Fracture analysis of healthy and osteoporotic femora using clinical CT images, phantomless densitometry, and linear FE method.

Computational fracture analysis has become a growing branch of orthopedic research. Particularly, the associated methods provide reliable tools for the analysis of 3D CT-based models of bone. This paper reports the results of such analyses for 15 human femora (healthy and osteoporotic) under different loading orientations (85 different analysis cases). A new method was developed for the calculation of the density distribution in the models from ordinary clinical CT images without calibration phantom. This method, along with a strain-energy-based linear finite element (FE) analysis scheme, was used to predict the fracture strength and pattern of 10 cadaveric femora, for which the mechanical testing results and calibrated FE models were already available. The very good agreement and consistency between different sets of results showed the reliability and accuracy of the new density calibration method, as well as the linear analysis scheme. Accordingly, the method was applied to five new clinical images, gathered from two clinics that used different scanners with different protocols. The strength and fracture pattern of each one of these specimens were analyzed under 15 different loading conditions. A consistent behavior was found for variation of the fracture load and pattern of all specimens with the loading orientations, while very clear contrasts were observed between the strength amplitudes of healthy and osteoporotic specimens. The proposed methods can be easily applied to ordinary daily (even archived) clinical CT scans to conduct fast and reliable fracture analysis of human femora for general bone research and opportunistic studies of osteoporosis and trauma.

Exosome-based strategies for diagnosis and therapy of glioma cancer.

Glioblastoma belongs to the most aggressive type of cancer with a low survival rate that is characterized by the ability in forming a highly immunosuppressive tumor microenvironment. Intercellular communication are created via exosomes in the tumor microenvironment through the transport of various biomolecules. They are primarily involved in tumor growth, differentiation, metastasis, and chemotherapy or radiation resistance. Recently several studies have highlighted the critical role of tumor-derived exosomes against immune cells. According to the structural and functional properties, exosomes could be essential instruments to gain a better molecular mechanism for tumor understanding. Additionally, they are qualified as diagnostic/prognostic markers and therapeutic tools for specific targeting of invasive tumor cells such as glioblastomas. Due to the strong dependency of exosome features on the original cells and their developmental status, it is essential to review their critical modulating molecules, clinical relevance to glioma, and associated signaling pathways. This review is a non-clinical study, as the possible role of exosomes and exosomal microRNAs in glioma cancer are reported. In addition, their content to overcome cancer resistance and their potential as diagnostic biomarkers are analyzed.

Exosome application in tumorigenesis: diagnosis and treatment of melanoma.

Melanoma is the most aggressive of skin cancer derived from genetic mutations in the melanocytes. Current therapeutic approaches include surgical resection, chemotherapy, photodynamic therapy, immunotherapy, biochemotherapy, and targeted therapy. However, the efficiency of these strategies may be decreased due to the development of diverse resistance mechanisms. Here, it has been proven that therapeutic monoclonal antibodies (mAbs) can improve the efficiency of melanoma therapies and also, cancer vaccines are another approach for the treatment of melanoma that has already improved clinical outcomes in these patients. The use of antibodies and gene vaccines provides a new perspective in melanoma treatment. Since the tumor microenvironment is another important factor for cancer progression and metastasis, in recent times, a mechanism has been identified to provide an opportunity for melanoma cells to communicate with remote cells. This mechanism is involved by a novel molecular structure, named extracellular vesicles (EVs). Depending on the functional status of origin cells, exosomes contain various cargos and different compositions. In this review, we presented recent progress of exosome applications in the treatment of melanoma. Different aspects of exosome therapy and ongoing efforts in this field will be discussed too.

A comparative study of 3D printing and heat-compressing methods for manufacturing the thermoplastic composite bone fixation plate: Design, characterization, and in vitro biomechanical experimentation.

Metallic bone fixations, due to their high rigidity, can cause long-term complications. To alleviate metallic biomaterials' drawbacks, in this research new Glass Fiber/Polypropylene (GF/PP) composite internal fixations were developed, and an investigation of their mechanical behavior was performed through in vitro biomechanical experiments. Short randomly oriented, long unidirectional prepreg, and long unidirectional fiber yarn were considered as reinforcements, and the effects on their mechanical properties of different manufacturing processes, that is, 3D printing and heat-compressing, were investigated. The constructed fixation plates were tested in the transversely fractured diaphysis of bovine tibia under axial compression loading. The overall stiffness and the Von Mises strain field of the fixation plates were obtained within stable and unstable fracture conditions. The samples were loaded until failure to determine their failure loads, strains, and mechanisms. Based on the results, the GF/PP composite fixation plates can provide adequate interfragmentary movement to amplify bone ossification, so they can provide proper support for bone healing. Moreover, their potential for stress shielding reduction and their load-bearing capacity suggest their merits in replacing traditional metallic plates.

