scanned using X-ray voltage of 45 kV and current of 150 μA. The reconstructed images have spatial resolution of 142.50 μm/pixel. Using image processing and analysis e.i segmentation by thresholding the gray values (which represent the pseudo density) and binarizing the images, we were able to visualize each part of the bone, i.e., the cortical and trabecular regions. Total volume of the bone is 4663.63 mm{sup 3}, and the surface area of the bone is 7913.42 mm{sup 2}. The volume of the cortical is approximately 1988.62 mm{sup 3} which is nearly 42.64% of the total bone volume. This pilot study has confirmed that the μCT is capable of quantifying 3D bone structural properties and defining its regions separately. For further development, these results can be improved for understanding the pathophysiology of bone abnormality, testing the efficacy of pharmaceutical intervention, or estimating bone biomechanical properties.

Methotrexate Toxicity in Growing Long Bones of Young Rats: A Model for Studying Cancer Chemotherapy-Induced Bone Growth Defects in Children

Directory of Open Access Journals (Sweden)

Chiaming Fan

2011-01-01

Full Text Available The advancement and intensive use of chemotherapy in treating childhood cancers has led to a growing population of young cancer survivors who face increased bone health risks. However, the underlying mechanisms for chemotherapy-induced skeletal defects remain largely unclear. Methotrexate (MTX, the most commonly used antimetabolite in paediatric cancer treatment, is known to cause bone growth defects in children undergoing chemotherapy. Animal studies not only have confirmed the clinical observations but also have increased our understanding of the mechanisms underlying chemotherapy-induced skeletal damage. These models revealed that high-dose MTX can cause growth plate dysfunction, damage osteoprogenitor cells, suppress bone formation, and increase bone resorption and marrow adipogenesis, resulting in overall bone loss. While recent rat studies have shown that antidote folinic acid can reduce MTX damage in the growth plate and bone, future studies should investigate potential adjuvant treatments to reduce chemotherapy-induced skeletal toxicities.

A hospital based study of biochemical markers of bone turnovers & bone mineral density in north Indian women

Science.gov (United States)

Kumar, Ashok; Devi, Salam Gyaneshwori; Mittal, Soniya; Shukla, Deepak Kumar; Sharma, Shashi

2013-01-01

Background & objectives: The osteoporotic risk for women increases soon after menopause. Bone turnover markers are known to be associated with bone loss and fracture risk. This study was aimed to assess bone turnover using bone markers and their correlation with bone mineral density (BMD) in pre- and post-menopausal women. Methods: A total of 255 healthy women (160 pre- and 95 post-menopausal) were enrolled. Serum bone alkaline phosphatase (sBAP) and serum N-terminal telopeptide of type I collagen (NTX) were measured to evaluate the bone formation and resorption, respectively. Bone mineral density was determined at lumbar spine (L2-L4) anteroposteriorly, femoral neck and Ward's triangle using Prodigy dual-energy X-ray absorptiometry (DXA) system. The comparison of years since menopause with respect to BMD and bone markers was also evaluated. Results: NTX and sBAP showed significant negative correlation with BMD of femur neck and Ward's triangle in postmenopausal women. BMD of all three sides were significant variables for NTX and BMD of femur neck and Ward's triangle for sBAP in postmenopausal women. BMD lumbar spine was a significant variable for sBAP in premenopausal women. The mean values of NTX increased significantly with increase in the duration of years since menopause. The BMD of all three sides decreased significantly with increase in the duration of years since menopause. Interpretation & conclusions: Serum NTX and sBAP were inversely correlated to BMD of femur neck and Ward's triangle in post-menopausal women. Simultaneous measurements of NTX and BMD in the north Indian women, suggest that bone resorption in women with low BMD remains high after menopause. PMID:23481051

Longitudinal in vivo evaluation of bone regeneration by combined measurement of multi-pinhole SPECT and micro-CT for tissue engineering

Science.gov (United States)

Lienemann, Philipp S.; Metzger, Stéphanie; Kiveliö, Anna-Sofia; Blanc, Alain; Papageorgiou, Panagiota; Astolfo, Alberto; Pinzer, Bernd R.; Cinelli, Paolo; Weber, Franz E.; Schibli, Roger; Béhé, Martin; Ehrbar, Martin

2015-05-01

Over the last decades, great strides were made in the development of novel implants for the treatment of bone defects. The increasing versatility and complexity of these implant designs request for concurrent advances in means to assess in vivo the course of induced bone formation in preclinical models. Since its discovery, micro-computed tomography (micro-CT) has excelled as powerful high-resolution technique for non-invasive assessment of newly formed bone tissue. However, micro-CT fails to provide spatiotemporal information on biological processes ongoing during bone regeneration. Conversely, due to the versatile applicability and cost-effectiveness, single photon emission computed tomography (SPECT) would be an ideal technique for assessing such biological processes with high sensitivity and for nuclear imaging comparably high resolution (designed poly(ethylene glycol)-based hydrogels that release bone morphogenetic protein to guide the healing of critical sized calvarial bone defects. By combined in vivo longitudinal multi-pinhole SPECT and micro-CT evaluations we determine the spatiotemporal course of bone formation and remodeling within this synthetic hydrogel implant. End point evaluations by high resolution micro-CT and histological evaluation confirm the value of this approach to follow and optimize bone-inducing biomaterials.

Comparative study of conventional and ultrasonically-assisted bone drilling.

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Alam, K; Ahmed, Naseer; Silberschmidt, V V

2014-01-01

Bone drilling is a well-known surgical procedure in orthopaedics and dentistry for fracture treatment and reconstruction. Advanced understanding of the mechanics of the drill-bone interaction is necessary to overcome challenges associated with the process and related postoperative complications. The aim of this study was to explore the benefits of a novel drilling technique, ultrasonically-assisted drilling (UAD), and its possible utilization in orthopaedic surgeries. The study was performed by conducting experiments to understand the basic mechanics of the drilling process using high speed filming of the drilling zone followed by measurements to quantify thrust force, surface roughness and cracking of the bone near the immediate vicinity of the hole with and without ultrasonic assistance. Compared to the spiral chips produced during conventional drilling (CD), UAD was found to break the chips in small pieces which facilitated their fast evacuation from the cutting region. In UAD, lower drilling force and better surface roughness was measured in drilling in the radial and longitudinal axis of the bone. UAD produced crack-free holes which will enhance postoperative performance of fixative devices anchoring the bone. UAD may be used as a possible substitute for CD in orthopaedic clinics.

Preclinical animal research on therapy dosimetry with dual isotopes

International Nuclear Information System (INIS)

Konijnenberg, Mark W.; Jong, Marion de

2011-01-01

Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray

Preclinical animal research on therapy dosimetry with dual isotopes

Energy Technology Data Exchange (ETDEWEB)

Konijnenberg, Mark W.; Jong, Marion de [Nuclear Medicine Department, Erasmus MC, Rotterdam (Netherlands)

2011-06-15

Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray

Preclinical Studies of Chemotherapy Using Histone Deacetylase Inhibitors in Endometrial Cancer

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Noriyuki Takai

2010-01-01

Full Text Available Because epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in endometrial cancers, novel compounds endowed with a histone deacetylase (HDAC inhibitory activity are an attractive therapeutic approach. In this review, we discuss the biologic and therapeutic effects of HDAC inhibitors (HDACIs in treating endometrial cancer. HDACIs were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and the expression of genes related to the malignant phenotype in a variety of endometrial cancer cell lines. Furthermore, HDACIs were able to induce the accumulation of acetylated histones in the chromatin of the p21WAF1 gene in human endometrial carcinoma cells. In xenograft models, some HDACIs have demonstrated antitumor activity with only few side effects. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating endometrial cancer, with a special focus on preclinical studies.

Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study.

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Kuo-Chen Wei

Full Text Available The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI-monitored focused ultrasound (FUS-induced blood-brain barrier (BBB disruption to enhance Temozolomide (TMZ delivery for improving Glioblastoma Multiforme (GBM treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI, animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.

Elective courses for medical students during the preclinical curriculum: a systematic review and evaluation

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Ankit Agarwal

2015-05-01

Full Text Available Objective: Preclinical medical student electives are prevalent at medical schools across the United States, but the range of electives available and their impact on medical student education are not well described in the literature. The objective of this article is to review the literature relating to preclinical medical student electives and their impact on medical student educational outcomes. Methods: We reviewed studies that met the following criteria: English-language articles describing preclinical US-based medical electives. We used PubMed journal databases and limited our search for the time period 1999–2014. We excluded electives based in other countries or electives designed for third or fourth year students. Data abstracted included the topic of the elective, qualitative descriptions of the electives, and any associated surveys or exam data associated with the electives. Data were synthesized using descriptive tables sorting electives by broad topic. Reported outcomes and statistical methods were analyzed to assess study quality. Results: We found a wide range of subjects taught in the form of preclinical medical school electives. We identified electives in clinical skills, the humanities, student lifestyle, specialty-specific electives, and an assortment of other miscellaneous electives. Surveys and exams administered to students showed that the electives were universally well received by students. Of the 37 electives identified, 15 electives used quantitative objective assessments, such as knowledge exams, while the remaining tended to use student self-reported results. Conclusions: Preclinical medical student electives are prevalent at medical schools across the United States and have a significant impact on medical student education.

Bone response to collagenized xenografts of porcine origin (mp3(®) ) and a bovine bone mineral grafting (4BONE(™) XBM) grafts in tibia defects: experimental study in rabbits.

Science.gov (United States)

Calvo-Guirado, José Luis; Aguilar-Salvatierra, Antonio; Ramírez-Fernández, Maria P; Maté Sánchez de Val, José E; Delgado-Ruiz, Rafael Arcesio; Gómez-Moreno, Gerardo

2016-08-01

This study aimed to carry out the evaluation of bone response of new bone formation to two different xenografts (bovine and porcine) biomaterials inserted in rabbit tibiae. The study used a total of 20 male New Zealand albino rabbits. They received a total of 40 grafts in the proximal metaphyseal areas of both tibiae. Two biomaterials were evaluated: 20 porcine xenografts, as a bone granulate (OsteoBiol(®) MP3(®) ; Tecnoss srl, Giaveno, Italy), were placed in the proximal metaphyseal area of the right tibia, 20 anorganic bovine bone mineral grafting (4BONE(™) XBM, MIS Implants Inc., BARLEV, Israel) were placed in the left tibia. Following graft insertion, the animals were sacrificed in two groups of 10 animals, after 1 and 4 months, respectively. For each group, biomaterials were analyzed: newly formed bone, residual graft materials and the connective tissue. Histomorphometric, EDX analysis and element mapping were performed at 1 and 4 months after graft insertion. At 4 months after treatment, the bone defects displayed radiological images that showed complete repair of osseous defects. Histomorphometric evaluation showed that for the porcine xenograft, the study averages for newly formed bone represented 84.23 ± 2.9%, while bovine matrix was 79.34 ± 2.1%. For residual graft material, the porcine biomaterial had 11.23 ± 1.7% and the bovine graft 31.56 ± 2.3%. Finally, the connective tissue for MP3 was 10.33 ± 1.8%, while for the 4BONE(™) XBM we obtained 14.34 ± 2.9%. Element analysis revealed higher percentages of Ca (54 ± 9%) and P (35 ± 6%) in the group B than group A and control group (P MP3 material; this supports new bone formation, creates a bridge between borders, and facilitates bone ingrowth in both biomaterials. Furthermore, this study observed partial dissolution of the mineral phase of four bone graft and complete resorption of porcine MP3 biomaterial and its incorporation into the surrounding bone. Depending on

Investigation of a pre-clinical mandibular bone notch defect model in miniature pigs: clinical computed tomography, micro-computed tomography, and histological evaluation.

Science.gov (United States)

Carlisle, Patricia L; Guda, Teja; Silliman, David T; Lien, Wen; Hale, Robert G; Brown Baer, Pamela R

2016-02-01

To validate a critical-size mandibular bone defect model in miniature pigs. Bilateral notch defects were produced in the mandible of dentally mature miniature pigs. The right mandibular defect remained untreated while the left defect received an autograft. Bone healing was evaluated by computed tomography (CT) at 4 and 16 weeks, and by micro-CT and non-decalcified histology at 16 weeks. In both the untreated and autograft treated groups, mineralized tissue volume was reduced significantly at 4 weeks post-surgery, but was comparable to the pre-surgery levels after 16 weeks. After 16 weeks, CT analysis indicated that significantly greater bone was regenerated in the autograft treated defect than in the untreated defect (P=0.013). Regardless of the treatment, the cortical bone was superior to the defect remodeled over 16 weeks to compensate for the notch defect. The presence of considerable bone healing in both treated and untreated groups suggests that this model is inadequate as a critical-size defect. Despite healing and adaptation, the original bone geometry and quality of the pre-injured mandible was not obtained. On the other hand, this model is justified for evaluating accelerated healing and mitigating the bone remodeling response, which are both important considerations for dental implant restorations.

Uranium in bone: metabolic and autoradiographic studies in the rat

International Nuclear Information System (INIS)

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

1982-01-01

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 on to all types of bone surface, but preferentially on to 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. (author)

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

Science.gov (United States)

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.

Bone marrow transplantations to study gene function in hematopoietic cells

NARCIS (Netherlands)

de Winther, Menno P. J.; Heeringa, Peter

2011-01-01

Immune cells are derived from hematopoietic stem cells in the bone marrow. Experimental replacement of bone marrow offers the unique possibility to replace immune cells, to study gene function in mouse models of disease. Over the past decades, this technique has been used extensively to study, for

Perfluoroalkyl substances in human bone: concentrations in bones and effects on bone cell differentiation.

Science.gov (United States)

Koskela, A; Koponen, J; Lehenkari, P; Viluksela, M; Korkalainen, M; Tuukkanen, J

2017-07-28

Perfluoroalkyl substances (PFAS), including two most commonly studied compounds perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), are widely distributed environmental pollutants, used extensively earlier. Due to their toxicological effects the use of PFAS is now regulated. Based on earlier studies on PFOA's distribution in bone and bone marrow in mice, we investigated PFAS levels and their possible link to bone microarchitecture of human femoral bone samples (n = 18). Soft tissue and bone biopsies were also taken from a 49-year old female cadaver for PFAS analyses. We also studied how PFOA exposure affects differentiation of human osteoblasts and osteoclasts. PFAS were detectable from all dry bone and bone marrow samples, PFOS and PFOA being the most prominent. In cadaver biopsies, lungs and liver contained the highest concentrations of PFAS, whereas PFAS were absent in bone marrow. Perfluorononanoic acid (PFNA) was present in the bones, PFOA and PFOS were absent. In vitro results showed no disturbance in osteogenic differentiation after PFOA exposure, but in osteoclasts, lower concentrations led to increased resorption, which eventually dropped to zero after increase in PFOA concentration. In conclusion, PFAS are present in bone and have the potential to affect human bone cells partly at environmentally relevant concentrations.

Preclinical deposition of pathological prion protein in muscle of experimentally infected primates.

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Susanne Krasemann

Full Text Available Prion diseases are transmissible fatal neurodegenerative disorders affecting humans and animals. A central step in disease progression is the accumulation of a misfolded form (PrP(Sc of the host encoded prion protein (PrP(C in neuronal and non-neuronal tissues. The involvement of peripheral tissues in preclinical states increases the risk of accidental transmission. On the other hand, detection of PrP(Sc in non-neuronal easy-accessible compartments such as muscle may offer a novel diagnostic tool. Primate models have proven invaluable to investigate prion diseases. We have studied the deposition of PrP(Sc in muscle and central nervous system of rhesus monkeys challenged with sporadic Creutzfeldt-Jakob disease (sCJD, variant CJD (vCJD and bovine spongiform encephalopathy (BSE in preclinical and clinical stage using biochemical and morphological methods. Here, we show the preclinical presence of PrP(Sc in muscle and central nervous system of rhesus monkeys experimentally infected with vCJD.

Are bone turnover markers associated with volumetric bone density, size, and strength in older men and women? The AGES-Reykjavik study.

Science.gov (United States)

Marques, E A; Gudnason, V; Sigurdsson, G; Lang, T; Johannesdottir, F; Siggeirsdottir, K; Launer, L; Eiriksdottir, G; Harris, T B

2016-05-01

Association between serum bone formation and resorption markers and bone mineral, structural, and strength variables derived from quantitative computed tomography (QCT) in a population-based cohort of 1745 older adults was assessed. The association was weak for lumbar spine and femoral neck areal and volumetric bone mineral density. The aim of this study was to examine the relationship between levels of bone turnover markers (BTMs; osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX), and procollagen type 1N propeptide (P1NP)) and quantitative computed tomography (QCT)-derived bone density, geometry, and strength indices in the lumbar spine and femoral neck (FN). A total of 1745 older individuals (773 men and 972 women, aged 66-92 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort were studied. QCT was performed in the lumbar spine and hip to estimate volumetric trabecular, cortical, and integral bone mineral density (BMD), areal BMD, bone geometry, and bone strength indices. Association between BTMs and QCT variables were explored using multivariable linear regression. Major findings showed that all BMD measures, FN cortical index, and compressive strength had a low negative correlation with the BTM levels in both men and women. Correlations between BTMs and bone size parameters were minimal or not significant. No associations were found between BTMs and vertebral cross-sectional area in women. BTMs alone accounted for only a relatively small percentage of the bone parameter variance (1-10 %). Serum CTX, OC, and P1NP were weakly correlated with lumbar spine and FN areal and volumetric BMD and strength measures. Most of the bone size indices were not associated with BTMs; thus, the selected bone remodeling markers do not reflect periosteal bone formation. These results confirmed the limited ability of the most sensitive established BTMs to predict bone structural integrity in older adults.

EGFR-targeted anti-cancer drugs in radiotherapy: Preclinical evaluation of mechanisms

International Nuclear Information System (INIS)

Baumann, Michael; Krause, Mechthild; Dikomey, Ekkehard; Dittmann, Klaus; Doerr, Wolfgang; Kasten-Pisula, Ulla; Rodemann, H. Peter

2007-01-01

Preclinical and clinical results indicate that the EGFR can mediate radioresistance in different solid human tumours. Combination of radiotherapy and EGFR inhibitors can improve local tumour control compared to irradiation alone and has been introduced into clinical radiotherapy practice. So far several mechanisms have been identified in preclinical studies to contribute to improved local tumour control after radiation combined with EGFR inhibitors. These include direct kill of cancer stem cells by EGFR inhibitors, cellular radiosensitization through modified signal transduction, inhibition of repair of DNA damage, reduced repopulation and improved reoxygenation during fractionated radiotherapy. Effects and mechanisms may differ for different classes of EGFR inhibitors, for different tumours and for normal tissues. The mechanisms underlying this heterogeneity are currently poorly understood, and predictive assays are not available yet. Importantly, mechanisms and predictors for the combined effects of radiation with EGFR inhibitors appear to be considerably different to those for application of EGFR inhibitors alone or in combination with chemotherapy. Therefore to further evaluate the efficacy and mechanisms of EGFR-inhibition in combined treatments, radiotherapy-specific preclinical research strategies, which include in vivo experiments using local tumour control as an endpoint, as well as animal studies on normal tissue toxicity are needed

Enhancing translation: guidelines for standard pre-clinical experiments in mdx mice.

Science.gov (United States)

Willmann, Raffaella; De Luca, Annamaria; Benatar, Michael; Grounds, Miranda; Dubach, Judith; Raymackers, Jean-Marc; Nagaraju, Kanneboyina

2012-01-01

Duchenne Muscular Dystrophy is an X-linked disorder that affects boys and leads to muscle wasting and death due to cardiac involvement and respiratory complications. The cause is the absence of dystrophin, a large structural protein indispensable for muscle cell function and viability. The mdx mouse has become the standard animal model for pre-clinical evaluation of potential therapeutic treatments. Recent years have seen a rapid increase in the number of experimental compounds being evaluated in the mdx mouse. There is, however, much variability in the design of these pre-clinical experimental studies. This has made it difficult to interpret and compare published data from different laboratories and to evaluate the potential of a treatment for application to patients. The authors therefore propose the introduction of a standard study design for the mdx mouse model. Several aspects, including animal care, sampling times and choice of tissues, as well as recommended endpoints and methodologies are addressed and, for each aspect, a standard procedure is proposed. Testing of all new molecules/drugs using a widely accepted and agreed upon standard experimental protocol would greatly improve the power of pre-clinical experimentations and help identifying promising therapies for the translation into clinical trials for boys with Duchenne Muscular Dystrophy. Copyright © 2011 Elsevier B.V. All rights reserved.

Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth.

Science.gov (United States)

Wan, Xinhai; Li, Zhi-Gang; Yingling, Jonathan M; Yang, Jun; Starbuck, Michael W; Ravoori, Murali K; Kundra, Vikas; Vazquez, Elba; Navone, Nora M

2012-03-01

Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo, the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with X-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro. As expected, LY2109761 reversed the TGF-β1-induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo, LY2109761 treatment for 6weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice (p<0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor-bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth

Novel bone substitute material in alveolar bone healing following tooth extraction: an experimental study in sheep.

Science.gov (United States)

Liu, Jinyi; Schmidlin, Patrick R; Philipp, Alexander; Hild, Nora; Tawse-Smith, Andrew; Duncan, Warwick

2016-07-01

Electrospun cotton wool-like nanocomposite (ECWN) is a novel synthetic bone substitute that incorporates amorphous calcium phosphate nanoparticles into a biodegradable synthetic copolymer poly(lactide-co-glycolide). The objectives of this study were to develop a tooth extraction socket model in sheep for bone graft research and to compare ECWN and bovine-derived xenograft (BX) in this model. Sixteen cross-bred female sheep were used. Bilateral mandibular premolars were extracted atraumatically. Second and third premolar sockets were filled (Latin-square allocation) with BX, ECWN or left unfilled. Resorbable collagen membranes were placed over BX and selected ECWN grafted sockets. Eight sheep per time period were sacrificed after 8 and 16 weeks. Resin-embedded undemineralised sections were analysed for descriptive histology and histomorphometric analyses. At 8 weeks, there were with no distinct differences in healing among the different sites. At 16 weeks, osseous healing followed a fine trabecular pattern in ECWN sites. Non-grafted sites showed thick trabeculae separated by large areas of fibrovascular connective tissue. In BX grafted sites, xenograft particles were surrounded by newly formed bone or fibrovascular connective tissue. There were no statistically significant differences in bone formation across the four groups. However, ECWN sites had significantly less residual graft material than BX sites at 16 weeks (P = 0.048). This first description of a tooth extraction socket model in sheep supports the utility of this model for bone graft research. The results of this study suggested that the novel material ECWN did not impede bone ingrowth into sockets and showed evidence of material resorption. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Neuroprotection in Parkinson's disease: A systematic review of the preclinical data

NARCIS (Netherlands)

Douna, H.; Bavelaar, B.M.; Pellikaan, H.; Olivier, B.; Pieters, T.

2012-01-01

Aim: This study aimed to systematically review the preclinical data of neuroprotective agents for Parkinson's disease (PD) to support the translation of these compounds. Methods: The study consisted of two phases. In phase I, Pubmed and Scopus were systematically searched for neuroprotective agents

No effect of Osteoset, a bone graft substitute, on bone healing in humans: a prospective randomized double-blind study

DEFF Research Database (Denmark)

Petruskevicius, Juozas; Nielsen, Mette Strange; Kaalund, Søren

2002-01-01

We studied the effects of a newly marketed bone substitute, Osteoset, on bone healing in a tibial defect in humans. 20 patients undergoing an ACL (anterior cruciate ligament) reconstruction with bone-patella tendon-bone graft were block-randomized into 2 groups of 10 each. In the treatment group......, the tibial defect was filled manually with Osteoset pellets, in the control group the defect was left empty. CTs of the defect were taken on the first day after the operation, 6 weeks, 3 and 6 months postoperatively. We found about the same amount of bone in the defect in the Osteoset and control groups...... after 6 weeks, 3, and 6 months. In the control group, but not in the Osteoset group, the bone volume increased from 6 weeks to 3 months. The Osteoset pellets were almost resorbed after 6 weeks....

Preliminary study of 24 h bone scintigraphy after dexamethason intervention for differentiating the benign from malignant bone lesions

International Nuclear Information System (INIS)

Fan Yang; Li Yaming; Han Chunqi; Li Deshun; Ma Aiping; Liang Chenrong; Sun Zhenqiu; Liu Hao; Sun Xiaorong; Yin Yafu

2001-01-01

Objective: To explore the clinical value of 24 h bone scintigraphy after dexamethason intervention for differentiating the benign and malignant bone lesions. Methods: Twenty patients with malignant bone lesion (242 foci) and 21 patients with benign bone lesion (102 foci) were randomly divided into non-intervention group and intervention group for the comparative study. The patients in the non-intervention group underwent bone scintigraphy 3 and 24 h after the tracer administration, while the patients in the intervention group were given dexamethason 6.75 mg orally after 3 h bone imaging, then underwent 24 h bone in aging. Different regions of interest were drawn in 3 and 24 h imaging, then the radionuclide uptake ratios (RUR) of 24 h to 3 h was calculated. Results: There were no significant differences in RUR of benign lesions between the non-intervention group and intervention group (q =0.94, P > 0.05). There were significant differences in RUR between the malignant lesions in the non-intervention group and that in the intervention group (q 20.10, P < 0.01); there were significant differences in RUR between the benign and the malignant lesions in the non-intervention group (q = 1.81, P < 0.05); and there were also significant differences in RUR between the benign and the malignant lesions in the intervention group (q = 16.39, P < 0.01). The sensitivity, specificity and accuracy of differentiating the benign and malignant bone lesions by RUR with non-intervention and intervention were 75.5%, 86.2%, 65.8% and 81.5%, 87.5%, 83.1%, respectively. Conclusions: Comparing with the routine bone imaging, 24 h bone scintigraphy after dexamethason intervention elevated the diagnosis efficiency for differentiation of the benign and malignant bone lesions. 24 h bone scintigraphy associated with dexamethason intervention is convenient and acceptable in differentiation of benign and malignant bone lesions, and it is proved to be of great value for clinical application

Radiographic study of bone changes on TMJ arthrosis

International Nuclear Information System (INIS)

You, Dong Soo

1982-01-01

The author analyzed the morphologic changes of bone structures from 1256 radiographs of 314 patients with temporomandibular joint arthrosis, which were obtained by the oblique-lateral projection and orthopantomography. The interrelations of the bone changes and clinical symptoms were examined. Also, the positional relationships of condylar head, articular fossa and articular eminence in the mouth open and closed state were observed in the patients with bone changes. The results were as follows; 1. The most frequent bone change in the TMJ arthrosis was eburnation of cortical bone (35.64%) of total cases. Then came bone surface erosion and localized radiolucency (26.18%), marginal proliferation (9.7%) and flattening of articular surface (9.58%) in that order. 2. The most frequent site of bone change was articular eminence (41.70%). The came condylar head (21.09%) and articular fossa (20.73%) in that order. 3. In the patients with bone changes, their clinical symptoms were pain (51.55%), clicking sound during mandibular movement (37.71%) and limited mandibular movement (10.73%). In the patients complaining pain, their radiographs showed eburnation of cortical bone (30.68%), bone surface erosion and localized radiolucency (27.45%) and flattening in the (30.68%), bone surface erosion and localized radiolucency (27.45%) and flattening of articular surface (10.68%). 4. The condylar positional changes in the TMJ arthrosis patients with bone changes were as follows: in the mouth closed state, there were the widening of joint space in 624 cases (50.00%), the narrowing of joint space in 543 cases (43.47%) and bone on bone relationships in 82 cases (6.57%). In the mouth open state, there were forward positioning of the condyle in 332 cases (28.55%), limitation of movement in 332 cases (28.55%), bone on bone relationships in 248 cases (21.31%) and downward positioning of condyle in 217 cases (18.66%). Bone on bone relationships in 248 cases (21.32%) and downward positioning of

Radiographic study of bone changes on TMJ arthrosis

Energy Technology Data Exchange (ETDEWEB)

You, Dong Soo [Dept. of Radiology, College of Dentistry, Seoul National University, Seoul (Korea, Republic of)

1982-11-15

The author analyzed the morphologic changes of bone structures from 1256 radiographs of 314 patients with temporomandibular joint arthrosis, which were obtained by the oblique-lateral projection and orthopantomography. The interrelations of the bone changes and clinical symptoms were examined. Also, the positional relationships of condylar head, articular fossa and articular eminence in the mouth open and closed state were observed in the patients with bone changes. The results were as follows; 1. The most frequent bone change in the TMJ arthrosis was eburnation of cortical bone (35.64%) of total cases. Then came bone surface erosion and localized radiolucency (26.18%), marginal proliferation (9.7%) and flattening of articular surface (9.58%) in that order. 2. The most frequent site of bone change was articular eminence (41.70%). The came condylar head (21.09%) and articular fossa (20.73%) in that order. 3. In the patients with bone changes, their clinical symptoms were pain (51.55%), clicking sound during mandibular movement (37.71%) and limited mandibular movement (10.73%). In the patients complaining pain, their radiographs showed eburnation of cortical bone (30.68%), bone surface erosion and localized radiolucency (27.45%) and flattening in the (30.68%), bone surface erosion and localized radiolucency (27.45%) and flattening of articular surface (10.68%). 4. The condylar positional changes in the TMJ arthrosis patients with bone changes were as follows: in the mouth closed state, there were the widening of joint space in 624 cases (50.00%), the narrowing of joint space in 543 cases (43.47%) and bone on bone relationships in 82 cases (6.57%). In the mouth open state, there were forward positioning of the condyle in 332 cases (28.55%), limitation of movement in 332 cases (28.55%), bone on bone relationships in 248 cases (21.31%) and downward positioning of condyle in 217 cases (18.66%). Bone on bone relationships in 248 cases (21.32%) and downward positioning of

ALVEOLAR BONE REGENERATION AFTER DEMINERALIZED FREEZE DRIED BONE ALOGRAFT (DFDBA BONE GRAFTING

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Sri Oktawati

2006-04-01

Full Text Available Periodontal treatment by conventional way will result in healing repair, which easily cause recurrence. Modification of treatment should be done to get an effective result, that is the regeneration of alveolar bone and to reduce inflammation. The objective of this study is to determine the alveolar bone regeneration after using DFDBA (Demineralized Freeze Dried Bone Allograft. Quasi experimental designs with pre and post test method was used in this study. From 13 patients, 26 defects got conventional or regenerative treatment. The indicator of alveolar bone regenaration in bone height in radiographic appearance and level of osteocalsin in gingival crevicular fluid (GCF were checked before and after the treatment, then the changes that occurred were analyzed. The result of the research showed that alveolar bone regeneration only occurred to the group of regenerative treatment using DFDBA. The conclusion is the effective periodontal tissue regeneration occurred at regenerative treatment by using DFDBA, and the osteocalsin in GCF can be used as indicator of bone growth.

Glucocorticoid induced osteopenia in cancellous bone of sheep: validation of large animal model for spine fusion and biomaterial research.

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Ding, Ming; Cheng, Liming; Bollen, Peter; Schwarz, Peter; Overgaard, Søren

2010-02-15

Glucocorticoid with low calcium and phosphorus intake induces osteopenia in cancellous bone of sheep. To validate a large animal model for spine fusion and biomaterial research. A variety of ovariectomized animals has been used to study osteoporosis. Most experimental spine fusions were based on normal animals, and there is a great need for suitable large animal models with adequate bone size that closely resemble osteoporosis in humans. Eighteen female skeletal mature sheep were randomly allocated into 3 groups, 6 each. Group 1 (GC-1) received prednisolone (GC) treatment (0.60 mg/kg/day, 5 times weekly) for 7 months. Group 2 (GC-2) received the same treatment as GC-1 for 7 months followed by 3 months without treatment. Group 3 was left untreated and served as the controls. All sheep received restricted diet with low calcium and phosphorus during experiment. After killing the animals, cancellous bone specimens from the vertebra, femurs, and tibias were micro-CT scanned and tested mechanically. Serum biomarkers were determined. In lumbar vertebra, the GC treatment resulted in significant decrease of cancellous bone volume fraction and trabecular thickness, and bone strength. However, the microarchitecture and bone strength of GC-2 recovered to a similar level of the controls. A similar trend of microarchitectural changes was also observed in the distal femur and proximal tibia of both GC treated sheep. The bone formation marker serum-osteocalcin was largely reduced in GC-1 compared to the controls, but recovered with a rebound increase at month 10 in GC-2. The current investigation demonstrates that the changes in microarchitecture and mechanical properties were comparable with those observed in humans after long-term GC treatment. A prolonged GC treatment is needed for a long-term observation to keep osteopenic bone. This model resembles long-term glucocorticoid treated osteoporotic model, and is useful in preclinical studies.

Morphological studies in the diagnosis of primary and secondary bone tumors

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Matveeva O.V.

2016-12-01

Full Text Available The aim: to show the possibility of morphological studies in the diagnosis of primary and secondary tumors of bones. Material and Methods. 105 (72% patients with primary bone tumors aged from 15 to 66 years and 42 (28% patients with metastatic bone lesions aged from 42 to 70 years were examined and treated for the period from 2008 till 2015. Material for morphological studies was prepared using an open biopsy tissue slices and a scraping resected tumor during surgery. Soft-tissue component is subjected to cytology. The material for histological study included changes in bone and soft tissue. Results. Giant cell tumor was verified in 45% of cases by histological examination. Multiple myeloma was diagnosed in 15% of patients. Osteogenic sarcoma was diagnosed in 14% of cases. Ewing's sarcoma was diagnosed in 3%, 2% of cases were matched by diagnosed chordoma. According to the data received, cancer metastasis of kidney and lung is mostly diagnosed in men from the group of patients with secondary bone defeat. Metastasis of cancer of the breast in women was predominated. Conclusion. The morphological (histological, cytological study plays an important role in the diagnosis of bone tumors. The coincidence of the cytological and histological diagnoses was 97%.

Bone scintigraphy and osteo-articular tuberculosis in transplant patients: a study of 50 bone scans

International Nuclear Information System (INIS)

Coulaud, J.P.; Mechali, D.; Morau, G.

1982-01-01

Bone scintigraphy with 99 m technecium labelled phosphorus compounds was achieved in 50 west Africans migrant workers in Paris. Bone and joint tuberculosis was assumed in 20 cases. In 5 of these 20 cases, bone scan, but not X-ray, showed abnormalities, and in 4, bone scan disclosed more localisations than X-rays. In 7 cases, yet, bone scan was normal, with major osteolytic X-rays lesions in 3 cases, minor in 2 cases, and isolated cold abcesses in two more cases: these means 7 false-negative results. Among the 30 other cases, 29 were considered as mechanical vertebral pathology, and 1 sacro-iliitis Brucellosis. Bone scan was normal in 28 cases the 2 others are unexplained false-positive. Although non-specific and not completely reliable, we think that bone-scanning is useful in bone-tuberculosis check-up, especially to obtain early diagnosis and detect multifocal localisations [fr

Bone scintigraphy and osteo-articular tuberculosis in transplant patients: a study of 50 bone scans

Energy Technology Data Exchange (ETDEWEB)

Coulaud, J.P.; Mechali, D.; Morau, G. (Hopital Claude-Bernard, Paris (France))

1982-01-01

Bone scintigraphy with 99 m technecium labelled phosphorus compounds was achieved in 50 west Africans migrant workers in Paris. Bone and joint tuberculosis was assumed in 20 cases. In 5 of these 20 cases, bone scan, but not X-ray, showed abnormalities, and in 4, bone scan disclosed more localisations than X-rays. In 7 cases, yet, bone scan was normal, with major osteolytic X-rays lesions in 3 cases, minor in 2 cases, and isolated cold abcesses in two more cases: these means 7 false-negative results. Among the 30 other cases, 29 were considered as mechanical vertebral pathology, and 1 sacro-iliitis Brucellosis. Bone scan was normal in 28 cases the 2 others are unexplained false-positive. Although non-specific and not completely reliable, we think that bone-scanning is useful in bone-tuberculosis check-up, especially to obtain early diagnosis and detect multifocal localisations.

A comparative study of bone scintigraphy and NMR for vertebral diseases

International Nuclear Information System (INIS)

Nakatani, Mariko; Sekiya, Toru; Hata, Yuichi; Mori, Yutaka; Yasuda, Masanobu; Kawakami, Kenji; Tada, Sinpei

1985-01-01

A comparative study of NMR and bone scintigraphy was performed in vertebral disorders, and the significance of both modalities was evaluated. Twelve patients with various vertebral abnormalities including ten cases of vertebral metastases, one case of cervical caries and one case of Granular cell tumor of L3, were examined. In 4 patients, NMR showed abnormalities in the same regions as the bone scintigrams. In another 3 patients. NMR did not show the disorders reported on bone scintigrams. This may be due to the low NMR sensitivity to tiny infiltration of tumor cells in the bone marrow. In 3 out of the remaining 5 patients, NMR demonstrated abnormal findings, whilst the bone scintigrams were normal. Previous bone scintigrams in these patients before treatment had shown abnormal accumulation of activity in the region of abnormal NMR findings. This may be due to the fact that NMR detects the irreversible change of bone marrow, and bone scintigram demonstrates the turn over of bone minerals. This limited experience suggests that both madalities are complementary in the evaluation of vertebral abnormalities. (author)

A Flexible, Preclinical, Medical School Curriculum Increases Student Academic Productivity and the Desire to Conduct Future Research

Science.gov (United States)

Peacock, Justin G.; Grande, Joseph P.

2015-01-01

In 2006, small blocks of flexible curriculum time, termed selectives, were implemented in the Mayo Medical School preclinical curriculum. Selectives permitted students to pursue professional endeavors, such as research, service, and career exploration, in the preclinical years. The purpose of this study was to survey current and former Mayo…

Studies on the distribution of hematopoietic bone marrow by bone marrow scintigraphy, 2

International Nuclear Information System (INIS)

Fujimori, Katsuhiko

1976-01-01

Distribution of the leukemic marrow was investigated in 42 cases by bone marrow scintigraphy using sup(99m)Tc sulfur colloid in association with clinical findings and ferrokinetics studies in order to clarify hematopoietic function in leukemia. 17 of chronic myelogenous leukemia, 3 of lymphatic leukemia, 2 of monocytic leukemia, 7 of atypical leukemia and one of erythroleukemia. 12 acute myelogenous leukemia were classified into 3 types A, B and C. Type A showed the distribution similar to those obtained with normal controls. Ferrokinetics studies, however, indicated complete absence of erythropoiesis. Type B showed complete lack of sup(99m)Tc activity in usual marrow sites, although ferrokinetics data showed normal erythropoeitic function. Type C showed abnormal concentration of sup(99m)Tc sulfur colloid in the tibiae. 17 chronic myelogenous leukemia showed reduced sup(99m)Tc activity in usual marrow sites and remarkable expanded marrow extending into distal femurs, proximal and distal tibiae and bones of feet. 2 acute lymphotic leukemia patients showed complete absence of sup(99m)Tc activity. The one chronic type showed almost normal distribution. Monocytic leukemia showed decreased marrow distribution in the sternum and vertebrae. Of 6 atypical leukemias one showed almost normal distribution. The others, including a case with hypoplastic luekemia, demonstrated marrow extension similar to that observed in chronic myelogenous leukemia or monocytic leukemia. Erythroleukemia showed increased concentrations of sup(99m)Tc activity in the usual marrow sites and marked marrow expansion throughout all long bones. These results suggest that there is a discrepancy between bone marrow distribution and hematopoietic function in the cases of acute myelogenous leukemia. (J.P.N.)

[Ex Vivo Testing of Mechanical Properties of Canine Metacarpal/Metatarsal Bones after Simulated Implant Removal].

Science.gov (United States)

Srnec, R; Fedorová, P; Pěnčík, J; Vojtová, L; Sedlinská, M; Nečas, A

2016-01-01

EXP, were compared and the difference was found to be statistically significant (p ≤ 0.05). CONCLUSIONS The recently developed biodegradable polymer-composite gel is easy and quick to apply to any defect, regardless of its shape, in bone tissue. The ex vivo mechanical tests on canine short bones showed that the composite applied to defects, which simulated holes left after screw removal, provided sufficient mechanical support to the bone architecture. The results of measuring maximum loading forces were statistically significant. However, before the composite could be recommended for use in veterinary or human medical practice, thorough pre-clinical studies will be required. fracture fixation, mechanical testing, bone plate, cortical screw, refracture.

Bioactive glass-ceramic bone repair associated or not with autogenous bone: a study of organic bone matrix organization in a rabbit critical-sized calvarial model.

Science.gov (United States)

Biguetti, Claudia Cristina; Cavalla, Franco; Tim, Carla Roberta; Saraiva, Patrícia Pinto; Orcini, Wilson; De Andrade Holgado, Leandro; Rennó, Ana Claudia Muniz; Matsumoto, Mariza Akemi

2018-04-26

The aim of the study was to analyze bone matrix (BMX) organization after bone grafting and repair using a new bioactive glass-ceramic (Biosilicate ® ) associated or not with particulate autogenous bone graft. Thirty rabbits underwent surgical bilateral parietal defects and divided into groups according to the materials used: (C) control-blood clot, (BG) particulate autogenous bone, (BS) bioactive glass-ceramic, and BG + BS. After 7, 14, and 30 days post-surgery, a fragment of each specimen was fixed in - 80 °C liquid nitrogen for zymographic evaluation, while the remaining was fixed in 10% formalin for histological birefringence analysis. The results of this study demonstrated that matrix organization in experimental groups was significantly improved compared to C considering collagenous organization. Zymographic analysis revealed pro-MMP-2, pro-MMP-9, and active (a)-MMP-2 in all groups, showing gradual decrease of total gelatinolytic activity during the periods. At day 7, BG presented more prominent gelatinolytic activity for pro-MMP-2 and 9 and a-MMP-2, when compared to the other groups. In addition, at day 7, a 53% activation ratio (active form/[active form + latent form]) was evident in C group, 33% in BS group, and 31% in BG group. In general, BS allowed the production of a BMX similar to BG, with organized collagen deposition and MMP-2 and MMP-9 disponibility, permitting satisfactory bone remodeling at the late period. The evaluation of new bone substitute, with favorable biological properties, opens the possibility for its use as a viable and efficient alternative to autologous bone graft.

Cortical bone drilling: An experimental and numerical study.

Science.gov (United States)

Alam, Khurshid; Bahadur, Issam M; Ahmed, Naseer

2014-12-16

Bone drilling is a common surgical procedure in orthopedics, dental and neurosurgeries. In conventional bone drilling process, the surgeon exerts a considerable amount of pressure to penetrate the drill into the bone tissue. Controlled penetration of drill in the bone is necessary for safe and efficient drilling. Development of a validated Finite Element (FE) model of cortical bone drilling. Drilling experiments were conducted on bovine cortical bone. The FE model of the bone drilling was based on mechanical properties obtained from literature data and additionally conducted microindentation tests on the cortical bone. The magnitude of stress in bone was found to decrease exponentially away from the lips of the drill in simulations. Feed rate was found to be the main influential factor affecting the force and torque in the numerical simulations and experiments. The drilling thrust force and torque were found to be unaffected by the drilling speed in numerical simulations. Simulated forces and torques were compared with experimental results for similar drilling conditions and were found in good agreement.CONCLUSIONS: FE schemes may be successfully applied to model complex kinematics of bone drilling process.

Cola beverage consumption delays alveolar bone healing: a histometric study in rats

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Juliana Mazzonetto Teófilo

2010-06-01

Full Text Available Epidemiological studies have suggested that cola beverage consumption may affect bone metabolism and increase bone fracture risk. Experimental evidence linking cola beverage consumption to deleterious effects on bone is lacking. Herein, we investigated whether cola beverage consumption from weaning to early puberty delays the rate of reparative bone formation inside the socket of an extracted tooth in rats. Twenty male Wistar rats received cola beverage (cola group or tap water (control group ad libitum from the age of 23 days until tooth extraction at 42 days and euthanasia 2 and 3 weeks later. The neoformed bone volume inside the alveolar socket was estimated in semi-serial longitudinal sections using a quantitative differential point-counting method. Histological examination suggested a decrease in the osteogenic process within the tooth sockets of rats from both cola groups, which had thinner and sparser new bone trabeculae. Histometric data confirmed that alveolar bone healing was significantly delayed in cola-fed rats at three weeks after tooth extraction (ANOVA, p = 0.0006, followed by Tukey's test, p < 0.01. Although the results of studies in rats cannot be extrapolated directly to human clinical dentistry, the present study provides evidence that cola beverage consumption negatively affect maxillary bone formation.

Marrow uptake index (MUI): A quantitative scintigraphic study of bone marrow in aplastic anaemia

International Nuclear Information System (INIS)

Padhy, A.K.; Garg, A.; Kochupillai, V.; Gopinath, P.G.; Basu, A.K.

1987-01-01

Aplastic anaemia affects the entire bone marrow. This prospective study was undertaken to develop and standardise a new nuclear medicine technique called 'dynamic bone marrow imaging'. Eleven patients and ten controls were studied. Serial images of the pelvis were obtained in frame mode following intravenous injection of 185-370 mBq of 99m Tc S. Colloid, and an index, called the bone marrow uptake index was calculated by taking into consideration the time activity curve obtained over the iliac crest. This was followed by static imaging of the entire bone marrow in all cases. It was possible to obtain excellent information regarding topographic distribution of bone marrow as well as detect early changes in bone marrow function following treatment. An attempt was also made to correlate bone marrow cellularity as obtained by bone marrow biopsy with results of dynamic bone marrow scintigraphy. On the basis of the encouraging results obtained in the present study, the authors feel that dynamic bone marrow imaging is an excellent technique for the objective evaluation of bone marrow in aplastic anaemia. 20 refs.; 4 figs.; 5 tabs

Numerical and experimental study on the wave attenuation in bone--FDTD simulation of ultrasound propagation in cancellous bone.

Science.gov (United States)

Nagatani, Yoshiki; Mizuno, Katsunori; Saeki, Takashi; Matsukawa, Mami; Sakaguchi, Takefumi; Hosoi, Hiroshi

2008-11-01

In cancellous bone, longitudinal waves often separate into fast and slow waves depending on the alignment of bone trabeculae in the propagation path. This interesting phenomenon becomes an effective tool for the diagnosis of osteoporosis because wave propagation behavior depends on the bone structure. Since the fast wave mainly propagates in trabeculae, this wave is considered to reflect the structure of trabeculae. For a new diagnosis method using the information of this fast wave, therefore, it is necessary to understand the generation mechanism and propagation behavior precisely. In this study, the generation process of fast wave was examined by numerical simulations using elastic finite-difference time-domain (FDTD) method and experimental measurements. As simulation models, three-dimensional X-ray computer tomography (CT) data of actual bone samples were used. Simulation and experimental results showed that the attenuation of fast wave was always higher in the early state of propagation, and they gradually decreased as the wave propagated in bone. This phenomenon is supposed to come from the complicated propagating paths of fast waves in cancellous bone.