Biomechanical evaluation of glass fiber/polypropylene composite bone fracture fixation plates: Experimental and numerical analysis.

Little is known about the impact behavior of composite fixation plate used in the fracture healing of long bones diaphysis. Hence, this study examined polypropylene composite fixation plates using different glass fibers and measured their biomechanical responses under axial impact loading experimentally and numerically. Short randomly oriented, long unidirectional prepregs and fiber yarn of glass were considered as reinforcements, and fixation plates were fabricated through two different heat-compressing and 3D printing processes. Furthermore, assessing the fixation plate structures impact behavior was carried out using in vitro impact test and finite element analysis (FEA). Impact damping behavior, damage mechanisms, and stress and strain pattern of the composite fixation plate structures were obtained under various bone fractures and impact energies. The impact load-time responses and the failure mechanisms demonstrated that fixation plate structures with more plastic behavior and lower stiffness could act as an initial shock absorber and dampen the transmission of axial impact load by distributing the impact energy over time. Therefore, considering the ability of stress shielding and adequate interfragmentary movement which amplifies bone ossification, the proposed Glass Fiber/PP (GF/PP) composite fixation plates could serve as a proper alternative in orthopedics.

Quantum Mechanics/Molecular Mechanics Study of the Reaction Mechanism of Glyoxalase I.

Glyoxalase I (GlxI) is a member of the glyoxalase system, which is important in cell detoxification and converts hemithioacetals of methylglyoxal (a cytotoxic byproduct of sugar metabolism that may react with DNA or proteins and introduce nucleic acid strand breaks, elevated mutation frequencies, and structural or functional changes of the proteins) and glutathione into d-lactate. GlxI accepts both the S and R enantiomers of hemithioacetal, but converts them to only the S-d enantiomer of lactoylglutathione. Interestingly, the enzyme shows this unusual specificity with a rather symmetric active site (a Zn ion coordinated to two glutamate residues; Glu-99 and Glu-172), making the investigation of its reaction mechanism challenging. Herein, we have performed a series of combined quantum mechanics and molecular mechanics calculations to study the reaction mechanism of GlxI. The substrate can bind to the enzyme in two different modes, depending on the direction of its alcoholic proton (H2; toward Glu-99 or Glu-172). Our results show that the S substrate can react only if H2 is directed toward Glu-99 and the R substrate only if H2 is directed toward Glu-172. In both cases, the reactions lead to the experimentally observed S-d enantiomer of the product. In addition, the results do not show any low-energy paths to the wrong enantiomer of the product from neither the S nor the R substrate. Previous studies have presented several opposing mechanisms for the conversion of R and S enantiomers of the substrate to the correct enantiomer of the product. Our results confirm one of them for the S substrate, but propose a new one for the R substrate.

European trends in radiology: investigating factors affecting the number of examinations and the effective dose.

The advances in technology have led to a growing trend in population exposure to radiation emerging from the invention of high-dose procedures. It is, for example, estimated that annually 1.2% of cancers are induced by radiological scans in Norway. This study aims to investigate and discuss the frequency and dose trends of radiological examinations in Europe. European Commission (EC) launched projects to gain information for medical exposures in 2004 and 2011. In this study, the European Commission Radiation Protection (RP) reports No. 154 and 180 have been reviewed. The RP 154 countries' data were extracted from both reports, and the average variation trend of the number of examinations and effective doses were studied. According to the results, plain radiography and fluoroscopy witnessed a reduction in the frequency and effective dose per examination. Nevertheless, European collective dose encountered an average increase of 23%, which resulted from a growing tendency for implementation of high-dose procedures such as CT scans and interventional examinations. It is worth noting that most of the CT procedures have undergone an increase in effective dose per examination. Although demand and dose per examination in some radiological procedures (such as intravenous urography (IVU) have been reduced, population collective dose is still rising due to the increasing demand for CT scan procedures. Even though the individual risks are not considerable, it can, in a large scale, threaten the health of the people at the present time. Due to this fact, better justification should be addressed so as to reduce population exposure.

Linear and nonlinear analyses of femoral fractures: Computational/experimental study.