Identification of new treatments for epilepsy: issues in preclinical methodology

Science.gov (United States)

Galanopoulou, Aristea S.; Buckmaster, Paul S.; Staley, Kevin J.; Moshé, Solomon L.; Perucca, Emilio; Engel, Jerome; Löscher, Wolfgang; Noebels, Jeffrey L.; Pitkänen, Asla; Stables, James; White, Steve H.; O’Brien, Terence J.; Simonato, Michele

2013-01-01

Summary Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (a) new symptomatic anti-seizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (b) disease modifying treatments that prevent or ameliorate the epileptogenic state, and (c) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, i.e. age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical anti-epilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis and comorbidities. PMID:22292566

In-vitro studies with 188Re-HEDP, a clinically used bone pain palliating agent, on bone cancer cells

International Nuclear Information System (INIS)

Sharma, Rohit; Kumar, Chandan; Mallia, Madhava B.; Banerjee, Sharmila; Kameswaran, Mythili

2017-01-01

Rhenium-188 is an attractive radioisotope for a wide variety of radiotherapy applications. 188 Re-HEDP (HEDPhydroxyethylidene- 1,1-diphosphonic acid) is one such, clinically useful, radiopharmaceutical for palliation of bone pain due to osseous metastasis. Herein, our aim was to study the uptake and retention of 188 Re-HEDP in mineralized bone and to assess its cellular toxicity, along with its underlying mechanism in human osteocarcinoma (MG-63 and Soas-2) cell lines. 188 Re-HEDP uptake was found to be significantly higher in mineralized bone. The 188 Re-HEDP complex also induces G2-M cell cycle arrest and thus contributing to apoptosis and cellular toxicity in bone cancer cells. (author)

Discrete tomography in an in vivo small animal bone study.

Science.gov (United States)

Van de Casteele, Elke; Perilli, Egon; Van Aarle, Wim; Reynolds, Karen J; Sijbers, Jan

2018-01-01

This study aimed at assessing the feasibility of a discrete algebraic reconstruction technique (DART) to be used in in vivo small animal bone studies. The advantage of discrete tomography is the possibility to reduce the amount of X-ray projection images, which makes scans faster and implies also a significant reduction of radiation dose, without compromising the reconstruction results. Bone studies are ideal for being performed with discrete tomography, due to the relatively small number of attenuation coefficients contained in the image [namely three: background (air), soft tissue and bone]. In this paper, a validation is made by comparing trabecular bone morphometric parameters calculated from images obtained by using DART and the commonly used standard filtered back-projection (FBP). Female rats were divided into an ovariectomized (OVX) and a sham-operated group. In vivo micro-CT scanning of the tibia was done at baseline and at 2, 4, 8 and 12 weeks after surgery. The cross-section images were reconstructed using first the full set of projection images and afterwards reducing them in number to a quarter and one-sixth (248, 62, 42 projection images, respectively). For both reconstruction methods, similar changes in morphometric parameters were observed over time: bone loss for OVX and bone growth for sham-operated rats, although for DART the actual values were systematically higher (bone volume fraction) or lower (structure model index) compared to FBP, depending on the morphometric parameter. The DART algorithm was, however, more robust when using fewer projection images, where the standard FBP reconstruction was more prone to noise, showing a significantly bigger deviation from the morphometric parameters obtained using all projection images. This study supports the use of DART as a potential alternative method to FBP in X-ray micro-CT animal studies, in particular, when the number of projections has to be drastically minimized, which directly reduces

Autologous cell therapy as a new approach to treatment of radiation-induced bone marrow aplasia: preliminary study in a baboon model

Energy Technology Data Exchange (ETDEWEB)

Herodin, F.; Drouet, M. [Radiohematology Unit, Centre de Recherches du Service de Sante des Armees, La Tronche CEDEX (France)

2002-07-01

The sparing of viable hematopoietic stem and progenitor cells located in underexposed bone marrow territories associated with the relative radioresistance of certain stem cell populations is the rationale for autologous cell therapy consisting of ex vivo expansion of residual cells after collection postirradiation. The feasibility of this treatment mainly depends on time constraints and hematopoietic cell threshold. We showed in this study that in the absence of early-acting mobilizing agent administration, subliminar amounts of CD34{sup +} cells can be collected (1 x 10{sup 6} CD34{sup +} cells/100 mL bone marrow or for 1 L apheresis) from 6-Gy {gamma} globally irradiated baboons. Residual CD34{sup +} cells were successfully expanded in serum-free medium in the presence of antiapoptotic cytokine combination (stem cell factor + FLT-3 ligand + thrombopoietin + interleukin 3, 50 ng/mL each, i.e., 4F): K{sub CD34{sup +}} = x2.8 and x13.7 (n=2). Moreover, we demonstrated the short-term neutrophil engraftment potential of a low-size mixed expanded graft (1.5 x 10{sup 6} final CD34{sup +}cells/kg) issued from the coculture of unirradiated (20%) and 2.5-Gy in vitro irradiated (80%) CD34{sup +} cells on an allogeneic stromal cell layer in the presence of 4F. Further preclinical research needs to be performed to clearly establish this therapeutic approach that could be optimized by the early administration of antiapoptotic cytokines. (author)

Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength.

Science.gov (United States)

Sinder, B P; White, L E; Salemi, J D; Ominsky, M S; Caird, M S; Marini, J C; Kozloff, K M

2014-08-01

Treatments to reduce fracture rates in adults with osteogenesis imperfecta are limited. Sclerostin antibody, developed for treating osteoporosis, has not been explored in adults with OI. This study demonstrates that treatment of adult OI mice respond favorably to sclerostin antibody therapy despite retention of the OI-causing defect. Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk. Although OI fracture risk is greatest before puberty, adults with OI remain at risk of fracture. Antiresorptive bisphosphonates are commonly used to treat adult OI, but have shown mixed efficacy. New treatments which consistently improve bone mass throughout the skeleton may improve patient outcomes. Neutralizing antibodies to sclerostin (Scl-Ab) are a novel anabolic therapy that have shown efficacy in preclinical studies by stimulating bone formation via the canonical wnt signaling pathway. The purpose of this study was to evaluate Scl-Ab in an adult 6 month old Brtl/+ model of OI that harbors a typical heterozygous OI-causing Gly > Cys substitution on Col1a1. Six-month-old WT and Brtl/+ mice were treated with Scl-Ab (25 mg/kg, 2×/week) or Veh for 5 weeks. OCN and TRACP5b serum assays, dynamic histomorphometry, microCT and mechanical testing were performed. Adult Brtl/+ mice demonstrated a strong anabolic response to Scl-Ab with increased serum osteocalcin and bone formation rate. This anabolic response led to improved trabecular and cortical bone mass in the femur. Mechanical testing revealed Scl-Ab increased Brtl/+ femoral stiffness and strength. Scl-Ab was successfully anabolic in an adult Brtl/+ model of OI.

Augmented reality in bone tumour resection: An experimental study.

Science.gov (United States)

Cho, H S; Park, Y K; Gupta, S; Yoon, C; Han, I; Kim, H-S; Choi, H; Hong, J

2017-03-01

We evaluated the accuracy of augmented reality (AR)-based navigation assistance through simulation of bone tumours in a pig femur model. We developed an AR-based navigation system for bone tumour resection, which could be used on a tablet PC. To simulate a bone tumour in the pig femur, a cortical window was made in the diaphysis and bone cement was inserted. A total of 133 pig femurs were used and tumour resection was simulated with AR-assisted resection (164 resection in 82 femurs, half by an orthropaedic oncology expert and half by an orthopaedic resident) and resection with the conventional method (82 resection in 41 femurs). In the conventional group, resection was performed after measuring the distance from the edge of the condyle to the expected resection margin with a ruler as per routine clinical practice. The mean error of 164 resections in 82 femurs in the AR group was 1.71 mm (0 to 6). The mean error of 82 resections in 41 femurs in the conventional resection group was 2.64 mm (0 to 11) (p Augmented reality in bone tumour resection: An experimental study. Bone Joint Res 2017;6:137-143. © 2017 Cho et al.

Radiologic study of the experimentally produced bone destruction and bone formation

International Nuclear Information System (INIS)

Chei, Soon Chul; Ahn, Hyung Kyu

1988-01-01

Bone destruction was induced experimentally by the insertion of a bit of the arsenic compound into the pulp chambers of the right premolars and the artificial bone defects were produced in the periapical regions of the left premolars in 7 dogs. The serial standardized periapical radiographs using aluminum stepwedge attached to the XCP instruments and resin bite blocks were taken following insertion of arsenic compound and at 2, 4, 7, 10, 14, 17, 21, 24 and 28 days in case of bone destruction and following bone injury and weekly thereafter for a total of 14 weeks in case of bone formation . The errors of the method were determined with error estimators described by the Duinkerke. All radiographs were evaluated by the visual examination after joint evaluation by three dental radiologists and analysed with densitometer. The following results were obtained; 1. Analysis of the bone destruction process 1) The error of the method in estimating two distances proved to be small (S.D. for the measuring error; 0.04 mm, S.D. for the over-all error; 0.06 mm, S.D. for the positioning error; 0.05 mm) 2) The radiographic changes were observed after 7 days in 6 cases, 4 days in 1 case and 10 days in 1 case by the visual examination. 3) Aluminum equivalent values were diminished after 2 days and the diminution of 0.58 ± 0.19 mm was demanded to be detected by the visual examination. 2. Analysis of the bone formation process 1) The error of the method in estimating two distances proved to be small (S.D. for the measuring error; 0.03 mm, S.D. for the over-all error; 0.04 mm, S.D. for the positioning error; 0.04 mm) 2) The radiographic changes were observed after 2 weeks in 5 cases and 3 weeks in 2 cases by the visual examination. 3) Aluminum equivalent values were increased after 1 week and the increase of 0.45 ± 0.15 mm was demanded to be detected by the visual examination. 4) Aluminum equivalent values were increased continuously for 7 or 9 weeks but there was only extremely small

Novel technology to prepare oral formulations for preclinical safety studies.

Science.gov (United States)

Niwa, Toshiyuki; Hashimoto, Naofumi

2008-02-28

A novel method to prepare oral formulations, normally suspended dosage form, for preclinical safety studies in animals has been developed using a rotation/revolution mixer. Small hard balls made of zirconia were added to the mixing process to evaluate effectiveness in making a high quality suspension. The driving with balls loaded in the cylindrical container (vessel) of the mixer was quite efficient in dispersing and milling the particles of the active pharmaceutical ingredient (API) in an aqueous medium. The API powder and a small amount of oral aqueous medium (vehicle) were successfully mixed by the spinning motion of the balls in the vessel as though the paste-like suspension was kneaded with a mortar and pestle. It was found that the milled suspension with the mean size of 10-20microm could be prepared, in addition finer milling of less than 10microm could be achieved by selecting the material of vessel. Optimum driving conditions including mixing time, size and quantity of balls, and the standard operational procedure was established using compounds varying in physicochemical properties. The particle size and quantitative analysis by HPLC showed that the resultant suspension was well-milled and highly homogeneous with the nearly intended concentration of API. The proposed method established by this experiment could be applied to the actual safety studies in the real preparation scale of oral suspension.

Contribution of gammagraphy to the diagnosis of bone tumours. Study of 270 patients

International Nuclear Information System (INIS)

Caballero Carpena, O.; Esteban Velasco, J.

1982-01-01

In this study, two hundred seventy patients with bone tumours were evaluated by whole-body radionuclide studies: bone and vascular scan, using 99mTc MDP. In the group of primary bone tumour: 50 cases, the gammagraphy was positive in all cases except one myeloma. The morphology of the abnormal scan area of a primary bone tumour depend more of the site of the bone lesion than on its histopathology, and the size is significant by larger in sarcoma than others. The positivity of gammagraphy in the group of secondary bone tumours: 220 cases, was 93%, and the gammagraphic diagnosis being earlier than the radiologic one in 27%. Finally, we have studied the location of metastases, and the correlation between the positive scan and the request of exploration

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

Science.gov (United States)

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

Histologic and histomorphometric evaluation of bone regeneration using nanocrystalline hydroxyapatite and human freeze-dried bone graft : An experimental study in rabbit.

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Sadeghi, Rokhsareh; Najafi, Mohammad; Semyari, Hassan; Mashhadiabbas, Fatemeh

2017-03-01

Bone regeneration is an important concern in periodontal treatment and implant dentistry. Different biomaterials and surgical techniques have been used for this purpose. The aim of the present study was to compare the effect of nanocrystalline hydroxyapatite and human freeze-dried bone graft (FDBG) in regeneration of rabbit calvarium bony defects by histologic and histomorphometric evaluation. In this experimental study, three similar defects, measuring 8 mm in diameter, were created in the calvaria of 16 white New Zealand rabbits. Two defects were filled with FDBG and nanocrystalline hydroxyapatite silica gel, while the other one remained unfilled to be considered as control. All the defects were covered with collagen membranes. During the healing period, two animals perished; so 14 rabbits were divided into two groups: half of them were euthanized after 6 weeks of healing and the other half after 12 weeks. The specimens were subjected to histologic and histomorphometric examinations for assessment of the following variables: percentage of bone formation and residual graft material, inflammation scores, patterns of bone formation and type of newly formed bone. The percentages of new bone formation after 6 weeks were 14.22 ± 7.85, 21.57 ± 6.91, and 20.54 ± 10.07% in FDBG, NanoBone, and control defects. These values were 27.54 ± 20.19, 23.86 ± 6.27, and 26.48 ± 14.18% in 12-week specimens, respectively. No significant differences were found in the amount of bone formation between the groups. With regard to inflammation, the control and NanoBone groups showed significantly less inflammation compared to FDBG at the 6-week healing phase (P = 0.04); this difference was not significant in the 12-week specimens. Based on the results of this experimental study, both NanoBone and FDBG exhibited a similar effect on bone formation.

Bone Marrow Regeneration Promoted by Biophysically Sorted Osteoprogenitors From Mesenchymal Stromal Cells

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Poon, Zhiyong; Lee, Wong Cheng; Guan, Guofeng; Nyan, Lin Myint; Lim, Chwee Teck; Han, Jongyoon

2015-01-01

Human tissue repair deficiencies can be supplemented through strategies to isolate, expand in vitro, and reimplant regenerative cells that supplant damaged cells or stimulate endogenous repair mechanisms. Bone marrow-derived mesenchymal stromal cells (MSCs), a subset of which is described as mesenchymal stem cells, are leading candidates for cell-mediated bone repair and wound healing, with hundreds of ongoing clinical trials worldwide. An outstanding key challenge for successful clinical translation of MSCs is the capacity to produce large quantities of cells in vitro with uniform and relevant therapeutic properties. By leveraging biophysical traits of MSC subpopulations and label-free microfluidic cell sorting, we hypothesized and experimentally verified that MSCs of large diameter within expanded MSC cultures were osteoprogenitors that exhibited significantly greater efficacy over other MSC subpopulations in bone marrow repair. Systemic administration of osteoprogenitor MSCs significantly improved survival rates (>80%) as compared with other MSC subpopulations (0%) for preclinical murine bone marrow injury models. Osteoprogenitor MSCs also exerted potent therapeutic effects as “cell factories” that secreted high levels of regenerative factors such as interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor A, bone morphogenetic protein 2, epidermal growth factor, fibroblast growth factor 1, and angiopoietin-1; this resulted in increased cell proliferation, vessel formation, and reduced apoptosis in bone marrow. This MSC subpopulation mediated rescue of damaged marrow tissue via restoration of the hematopoiesis-supporting stroma, as well as subsequent hematopoiesis. Together, the capabilities described herein for label-freeisolation of regenerative osteoprogenitor MSCs can markedly improve the efficacy of MSC-based therapies. PMID:25411477

Cells at risk for the production of bone tumors in man: an electron microscope study of the endosteal surface of control bone and bone from a human radium case

International Nuclear Information System (INIS)

Lloyd, E.L.; Henning, C.B.

1979-01-01

The endosteal cells of bone from a radium dial worker are documented for the first time by electron microscopy. Fresh samples of bone and tumor tissue from the femur were made available as a result of amputation for a fibrosarcoma in the region of the right knee joint. Bone was examined from a site proximal to the tumor where no invasion of tumor tissue was evident. The patient, who was exposed at age 16 in 1918, died in 1978 with a terminal body burden, calculated to be 1.2 μCi, 226 Ra. A sample of bone, also obtained at amputation from an unirradiated control patient, age 65, was examined from the same site in the femur. A comparison of the bone bone-marrow interface from the two patients showed that, unlike the control bone where cells were seen close to bone mineral, an intervening fibrotic layer was interposed between the marrow cells and the bone mineral in the radium bone. This layer varied in thickness up to 50 μm and was usually acellular, although cell remnants and occasionally cells, which appeared viable, were seen. Autoradiographs of sections of bone adjacent to those used for the electron microscope studies are being evaluated

Effects of the Natural β-Carboline Alkaloid Harmine, a Main Constituent of Ayahuasca, in Memory and in the Hippocampus: A Systematic Literature Review of Preclinical Studies.

Science.gov (United States)

Dos Santos, Rafael G; Hallak, Jaime E C

2017-01-01

Harmine is a natural β-carboline alkaloid found in several botanical species, such as the Banisteriopsis caapi vine used in the preparation of the hallucinogenic beverage ayahuasca and the seeds of Syrian rue (Peganum harmala). Preclinical studies suggest that harmine may have neuroprotective and cognitive-enhancing effects, and retrospective/observational investigations of the mental health of long-term ayahuasca users suggest that prolonged use of this harmine-rich hallucinogen is associated with better neuropsychological functioning. Thus, in order to better investigate these possibilities, we performed a systematic literature review of preclinical studies analyzing the effects of harmine on hippocampal neurons and in memory-related behavioral tasks in animal models. We found two studies involving hippocampal cell cultures and nine studies using animal models. Harmine administration was associated with neuroprotective effects such as reduced excitotoxicity, inflammation, and oxidative stress, and increased brain-derived neurotrophic factor (BDNF) levels. Harmine also improved memory/learning in several animal models. These effects seem be mediated by monoamine oxidase or acetylcholinesterase inhibition, upregulation of glutamate transporters, decreases in reactive oxygen species, increases in neurotrophic factors, and anti-inflammatory effects. The neuroprotective and cognitive-enhancing effects of harmine should be further investigated in both preclinical and human studies.

Studies on the distribution of hematopoietic bone marrow by bone marrow scintigraphy, 2. The bone marrow distribution in leukemia

Energy Technology Data Exchange (ETDEWEB)

Fujimori, K [Kyoto Univ. (Japan). Faculty of Medicine

1976-04-01

Distribution of the leukemic marrow was investigated in 42 cases by bone marrow scintigraphy using sup(99m)Tc sulfur colloid in association with clinical findings and ferrokinetics studies in order to clarify hematopoietic function in leukemia. 17 of chronic myelogenous leukemia, 3 of lymphatic leukemia, 2 of monocytic leukemia, 7 of atypical leukemia and one of erythroleukemia. 12 acute myelogenous leukemia were classified into 3 types A, B and C. Type A showed the distribution similar to those obtained with normal controls. Ferrokinetics studies, however, indicated complete absence of erythropoiesis. Type B showed complete lack of sup(99m)Tc activity in usual marrow sites, although ferrokinetics data showed normal erythropoeitic function. Type C showed abnormal concentration of sup(99m)Tc sulfur colloid in the tibiae. 17 chronic myelogenous leukemia showed reduced sup(99m)Tc activity in usual marrow sites and remarkable expanded marrow extending into distal femurs, proximal and distal tibiae and bones of feet. 2 acute lymphotic leukemia patients showed complete absence of sup(99m)Tc activity. The one chronic type showed almost normal distribution. Monocytic leukemia showed decreased marrow distribution in the sternum and vertebrae. Of 6 atypical leukemias one showed almost normal distribution. The others, including a case with hypoplastic luekemia, demonstrated marrow extension similar to that observed in chronic myelogenous leukemia or monocytic leukemia. Erythroleukemia showed increased concentrations of sup(99m)Tc activity in the usual marrow sites and marked marrow expansion throughout all long bones. These results suggest that there is a discrepancy between bone marrow distribution and hematopoietic function in the cases of acute myelogenous leukemia.

Histological evolution of the regenerate during bone transport: an experimental study in sheep.

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López-Pliego, Esperanza Macarena; Giráldez-Sánchez, Miguel Ángel; Mora-Macías, Juan; Reina-Romo, Esther; Domínguez, Jaime

2016-09-01

Bone transport (BT) for segmentary bone defects is a well-known technique as it enables correction with new bone formation, which is similar to the previous bone. Despite the high number of experimental studies of distraction osteogenesis in bone lengthening, the types of ossification and histological changes that occur in the regenerate of the bone transport process remain controversial. The aim of this study is to provide the complete evolution of tissues and the types of ossification in the regenerate during the different phases of bone formation after BT until the end of the remodelling period. A histological study was performed using ten adult sheep that were submitted to BT. The types of ossification as well as the evolution of different tissues in the regenerate were determined using histomorphometry and inmunohistochemical studies. The evolution of trabeculae thickness, osteoblast and osteoclast densities, relationship between collagen types and changes in vascularization were also studied. Ossification was primarily intramembranous, with some focus of endochondral ossification in isolated animals. The cell counts showed a progression of cellular activity from the periphery to the centre, presenting the same progression as the growth of bone trabeculae, whose trabeculae thickness was quadrupled at the end of remodelling. Inmunohistochemical studies confirmed the prevalence of type I collagen and the ratio of the Type I/Type II collagen ratio was found to be 2.48. The percentages of the vascularized areas were proximally higher than distally in all animals, but distal zone obtained higher rates than the central region. Bone transport regenerate exhibits a centripetal ossification model and a mixed pattern with predominance of intramembranous over endochondral ossification. The data obtained resemble partially to those found in models of bone lengthening applied to large animals. This study provides a detailed structural characterization of the newly formed

Preclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of action of its cytotoxic component retained with improved tolerability

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Poon, Kirsten Achilles, E-mail: achilles.kirsten@gene.com [Genentech, Inc., South San Francisco, CA (United States); Flagella, Kelly; Beyer, Joseph [Genentech, Inc., South San Francisco, CA (United States); Tibbitts, Jay [UCB, Brussels (Belgium); Kaur, Surinder; Saad, Ola; Yi, Joo-Hee; Girish, Sandhya; Dybdal, Noel; Reynolds, Theresa [Genentech, Inc., South San Francisco, CA (United States)

2013-12-01

Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats, respectively, in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (∼ 4400 μg DM1/m{sup 2}) and 30 mg/kg (∼ 6000 μg DM1/m{sup 2}) in rats and monkeys, respectively. In contrast, DM1 was only tolerated up to 0.2 mg/kg (1600 μg DM1/m{sup 2}). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date. - Highlights: • T-DM1 was well tolerated in preclinical studies in rats and cynomolgus monkeys. • T-DM1 is associated with bone marrow/hematologic, hepatic, and neuronal toxicities. • T-DM1 toxicities are related to DM1 mechanisms of action and pharmacologic

Influence of bone marrow on osseointegration in long bones: an experimental study in sheep.

Science.gov (United States)

Morelli, Fabrizio; Lang, Niklaus P; Bengazi, Franco; Baffone, Davide; Vila Morales, C Dadonim; Botticelli, Daniele

2015-03-01

To evaluate the influence of yellow bone marrow on osseointegration of titanium oral implants using a long bone model. The two tibiae of eight sheep were used as experimental sites. Two osteotomies for implant installation were prepared in each tibia. At the control sites, no further treatments were performed while, at the test sites, bone marrow was removed from the osteotomy site with a curette to an extent that exceeded the implant dimensions. As a result, the apical portion of the implants at the control sites was in contact with bone marrow while, at the test sites, it was in contact with the blood clot. After 2 months, the same procedures were performed in the contralateral side. After another month, the animal was sacrificed. Ground sections were obtained for histological analysis. After 1 month of healing, no differences between test and control sites were found in the apical extension of osseointegration and the percentage of new bone-to-implant contact. However, after 3 months of healing, a higher percentage of new bone-to-implant contact was found at the test compared to the control sites in the marrow compartment. The apical extension of osseointegration, however, was similar to that found at the 1-month healing period both for test and control sites. Osseointegration appeared to be favored by the presence of a blood clot when compared to the presence of yellow fatty bone marrow. Moreover, the contact with cortical bone appeared to be a prerequisite for the osseointegration process in the long bone model. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Comparative study of longitudinal changes in peri-implant bone microstructure

International Nuclear Information System (INIS)

Suzuki, Yusuke; Matsunaga, Satoru; Abe, Shinichi; Ide, Yoshinobu; Usami, Akinobu

2010-01-01

The load applied to an implant is directly transmitted to the jaw and is considered to be one of the causes of remodeling of internal trabecular bones. However, the longitudinal changes during loading and the rearrangement of the trabecular bone structure are mostly unknown. The aim of this study was to clarify the changes in internal jaw bone structure longitudinally during natural tooth eruption as well as tooth extraction and post-implantation periods in a dog model by micro computed tomography (micro-CT). Maxillae of 16 male beagle dogs were used in this study. First, 4 dogs with all maxillary molar teeth erupted were euthanized as a control group. Next, 6 teeth consisting of the bilateral maxillary fourth premolars, and first and second molars were extracted from each of the 12 dogs. Then, 4 dogs of the tooth-extracted group were euthanized 3 months after extraction of the teeth. At this time, three implants were inserted in the left side of the maxilla of the remaining 8 dogs, and the superstructures were placed after 3 months. Four of these 8 dogs with implants were euthanized at 3 months and the other 4 at 1 year after placement of the superstructure. Then, the maxillary bone was removed from each dog as a specimen and sequential micro-CT images were taken. After reconstruction of three-dimensional images, morphological and metrical observation of the jaw trabecular bone structure was performed. A decrease of the trabecular bone in the tooth-extracted group was morphologically and morphometrically observed, whereas the implanted group showed thick, rich trabecular bone. Although a longitudinal decrease in the bone tissue volume was recognized both in the tooth-extracted and the implanted groups, the amount was smaller in the implanted group than in the tooth-extracted group. The results suggested that the application of load by implants in the case of tooth loss inhibits resorption of the alveolar bone and prevents thinning of the jaw. (author)

Utilization of blended learning to teach preclinical endodontics.

Science.gov (United States)

Maresca, Cristina; Barrero, Carlos; Duggan, Dereck; Platin, Enrique; Rivera, Eric; Hannum, Wallace; Petrola, Frank

2014-08-01

Blended learning (BL) is the integration of classroom learning with an online environment. The purpose of this study was to determine whether dental students who experienced BL in a preclinical endodontic course demonstrated better manual skills, conceptual knowledge, and learning experience compared to those experiencing traditional learning. All eighty-one students (100 percent) in a preclinical endodontics course agreed to participate and were assigned to either the traditional or BL group. A root canal procedure was used to determine the level of manual skills gained by each group. Pre- and post-intervention quizzes were given to all students to evaluate conceptual knowledge gained, and the students' perspectives on the methods were evaluated with a survey. The BL group scored better than the traditional group on the manual skills exercise at a statistically significant level (p=0.0067). There were no differences in the post-intervention quiz scores between the two groups, and the students' opinions were positive regarding BL. With BL, the students were able to learn and demonstrate dental skills at a high level.

Use of a collaborative tool to simplify the outsourcing of preclinical safety studies: an insight into the AstraZeneca-Charles River Laboratories strategic relationship.

Science.gov (United States)

Martin, Frederic D C; Benjamin, Amanda; MacLean, Ruth; Hollinshead, David M; Landqvist, Claire

2017-12-01

In 2012, AstraZeneca entered into a strategic relationship with Charles River Laboratories whereby preclinical safety packages comprising safety pharmacology, toxicology, formulation analysis, in vivo ADME, bioanalysis and pharmacokinetics studies are outsourced. New processes were put in place to ensure seamless workflows with the aim of accelerating the delivery of new medicines to patients. Here, we describe in more detail the AstraZeneca preclinical safety outsourcing model and the way in which a collaborative tool has helped to translate the processes in AstraZeneca and Charles River Laboratories into simpler integrated workflows that are efficient and visible across the two companies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Restoflex--a revolutionary change in preclinical practice for restorative dentistry and endodontics.

Science.gov (United States)

Jain, Shweta; Khaiser, Imran M; Thakur, Sophia; Jain, Shikha

2014-05-01

Preclinical exercises are very important for the dental students in order to master various dental techniques. The objective of this article is to introduce a new preclinical working model named Restoflex. It is especially designed for the students to carry out various restorative and endodontic procedures in an environment that closely simulate clinical situations. This will help them to provide a smooth transition from preclinical environment to the clinical one. It would also mean an increased confidence level and the efficiency with which the students would deal with their cases.

Study on de novo collagen biosynthesis and degradation markers of bone

International Nuclear Information System (INIS)

Hanna, L.S.; Matta, T.F.; Ibrahim, I.; Meky, N.H.

2003-01-01

This investigation was carried out to study the performance of de novo biochemical markers of serum pro collagen type-1 amino terminal extension (PINP), as a marker of collagen biosynthesis, and urinary collagen crosslink free deoxypyridinoline (DPD) as a marker of collagen degradation. Moreover, urinary calcium C Ca) and inorganic phosphorus (P), as markers of bone demineralization, in addition to urinary creatinine (Cr), to reflect status of renal function, were also studied in order to assess the activity of bone turnover in osteoporotic (OST), postmenopausal (POST), peri menopausal(PERI), premenopausal (PRE) women and also in young adult (YON) ones. The obtained results showed that urinary creatinine levels were within the normal ranges in all women even in the elderly osteoporotic and postmenopausal women. Serum PINP did not reflect osteoblastic activity. Urinary DPD proved to be a good marker in monitoring the postmenopausal bone resorption and urinary Ca was a reliable marker for bone loss in osteoporosis and bone turnover in the postmenopausal status

Collaborative learning in pre-clinical dental hygiene education.

Science.gov (United States)

Mueller-Joseph, Laura J; Nappo-Dattoma, Luisa

2013-04-01

Dental hygiene education continues to move beyond mastery of content material and skill development to learning concepts that promote critical-thinking and problem-solving skills. The purpose of this research was to evaluate the effectiveness of collaborative learning and determine the growth in intellectual development of 54 first-year dental hygiene students. The control group used traditional pre-clinical teaching and the experimental group used collaborative pedagogy for instrument introduction. All students were subjected to a post-test evaluating their ability to apply the principles of instrumentation. Intellectual development was determined using pre- and post-tests based on the Perry Scheme of Intellectual Development. Student attitudes were assessed using daily Classroom Assessment Activities and an end-of-semester departmental course evaluation. Findings indicated no significant difference between collaborative learning and traditional learning in achieving pre-clinical competence as evidenced by the students' ability to apply the principles of instrumentation. Advancement in intellectual development did not differ significantly between groups. Value added benefits of a collaborative learning environment as identified by the evaluation of student attitudes included decreased student reliance on authority, recognition of peers as legitimate sources of learning and increased self-confidence. A significant difference in student responses to daily classroom assessments was evident on the 5 days a collaborative learning environment was employed. Dental hygiene students involved in a pre-clinical collaborative learning environment are more responsible for their own learning and tend to have a more positive attitude toward the subject matter. Future studies evaluating collaborative learning in clinical dental hygiene education need to investigate the cost/benefit ratio of the value added outcomes of collaborative learning.

Acceleration of vascularized bone tissue-engineered constructs in a large animal model combining intrinsic and extrinsic vascularization.

Science.gov (United States)

Weigand, Annika; Beier, Justus P; Hess, Andreas; Gerber, Thomas; Arkudas, Andreas; Horch, Raymund E; Boos, Anja M

2015-05-01

ingrowth and remodeling processes of the bone substitute. Extrinsic vessels contribute to faster vascularization and finally anastomose with intrinsic vasculature, allowing microvascular transplantation of the bone substitute after a shorter prevascularization time than using the intrinsic method only. It can be reasonably assumed that the usage of perforated chambers can significantly reduce the time until transplantation of bone constructs. Finally, this study paves the way for further preclinical testing for proof of the concept as a basis for early clinical applicability.

Advances in Bone Marrow Stem Cell Therapy for Retinal Dysfunction

Science.gov (United States)

Park, Susanna S.; Moisseiev, Elad; Bauer, Gerhard; Anderson, Johnathon D.; Grant, Maria B.; Zam, Azhar; Zawadzki, Robert J.; Werner, John S.; Nolta, Jan A.

2016-01-01

The most common cause of untreatable vision loss is dysfunction of the retina. Conditions, such as age-related macular degeneration, diabetic retinopathy and glaucoma remain leading causes of untreatable blindness worldwide. Various stem cell approaches are being explored for treatment of retinal regeneration. The rationale for using bone marrow stem cells to treat retinal dysfunction is based on preclinical evidence showing that bone marrow stem cells can rescue degenerating and ischemic retina. These stem cells have primarily paracrine trophic effects although some cells can directly incorporate into damaged tissue. Since the paracrine trophic effects can have regenerative effects on multiple cells in the retina, the use of this cell therapy is not limited to a particular retinal condition. Autologous bone marrow-derived stem cells are being explored in early clinical trials as therapy for various retinal conditions. These bone marrow stem cells include mesenchymal stem cells, mononuclear cells and CD34+ cells. Autologous therapy requires no systemic immunosuppression or donor matching. Intravitreal delivery of CD34+ cells and mononuclear cells appears to be tolerated and is being explored since some of these cells can home into the damaged retina after intravitreal administration. The safety of intravitreal delivery of mesenchymal stem cells has not been well established. This review provides an update of the current evidence in support of the use of bone marrow stem cells as treatment for retinal dysfunction. The potential limitations and complications of using certain forms of bone marrow stem cells as therapy are discussed. Future directions of research include methods to optimize the therapeutic potential of these stem cells, non-cellular alternatives using extracellular vesicles, and in vivo high-resolution retinal imaging to detect cellular changes in the retina following cell therapy. PMID:27784628

Large Bone Vertical Augmentation Using a Three-Dimensional Printed TCP/HA Bone Graft: A Pilot Study in Dog Mandible.

Science.gov (United States)

Carrel, Jean-Pierre; Wiskott, Anselm; Scherrer, Susanne; Durual, Stéphane

2016-12-01

Osteoflux is a three-dimensional printed calcium phosphate porous structure for oral bone augmentation. It is a mechanically stable scaffold with a well-defined interconnectivity and can be readily shaped to conform to the bone bed's morphology. An animal experiment is reported whose aim was to assess the performance and safety of the scaffold in promoting vertical growth of cortical bone in the mandible. Four three-dimensional blocks (10 mm length, 5 mm width, 5 mm height) were affixed to edentulous segments of the dog's mandible and covered by a collagen membrane. During bone bed preparation, particular attention was paid not to create defects 0.5 mm or more so that the real potential of the three-dimensional block in driving vertical bone growth can be assessed. Histomorphometric analyses were performed after 8 weeks. At 8 weeks, the three-dimensional blocks led to substantial vertical bone growth up to 4.5 mm from the bone bed. Between 0 and 1 mm in height, 44% of the surface was filled with new bone, at 1 to 3 mm it was 20% to 35%, 18% at 3 to 4, and ca. 6% beyond 4 mm. New bone was evenly distributed along in mesio-distal direction and formed a new crest contour in harmony with the natural mandibular shape. After two months of healing, the three-dimensional printed blocks conducted new bone growth above its natural bed, up to 4.5 mm in a canine mandibular model. Furthermore, the new bone was evenly distributed in height and density along the block. These results are very promising and need to be further evaluated by a complete powerful study using the same model. © 2016 Wiley Periodicals, Inc.

Stroke Lesions in a Large Upper Limb Rehabilitation Trial Cohort Rarely Match Lesions in Common Preclinical Models

Science.gov (United States)

Edwardson, Matthew A.; Wang, Ximing; Liu, Brent; Ding, Li; Lane, Christianne J.; Park, Caron; Nelsen, Monica A.; Jones, Theresa A; Wolf, Steven L; Winstein, Carolee J; Dromerick, Alexander W.

2017-01-01

Background Stroke patients with mild-moderate upper extremity (UE) motor impairments and minimal sensory and cognitive deficits provide a useful model to study recovery and improve rehabilitation. Laboratory-based investigators use lesioning techniques for similar goals. Objective Determine whether stroke lesions in an UE rehabilitation trial cohort match lesions from the preclinical stroke recovery models used to drive translational research. Methods Clinical neuroimages from 297 participants enrolled in the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) study were reviewed. Images were characterized based on lesion type (ischemic or hemorrhagic), volume, vascular territory, depth (cortical gray matter, cortical white matter, subcortical), old strokes, and leukoaraiosis. Lesions were compared with those of preclinical stroke models commonly used to study upper limb recovery. Results Among the ischemic stroke participants, median infarct volume was 1.8 mL, with most lesions confined to subcortical structures (61%) including the anterior choroidal artery territory (30%) and the pons (23%). Of ICARE participants, stroke patients, but they represent a clinically and scientifically important subgroup. Compared to lesions in general stroke populations and widely-studied animal models of recovery, ICARE participants had smaller, more subcortically-based strokes. Improved preclinical-clinical translational efforts may require better alignment of lesions between preclinical and human stroke recovery models. PMID:28337932

Cryostored autologous skull bone for cranioplasty? A study on cranial bone flaps' viability and microbial contamination after deep-frozen storage at -80°C.

Science.gov (United States)

Chan, David Yuen Chung; Mok, Yi Tan; Lam, Ping Kuen; Tong, Cindy See Wai; Ng, Stephanie Chi Ping; Sun, Tin Fung David; Poon, Wai Sang

2017-08-01

Craniectomy is a life-saving procedure. Subsequent cranioplasty with autologous skull bone has a bone resorption rate from 4% to 22.8% and an infection rate from 3.3% to 26%. There are concerns with their viability and the potential microbial contamination as they were explanted for a long period of time. Eighteen cranial bone flaps stored at Prince of Wales Hospital Skull Bone Bank during the period from June 2011 to March 2016 were identified. Ethics approval was obtained. Bone chips and deep bone swabs were collected for osteoblast culture and microbial culture. Skull Bone Bank was kept at -80°C under strict aseptic technique during the study period. The storage period ranged from 4months to 55months. For the osteoblast culture, all eighteen bone flaps had no viable osteoblast growth. For the bacterial culture, five had positive bacteria growth (27.8%). Three were Pasteurella multocida and two were Methicillin-resistant Staphylococcus aureus. The mean duration of storage of the infected bone flap was 32.9months (±15.1months) versus 19.9months (±17.9months) of those bone flaps with no bacterial growth (p=0.1716). The mean size of the infected versus non-infected bone flaps was 117.7cm 2 (±44.96cm 2 ) versus 76.8cm 2 (±50.24cm 2 ) respectively (p=0.1318). Although in this study statistical significance was not reached, it was postulated that infected bone flaps tended to be larger in size and had a longer duration of storage. In conclusion, cryostored skull bone flaps beyond four months showed no viable osteoblasts. Bacterial contamination rate of bone flaps was 27.8% in this study. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models.

Science.gov (United States)

Portwood, Scott; Lal, Deepika; Hsu, Yung-Chun; Vargas, Rodrigo; Johnson, Megan K; Wetzler, Meir; Hart, Charles P; Wang, Eunice S

2013-12-01

Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm. Recent evidence has shown the bone marrow microenvironment in patients with AML to be intrinsically hypoxic. Adaptive cellular responses by leukemia cells to survive under low oxygenation also confer chemoresistance. We therefore asked whether therapeutic exploitation of marrow hypoxia via the hypoxia-activated nitrogen mustard prodrug, TH-302, could effectively inhibit AML growth. We assessed the effects of hypoxia and TH-302 on human AML cells, primary samples, and systemic xenograft models. We observed that human AML cells and primary AML colonies cultured under chronic hypoxia (1% O2, 72 hours) exhibited reduced sensitivity to cytarabine-induced apoptosis as compared with normoxic controls. TH-302 treatment resulted in dose- and hypoxia-dependent apoptosis and cell death in diverse AML cells. TH-302 preferentially decreased proliferation, reduced HIF-1α expression, induced cell-cycle arrest, and enhanced double-stranded DNA breaks in hypoxic AML cells. Hypoxia-induced reactive oxygen species by AML cells were also diminished. In systemic human AML xenografts (HEL, HL60), TH-302 [50 mg/kg intraperitoneally (i.p.) 5 times per week] inhibited disease progression and prolonged overall survival. TH-302 treatment reduced the number of hypoxic cells within leukemic bone marrows and was not associated with hematologic toxicities in nonleukemic or leukemic mice. Later initiation of TH-302 treatment in advanced AML disease was as effective as earlier TH-302 treatment in xenograft models. Our results establish the preclinical activity of TH-302 in AML and provide the rationale for further clinical studies of this and other hypoxia-activated agents for leukemia therapy. ©2013 AACR.

A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies

Directory of Open Access Journals (Sweden)

Jody E. Hooper

2015-01-01

Full Text Available Embryonal rhabdomyosarcoma (eRMS is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

Anatomical study of the pigs temporal bone by microdissection.

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Garcia, Leandro de Borborema; Andrade, José Santos Cruz de; Testa, José Ricardo Gurgel

2014-01-01

Initial study of the pig`s temporal bone anatomy in order to enable a new experimental model in ear surgery. Dissection of five temporal bones of Sus scrofa pigs obtained from UNIFESP - Surgical Skills Laboratory, removed with hole saw to avoid any injury and stored in formaldehyde 10% for better conservation. The microdissection in all five temporal bone had the following steps: inspection of the outer part, external canal and tympanic membrane microscopy, mastoidectomy, removal of external ear canal and tympanic membrane, inspection of ossicular chain and middle ear. Anatomically it is located at the same position than in humans. Some landmarks usually found in humans are missing. The tympanic membrane of the pig showed to be very similar to the human, separating the external and the middle ear. The middle ear`s appearance is very similar than in humans. The ossicular chain is almost exactly the same, as well as the facial nerve, showing the same relationship with the lateral semicircular canal. The temporal bone of the pigs can be used as an alternative for training in ear surgery, especially due the facility to find it and its similarity with temporal bone of the humans.

Lessons from the Bone Chapter of the Malaysian Aging Men Study

Directory of Open Access Journals (Sweden)

Kok-Yong Chin

2016-05-01

Full Text Available Male osteoporosis in Malaysia is a largely neglected problem. Therefore, a bone health study in men using quantitative ultrasonometry was launched as part of the Malaysian Aging Men Study in 2009–2012. This review aimed to summarize the findings of the aforementioned bone health study. The study examined the bone health of Chinese and Malaysian men aged 20 years and above living in Kuala Lumpur using a quantitative ultrasound device. Participants answered a questionnaire on their demographic details and physical activity status. Body anthropometry of the participants was measured and their blood collected for biochemical analysis. Results showed that a significant proportion of the Malaysian Chinese and Malay men had suboptimal bone health indicated by calcaneal speed of sound and vitamin D status. Age-related decline of the calcaneal speed of sound in these men was gradual and biphasic without ethnic difference. Body anthropometry such as height, weight, body mass index, and body fat percentage contributed to the variation of the calcaneal speed of sound in Malaysian men. Age-related changes in testosterone, insulin-like growth factor 1, and thyroid stimulating hormone also influenced the calcaneal speed of sound in these men. This study serves as a reminder that male osteoporosis in Malaysia should be an issue of concern. It is also a basis for a more comprehensive study on bone health in men in the future.

Lessons from the Bone Chapter of the Malaysian Aging Men Study.

Science.gov (United States)

Chin, Kok-Yong; Wan Ngah, Wan Zurinah; Ima-Nirwana, Soelaiman

2016-05-25

Male osteoporosis in Malaysia is a largely neglected problem. Therefore, a bone health study in men using quantitative ultrasonometry was launched as part of the Malaysian Aging Men Study in 2009-2012. This review aimed to summarize the findings of the aforementioned bone health study. The study examined the bone health of Chinese and Malaysian men aged 20 years and above living in Kuala Lumpur using a quantitative ultrasound device. Participants answered a questionnaire on their demographic details and physical activity status. Body anthropometry of the participants was measured and their blood collected for biochemical analysis. Results showed that a significant proportion of the Malaysian Chinese and Malay men had suboptimal bone health indicated by calcaneal speed of sound and vitamin D status. Age-related decline of the calcaneal speed of sound in these men was gradual and biphasic without ethnic difference. Body anthropometry such as height, weight, body mass index, and body fat percentage contributed to the variation of the calcaneal speed of sound in Malaysian men. Age-related changes in testosterone, insulin-like growth factor 1, and thyroid stimulating hormone also influenced the calcaneal speed of sound in these men. This study serves as a reminder that male osteoporosis in Malaysia should be an issue of concern. It is also a basis for a more comprehensive study on bone health in men in the future.

Experimental aspect of solid-state nuclear magnetic resonance studies of biomaterials such as bones.

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Singh, Chandan; Rai, Ratan Kumar; Sinha, Neeraj

2013-01-01

Solid-state nuclear magnetic resonance (SSNMR) spectroscopy is increasingly becoming a popular technique to probe micro-structural details of biomaterial such as bone with pico-meter resolution. Due to high-resolution structural details probed by SSNMR methods, handling of bone samples and experimental protocol are very crucial aspects of study. We present here first report of the effect of various experimental protocols and handling methods of bone samples on measured SSNMR parameters. Various popular SSNMR experiments were performed on intact cortical bone sample collected from fresh animal, immediately after removal from animal systems, and results were compared with bone samples preserved in different conditions. We find that the best experimental conditions for SSNMR parameters of bones correspond to preservation at -20 °C and in 70% ethanol solution. Various other SSNMR parameters were compared corresponding to different experimental conditions. Our study has helped in finding best experimental protocol for SSNMR studies of bone. This study will be of further help in the application of SSNMR studies on large bone disease related animal model systems for statistically significant results. © 2013 Elsevier Inc. All rights reserved.

Kinetic modeling in pre-clinical positron emission tomography

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Kuntner, Claudia [AIT Austrian Institute of Technology GmbH, Seibersdorf (Austria). Biomedical Systems, Health and Environment Dept.

2014-07-01

Pre-clinical positron emission tomography (PET) has evolved in the last few years from pure visualization of radiotracer uptake and distribution towards quantification of the physiological parameters. For reliable and reproducible quantification the kinetic modeling methods used to obtain relevant parameters of radiotracer tissue interaction are important. Here we present different kinetic modeling techniques with a focus on compartmental models including plasma input models and reference tissue input models. The experimental challenges of deriving the plasma input function in rodents and the effect of anesthesia are discussed. Finally, in vivo application of kinetic modeling in various areas of pre-clinical research is presented and compared to human data.

Marginal Bone Loss after Ten Years in an Adult Danish Population: A Radiographic Study.