This paper describes two new methods for computational fracture analysis of human femur using Quantitative Computed Tomography (QCT) voxel-based finite element (FE) simulation. The paper also reports comprehensive mechanical testing for validation of the methods and evaluation of the required material properties. The analyses and tests were carried out on 15 human femurs under 11 different stance-type loading orientations. Several classical forms of subcapital, transcervical, basicervical, and intertrochanteric fractures plus a specific type of subtrochanteric fracture were created and analyzed. A new procedure was developed for prediction of the strengths and the fracture initiation patterns using a FE-based linear scheme. The predicted and observed fracture patterns were in correspondence, and the FE predictions of the fracture loads were in very good agreement with the experimental results. Moreover, the crack initiation and growth behaviors of two subtrochanteric fractures were successfully simulated through a novel implementation of the cohesive zone model (CZM) within a nonlinear FE analysis scheme. The CZM parameters were obtained through a series of experimental tests on different types of specimens and determination of a variety of material properties for different anatomic regions and orientations. The presented results indicated that the locations and patterns of crack initiation, the sequences of crack growth on different paths, and the compatibility of growth increments agreed very well with the observed specifications. Also, very good agreements were achieved between the measured and simulated fracture loads.

A novel mechanism of heme degradation to biliverdin studied by QM/MM and QM calculations.

Heme degradation by heme oxygenase enzymes is important for maintaining iron homeostasis and prevention of oxidative stress. Previous studies have reported that heme degradation proceeds through three consecutive steps of O2 activation: the regiospecific self-hydroxylation of heme, the conversion of hydroxyheme to verdoheme and CO, and the cleavage of the verdoheme macrocycle to release biliverdin and free ferrous iron. Our results indicate that in the second step of heme degradation, not only verdoheme is generated but ring opening and biliverdin production also occur. We have performed QM-cluster and QM/MM calculations, which show that calculations with H2O as the axial ligand of Fe give the lowest barrier. In the QM-cluster calculation, the reaction is exothermic by -85 kcal mol-1 and the rate-limiting barrier is 5 kcal mol-1, whereas the corresponding QM/MM calculations give a slightly lower barrier of 3 kcal mol-1, owing to strong hydrogen bonds and the protein environment.

QM/MM Study of the Conversion of Oxophlorin into Verdoheme by Heme Oxygenase.

Heme oxygenase is an enzyme that degrades heme, thereby recycling iron in most organisms, including humans. Pervious density functional theory (DFT) calculations have suggested that iron(III) hydroxyheme, an intermediate generated in the first step of heme degradation by heme oxygenase, is converted to iron(III) superoxo oxophlorin in the presence of dioxygen. In this article, we have studied the detailed mechanism of conversion of iron(III) superoxo oxophlorin to verdoheme by using combined quantum mechanics and molecular mechanics (QM/MM) calculations. The calculations employed the B3LYP method and the def2-QZVP basis set, considering dispersion effects with the DFT-D3 approach, obtaining accurate energies with large QM regions of almost 1000 atoms. The reaction was found to be exothermic by -35 kcal/mol, with a rate-determining barrier of 19 kcal/mol in the doublet state. The protein environment and especially water in the enzyme pocket significantly affects the reaction by decreasing the reaction activation energies and changing the structures by providing strategic hydrogen bonds.

Evaluation of the effect of the chiral centers of Taxol on binding to ß-tubulin: A docking and molecular dynamics simulation study.

Taxol is one of the most important anti-cancer drugs. The interaction between different variants of Taxol, by altering one of its chiral centers at a time, with ß-tubulin protein has been investigated. To achieve such goal, docking and molecular dynamics (MD) simulation studies have been performed. In docking studies, the preferred conformers have been selected to further study by MD method based on the binding energies reported by the AutoDock program. The best result of docking study which shows the highest affinity between ligand and protein has been used as the starting point of the MD simulations. All of the complexes have shown acceptable stability during the simulation process, based on the RMSDs of the backbone of the protein structure. Finally, MM-GBSA calculations have been carried out to select the best ligand, considering the binding energy criteria. The results predict that two of the structures have better affinity toward the mentioned protein, in comparison with Taxol. Three of the structures have affinity similar to that of the Taxol toward the ß-tubulin.

QCT-based failure analysis of proximal femurs under various loading orientations.

In this paper, the variations of the failure strength and pattern of human proximal femur with loading orientation were analysed using a novel quantitative computed tomography (QCT)-based linear finite element (FE) method. The QCT images of 4 fresh-frozen femurs were directly converted into voxel-based finite element models for the analyses of the failure loads and patterns. A new geometrical reference system was used for the alignment of the mechanical loads on the femoral head. A new method was used for recognition and assortment of the high-risk elements using a strain energy-based measure. The FE results were validated with the experimental results of the same specimens and the results of similar case studies reported in the literature. The validated models were used for the computational investigation of the failure loads and patterns under 15 different loading conditions. A consistent variation of the failure loads and patterns was found for the 60 different analysed cases. Finally, it was shown that the proposed procedure can be used as a reliable tool for the failure analysis of proximal femurs, e.g. identification of the relevant loading directions for specific failure patterns, or determination of the loading conditions under which the proximal femurs are failure-prone.