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Bahrami, Golnosh; Vaeth, Michael; Wenzel, Ann; Isidor, Flemming

To evaluate marginal bone loss over a 10-year period in individuals and in tooth groups in relation to age and level of marginal bone. In 1997, 616 randomly selected individuals (mean age: 42 years, range: 21-63 years) underwent a full-mouth radiographic survey. In 2008, the survey was repeated in 362 of the same individuals (182 women and 180 men). The marginal bone level of each tooth was measured in mm from the cementoenamel junction to the marginal bone. These measurements were used to calculate marginal bone loss during the 10-year period for individuals and tooth groups in relation to age and to baseline marginal bone level, calculated as the average between measurements in 1997 and 2008 to circumvent regression towards the mean. The average annual marginal bone loss was 0.09 mm (SD ± 0.04 mm) during the 10-year study period. The association between marginal bone loss and baseline marginal bone level was more pronounced in the youngest age group, compared to the other age groups. Molars displayed the most severe bone loss during the study period. Marginal bone loss over a 10-year period is associated with age and baseline marginal bone level. Younger individuals with a reduced marginal bone level were at higher risk for further bone loss. Molars lose marginal bone more rapidly than other tooth groups.

Study and rheological characterization of various bone ash porcelain formulations

International Nuclear Information System (INIS)

Carus, L.A.; Bento, L.; Braganca, S.R.

2012-01-01

The bone ash porcelain is a widely accepted product on the market because their qualities such as high strength and whiteness, to differ from common table porcelains. Its traditional formulation comes from an English recipe, consisting of 25% of kaolin, 25% of feldspar and 50% of bovine bone ash. In some studies, this proportion is adapted to regional conditions, optimizing the formulation according to the raw materials available. In this study, the rheological behavior of bone porcelain suspensions, in which the flux feldspar is partially substituted by an alternative flux (espudomenio, wollastonite and glass). The results show that the rheological behavior of porcelain is affected by the size, shape, surface area and particle size distribution of particles in suspension

Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease.

Science.gov (United States)

Gomar, Jesus J; Conejero-Goldberg, Concepcion; Davies, Peter; Goldberg, Terry E

2016-01-01

The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood. To examine dynamic interrelationships between Aβ42 and tau in preclinical AD. We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18). In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.

A modified PMMA cement (Sub-cement) for accelerated fatigue testing of cemented implant constructs using cadaveric bone.

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Race, Amos; Miller, Mark A; Mann, Kenneth A

2008-10-20

Pre-clinical screening of cemented implant systems could be improved by modeling the longer-term response of the implant/cement/bone construct to cyclic loading. We formulated bone cement with degraded fatigue fracture properties (Sub-cement) such that long-term fatigue could be simulated in short-term cadaver tests. Sub-cement was made by adding a chain-transfer agent to standard polymethylmethacrylate (PMMA) cement. This reduced the molecular weight of the inter-bead matrix without changing reaction-rate or handling characteristics. Static mechanical properties were approximately equivalent to normal cement. Over a physiologically reasonable range of stress-intensity factor, fatigue crack propagation rates for Sub-cement were higher by a factor of 25+/-19. When tested in a simplified 2 1/2-D physical model of a stem-cement-bone system, crack growth from the stem was accelerated by a factor of 100. Sub-cement accelerated both crack initiation and growth rate. Sub-cement is now being evaluated in full stem/cement/femur models.

A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies : important issues and lessons relevant to the design of future clinical research

NARCIS (Netherlands)

Disma, Nicola; Mondardini, Maria C.; Terrando, Niccolo; Absalom, Anthony R.; Bilotta, Federico

Preclinical evidence suggests that anesthetic agents harm the developing brain thereby causing long-term neurocognitive impairments. It is not clear if these findings apply to humans, and retrospective epidemiological studies thus far have failed to show definitive evidence that anesthetic agents

Early bedside care during preclinical medical education: can technology-enhanced patient simulation advance the Flexnerian ideal?

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Gordon, James A; Hayden, Emily M; Ahmed, Rami A; Pawlowski, John B; Khoury, Kimberly N; Oriol, Nancy E

2010-02-01

Flexner wanted medical students to study at the patient bedside-a remarkable innovation in his time-so that they could apply science to clinical care under the watchful eye of senior physicians. Ever since his report, medical schools have reserved the latter years of their curricula for such an "advanced" apprenticeship, providing clinical clerkship experiences only after an initial period of instruction in basic medical sciences. Although Flexner codified the segregation of preclinical and clinical instruction, he was committed to ensuring that both domains were integrated into a modern medical education. The aspiration to fully integrate preclinical and clinical instruction continues to drive medical education reform even to this day. In this article, the authors revisit the original justification for sequential preclinical-clinical instruction and argue that modern, technology-enhanced patient simulation platforms are uniquely powerful for fostering simultaneous integration of preclinical-clinical content in a way that Flexner would have applauded. To date, medical educators tend to focus on using technology-enhanced medical simulation in clinical and postgraduate medical education; few have devoted significant attention to using immersive clinical simulation among preclinical students. The authors present an argument for the use of dynamic robot-mannequins in teaching basic medical science, and describe their experience with simulator-based preclinical instruction at Harvard Medical School. They discuss common misconceptions and barriers to the approach, describe their curricular responses to the technique, and articulate a unifying theory of cognitive and emotional learning that broadens the view of what is possible, feasible, and desirable with simulator-based medical education.

Comparative study on skull CT scan and bone scintigraphy in chronic hemodialysed patients

International Nuclear Information System (INIS)

Ochi, Hironobu; Inoue, Yuichi; Fukuda, Teruo; Shibakiri, Ippei; Tsuda, Kazuyoshi

1981-01-01

A comparative study of computed tomography (XCT) scan utilizing EMI head unit and radionuclide bone scan was performed in 17 patients with chronic renal failure on maintenance hemodialysis. Bone scintigram was positive in 7 out of 17 patients. EMI number of the skull in the positive bone scintigram group was significantly lower than that of the negative bone scintigram. Radionuclide bone scan is the most useful method to detect early bone change and XCT scan will determine the grade of the bone mineral contents. XCT is especially useful to follow patients under the medical treatment (active vitamine D 3 therapy) in order to know the therapeutic effect. (author)

Experimental design and reporting standards for improving the internal validity of pre-clinical studies in the field of pain: Consensus of the IMI-Europain consortium

DEFF Research Database (Denmark)

Knopp, K.L.; Stenfors, C.; Baastrup, Cathrine Søndergaard

2015-01-01

that recommendations on how to improve these factors are warranted. Methods Members of Europain, a pain research consortium funded by the European Innovative Medicines Initiative (IMI), developed internal recommendations on how to improve the reliability of pre-clinical studies between laboratories. This guidance...... and conduct, and data analysis and interpretation. Key principles such as sample size calculation, a priori definition of a primary efficacy measure, randomization, allocation concealments, and blinding are discussed. In addition, considerations of how stress and normal rodent physiology impact outcome...... development in order to estimate possible publication bias is discussed. Conclusions More systematic research is needed to analyze how inadequate internal validity and/or experimental bias may impact reproducibility across pre-clinical pain studies. Addressing the potential threats to internal validity...

Frequency of bone-bruises in ankle sprains. Magnetic resonance imaging studies

International Nuclear Information System (INIS)

Uto, Yuji; Morooka, Masaaki

2002-01-01

We retrospectively studied MRI on the frequency of bone-bruises in ankle sprains, especially those of the lateral collateral ligaments of the ankle joint. Bone-bruises occurred in 3.8% (4/106) of ruptures of anterior talofibular ligament (ATFL), and 6.3% (5/79) of ruptures of ATFL and calcaneofibular ligament (CFL). Bone-bruises were more likely to be seen in ATFL and CFL ruptures than in ATFL rupture alone. (author)

Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model.

Science.gov (United States)

Perosky, Joseph E; Khoury, Basma M; Jenks, Terese N; Ward, Ferrous S; Cortright, Kai; Meyer, Bethany; Barton, David K; Sinder, Benjamin P; Marini, Joan C; Caird, Michelle S; Kozloff, Kenneth M

2016-12-01

Sclerostin antibody has demonstrated a bone-forming effect in pre-clinical models of osteogenesis imperfecta, where mutations in collagen or collagen-associated proteins often result in high bone fragility in pediatric patients. Cessation studies in osteoporotic patients have demonstrated that sclerostin antibody, like intermittent PTH treatment, requires sequential anti-resorptive therapy to preserve the anabolic effects in adult populations. However, the persistence of anabolic gains from either drug has not been explored clinically in OI, or in any animal model. To determine whether cessation of sclerostin antibody therapy in a growing OI skeleton requires sequential anti-resorptive treatment to preserve anabolic gains in bone mass, we treated 3week old Brtl/+ and wild type mice for 5weeks with SclAb, and then withdrew treatment for an additional 6weeks. Trabecular bone loss was evident following cessation, but was preserved in a dose-dependent manner with single administration of pamidronate at the time of cessation. In vivo longitudinal near-infrared optical imaging of cathepsin K activation in the proximal tibia suggests an anti-resorptive effect of both SclAb and pamidronate which is reversed after three weeks of cessation. Cortical bone was considerably less susceptible to cessation effects, and showed no structural or functional deficits in the absence of pamidronate during this cessation period. In conclusion, while SclAb induces a considerable anabolic gain in the rapidly growing Brtl/+ murine model of OI, a single sequential dose of antiresorptive drug is required to maintain bone mass at trabecular sites for 6weeks following cessation. Copyright © 2016 Elsevier Inc. All rights reserved.

Continuous decompression of unicameral bone cyst with cannulated screws: a comparative study.

Science.gov (United States)

Brecelj, Janez; Suhodolcan, Lovro

2007-09-01

We determined the role of mechanical decompression in the resolution of unicameral bone cyst. A total of 69 children with unicameral bone cysts were treated either by (i) open curettage and bone grafting, (ii) steroid injection or (iii) cannulated screw insertion. During a mean follow-up of 69 months (range, 12-58), the cysts were evaluated by radiological criteria. The healing rates in the three groups were 25, 12 and 29% after the first treatment, and a further 50, 19 and 65% after the second. The study has demonstrated the advantages of the decompression technique for unicameral bone cysts over other treatment modalities studied.

A crowdsourcing model for creating preclinical medical education study tools.

Science.gov (United States)

Bow, Hansen C; Dattilo, Jonathan R; Jonas, Andrea M; Lehmann, Christoph U

2013-06-01

During their preclinical course work, medical students must memorize and recall substantial amounts of information. Recent trends in medical education emphasize collaboration through team-based learning. In the technology world, the trend toward collaboration has been characterized by the crowdsourcing movement. In 2011, the authors developed an innovative approach to team-based learning that combined students' use of flashcards to master large volumes of content with a crowdsourcing model, using a simple informatics system to enable those students to share in the effort of generating concise, high-yield study materials. The authors used Google Drive and developed a simple Java software program that enabled students to simultaneously access and edit sets of questions and answers in the form of flashcards. Through this crowdsourcing model, medical students in the class of 2014 at the Johns Hopkins University School of Medicine created a database of over 16,000 questions that corresponded to the Genes to Society basic science curriculum. An analysis of exam scores revealed that students in the class of 2014 outperformed those in the class of 2013, who did not have access to the flashcard system, and a survey of students demonstrated that users were generally satisfied with the system and found it a valuable study tool. In this article, the authors describe the development and implementation of their crowdsourcing model for creating study materials, emphasize its simplicity and user-friendliness, describe its impact on students' exam performance, and discuss how students in any educational discipline could implement a similar model of collaborative learning.

Advances in imaging: impact on studying craniofacial bone structure.

Science.gov (United States)

Majumdar, S

2003-01-01

Methods for measuring the structure of craniofacial bones are discussed in this paper. In addition to the three-dimensional macro-structure of the craniofacial skeleton, there is considerable interest in imaging the bone at a microscopic resolution in order to depict the micro-architecture of the trabecular bone itself. In addition to the density of the bone, the microarchitecture reflects bone quality. An understanding of bone quality and density changes has implications for a number of craniofacial pathologies, as well as for implant design and understanding the biomechanical function and loading of the jaw. Trabecular bone micro-architecture has been recently imaged using imaging methods such as micro-computed tomography, magnetic resonance imaging, and the images have been used in finite element models to assess bone mechanical properties. In this paper, some of the recent advances in micro-computed tomography and magnetic resonance imaging are reviewed, and their potential for imaging the trabecular bone in mandibular bones is presented. Examples of in vitro and in vivo images are presented.

Longitudinal trends and subgroup analysis in publication patterns for preclinical data of newly approved drugs.

Science.gov (United States)

Köster, Ursula; Nolte, Ingo; Michel, Martin C

2016-02-01

Having observed a large variation in the number and type of original preclinical publications for newly registered drugs, we have explored whether longitudinal trends and/or factors specific for certain drugs or their manufacturers may explain such variation. Our analysis is based on 1954 articles related to 170 newly approved drugs. The number of preclinical publications per compound declined from a median of 10.5 in 1991 to 3 in 2011. A similar trend was observed for the number of in vivo studies in general, but not in the subset of in vivo studies in animal models of disease. The percentage of compounds with studies using isolated human cells or cell lines almost doubled over time from 37 to 72%. Number of publications did not exhibit major differences between compounds intended for human versus veterinary use, therapeutic areas, small molecules versus biologicals, or innovator versus follow-up compounds; however, some companies may publish fewer studies per compound than others. However, there were qualitative differences in the types of models being used depending on the therapeutic area; specifically, compounds for use in oncology very often used isolated cells and cell lines, often from human origin. We conclude that the large variation in number and type of reported preclinical data is not easily explained. We propose that pharmaceutical companies should consistently provide a comprehensive documentation of the preclinical data they generate as part of their development programs in the public domain to enable a better understanding of the drugs they intend to market.

A study of changes in bone metabolism in cases of gender identity disorder.

Science.gov (United States)

Miyajima, Tsuyoshi; Kim, Yoon Taek; Oda, Hiromi

2012-07-01

The aim of this study was to determine the effect of increasing estrogen and decreasing androgen in males and increasing androgen and decreasing estrogen in females on bone metabolism in patients with gender identity disorder (GID). We measured and examined bone mineral density (BMD) and bone metabolism markers retrospectively in GID patients who were treated in our hospital. In addition, we studied the effects of treatment on those who had osteoporosis. Patients who underwent a change from male to female (MtF) showed inhibition of bone resorption and increased L2-4 BMD whereas those who underwent a change from female to male (FtM) had increased bone resorption and decreased L2-4 BMD. Six months after administration of risedronate to FtM patients with osteoporosis, L2-4 BMD increased and bone resorption markers decreased. These results indicate that estrogen is an important element with regard to bone metabolism in males.

Recombinant human bone morphogenetic protein induces bone formation

International Nuclear Information System (INIS)

Wang, E.A.; Rosen, V.; D'Alessandro, J.S.; Bauduy, M.; Cordes, P.; Harada, T.; Israel, D.I.; Hewick, R.M.; Kerns, K.M.; LaPan, P.; Luxenberg, D.P.; McQuaid, D.; Moutsatsos, I.K.; Nove, J.; Wozney, J.M.

1990-01-01

The authors have purified and characterized active recombinant human bone morphogenetic protein (BMP) 2A. Implantation of the recombinant protein in rats showed that a single BMP can induce bone formation in vivo. A dose-response and time-course study using the rat ectopic bone formation assay revealed that implantation of 0.5-115 μg of partially purified recombinant human BMP-2A resulted in cartilage by day 7 and bone formation by day 14. The time at which bone formation occurred was dependent on the amount of BMP-2A implanted; at high doses bone formation could be observed at 5 days. The cartilage- and bone-inductive activity of the recombinant BMP-2A is histologically indistinguishable from that of bone extracts. Thus, recombinant BMP-2A has therapeutic potential to promote de novo bone formation in humans

Evaluation of Cholinergic Deficiency in Preclinical Alzheimer’s Disease Using Pupillometry

Directory of Open Access Journals (Sweden)

Shaun Frost

2017-01-01

Full Text Available Cortical cholinergic deficiency is prominent in Alzheimer’s disease (AD, and published findings of diminished pupil flash response in AD suggest that this deficiency may extend to the visual cortical areas and anterior eye. Pupillometry is a low-cost, noninvasive technique that may be useful for monitoring cholinergic deficits which generally lead to memory and cognitive disorders. The aim of the study was to evaluate pupillometry for early detection of AD by comparing the pupil flash response (PFR in AD (N=14 and cognitively normal healthy control (HC, N=115 participants, with the HC group stratified according to high (N=38 and low (N=77 neocortical amyloid burden (NAB. Constriction phase PFR parameters were significantly reduced in AD compared to HC (maximum acceleration p<0.05, maximum velocity p<0.0005, average velocity p<0.005, and constriction amplitude p<0.00005. The high-NAB HC subgroup had reduced PFR response cross-sectionally, and also a greater decline longitudinally, compared to the low-NAB subgroup, suggesting changes to pupil response in preclinical AD. The results suggest that PFR changes may occur in the preclinical phase of AD. Hence, pupillometry has a potential as an adjunct for noninvasive, cost-effective screening for preclinical AD.

Monochromatic minibeam radiotherapy: theoretical and experimental dosimetry for preclinical treatment plans

Energy Technology Data Exchange (ETDEWEB)

Deman, P; Vautrin, M; Stupar, V; Barbier, E L; Elleaume, H; Esteve, F; Adam, J F, E-mail: adam@esrf.fr [INSERM, U836, BP 170, Grenoble Cedex 9, F-38042 (France)

2011-07-21

Monochromatic x-ray minibeam radiotherapy is a new radiosurgery approach based on arrays of submillimetric interlaced planar x-ray beams. The aim of this study was to characterize the dose distributions obtained with this new modality when being used for preclinical trials. Monte Carlo simulations were performed in water phantoms. Percentage depth-dose curves and dose profiles were computed for single incidences and interleaved incidences of 80 keV planar x-ray minibeam (0.6 x 5 mm) arrays. Peak to valley dose ratios were also computed at various depths for an increasing number of minibeams. 3D experimental polymer gel (nPAG) dosimetry measurements were performed using MRI devices designed for small animal imaging. These very high spatial resolution (50 {mu}m) dose maps were compared to the simulations. Preclinical minibeams dose distributions were fully characterized. Experimental dosimetry correlated well with Monte Carlo calculations (Student t-tests: p > 0.1). F98 tumor-bearing rats were also irradiated with interleaved minibeams (80 keV, prescribed dose: 25 Gy). This associated preclinical trial serves as a proof of principle of the technique. The mean survival time of irradiated glioma-bearing rats increased significantly, when compared to the untreated animals (59.6 {+-} 2.8 days versus 28.25 {+-} 0.75 days, p < 0.001).

Value of bone scintigraphy for pre-, postoperative assessment and follow-up study of breast cancer

International Nuclear Information System (INIS)

Lee, Hae Giu; Park, Jeong Mi; Chung, Soo Kyo; Kim, Choon Yul; Bahk, Yong Whee

1985-01-01

Early detection of neoplastic disease and metastatic spread is very important. Carcinoma of the breast is known to readily metastasize to the bone. The use of Tc-99m-phosphate as bone imaging agent has been shown to demonstrate early evidence of bone metastasis well before radiographic evidence is visualized and as thus become a very useful technique for establishing and monitoring the bony metastatic element of breast cancer. In this study, serial bone imaging studies were performed to monitor the management of 84 breast cancer patients before and after mastectomy and biopsy. We attempted to analyse bone scans of breast cancer and to correlate the scan findings with the clinical stage, status of lymph nodes, distant metastasis, bone pain, and laboratory data. The following useful patterns were emerged: 1. Positive bone scan rate was definitely higher in clinical stage III and IV (42, 57%) than in stage I and II (4, 18%) in initial studies. However, no correlation between positive bone scan rate and clinical stage was found in follow up studies. 2. Positive bone scan rate was high in both groups with locally advanced tumor (T3 and T4) and distant metastasis. 3. No correlation between positive bone scan and status of lymph node involvement was noted. 4. Positive bone scan rate was also very high in patients with bone pain and abnormal laboratory data

Studies of coherent/Compton scattering method for bone mineral content measurement

International Nuclear Information System (INIS)

Sakurai, Kiyoko; Iwanami, Shigeru; Nakazawa, Keiji; Matsubayashi, Takashi; Imamura, Keiko.

1980-01-01

A measurement of bone mineral content by a coherent/Compton scattering method was described. A bone sample was irradiated by a collimated narrow beam of 59.6 keV gamma-rays emitted from a 300 mCi 241 Am source, and the scattered radiations were detected using a collimated pure germanium detector placed at 90 0 to the incident beam. The ratio of coherent to Compton peaks in a spectrum of the scattered radiations depends on the bone mineral content of the bone sample. The advantage of this method is that bone mineral content of a small region in a bone can be accurately measured. Assuming that bone consists of two components, protein and bone mineral, and that the mass absorption coefficient for Compton scattering is independent of material, the coherent to Compton scattering ratio is linearly related to the percentage in weight of bone mineral. A calibration curve was obtained by measuring standard samples which were mixed with Ca 3 (PO 4 ) 2 and H 2 O. The error due to the assumption about the mass absorption coefficient for Compton scattering and to the difference between true bone and standard samples was estimated to be less than 3% within the range from 10 to 60% in weight of bone mineral. The fat in bone affects an estimated value by only 1.5% when it is 20% in weight. For the clinical application of this method, the location to be analyzed should be selected before the measurement with two X-ray images viewed from the source and the detector. These views would be also used to correct the difference in absorption between coherent and Compton scattered radiations whose energies are slightly different from each other. The absorbed dose to the analyzed region was approximately 150 mrad. The time required for one measurement in this study was about 10 minutes. (author)

Development of computational small animal models and their applications in preclinical imaging and therapy research.

Science.gov (United States)

Xie, Tianwu; Zaidi, Habib

2016-01-01

The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future.

Development of computational small animal models and their applications in preclinical imaging and therapy research

Energy Technology Data Exchange (ETDEWEB)

Xie, Tianwu [Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospital, Geneva 4 CH-1211 (Switzerland); Zaidi, Habib, E-mail: habib.zaidi@hcuge.ch [Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospital, Geneva 4 CH-1211 (Switzerland); Geneva Neuroscience Center, Geneva University, Geneva CH-1205 (Switzerland); Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen 9700 RB (Netherlands)

2016-01-15

The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future.

Development of computational small animal models and their applications in preclinical imaging and therapy research

International Nuclear Information System (INIS)

Xie, Tianwu; Zaidi, Habib

2016-01-01

The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future

3D artificial bones for bone repair prepared by computed tomography-guided fused deposition modeling for bone repair.

Science.gov (United States)

Xu, Ning; Ye, Xiaojian; Wei, Daixu; Zhong, Jian; Chen, Yuyun; Xu, Guohua; He, Dannong

2014-09-10

The medical community has expressed significant interest in the development of new types of artificial bones that mimic natural bones. In this study, computed tomography (CT)-guided fused deposition modeling (FDM) was employed to fabricate polycaprolactone (PCL)/hydroxyapatite (HA) and PCL 3D artificial bones to mimic natural goat femurs. The in vitro mechanical properties, in vitro cell biocompatibility, and in vivo performance of the artificial bones in a long load-bearing goat femur bone segmental defect model were studied. All of the results indicate that CT-guided FDM is a simple, convenient, relatively low-cost method that is suitable for fabricating natural bonelike artificial bones. Moreover, PCL/HA 3D artificial bones prepared by CT-guided FDM have more close mechanics to natural bone, good in vitro cell biocompatibility, biodegradation ability, and appropriate in vivo new bone formation ability. Therefore, PCL/HA 3D artificial bones could be potentially be of use in the treatment of patients with clinical bone defects.

The preclinical discovery and development of quetiapine for the treatment of mania and depression.

Science.gov (United States)

Miranda, Aline Silva de; Moreira, Fabrício A; Teixeira, Antônio Lúcio

2017-05-01

Bipolar disorder is a chronic disabling condition characterized by alternating manic and depressive episodes. Bipolar disorder has been associated with functional impairment, poor quality of life, morbidity and mortality. Despite its significant clinical, social and economic burden, treatment options for bipolar disorder are still limited. Several clinical trials have shown efficacy of the atypical antipsychotic quetiapine (QTP) in the treatment of this condition. However, the mechanisms underlying the antidepressant and anti-manic effects of QTP remain poorly understood. Areas covered: The article provides the emerging evidence from pre-clinical studies regarding the antidepressant and anti-manic mechanisms of action of QTP. In combination with its primary active metabolite norquetiapine, QTP modulates several neurotransmitter systems, including serotonin, dopamine, noradrenaline and histamine. QTP also seems to influence mediators of the immune system. Expert opinion: Pre-clinical studies have provided valuable information on the potential antidepressant mechanisms of action of QTP, but pre-clinical studies on QTP's anti-manic effects are still scarce. A major problem refers to the lack of valid experimental models for bipolar disorder. Additionally, immune and genetic based studies are largely descriptive. The role of the QTP metabolite norquetiapine in modulating non-neurotransmitter systems also needs to be further addressed.

Experimental study of the effects of radiation on growing bone by bone scintigraphy

Energy Technology Data Exchange (ETDEWEB)

Ohtake, Hisashi; Sakai, Yasuhiko; Morita, Seiichiro; Bussaka, Yoshitaka; Kikuchi, Shigeru; Okinaga, Toshichika; Oshibuchi, Masao; Umezaki, Noriyoshi

1987-02-01

Bones of immature rabbits were irradiated during the growth period, and followed with bone scintigraphy using Tc-99m methylene diphosphonate. The accumulation of the radionuclide was decreased in the irradiated bone at an early period as compared to the control side, and the decrease was more pronounced as the dose of irradiation was increased. In the groups irradiated with less than 4,000 rad, the accumulation ratio reached a minimum at 5 weeks and was followed by a gradual recovery. In the group irradiated with 6,000 rad, the recovery was small; and no recovery was observed in the 8,000 rad group. These changes were compared to the inhibition of the longitudinal growth of the bone. The accumulation ratio for the radionuclide was a more sensitive index of the effect of radiation than the growth rate.

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

Science.gov (United States)

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

Study of irradiated bone: Part III. /sup 99m/Tc pyrophosphate autoradiographic changes

International Nuclear Information System (INIS)

King, M.A.; Corriveau, O.; Casarett, G.W.; Weber, D.A.

1978-01-01

The macroautoradiographic and microautoradiographic localization of /sup 99m/Tc-pyrophosphate (/sup 99m/TcPPi) was studied in x-irradiated bone of rabbits up to one year post-irradiation. In cortical bone, /sup 99m/TcPPi was concentrated on bone surfaces near vasculature. Both forming and resorbing bone surfaces were comparably labeled at 2 hrs post-injection. Uptake on the surface of sites of haversian bone remodeling was observed to be at least part of the increased /sup 99m/TcPPi observed in irradiated bone in camera images. In irradiated trabecular bone 12 months following irradiation, a patchy decrease in /sup 99m/TcPPi uptake was correlated with localized decreases in vasculature

Graphene oxide scaffold accelerates cellular proliferative response and alveolar bone healing of tooth extraction socket.

Science.gov (United States)

Nishida, Erika; Miyaji, Hirofumi; Kato, Akihito; Takita, Hiroko; Iwanaga, Toshihiko; Momose, Takehito; Ogawa, Kosuke; Murakami, Shusuke; Sugaya, Tsutomu; Kawanami, Masamitsu

2016-01-01

Graphene oxide (GO) consisting of a carbon monolayer has been widely investigated for tissue engineering platforms because of its unique properties. For this study, we fabricated a GO-applied scaffold and assessed the cellular and tissue behaviors in the scaffold. A preclinical test was conducted to ascertain whether the GO scaffold promoted bone induction in dog tooth extraction sockets. For this study, GO scaffolds were prepared by coating the surface of a collagen sponge scaffold with 0.1 and 1 µg/mL GO dispersion. Scaffolds were characterized using scanning electron microscopy (SEM), physical testing, cell seeding, and rat subcutaneous implant testing. Then a GO scaffold was implanted into a dog tooth extraction socket. Histological observations were made at 2 weeks postsurgery. SEM observations show that GO attached to the surface of collagen scaffold struts. The GO scaffold exhibited an interconnected structure resembling that of control subjects. GO application improved the physical strength, enzyme resistance, and adsorption of calcium and proteins. Cytocompatibility tests showed that GO application significantly increased osteoblastic MC3T3-E1 cell proliferation. In addition, an assessment of rat subcutaneous tissue response revealed that implantation of 1 µg/mL GO scaffold stimulated cellular ingrowth behavior, suggesting that the GO scaffold exhibited good biocompatibility. The tissue ingrowth area and DNA contents of 1 µg/mL GO scaffold were, respectively, approximately 2.5-fold and 1.4-fold greater than those of the control. Particularly, the infiltration of ED2-positive (M2) macrophages and blood vessels were prominent in the GO scaffold. Dog bone-formation tests showed that 1 µg/mL GO scaffold implantation enhanced bone formation. New bone formation following GO scaffold implantation was enhanced fivefold compared to that in control subjects. These results suggest that GO was biocompatible and had high bone-formation capability for the scaffold

Effects of LED phototherapy on bone defects grafted with MTA, bone morphogenetic proteins and guided bone regeneration: a Raman spectroscopic study.

Science.gov (United States)

Pinheiro, Antonio L B; Soares, Luiz G P; Cangussú, Maria Cristina T; Santos, Nicole R S; Barbosa, Artur Felipe S; Silveira Júnior, Landulfo

2012-09-01

We studied peaks of calcium hydroxyapatite (CHA) and protein and lipid CH groups in defects grafted with mineral trioxide aggregate (MTA) treated or not with LED irradiation, bone morphogenetic proteins and guided bone regeneration. A total of 90 rats were divided into ten groups each of which was subdivided into three subgroups (evaluated at 15, 21 and 30 days after surgery). Defects were irradiated with LED light (wavelength 850 ± 10 nm) at 48-h intervals for 15 days. Raman readings were taken at the surface of the defects. There were no statistically significant differences in the CHA peaks among the nonirradiated defects at any of the experimental time-points. On the other hand, there were significant differences between the defects filled with blood clot and the irradiated defects at all time-points (p Raman spectral analysis indicate that infrared LED light irradiation improves the deposition of CHA in healing bone grafted or not with MTA.

Effects of low-intensity pulsed ultrasound on new trabecular bone during bone-tendon junction healing in a rabbit model: a synchrotron radiation micro-CT study.

Directory of Open Access Journals (Sweden)

Hongbin Lu

Full Text Available This study was designed to evaluate the effects of low-intensity pulsed ultrasound on bone regeneration during the bone-tendon junction healing process and to explore the application of synchrotron radiation micro computed tomography in three dimensional visualization of the bone-tendon junction to evaluate the microarchitecture of new trabecular bone. Twenty four mature New Zealand rabbits underwent partial patellectomy to establish a bone-tendon junction injury model at the patella-patellar tendon complex. Animals were then divided into low-intensity pulsed ultrasound treatment (20 min/day, 7 times/week and placebo control groups, and were euthanized at week 8 and 16 postoperatively (n = 6 for each group and time point. The patella-patellar tendon specimens were harvested for radiographic, histological and synchrotron radiation micro computed tomography detection. The area of the newly formed bone in the ultrasound group was significantly greater than that of control group at postoperative week 8 and 16. The high resolution three dimensional visualization images of the bone-tendon junction were acquired by synchrotron radiation micro computed tomography. Low-intensity pulsed ultrasound treatment promoted dense and irregular woven bone formation at week 8 with greater bone volume fraction, number and thickness of new trabecular bone but with lower separation. At week 16, ultrasound group specimens contained mature lamellar bone with higher bone volume fraction and thicker trabeculae than that of control group; however, there was no significant difference in separation and number of the new trabecular bone. This study confirms that low-intensity pulsed ultrasound treatment is able to promote bone formation and remodeling of new trabecular bone during the bone-tendon junction healing process in a rabbit model, and the synchrotron radiation micro computed tomography could be applied for three dimensional visualization to quantitatively evaluate

Behavioral, medical imaging and histopathological features of a new rat model of bone cancer pain.

Directory of Open Access Journals (Sweden)

Louis Doré-Savard

2010-10-01

Full Text Available Pre-clinical bone cancer pain models mimicking the human condition are required to respond to clinical realities. Breast or prostate cancer patients coping with bone metastases experience intractable pain, which affects their quality of life. Advanced monitoring is thus required to clarify bone cancer pain mechanisms and refine treatments. In our model of rat femoral mammary carcinoma MRMT-1 cell implantation, pain onset and tumor growth were monitored for 21 days. The surgical procedure performed without arthrotomy allowed recording of incidental pain in free-moving rats. Along with the gradual development of mechanical allodynia and hyperalgesia, behavioral signs of ambulatory pain were detected at day 14 by using a dynamic weight-bearing apparatus. Osteopenia was revealed from day 14 concomitantly with disorganization of the trabecular architecture (µCT. Bone metastases were visualized as early as day 8 by MRI (T(1-Gd-DTPA before pain detection. PET (Na(18F co-registration revealed intra-osseous activity, as determined by anatomical superimposition over MRI in accordance with osteoclastic hyperactivity (TRAP staining. Pain and bone destruction were aggravated with time. Bone remodeling was accompanied by c-Fos (spinal and ATF3 (DRG neuronal activation, sustained by astrocyte (GFAP and microglia (Iba1 reactivity in lumbar spinal cord. Our animal model demonstrates the importance of simultaneously recording pain and tumor progression and will allow us to better characterize therapeutic strategies in the future.

Study of the reaction of uranium and plutonium with bone char

International Nuclear Information System (INIS)

Silver, G.L.; Koenst, J.W.

1977-01-01

A study of the reaction of plutonium with a commercial bone char indicates that this bone char has a high capacity for removing plutonium from aqueous wastes. The adsorption of plutonium by bone char is pH dependent, and for plutonium(IV) polymer appears to be maximized near pH 7.3 for plutonium concentrations typical of some waste streams. Adsorption is affected by dissolved salts, especially calcium and phosphate salts. Freundlich isotherms representing the adsorption of uranium and plutonium have been prepared. The low potential imposed upon aqueous solutions by commercial bone char is adequate for reduction of hexavalent plutonium to a lower plutonium oxidation state

Atomoxetine for hoarding disorder: A pre-clinical and clinical investigation.

Science.gov (United States)

Grassi, Giacomo; Micheli, Laura; Di Cesare Mannelli, Lorenzo; Compagno, Elisa; Righi, Lorenzo; Ghelardini, Carla; Pallanti, Stefano

2016-12-01

Despite several studies suggested that inattention and impulsivity-compulsivity could represent two core dimensions of hoarding disorder (HD), only a small case series study investigated the effectiveness of attention-deficit-hyperactivity-disorder (ADHD) medications in HD. The aim of the present study was to target attentional and inhibitory control networks in HD patients through the ADHD medication atomoxetine, moving from a preclinical investigation on an animal model of compulsive-like behavior (marble burying test) to a clinical investigation on both medicated and unmedicated patients with a primary diagnosis of HD without ADHD. Our preclinical investigation showed that acute administration of atomoxetine significantly reduced the compulsive-like behaviours of mice in the marble burying test without affecting neither locomotor activity and coordination nor exploration behaviours. When compared, atomoxetine and fluoxetine showed similar effects on the marble burying test. However, fluoxetine impaired both locomotor and exploratory activity. In our clinical investigation 12 patients were enrolled and 11 patients completed an open trial with atomoxetine at flexible dose (40-80 mg) for 12 weeks. At the endpoint the mean UCLA Hoarding Severity Scale score decreased by 41.3% for the whole group (p = 0003). Six patients were classified as full responders (mean symptom reduction of 57.2%) and three patients as partial responders (mean symptom reduction of 27.3%). Inattentive and impulsivity symptoms showed a significant mean score reduction of 18.5% from baseline to the endpoint (F (1,9) = 20.9, p = 0.0013). Hoarding symptoms improvement was correlated to reduction of patients' disability and increased in their global functioning. These preclinical and clinical data suggest that atomoxetine may be effective for HD and therefore should be considered for future controlled trials. Copyright © 2016 Elsevier Ltd. All rights reserved.

Quantitative bone scintigraphy. A study in patients with prostatic carcinoma

International Nuclear Information System (INIS)

Sundkvist, G.

1991-01-01

Quantitative bone scintigraphy was performed in patients with prostatic carcinoma before orchiectomy as well as two weeks, two and six months after operation. The count rate was recorded as serial gamma camera images over the lower thoracic and all lumbar vertebrae from 1 to 240 min and at 24 h after injection of 99T c m -MDP. In almost all abnormal vertebrae an increased count rate was observed within one hour after injection. Most of the vertebrae which were considered normal at 4 h after injection, but had an increased 24h/4h ratio developed into abnormal vertebrae later in the study. The patients with normal bone scintigrams showed no change in 99 Tc m -MDP uptake during the study. The reproducibility of quantitative bone scintigraphy was found to be ± 7% (1 SD). In response to therapy, most of the patients with abnormal bone scintigrams showed an increase in count rate two weeks after operation followed by a decrease to the pre-operative level after two months and a further decrease after six months. This so called 'flare phenomenon' was found to indicate 99 Tc m -MDP in the vascular phase as well as an active bone uptake. In some of the patients the whole-body retention of 99 Tc m -MDP after 24 h and the bone mineral density in the vertebrae were determined and found to be valuable in the interpretation of skeletal metastases and the assessment of response to therapy. (71 refs.)

A radiographic study of alveolar bone loss in Irish schoolchildren

International Nuclear Information System (INIS)

Buckley, L.A.

1982-01-01

Bitewing radiographs were used to assess evidence of alveolar bone loss in 1492 children in the age range 7-12 years. According to the method used in this study, alveolar bone loss was shown to occur in 1.7% of the children, and maxillary teeth were affected twice as frequently as mandibular teeth. (Author)

Bone healing around nanocrystalline hydroxyapatite, deproteinized bovine bone mineral, biphasic calcium phosphate, and autogenous bone in mandibular bone defects

DEFF Research Database (Denmark)

Broggini, Nina; Bosshardt, Dieter D; Jensen, Simon S

2015-01-01

The individual healing profile of a given bone substitute with respect to osteogenic potential and substitution rate must be considered when selecting adjunctive grafting materials for bone regeneration procedures. In this study, standardized mandibular defects in minipigs were filled...... with nanocrystalline hydroxyapatite (HA-SiO), deproteinized bovine bone mineral (DBBM), biphasic calcium phosphate (BCP) with a 60/40% HA/β-TCP (BCP 60/40) ratio, or particulate autogenous bone (A) for histological and histomorphometric analysis. At 2 weeks, percent filler amongst the test groups (DBBM (35.65%), HA......-SiO (34.47%), followed by BCP 60/40 (23.64%)) was significantly higher than the more rapidly substituted autogenous bone (17.1%). Autogenous bone yielded significantly more new bone (21.81%) over all test groups (4.91%-7.74%) and significantly more osteoid (5.53%) than BCP 60/40 (3%) and DBBM (2...

Multicellular tumor spheroid interactions with bone cells and bone

International Nuclear Information System (INIS)

Wezeman, F.H.; Guzzino, K.M.; Waxler, B.

1985-01-01

In vitro coculture techniques were used to study HSDM1C1 murine fibrosarcoma multicellular tumor spheroid (HSDM1C1-MTS) interactions with mouse calvarial bone cells having osteoblastic characteristics and mouse bone explants. HSDM1C1-MTS attached to confluent bone cell monolayers and their attachment rate was quantified. HSDM1C1-MTS interaction with bone cells was further demonstrated by the release of 3 H-deoxyuridine from prelabeled bone cells during coculture with multicellular tumor spheroids. HSDM1C1-MTS-induced cytotoxicity was mimicked by the addition of 10(-5) M prostaglandin E2 (PGE2) to 3 H-deoxyuridine-labeled bone cells. The effects of low (10(-9) M) and high (10(-5) M) concentrations of PGE2 on bone cell proliferation were also studied. Higher concentrations of PGE2 inhibited bone cell proliferation. HSDM1C1-MTS resorbed living explants in the presence of indomethacin, suggesting that other tumor cell products may also participate in bone resorption. HSDM1C1-MTS caused direct bone resorption as measured by the significantly elevated release of 45 Ca from prelabeled, devitalized calvaria. However, the growth of a confluent bone cell layer on devitalized, 45 Ca-prelabeled calvaria resulted in a significant reduction in the amount of 45 Ca released subsequent to the seeding of HSDM1C1-MTS onto the explants. Bone cells at the bone surface may act as a barrier against invasion and tumor cell-mediated bone resorption. Violation of this cellular barrier is achieved, in part, by tumor cell products

SEM corrosion-casts study of the microcirculation of the flat bones in the rat.

Science.gov (United States)

Pannarale, L; Morini, S; D'Ubaldo, E; Gaudio, E; Marinozzi, G

1997-04-01

Little is known about the organization of microcirculation in flat bones in comparison with long bones. This study, therefore, helps us to determine the design of this vascular system in flat bones in relation to their structure and function. The organization of microvasculature in parietal, scapula, and ileum bones of 15 young sexually mature rats, aged 6-7 weeks, was studied by light and scanning electron microscopy (SEM) from vascular corrosion cast (vcc), a resin-cast obtained material. Our observations show that the pattern of the microcirculation in flat bones is different in the thick and thin parts of such bones. Where the bone is thinner than 0.4 mm, only periosteal and dural network exist. Larger vessels which do not form a real network connect the two tables of the bones in these regions. In thicker areas, the organization of the microvasculature is similar to that in long bones, with distinct periosteal, cortical and bone marrow networks. Moreover, in different bones, outer networks show slightly different characteristics according to the different adjacent structures (dura mater, muscles etc.). Different types of vessels were recognized by comparing their different diameter, course and endothelial imprints. The microvascular patterns of the flat bones are strongly influenced by the bone thickness. The different microvascular systems can interact both with the bone modelling and remodeling and with the variable metabolic needs, modifying the microvascular pattern and the blood flow. This is even more important in view of the reciprocal influence of the different networks within the same bone.

Genetic Expression in Cystic Fibrosis Related Bone Disease. An Observational, Transversal, Cross-Sectional Study.

Science.gov (United States)

Ciuca, Ioana M; Pop, Liviu L; Rogobete, Alexandru F; Onet, Dan I; Guta-Almajan, Bogdan; Popa, Zoran; Horhat, Florin G

2016-09-01

Cystic fibrosis (CF) is the most frequent monogenic genetic disease with autosomal recessive transmission and characterized by important clinical polymorphism and significant lethal prospective. CF related bone disease occurs frequently in adults with CF. Childhood is the period of bone formation, and therefore, children are more susceptible to low bone density. Several factors like pancreatic insufficiency, hormone imbalance, and physical inactivity contribute to CF bone disease development. Revealing this would be important for prophylactic treatment against bone disease occurrence. The study was observational, transversal, with a cross-sectional design. The study included 68 children with cystic fibrosis, genotyped and monitored in the National CF Centre. At the annual assessment, besides clinical examination, biochemical evaluation for pancreatic insufficiency, and diabetes, they were evaluated for bone mineral density using dual energy X-ray absorptiometry (DXA). Twenty-six patients, aged over 10 years were diagnosed with CF bone disease, without significant gender gap. Bone disease was frequent in patients aged over 10 years with exocrine pancreatic insufficiency, carriers of severe mutations, and CF liver disease. CF carriers of a severe genotype which associates pancreatic insufficiency and CF liver disease, are more likely predisposed to low bone mineral density. Further studies should discover other significant influences in order to prevent the development of CF bone disease and an improved quality of life in cystic fibrosis children.

Surface structural damage study in cortical bone due to medical drilling.

Science.gov (United States)

Tavera R, Cesar G; De la Torre-I, Manuel H; Flores-M, Jorge M; Hernandez M, Ma Del Socorro; Mendoza-Santoyo, Fernando; Briones-R, Manuel de J; Sanchez-P, Jorge

2017-05-01

A bone's fracture could be produced by an excessive, repetitive, or sudden load. A regular medical practice to heal it is to fix it in two possible ways: external immobilization, using a ferule, or an internal fixation, using a prosthetic device commonly attached to the bone by means of surgical screws. The bone's volume loss due to this drilling modifies its structure either in the presence or absence of a fracture. To observe the bone's surface behavior caused by the drilling effects, a digital holographic interferometer is used to analyze the displacement surface's variations in nonfractured post-mortem porcine femoral bones. Several nondrilled post-mortem bones are compressed and compared to a set of post-mortem bones with a different number of cortical drillings. During each compression test, a series of digital interferometric holograms were recorded using a high-speed CMOS camera. The results are presented as pseudo 3D mesh displacement maps for comparisons in the physiological range of load (30 and 50 lbs) and beyond (100, 200, and 400 lbs). The high resolution of the optical phase gives a better understanding about the bone's microstructural modifications. Finally, a relationship between compression load and bone volume loss due to the drilling was observed. The results prove that digital holographic interferometry is a viable technique to study the conditions that avoid the surgical screw from loosening in medical procedures of this kind.

A New Piezoelectric Actuator Induces Bone Formation In Vivo: A Preliminary Study

Directory of Open Access Journals (Sweden)

Joana Reis

2012-01-01

Full Text Available This in vivo study presents the preliminary results of the use of a novel piezoelectric actuator for orthopedic application. The innovative use of the converse piezoelectric effect to mechanically stimulate bone was achieved with polyvinylidene fluoride actuators implanted in osteotomy cuts in sheep femur and tibia. The biological response around the osteotomies was assessed through histology and histomorphometry in nondecalcified sections and histochemistry and immunohistochemistry in decalcified sections, namely, through Masson's trichrome, and labeling of osteopontin, proliferating cell nuclear antigen, and tartrate-resistant acid phosphatase. After one-month implantation, total bone area and new bone area were significantly higher around actuators when compared to static controls. Bone deposition rate was also significantly higher in the mechanically stimulated areas. In these areas, osteopontin increased expression was observed. The present in vivo study suggests that piezoelectric materials and the converse piezoelectric effect may be used to effectively stimulate bone growth.

Combination of Micro nutrients for Bone (COMB) Study: Bone Density after Micro nutrient Intervention

International Nuclear Information System (INIS)

Genuis, S.J.; Bouchard, Th.P.