Diagnostic stability of psychiatric disorders in re-admitted psychiatric patients in Kerman, Iran.

BACKGROUND: Several studies have evaluated the stability of psychiatric diagnosis follow in readmission of patients in psychiatric hospitals. However, there is little data concerning this matter from Iran. This study is designed to evaluate this diagnostic stability of the commonest psychiatric disorders in Iran. OBJECTIVES: The objective of this study was to determine the long-term diagnostic stability of the most prevalent psychiatric disorders among re-admitted patients at the Shahid Beheshti teaching hospital in Kerman, Iran. PATIENTS &METHODS: This study was based on 485 adult patients re-admitted at the Shahid Beheshti hospital between July and November 2012.All of the diagnoses were made according to DSM IV TR.Prospective and retrospective consistency and the ratio of patients who were obtained a diagnosis in at least 75%, 100% of the admissions were calculated. RESULTS: The most frequent diagnoses at the first admission were bipolar disorder (48.5%) and Major depressive disorder (18.8%). The most stable diagnosis was bipolar disorder (71% prospective consistency, 69.4% retrospective consistency). Schizoaffective disorder had the greatest diagnostic instability (28.5% prospective consistency, 16.6% retrospective consistency). CONCLUSIONS: Among the cases evaluated, bipolar disorder had the most stability in diagnosis and the stability of schizoaffective disorder was poor.

Efficacy of Cisplatin-loaded poly butyl cyanoacrylate nanoparticles on the ovarian cancer: an in vitro study.

One of the main challenges of treatment of ovarian cancer is initial response to treatment and then acquisition of resistance to Cisplatin. Nanotechnology-based approaches are considered as one way to overcome drug resistance. In this study, the cytotoxicity effects of Cisplatin-loaded poly butyl cyanoacrylate (PBCA) nanoparticles (NPs) on the ovarian cancer cell line A2780cp resistant to Cisplatin were studied. NPs were synthesized by miniemulsion polymerization method. Size, size distribution and zeta potential of NPs were estimated as 489 nm, 0.429, and -20 mV, respectively. Drug loading and encapsulation efficiency were recognized as 5 % and 25 %, respectively. Drug release pattern (3.18 % release after 51 h) demonstrated high level of retention. Toxicological studies showed that cytotoxicity of the nanodrug Cisplatin was about three times as much as that of a free drug. Moreover, NPs presented acceptable stability after 2 months. The results of study suggest the use of this formulation for in vivo experiments.

Drug delivery of hydroxyurea to breast cancer using liposomes.

It is clear that cancer is one of the most mortal diseases in the world and the most prevalent among women is breast cancer. As hydroxyurea (HU)-a drug which is used in chemotherapy-has many adverse effects in long-term despite of its therapeutic properties, we made use of nano drug delivery technology in order to reduce adverse effects and increase therapeutic index. Thus, liposomation is a novel way in drug delivery systems. In this study a mixture of phosphatidylcholine and cholesterol was mixed and HU was added to the resultant mixture. The mean diameter of the nanoliposomal HU measured with the Zeta Sizer device (equal to 402.5 nm) and its encapsulation efficiency was 70.8 %. Besides, using dialysis, the pattern of drug release from nanoliposomes has been studied and the results showed that the drug release of nanoliposomal drug within 28 h was equal to 25.85 %. This study showed that the cytotoxicity effect of nanoliposomal drug is more than that of the standard drug.

Cytotoxicity of liposomal Paclitaxel in breast cancer cell line mcf-7.

Regarding that the breast cancer is the most prevalent disease among women, paclitaxel, an anti-cancer drug, could be used in treatment of this disease. As paclitaxel has adverse effects, it was used of nanoliposome drug delivery technology in order to reduce adverse effects and improve drug efficacy. Certain ratios of phosphatidylcholine, cholesterol and paclitaxel were synthesized to prepare nanoliposomal paclitaxel. Using Zeta sizer device, the mean diameter of nanoliposomal paclitaxel was obtained 421.4 nm and its encapsulation efficiency was 91.3 %. By dialysis, drug release in nanoliposome paclitaxel formulation within 28 h was studied which was 5.53 %. This study showed that cytotoxicity effect of nanoliposomal paclitaxel is more than that of the standard form.