2012-01-01

Along with other investigations, patients presenting to an environmental health clinic with various chronic conditions were assessed for bone health status. Individuals with compromised bone strength were educated about skeletal health issues and provided with therapeutic options for potential amelioration of their bone health. Patients who declined pharmacotherapy or who previously experienced failure of drug treatment were offered other options including supplemental micro nutrients identified in the medical literature as sometimes having a positive impact on bone mineral density (BMD). After 12 months of consecutive supplemental micro nutrient therapy with a combination that included vitamin D3, vitamin K2, strontium, magnesium and docosahexaenoic acid (DHA), repeat bone densitometry was performed. The results were analyzed in a group of compliant patients and demonstrate improved BMD in patients classified with normal, osteopenic and osteoporotic bone density. According to the results, this combined micro nutrient supplementation regimen appears to be at least as effective as bis phosphonates or strontium ranelate in raising BMD levels in hip, spine, and femoral neck sites. No fractures occurred in the group taking the micro nutrient protocol. This micro nutrient regimen also appears to show efficacy in individuals where bis phosphonate therapy was previously unsuccessful in maintaining or raising BMD. Prospective clinical trials are required to confirm efficacy

Tendinopathies and platelet-rich plasma (PRP: from pre-clinical experiments to therapeutic use

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Kaux JF

2015-05-01

Full Text Available Objectives: The restorative properties of platelets, through the local release of growth factors, are used in various medical areas. This article reviews fundamental and clinical research relating to platelet-rich plasma applied to tendinous lesions. Materials and method: Articles in French and English, published between 1 January 2012 and 31 December 2014. dealing with PRP and tendons were searched for using the Medline and Scopus data bases. Results: Forty-seven articles were identified which addressed pre-clinical and clinical studies: 27 relating to in vitro and in vivo animal studies and 20 relating to human studies. Of these, five addressed lateral epicondylitis, two addressed rotator cuff tendinopathies, ten dealt with patellar tendinopathies and three looked at Achilles tendinopathies. Conclusions: The majority of pre-clinical studies show that PRP stimulates the tendon's healing process. However, clinical series remain more controversial and level 1, controlled, randomised studies are still needed.

Treatment for unicameral bone cysts in long bones: an evidence based review.

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Donaldson, Sandra; Chundamala, Josie; Yandow, Suzanne; Wright, James G

2010-03-20

The purpose of this paper is to perform an evidence based review for treatment of unicameral bone cysts. A search of MEDLINE (1966 to 2009) was conducted and the studies were classified according to levels of evidence. This review includes only comparative Level I-III studies. The systematic review identified 16 studies. There is one level I study, one level II study and the remaining 14 studies are level III. Seven of the sixteen studies had statistically different results: three studies indicated that steroid injection was superior to bone marrow injection or curettage and bone grafting; one study indicated that cannulated screws were superior to steroid injections; one study indicated resection and myoplasty was superior to steroid injection; one study indicated a combination of steroid, demineralized bone matrix and bone marrow aspirate, and curettage and bone grafting were superior to steroid injection; and one study indicated that curettage and bone grafting was superior to non-operative immobilization. Based on one Level I study, including a limited number of individuals, steroid injection seems to be superior to bone marrow injection. As steroid injections have already demonstrated superiority over bone marrow injections in a randomized clinical trial, the next step would be a prospective trial comparing steroid injections with other treatments.

Treatment for unicameral bone cysts in long bones: an evidence based review

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Sandra E. Donaldson

2010-05-01

Full Text Available The purpose of this paper is to perform an evidence based review for treatment of unicameral bone cysts. A search of MEDLINE (1966 to 2009 was conducted and the studies were classified according to levels of evidence. This review includes only comparative Level I-III studies. The systematic review identified 16 studies. There is one level I study, one level II study and the remaining 14 studies are level III. Seven of the sixteen studies had statistically different results: three studies indicated that steroid injection was superior to bone marrow injection or curettage and bone grafting; one study indicated that cannulated screws were superior to steroid injections; one study indicated resection and myoplasty was superior to steroid injection; one study indicated a combination of steroid, demineralized bone matrix and bone marrow aspirate, and curettage and bone grafting were superior to steroid injection; and one study indicated that curettage and bone grafting was superior to non-operative immobilization. Based on one Level I study, including a limited number of individuals, steroid injection seems to be superior to bone marrow injection. As steroid injections have already demonstrated superiority over bone marrow injections in a randomized clinical trial, the next step would be a prospective trial comparing steroid injections with other treatments.

Correlative study of SPECT bone scan, serum tPSA and fPSA/tPSA ratio and the pathological grade of prostate cancer with bone metastasis

International Nuclear Information System (INIS)

Xu Haiqing; Duan Jun

2011-01-01

Objective: To study the rules and characteristics of SPECT bone scan, serum TPSA, fPSA/tPSA ratio and the pathological grade of prostate cancer with bone metastasis. Methods: Nuclear medicine SPECT bone scan as the gold standard, retrospective analysis of the in vitro radioimmunoassay in 107 patients with prostate cancer serum PSA (prostate specific antigen) levels, serum fPSA/tPSA ratio and whole body bone imaging studies and pathological classification. Results: 107 patients with prostate cancer : 49 patients had bone metastases, accounting for 45.8% (49/107), in which groups of different pathological comparison between the incidence of bone metastasis significantly, the lower the degree of differentiation, the more the incidence of bone metastases high; with elevated levels of tPSA, the incidence of bone metastasis increased significantly; serum tPSA 4 - 40 ng/ml, the use of fPSA/tPSA ratio may improve the diagnostic specificity of prostate cancer. Conclusion: Patients with bone metastases of prostate cancer incidence and degree of differentiation of prostate cancer, serum PSA levels and fPSA/tPSA ratio of a certain relationship. The lower degree of differentiation,the higher the incidence of bone metastasis. (authors)

Radiosteoplasty study in animal bone and radiodosimetric evaluation using Monte Carlo code

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Silveira, Marcia Flavia; Campos, Tarcisio Passos Ribeiro [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Dept. de Engenharia Nuclear]. E-mail: marciaflaviafisio@gmail.com; campos@nuclear.ufmg.br

2007-07-01

The radiosteoplasty is a procedure that consists of the injection of a radioactive biomaterial incorporated to the bone cement into the osseous structure affected by cancer. This technique has been developed with the major objective to control the tumor or the regional bone metastasis (in situ) besides pain reduction and structural resistance increasing. In the present study the radiosteoplasty is applied to the bovine and swine bones in vitro using non-radioactive cement. The objective is to know the spatial distribution of the cold compound (non radioactive) in pig and ox bones after implant. A 2 mm needle was introduced into the cortical bone previously perforated. The distribution of this biomaterial was observed trough radiological images obtained just after the compound application. Recent dosimetric studies using Monte Carlo N-Particle method (MCNP-5) concluded that the spatial dose distribution is suitable for the protocol namely radiosteoplasty applied to treat bone tumors on superior and inferior members. The Monte Carlo method simulates the present process and it is particularly interesting tool to solve the complex photon and electron particle transport problems that can not be modeled by codes based on deterministic methods. These related radiodosimetric studies are presented and discussed. (author)

Receptor tyrosine kinase inhibition causes simultaneous bone loss and excess bone formation within growing bone in rats

International Nuclear Information System (INIS)

Nurmio, Mirja; Joki, Henna; Kallio, Jenny; Maeaettae, Jorma A.; Vaeaenaenen, H. Kalervo; Toppari, Jorma; Jahnukainen, Kirsi; Laitala-Leinonen, Tiina

2011-01-01

During postnatal skeletal growth, adaptation to mechanical loading leads to cellular activities at the growth plate. It has recently become evident that bone forming and bone resorbing cells are affected by the receptor tyrosine kinase (RTK) inhibitor imatinib mesylate (STI571, Gleevec (registered) ). Imatinib targets PDGF, ABL-related gene, c-Abl, c-Kit and c-Fms receptors, many of which have multiple functions in the bone microenvironment. We therefore studied the effects of imatinib in growing bone. Young rats were exposed to imatinib (150 mg/kg on postnatal days 5-7, or 100 mg/kg on postnatal days 5-13), and the effects of RTK inhibition on bone physiology were studied after 8 and 70 days (3-day treatment), or after 14 days (9-day treatment). X-ray imaging, computer tomography, histomorphometry, RNA analysis and immunohistochemistry were used to evaluate bone modeling and remodeling in vivo. Imatinib treatment eliminated osteoclasts from the metaphyseal osteochondral junction at 8 and 14 days. This led to a resorption arrest at the growth plate, but also increased bone apposition by osteoblasts, thus resulting in local osteopetrosis at the osteochondral junction. The impaired bone remodelation observed on day 8 remained significant until adulthood. Within the same bone, increased osteoclast activity, leading to bone loss, was observed at distal bone trabeculae on days 8 and 14. Peripheral quantitative computer tomography (pQCT) and micro-CT analysis confirmed that, at the osteochondral junction, imatinib shifted the balance from bone resorption towards bone formation, thereby altering bone modeling. At distal trabecular bone, in turn, the balance was turned towards bone resorption, leading to bone loss. - Research highlights: → 3-Day imatinib treatment. → Causes growth plate anomalies in young rats. → Causes biomechanical changes and significant bone loss at distal trabecular bone. → Results in loss of osteoclasts at osteochondral junction.

Study of /sup 201/Tl uptake by bone and bone marrow on /sup 201/Tl scintigraphy. With special reference to bone marrow abnormalities

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Fujii, Tadashige; Tanaka, Masao; Hirose, Yoshiki; Hirayama, Jiro; Handa, Kenjiro; Nakanishi, Fumiko; Yano, Kesato; Ueda, Hitoshi

1989-04-01

Thallium-201 (Tl-201) uptake in the bone and bone marrow was examined in a total of 93 patients with various diseases. Sternal uptake of Tl-201 was observed when patients had bone marrow abnormality especially associated with hematopoietic disease. It was associated with proliferation of immature cells and of various types of bone marrow cells, especially erythroblastic and plasma cells. Whole-body Tl-201 scanning showed a high uptake (82%) in the sternum, chest, lumbar vertebrae, and pelvis. Thallium-201 was definitively taken up by the sternum in polycythemia (5/41), hemolytic anemia (2/2), iron deficiency anemia (2/2), and multiple myeloma (2/5). For leukemia, Tl-201 uptake was slight or negative. Thallium-201 scanning proved useful in visualizing bone marrow abnormality, although careful interpretation of bone and bone marrow uptake is required. (Namekawa, K).

Preclinical characterization of three transient receptor potential vanilloid receptor 1 antagonists for early use in human intradermal microdose analgesic studies.

Science.gov (United States)

Sjögren, E; Halldin, M M; Stålberg, O; Sundgren-Andersson, A K

2018-05-01

The transient receptor potential vanilloid receptor 1 (TRPV1) is a nonselective cation channel involved in the mediation of peripheral pain to the central nervous system. As such, the TRPV1 is an accessible molecular target that lends itself well to the understanding of nociceptive signalling. This study encompasses preclinical investigations of three molecules with the prospect to establish them as suitable analgesic model compounds in human intradermal pain relief studies. The inhibitory effectiveness was evaluated by means of in vitro assays, TRPV1 expressing Chinese hamster ovary cells (CHO-K1) and rat dorsal root ganglion cultures in fluorescent imaging plate reader and whole cell patch clamp systems, as well as in vivo by capsaicin-evoked pain-related behavioural response studies in rat. Secondary pharmacology, pharmacokinetics and preclinical safety were also assessed. In vitro, all three compounds were effective at inhibiting capsaicin-activated TRPV1. The concentration producing 50% inhibition (IC 50 ) determined was in the range of 3-32 nmol/L and 10-501 nmol/L using CHO-K1 and dorsal root ganglion cultures, respectively. In vivo, all compounds showed dose-dependent reduction in capsaicin-evoked pain-related behavioural responses in rat. None of the three compounds displayed any significant activity on any of the secondary targets tested. The compounds were also shown to be safe from a toxicological, drug metabolism and pharmacokinetic perspective, for usage in microgram doses in the human skin. The investigated model compounds displayed ideal compound characteristics as pharmacological and translational tools to address efficacy on the human native TRPV1 target in human skin in situ. This work details the pharmaceutical work-up of three TRPV1-active investigational compounds, to obtain regulatory approval, for subsequent use in humans. This fast and cost-effective preclinical development path may impact research beyond the pain management area, as

A structural approach in the study of bones: fossil and burnt bones at nanosize scale

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Piga, Giampaolo; Baró, Maria Dolors; Escobal, Irati Golvano; Gonçalves, David; Makhoul, Calil; Amarante, Ana; Malgosa, Assumpció; Enzo, Stefano; Garroni, Sebastiano

2016-12-01

We review the different factors affecting significantly mineral structure and composition of bones. Particularly, it is assessed that micro-nanostructural and chemical properties of skeleton bones change drastically during burning; the micro- and nanostructural changes attending those phases manifest themselves, amongst others, in observable alterations to the bones colour, morphology, microstructure, mechanical strength and crystallinity. Intense changes involving the structure and chemical composition of bones also occur during the fossilization process. Bioapatite material is contaminated by an heavy fluorination process which, on a long-time scale reduces sensibly the volume of the original unit cell, mainly the a-axis of the hexagonal P63/m space group. Moreover, the bioapatite suffers to a varying degree of extent by phase contamination from the nearby environment, to the point that rarely a fluorapatite single phase may be found in fossil bones here examined. TEM images supply precise and localized information, on apatite crystal shape and dimension, and on different processes that occur during thermal processes or fossilization of ancient bone, complementary to that given by X-ray diffraction and Attenuated Total Reflection Infrared spectroscopy. We are presenting a synthesis of XRD, ATR-IR and TEM results on the nanostructure of various modern, burned and palaeontological bones.

GIANT CELL-RICH LESIONS OF BONE AND JOINTS: A ONE YEAR PROSPECTIVE STUDY

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Sri Nithisa H

2016-07-01

Full Text Available BACKGROUND Giant cell-rich lesions constitute a group of biologically and morphologically diverse bone and joint tumours. The common feature is presence of numerous multinucleated osteoclast-like giant cells. However, they differ from each other by in terms of clinical and radiographic features and in many cases by their distinct morphological features. METHODS All the bone and joint specimens with giant cell-rich lesions received in the period of one year were studied along with clinical and radiological data available. Gross and microscopic findings were noted. RESULTS In a period of one year, 10 cases of giant cell-rich lesions of bone and joints have been studied, which were and correlated with clinical and radiological findings. Five were lesions from bone and two were from joints, which are chondroblastoma, chondromyxoid fibroma, osteoclastoma, aneurysmal bone cyst, pigmented villonodular synovitis, giant cell lesion of tendon sheath, and tendinous xanthoma. CONCLUSION In the present study, variety of giant cell lesions of bone and joints are studied. Of which, the mean age in young patients being 20 years and in elderly patients being 50 years. The common site being lower end of femur.

Bone metastasis pattern in initial metastatic breast cancer: a population-based study

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Xiong Z

2018-02-01

Full Text Available Zhenchong Xiong,1–3,* Guangzheng Deng,1–3,* Xinjian Huang,1–3,* Xing Li,1–3 Xinhua Xie,1–3 Jin Wang,1–3 Zeyu Shuang,1–3 Xi Wang1–3 1Department of Breast Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China; 2State Key Laboratory of Oncology in Southern China, Guangzhou, China; 3Collaborative Innovation Center for Cancer Medicine, Guangzhou, China *These authors contributed equally to this work Purpose: Bone is one of the most common sites of breast cancer metastasis, and population-based studies of patients with bone metastasis in initial metastatic breast cancer (MBC are lacking. Materials and methods: From 2010 to 2013, 245,707 breast cancer patients and 8901 patients diagnosed with initial bone metastasis were identified by Surveillance, Epidemiology, and End Results database of the National Cancer Institute. Multivariate logistic and Cox regression were used to identify predictive factors for the presence of bone metastasis and prognosis factors. Kaplan–Meier method and log-rank test were used for survival analysis. Results: Eight thousand nine hundred one patients with initial MBC had bone involvement, accounting for 3.6% of the entire cohort and 62.5% of the patients with initial MBC. Also, 70.5% of patients with bone metastasis were hormone receptor (HR positive (HR+/human epidermal growth factor receptor 2 [HER2]−: 57.6%; HR+/HER2+: 12.9%. Patients with initial bone metastasis had a better 5-year survival rate compared to those with initial brain, liver, or lung metastasis. HR+/HER2− and HR+/HER2+ breast cancer had a propensity of bone metastasis in the entire cohort and were correlated with better prognosis in patients with initial bone metastasis. Local surgery had significantly improved overall survival in initial MBC patients with bone metastasis. Conclusion: Our study has provided population-based estimates of epidemiologic characteristics and prognosis in patients with bone metastasis at the time of

Longitudinal study on osteoarthritis and bone metabolism

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L. Postiglione

2011-09-01

Full Text Available Objective: The relationship between Osteoarthritis (OA and Osteoporosis (OP is not well defined due to lacking in longitudinal data, mainly regarding correlations between biochemical factors and OA incidence. Aim of this paper was to investigate the predictive value for OA incidence of bone mass variations and of selected biochemical markers in healthy women participating in a population-based longitudinal study carried out in Naples (Italy. Subjects and Methods: High completion rate (85.2% and statistically adequate sample size were obtained: 139 women (45 to 79 years of age were examined and follow up visit was performed after two years (24±2 months, following the same protocol. Patients underwent medical examination, questionnaire, anthropometric measurements, blood sampling and urine collection. Bone mineral density (BMD measurement was performed by dual energy X-ray absorptiometry (DEXA at the lumbar spine (L1-L4 and femoral neck. Radiographs of dorsal and lumbar spine in lateral view were performed at basal and at 24 months visits; a team of three experts scored radiographs using Kellegren and Lawrence grading. Results: The score was calculated for two individual radiographic features (narrowing of the joint space, presence of osteophytes and as a global score. Results show a relevant percentage, 23% up, of subjects presenting both OA and OP. In the cross-sectional study the presence of osteophytosis correlates with anthropometric variables and PTH levels. In the longitudinal study results show a correlation between serum vitamin D and delta score for osteophytosis (β=0.02 p<0.05. Conclusions: Data obtained outline the importance of further studies on the pathogenetic link between OA and bone metabolism.

Preclinical Models in Chimeric Antigen Receptor-Engineered T-Cell Therapy.

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Siegler, Elizabeth Louise; Wang, Pin

2018-05-01

Cancer immunotherapy has enormous potential in inducing long-term remission in cancer patients, and chimeric antigen receptor (CAR)-engineered T cells have been largely successful in treating hematological malignancies in the clinic. CAR-T therapy has not been as effective in treating solid tumors, in part due to the immunosuppressive tumor microenvironment. Additionally, CAR-T therapy can cause dangerous side effects, including off-tumor toxicity, cytokine release syndrome, and neurotoxicity. Animal models of CAR-T therapy often fail to predict such adverse events and frequently overestimate the efficacy of the treatment. Nearly all preclinical CAR-T studies have been performed in mice, including syngeneic, xenograft, transgenic, and humanized mouse models. Recently, a few studies have used primate models to mimic clinical side effects better. To date, no single model perfectly recapitulates the human immune system and tumor microenvironment, and some models have revealed CAR-T limitations that were contradicted or missed entirely in other models. Careful model selection based on the primary goals of the study is a crucial step in evaluating CAR-T treatment. Advancements are being made in preclinical models, with the ultimate objective of providing safer, more effective CAR-T therapy to patients.

The influence of platelet-rich fibrin on angiogenesis in guided bone regeneration using xenogenic bone substitutes: a study of rabbit cranial defects.

Science.gov (United States)

Yoon, Jong-Suk; Lee, Sang-Hwa; Yoon, Hyun-Joong

2014-10-01

The purpose of this study was to investigate the influence of platelet-rich fibrin (PRF) on angiogenesis and osteogenesis in guided bone regeneration (GBR) using xenogenic bone in rabbit cranial defects. In each rabbit, 2 circular bone defects, one on either side of the midline, were prepared using a reamer drill. Each of the experimental sites received bovine bone with PRF, and each of the control sites received bovine bone alone. The animals were sacrificed at 1 week (n = 4), 2 weeks (n = 3) and 4 weeks (n = 3). Biopsy samples were examined histomorphometrically by light microscopy, and expression of vascular endothelial growth factor (VEGF) was determined by immunohistochemical staining. At all experimental time points, immunostaining intensity for VEGF was consistently higher in the experimental group than in the control group. However, the differences between the control group and the experimental group were not statistically significant in the histomorphometrical and immunohistochemical examinations. The results of this study suggest that PRF may increase the number of marrow cells. However, PRF along with xenogenic bone substitutes does not show a significant effect on bony regeneration. Further large-scale studies are needed to confirm our results. Copyright © 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

New bone formation and trabecular bone microarchitecture of highly porous tantalum compared to titanium implant threads: A pilot canine study.

Science.gov (United States)

Lee, Jin Whan; Wen, Hai Bo; Gubbi, Prabhu; Romanos, Georgios E

2018-02-01

This study evaluated new bone formation activities and trabecular bone microarchitecture within the highly porous region of Trabecular Metal™ Dental Implants (TM) and between the threads of Tapered Screw-Vent® Dental Implants (TSV) in fresh canine extraction sockets. Eight partially edentulated dogs received four implants (4.1 mmD × 13 mmL) bilaterally in mandibular fresh extraction sockets (32 TM, 32 TSV implants), and allowed to heal for 2, 4, 8, and 12 weeks. Calcein was administered to label mineralizing bone at 11 and 4 days before euthanasia for dogs undergoing all four healing periods. Biopsies taken at each time interval were examined histologically. Histomorphometric assay was conducted for 64 unstained and 64 stained slides at the region of interest (ROI) (6 mm long × 0.35 mm deep) in the midsections of the implants. Topographical and chemical analyses were also performed. Histomorphometry revealed significantly more new bone in the TM than in the TSV implants at each healing time (p = .0014, .0084, .0218, and .0251). Calcein-labeled data showed more newly mineralized bone in the TM group than in the TSV group at 2, 8, and 12 weeks (p = .045, .028, .002, respectively) but not at 4 weeks (p = .081). Histologically TM implants exhibited more bone growth and dominant new immature woven bone at an earlier time point than TSV implants. The parameters representing trabecular bone microarchitecture corroborated faster new bone formation in the TM implants when compared to the TSV implants. TM exhibited an irregular faceted topography compared to a relatively uniform microtextured surface for TSV. Chemical analysis showed peaks associated with each implant's composition material, and TSV also showed peaks reflecting the elements of the calcium phosphate blasting media. Results suggest that the healing pathway associated with the highly porous midsection of TM dental implant could enable faster and stronger secondary implant stability than

Process dissociation analyses of memory changes in healthy aging, preclinical, and very mild Alzheimer disease: Evidence for isolated recollection deficits.

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Millar, Peter R; Balota, David A; Maddox, Geoffrey B; Duchek, Janet M; Aschenbrenner, Andrew J; Fagan, Anne M; Benzinger, Tammie L S; Morris, John C

2017-10-01

Recollection and familiarity are independent processes that contribute to memory performance. Recollection is dependent on attentional control, which has been shown to be disrupted in early stage Alzheimer's disease (AD), whereas familiarity is independent of attention. The present longitudinal study examines the sensitivity of recollection estimates based on Jacoby's (1991) process dissociation procedure to AD-related biomarkers in a large sample of well-characterized cognitively normal middle-aged and older adults (N = 519) and the extent to which recollection discriminates these individuals from individuals with very mild symptomatic AD (N = 64). Participants studied word pairs (e.g., knee bone), then completed a primed, explicit, cued fragment-completion memory task (e.g., knee b_n_). Primes were either congruent with the correct response (e.g., bone), incongruent (e.g., bend), or neutral (e.g., &). This design allowed for the estimation of independent contributions of recollection and familiarity processes, using the process dissociation procedure. Recollection, but not familiarity, was impaired in healthy aging and in very mild AD. Recollection discriminated cognitively normal individuals from the earliest detectable stage of symptomatic AD above and beyond standard psychometric tests. In cognitively normal individuals, baseline CSF measures indicative of AD pathology were related to lower initial recollection and less practice-related improvement in recollection over time. Finally, presence of amyloid plaques, as imaged by PIB-PET, was also related to less improvement in recollection over time. These findings suggest that attention-demanding memory processes, such as recollection, may be particularly sensitive to both symptomatic and preclinical AD pathology. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Promoting evidence based medicine in preclinical medical students via a federated literature search tool.

Science.gov (United States)

Keim, Samuel Mark; Howse, David; Bracke, Paul; Mendoza, Kathryn

2008-01-01

Medical educators are increasingly faced with directives to teach Evidence Based Medicine (EBM) skills. Because of its nature, integrating fundamental EBM educational content is a challenge in the preclinical years. To analyse preclinical medical student user satisfaction and feedback regarding a clinical EBM search strategy. The authors introduced a custom EBM search option with a self-contained education structure to first-year medical students. The implementation took advantage of a major curricular change towards case-based instruction. Medical student views and experiences were studied regarding the tool's convenience, problems and the degree to which they used it to answer questions raised by case-based instruction. Surveys were completed by 70% of the available first-year students. Student satisfaction and experiences were strongly positive towards the EBM strategy, especially of the tool's convenience and utility for answering issues raised during case-based learning sessions. About 90% of the students responded that the tool was easy to use, productive and accessed for half or more of their search needs. This study provides evidence that the integration of an educational EBM search tool can be positively received by preclinical medical students.

SU-E-T-606: Performance of MR-Based 3D FXG Dosimetry for Preclinical Irradiation

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Welch, M [Department of Medical Biophysics, University of Toronto, Toronto, ON (Canada); Jaffray, D [Department of Medical Biophysics, University of Toronto, Toronto, ON (Canada); Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON (Canada); Department of Radiation Oncology, University of Toronto, Toronto, ON (Canada); TECHNA Institute for the Advancement of Technology for Health, Toronto, ON (Canada)

2015-06-15

Purpose: Technological advances have revolutionized preclinical radiation research to enable precise radiation delivery in preclinical models. Kilovoltage x-rays and complex geometries in preclinical radiation studies challenge conventional dosimetry methods. Previously developed gel-based dosimetry provides a viable means of accommodating complex geometries and accurately reporting dose at kV energies. This paper will describe the development and evaluation of gel-based ferrous xylenol-orange (FXG) dosimetry using a 7T preclinical imaging system. Methods: To confirm water equivalence, Zeff values were calculated for the FXG material, water and ICRU defined soft tissue. Proton T1 relaxivity response in FXG was measured using a preclinical 7T MR and a small animal irradiator for a dose range of 1–22 Gy. FXG was contained in 50 ml centrifuge tubes and irradiated with a 225 kVp x-ray beam at a nominal dose rate of 2.3 Gy/min. Pre and post irradiation maps of the T1 relaxivity were collected using variable TR spin-echo imaging (TE 6.65 ms; TR 500, 750, 1000, 1500, 2000, 3000 and 5000 ms) with 2 mm thick slices, 0.325 mm/pixel, 3 averages and an acquisition time of 26 minutes. A linear fit to the change in relaxation rate (1/T1) for the delivered doses reported the gel sensitivity in units of ms{sup -1}Gy{sup -1}. Irradiation and imaging studies were repeated using three batches of gel over 72 hrs. Results: FXG has a Zeff of 3.8 for the 225 kVp spectrum used; differing from water and ICRU defined soft tissue by 0.5% and 2.5%, respectively. The average sensitivity for the FXG dosimeter was 31.5 ± 0.7 ms{sup -1}Gy{sup -1} (R{sup 2} = 0.9957) with a y-intercept of −29.4 ± 9.0 ms{sup -1}. Conclusion: Preliminary results for the FXG dosimeter properties, sensitivity, and dose linearity at preclinical energies is promising. Future work will explore anatomically relevant tissue inclusions to test MR performance. Student funding provided by The Terry Fox Foundation

Confocal laser scanning microscopy in study of bone calcification

International Nuclear Information System (INIS)

Nishikawa, Tetsunari; Kokubu, Mayu; Kato, Hirohito; Imai, Koichi; Tanaka, Akio

2012-01-01

Highlights: ► High-magnification images with depth selection, and thin sections were observed using CLSM. ► The direction and velocity of calcification of the bone was observed by administration of 2 fluorescent dyes. ► In dog femora grafted with coral blocks, newly-formed bone was observed in the coral block space with a rough surface. ► Twelve weeks after dental implant was grafted in dog femora, the space between screws was filled with newly-formed bones. - Abstract: Bone regeneration in mandible and maxillae after extraction of teeth or tumor resection and the use of rough surface implants in bone induction must be investigated to elucidate the mechanism of calcification. The calcified tissues are subjected to chemical decalcification or physical grinding to observe their microscopic features with light microscopy and transmission electron microscopy where the microscopic tissue morphology is significantly altered. We investigated the usefulness of confocal laser scanning microscopy (CLSM) for this purpose. After staggering the time of administration of calcein and alizarin red to experimental rats and dogs, rat alveolar bone and dog femur grafted with coral as scaffold or dental implants were observed with CLSM. In rat alveolar bone, the calcification of newly-formed bone and net-like canaliculi was observed at the mesial bone from the roots progressed at the rate of 15 μm/day. In dog femur grafted with coral, newly-formed bones along the space of coral were observed in an orderly manner. In dog femur with dental implants, after 8 weeks, newly-formed bone proceeded along the rough surface of the implants. CLSM produced high-magnification images of newly-formed bone and thin sections were not needed.

Bones and oil reservoirs : bioengineers use oilpatch technology to study fluid flow in bones

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Marsters, S.

2003-06-01

The fact that porosity and the presence of channels are qualities that are common to oil reservoirs and bones, led to the use of reservoir modelling technology in investigating bone disorders and to the discovery of dramatic changes in the structure and blood supply of osteoarthritic bones that lie under degenerating cartilage. CMG (Computer Modelling Group) Ltd., developers of reservoir simulation software claim that their software packages can help with the modelling of cellular responses to strains and deformations that occur as fluid flows through bone after a traumatic event such as a tear in the anterior cruciate ligament, a common sports-related injury. Researchers at the University of Calgary expect that by looking at the changes in blood and fluid flow within the bone, they can attain a better understanding of the chain of events that leads to osteoarthritis. Better understanding of the progression of the disease could eventually lead to more precise administration of drugs to deal with osteoarthritic pain, and even to the prevention of painful arthritic joints.

Confocal laser scanning microscopy in study of bone calcification

Science.gov (United States)

Nishikawa, Tetsunari; Kokubu, Mayu; Kato, Hirohito; Imai, Koichi; Tanaka, Akio

2012-12-01

Bone regeneration in mandible and maxillae after extraction of teeth or tumor resection and the use of rough surface implants in bone induction must be investigated to elucidate the mechanism of calcification. The calcified tissues are subjected to chemical decalcification or physical grinding to observe their microscopic features with light microscopy and transmission electron microscopy where the microscopic tissue morphology is significantly altered. We investigated the usefulness of confocal laser scanning microscopy (CLSM) for this purpose. After staggering the time of administration of calcein and alizarin red to experimental rats and dogs, rat alveolar bone and dog femur grafted with coral as scaffold or dental implants were observed with CLSM. In rat alveolar bone, the calcification of newly-formed bone and net-like canaliculi was observed at the mesial bone from the roots progressed at the rate of 15 μm/day. In dog femur grafted with coral, newly-formed bones along the space of coral were observed in an orderly manner. In dog femur with dental implants, after 8 weeks, newly-formed bone proceeded along the rough surface of the implants. CLSM produced high-magnification images of newly-formed bone and thin sections were not needed.

Surgeon Involvement in Pre-Clinical Medical Education: Attitudes of Directors of Education

Directory of Open Access Journals (Sweden)

Simon Turner

2012-04-01

Full Text Available Background: Application rates to surgical residencies have shown a downward trend recently. Introducing students to surgeons early in medical school can increase interest in surgery as a career and enhance the instruction of important surgical topics. Directors of undergraduate medical education have unique insight and influence regarding the participation of surgeons in pre-clinical education. Methods: To understand the attitudes of these educators towards surgeons as teachers in pre-clinical programs, a survey was administered to the directors of undergraduate medical education at each of the English-language medical schools in Canada. Results: Educators estimate the participation of surgeons in all categories of pre-clinical education to be low, despite being valuable, and think that it should be increased. The most significant barrier to participation identified was a lack of surgeons’ time. Conclusions: Despite the value of surgeons participating in pre-clinical education, their rate of participation is low. Steps should be taken to facilitate the involvement of surgeons in this phase of education, which may lead to improved education for students and increased student interest in surgery residencies.

The preclinical sheep model of high tibial osteotomy relating basic science to the clinics: standards, techniques and pitfalls.

Science.gov (United States)

Pape, Dietrich; Madry, Henning

2013-01-01

To develop a preclinical large animal model of high tibial osteotomy to study the effect of axial alignment on the lower extremity on specific issues of the knee joint, such as in articular cartilage repair, development of osteoarthritis and meniscal lesions. Preoperative planning, surgical procedure and postoperative care known from humans were adapted to develop a HTO model in the adult sheep. Thirty-five healthy, skeletally mature, female Merino sheep between 2 and 4 years of age underwent a HTO of their right tibia in a medial open-wedge technique inducing a normal (group 1) and an excessive valgus alignment (group 2) and a closed-wedge technique (group 3) inducing a varus alignment with the aim of elucidating the effect of limb alignment on cartilage repair in vivo. Animals were followed up for 6 months. Solid bone healing and maintenance of correction are most likely if the following surgical principles are respected: (1) medial and longitudinal approach to the proximal tibia; (2) biplanar osteotomy to increase initial rotatory stability regardless of the direction of correction; (3) small, narrow but long implant with locking screws; (4) posterior plate placement to avoid slope changes; (5) use of bicortical screws to account for the brittle bone of the tibial head and to avoid tibial head displacement. Although successful high tibial osteotomy in sheep is complex, the sheep may--because of its similarities with humans--serve as an elegant model to induce axial malalignment in a clinically relevant environment, and osteotomy healing under challenging mechanical conditions.

The effect of 12-month participation in osteogenic and non-osteogenic sports on bone development in adolescent male athletes. The PRO-BONE study

DEFF Research Database (Denmark)

Vlachopoulos, Dimitris; Barker, Alan R; Ubago-Guisado, Esther

2018-01-01

OBJECTIVES: Research investigating the longitudinal effects of the most popular sports on bone development in adolescent males is scarce. The aim is to investigate the effect of 12-month participation in osteogenic and non-osteogenic sports on bone development. DESIGN: A 12-month study...... by dual-energy X-ray absorptiometry, and bone stiffness was measured by quantitative ultrasound. Bone outcomes at 12 months were adjusted for baseline bone status, age, height, lean mass and moderate to vigorous physical activity. RESULTS: Footballers had higher improvement in adjusted BMC at the total...... body, total hip, shaft, Ward's triangle, legs and bone stiffness compared to cyclists (6.3-8.0%). Footballers had significantly higher adjusted BMC at total body, shaft and legs compared to swimmers (5.4-5.6%). There was no significant difference between swimmers and cyclists for any bone outcomes...

Perceptions of Teaching Methods for Preclinical Oral Surgery: A Comparison with Learning Styles.

Science.gov (United States)

Omar, Esam

2017-01-01

Dental extraction is a routine part of clinical dental practice. For this reason, understanding the way how students' extraction knowledge and skills development are important. To date, there is no accredited statement about the most effective method for the teaching of exodontia to dental students. Students have different abilities and preferences regarding how they learn and process information. This is defined as learning style. In this study, the effectiveness of active learning in the teaching of preclinical oral surgery was examined. The personality type of the groups involved in this study was determined, and the possible effect of personality type on learning style was investigated. This study was undertaken over five years from 2011 to 2015. The sample consisted of 115 students and eight staff members. Questionnaires were submitted by 68 students and all eight staff members involved. Three measures were used in the study: The Index of Learning Styles (Felder and Soloman, 1991), the Myers-Briggs Type Indicator (MBTI), and the styles of learning typology (Grasha and Hruska-Riechmann). Findings indicated that demonstration and minimal clinical exposure give students personal validation. Frequent feedback on their work is strongly indicated to build the cognitive, psychomotor, and interpersonal skills needed from preclinical oral surgery courses. Small group cooperative active learning in the form of demonstration and minimal clinical exposure that gives frequent feedback and students' personal validation on their work is strongly indicated to build the skills needed for preclinical oral surgery courses.

Management of unicameral bone cyst by using freeze dried radiation sterilized bone allograft impregnate with autogenous bone marrow.

Science.gov (United States)

Datta, N K; Das, K P; Alam, M S; Kaiser, M S

2014-07-01

Unicameral bone cyst is a common benign bone tumor and most frequent cause of the pathological fracture in children. We have started a prospective study for that treatment of unicameral bone cyst by using freeze dried radiation sterilized bone allograft impregnated with autogenous bone marrow in the department of Orthopaedics, Bangabandhu Sheikh Mujib Medical University (BSMMU) during May 1999 to April 2012. Aim of this study was to see Freeze dried radiation sterilized bone allograft impregnate with autogenous bone marrow a satisfactory graft material in the treatment of unicameral bone cyst as well as factors such as patients age, sex, cyst size and site of lesion influence on cyst healing. A total 35 patients of unicameral bone cyst were operated. In this study out of 35 patients, male were 22(62.86%) and female were 13(37.14). Male Female ratio 22:13(1.70:1) Age of the patients ranging from 2 years 6 month to 20 years, mean age 12.18 years more common 11 years to 20 years 29(82.86%) patients. Common bones sites involvements are proximal end of Humerus 20(57.14%), proximal end of Femur 7(20 %), proximal end of Tibia 3(8.57%), Calcanium 2(5.71%), proximal end of Ulna 1(2.86%), shaft of Radius 1(2.86%) and Phalanx 1(2.86%). Final clinical outcome of unicameral bone cyst treated by thorough curettage of cavity and tightly filled with freeze dried radiation sterilized bone allograft impregnate with autogenous bone marrow in which healed (success rate) 88.57% (31) and recurrence rate is 11.43% (4). P value is unicameral bone cyst.

Preclinical studies of lymphographic applilcation of 99mTc-dextrans of different molecular weight

International Nuclear Information System (INIS)

Lamka, J.; Kvetina, J.; Kafka, P.

1986-01-01

In a preclinical investigation on rabbits the distribution was tested of dextrans of two molecular weights (40,000 and 70,000) with regard to their use as a carrier in indirect lymphography. The tests showed that both 99m Tc-dextrans achieve high ratios of lymph/blood levels. It is suggested that for clinical work it is better to use dextran with a molecular weight of 70,000 than that with a molecular weight of 40,000. (author)

Genetic and environmental variances of bone microarchitecture and bone remodeling markers: a twin study.

Science.gov (United States)

Bjørnerem, Åshild; Bui, Minh; Wang, Xiaofang; Ghasem-Zadeh, Ali; Hopper, John L; Zebaze, Roger; Seeman, Ego

2015-03-01

All genetic and environmental factors contributing to differences in bone structure between individuals mediate their effects through the final common cellular pathway of bone modeling and remodeling. We hypothesized that genetic factors account for most of the population variance of cortical and trabecular microstructure, in particular intracortical porosity and medullary size - void volumes (porosity), which establish the internal bone surface areas or interfaces upon which modeling and remodeling deposit or remove bone to configure bone microarchitecture. Microarchitecture of the distal tibia and distal radius and remodeling markers were measured for 95 monozygotic (MZ) and 66 dizygotic (DZ) white female twin pairs aged 40 to 61 years. Images obtained using high-resolution peripheral quantitative computed tomography were analyzed using StrAx1.0, a nonthreshold-based software that quantifies cortical matrix and porosity. Genetic and environmental components of variance were estimated under the assumptions of the classic twin model. The data were consistent with the proportion of variance accounted for by genetic factors being: 72% to 81% (standard errors ∼18%) for the distal tibial total, cortical, and medullary cross-sectional area (CSA); 67% and 61% for total cortical porosity, before and after adjusting for total CSA, respectively; 51% for trabecular volumetric bone mineral density (vBMD; all p accounted for 47% to 68% of the variance (all p ≤ 0.001). Cross-twin cross-trait correlations between tibial cortical porosity and medullary CSA were higher for MZ (rMZ  = 0.49) than DZ (rDZ  = 0.27) pairs before (p = 0.024), but not after (p = 0.258), adjusting for total CSA. For the remodeling markers, the data were consistent with genetic factors accounting for 55% to 62% of the variance. We infer that middle-aged women differ in their bone microarchitecture and remodeling markers more because of differences in their genetic factors than

Bone Formation Following Sinus Augmentation with an Equine-Derived Bone Graft: A Retrospective Histologic and Histomorphometric Study with 36-Month Follow-up.

Science.gov (United States)

Di Stefano, Danilo Alessio; Gastaldi, Giorgio; Vinci, Raffaele; Polizzi, Elisabetta Maria; Cinci, Lorenzo; Pieri, Laura; Gherlone, Enrico

2016-01-01

The aim of this study was to investigate bone formation over time following maxillary sinus augmentation with an enzyme-deantigenic, bone collagen-preserving equine bone graft by retrospective assessment of histomorphometric data. Records of patients with atrophic ridges who underwent maxillary sinus augmentation with the enzyme-deantigenic equine bone graft and two-step implant placement between 3 and 12 months after the sinus-augmentation surgery were assessed retrospectively. The histomorphometric data were clustered in three classes according to time of collection from the augmentation surgery and analyzed to assess newly formed bone deposition and residual biomaterial degradation rates. Data concerning the 36-month clinical follow-up were also assessed. Records of 77 patients and 115 biopsy specimens were retrieved, and histomorphometric data were clustered (3 to 5 months, n = 33; 6 to 8 months, n = 57; 9 to 12 months, n = 25). Mean minimum atrophic ridge thickness was 4.9 ± 0.5 mm (range, 4.0 to 7.1 mm). The amount of newly formed bone and residual biomaterial did not significantly differ among the three clusters. Qualitative analysis showed a denser trabecular structure in late (> 8 months) samples. At the 36-month clinical follow-up, no differences were found among the implant success rates in the three groups, according to the Albrektsson and Zarb criteria for success. The overall implant success rate was 98.3%. Based upon this retrospective human study of 77 patients with 4 to 7 mm of residual bone, when enzyme-deantigenic equine bone is used for sinus augmentation, new bone formation occurs at an early time (augmentation surgery.

Comparative Plasma Exposure and Lung Distribution of Two Human Use Commercial Azithromycin Formulations Assessed in Murine Model: A Preclinical Study

OpenAIRE

Rivulgo, Virginia Margarita; Sparo, Mónica; Ceci, Mónica; Fumuso, Elida; Confalonieri, Alejandra; Delpech, Gastón; Sanchez Bruni, Sergio Fabian

2016-01-01

Azithromycin(AZM)therapeutic failure and relapses of patients treated with generic -35 formulations have been observed in clinical practice.The main goal of this research was 36 to compare in a pre-clinical study the serum exposure and lung tissue concentrationof 37 two commercial formulations AZM-based in murine model. The current study involved 38 264 healthy Balb-C.Mice were divided in two groups (n=44): Animals of Group A 39 (Reference Formulation ?R-) were orally treated with AZM suspens...

Curcumin nanoformulations : A review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment

NARCIS (Netherlands)

Naksuriya, Ornchuma; Okonogi, Siriporn; Schiffelers, Raymond M.|info:eu-repo/dai/nl/212909509; Hennink, Wim E.|info:eu-repo/dai/nl/070880409

2014-01-01

Curcumin, a natural yellow phenolic compound, is present in many kinds of herbs, particularly in Curcuma longa Linn. (turmeric). It is a natural antioxidant and has shown many pharmacological activities such as anti-inflammatory, anti-microbial, anti-cancer, and anti-Alzheimer in both preclinical

Confocal laser scanning microscopy in study of bone calcification

Energy Technology Data Exchange (ETDEWEB)

Nishikawa, Tetsunari, E-mail: tetsu-n@cc.osaka-dent.ac.jp [Department of Oral Pathology, Osaka Dental University, Osaka (Japan); Kokubu, Mayu; Kato, Hirohito [Department of Oral Pathology, Osaka Dental University, Osaka (Japan); Imai, Koichi [Department of Biomaterials, Osaka Dental University, Osaka (Japan); Tanaka, Akio [Department of Oral Pathology, Osaka Dental University, Osaka (Japan)

2012-12-01

Highlights: Black-Right-Pointing-Pointer High-magnification images with depth selection, and thin sections were observed using CLSM. Black-Right-Pointing-Pointer The direction and velocity of calcification of the bone was observed by administration of 2 fluorescent dyes. Black-Right-Pointing-Pointer In dog femora grafted with coral blocks, newly-formed bone was observed in the coral block space with a rough surface. Black-Right-Pointing-Pointer Twelve weeks after dental implant was grafted in dog femora, the space between screws was filled with newly-formed bones. - Abstract: Bone regeneration in mandible and maxillae after extraction of teeth or tumor resection and the use of rough surface implants in bone induction must be investigated to elucidate the mechanism of calcification. The calcified tissues are subjected to chemical decalcification or physical grinding to observe their microscopic features with light microscopy and transmission electron microscopy where the microscopic tissue morphology is significantly altered. We investigated the usefulness of confocal laser scanning microscopy (CLSM) for this purpose. After staggering the time of administration of calcein and alizarin red to experimental rats and dogs, rat alveolar bone and dog femur grafted with coral as scaffold or dental implants were observed with CLSM. In rat alveolar bone, the calcification of newly-formed bone and net-like canaliculi was observed at the mesial bone from the roots progressed at the rate of 15 {mu}m/day. In dog femur grafted with coral, newly-formed bones along the space of coral were observed in an orderly manner. In dog femur with dental implants, after 8 weeks, newly-formed bone proceeded along the rough surface of the implants. CLSM produced high-magnification images of newly-formed bone and thin sections were not needed.

In vivo experimental study on bone regeneration in critical bone defects using PIB nanogels/boron-containing mesoporous bioactive glass composite scaffold

Directory of Open Access Journals (Sweden)

Chen XH

2015-01-01

Full Text Available Xiaohui Chen,1,2,* Yanbing Zhao,3,* Shinan Geng,3 Richard J Miron,1 Qiao Zhang,1 Chengtie Wu,4 Yufeng Zhang1,2 1State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, People’s Republic of China; 2Department of Dental Implantology, School and Hospital of Stomatology, Wuhan University, People’s Republic of China; 3National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: In the present study, the fabrication of novel p(N-isopropylacrylamide-co-butyl methylacrylate (PIB nanogels was combined with boron-containing mesoporous bioactive glass (B-MBG scaffolds in order to improve the mechanical properties of PIB nanogels alone. Scaffolds were tested for mechanical strength and the ability to promote new bone formation in vivo.Patients and methods: To evaluate the potential of each scaffold in bone regeneration, ovariectomized rats were chosen as a study model to determine the ability of PIB nanogels to stimulate bone formation in a complicated anatomical bone defect. PIB nanogels and PIB nanogels/B-MBG composites were respectively implanted into ovariectomized rats with critical-sized femur defects following treatment periods of 2, 4, and 8 weeks post-implantation.Results: Results from the present study demonstrate that PIB nanogels/B-MBG composites showed greater improvement in mechanical strength when compared to PIB nanogels alone. In vivo, hematoxylin and eosin staining revealed significantly more newly formed bone in defects containing PIB