BioMed Research International The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Clinical Outcome of Bortezomib Retreatment in Patients with Relapsed or Refractory Multiple Myeloma Thu, 30 Oct 2014 13:09:19 +0000 This retrospective study investigated the clinical efficacy and safety of bortezomib retreatment in patients with relapsed or refractory multiple myeloma (MM). A total of 30 patients who relapsed or progressed after 6 months since the last dose of their previous bortezomib therapy were included in this study. During the median 6 cycles (range: 2–12) of bortezomib retreatment, 10 (33.3%), 2 (6.7%), and 6 (20.0%) patients achieved complete response, very good partial response, and partial response, respectively. Grade 3 or 4 neutropenia (47.0%), thrombocytopenia (43.0%), anemia (10.0%), and peripheral sensory neuropathy (3.0%) were observed. The median time to progression, progression-free survival, and overall survival were 5.8 months (95% CI: 2.6–9.0), 5.5 months (95% CI: 4.2–6.8), and 13.4 months (95% CI: 6.1–20.7), respectively. Patients who received bortezomib retreatment 12 months from initial last therapy had a 1-year OS rate of 65.8% (95% CI: 43.5–88.1) while patients receiving retreatment after 6–12 months interval had a 1-year OS rate of 41.7% (95% CI: 13.9–69.5) (). In conclusion, this study demonstrates that retreatment with bortezomib is an effective strategy for patients with MM who relapsed at a long interval after initial bortezomib therapy. Jae-Sook Ahn, Sung-Hoon Jung, Seung-Shin Lee, Seo-Yeon Ahn, Deok-Hwan Yang, Yeo-Kyeoung Kim, Hyeoung-Joon Kim, and Je-Jung Lee Copyright © 2014 Jae-Sook Ahn et al. All rights reserved. Pathophysiology of Spasticity: Implications for Neurorehabilitation Thu, 30 Oct 2014 07:11:25 +0000 Spasticity is the velocity-dependent increase in muscle tone due to the exaggeration of stretch reflex. It is only one of the several components of the upper motor neuron syndrome (UMNS). The central lesion causing the UMNS disrupts the balance of supraspinal inhibitory and excitatory inputs directed to the spinal cord, leading to a state of disinhibition of the stretch reflex. However, the delay between the acute neurological insult (trauma or stroke) and the appearance of spasticity argues against it simply being a release phenomenon and suggests some sort of plastic changes, occurring in the spinal cord and also in the brain. An important plastic change in the spinal cord could be the progressive reduction of postactivation depression due to limb immobilization. As well as hyperexcitable stretch reflexes, secondary soft tissue changes in the paretic limbs enhance muscle resistance to passive displacements. Therefore, in patients with UMNS, hypertonia can be divided into two components: hypertonia mediated by the stretch reflex, which corresponds to spasticity, and hypertonia due to soft tissue changes, which is often referred as nonreflex hypertonia or intrinsic hypertonia. Compelling evidences state that limb mobilisation in patients with UMNS is essential to prevent and treat both spasticity and intrinsic hypertonia. Carlo Trompetto, Lucio Marinelli, Laura Mori, Elisa Pelosin, Antonio Currà, Luigi Molfetta, and Giovanni Abbruzzese Copyright © 2014 Carlo Trompetto et al. All rights reserved. Clinical Significance of Resistin Expression in Osteoarthritis: A Meta-Analysis Wed, 29 Oct 2014 13:25:20 +0000 Background. The objective of this study was to conduct a systematic review of literature evaluating human resistin expression as a diagnostic factor in osteoarthritis development and to quantify the overall diagnostic effect. Method. Relevant studies were identified and evaluated for quality through multiple search strategies. Studies analyzing resistin expression in the development of OA were eligible for inclusion. Data from eligible studies were extracted and included into the meta-analysis using a random-effects model. Results. Four case-control studies consisting of a total of 375 OA patients and 214 controls as well as three sex-stratified analyses composed of 53 males and 104 females were incorporated into our meta-analysis. Our results revealed that resistin levels were significantly higher in male OA subjects and OA patients overall. Country-stratified analysis yielded significantly different estimates in resistin levels between male OA subjects and female OA subjects in the Canadian subgroup but not among the French and USA subgroups. Based on the resistin levels in OA cases and controls, resistin levels were heightened in OA patients in the Dutch population. Conclusion. These results support the hypothesis that high expression of resistin represents a significant and reproducible marker of poor progression in OA patients, especially in males. Xiao-Chuan Li, Feng Tian, and Fei Wang Copyright © 2014 Xiao-Chuan Li et al. All rights reserved. Lipolytic Potential of Aspergillus japonicus LAB01: Production, Partial Purification, and Characterisation of an Extracellular Lipase Wed, 29 Oct 2014 12:45:20 +0000 Lipolytic potential of Aspergillus japonicus LAB01 was investigated by describing the catalytic properties and stability of a secreted extracellular lipase. Enzyme production was considered high under room temperature after 4 days using sunflower oil and a combination of casein with sodium nitrate. Lipase was partially purified by 3.9-fold, resulting in a 44.2% yield using ammonium sulphate precipitation (60%) quantified with Superose 12 HR gel filtration chromatography. The activity of the enzyme was maximised at pH 8.5, and the enzyme demonstrated stability under alkaline conditions. The optimum temperature was found to be 45°C, and the enzyme was stable for up to 100 minutes, with more than 80% of initial activity remaining after incubation at this temperature. Partially purified enzyme showed reasonable stability with triton X-100 and was activated in the presence of organic solvents (toluene, hexane, and methanol). Among the tested ions, only Cu2+, Ni2+, and Al3+ showed inhibitory effects. Substrate specificity of the lipase was higher for C14 among various p-nitrophenyl esters assayed. The and values of the purified enzyme for p-nitrophenyl palmitate were 0.13 mM and 12.58 umol/(L·min), respectively. These features render a novel biocatalyst for industrial applications. Lívia Tereza Andrade Souza, Jamil S. Oliveira, Vera L. dos Santos, Wiliam C. B. Regis, Marcelo M. Santoro, and Rodrigo R. Resende Copyright © 2014 Lívia Tereza Andrade Souza et al. All rights reserved. Prepubertal Exposure to Genistein Alleviates Di-(2-ethylhexyl) Phthalate Induced Testicular Oxidative Stress in Adult Rats Wed, 29 Oct 2014 08:15:33 +0000 Di-(2-ethylhexyl) phthalate (DEHP) is the most widely used plastizer in the world and can suppress testosterone production via activation of oxidative stress. Genistein (GEN) is one of the isoflavones ingredients exhibiting weak estrogenic and potentially antioxidative effects. However, study on reproductive effects following prepubertal multiple endocrine disrupters exposure has been lacking. In this study, DEHP and GEN were administrated to prepubertal male Sprague-Dawley rats by gavage from postnatal day 22 (PND22) to PND35 with vehicle control, GEN at 50 mg/kg body weight (bw)/day (G), DEHP at 50, 150, 450 mg/kg bw/day (D50, D150, D450) and their mixture (G + D50, G + D150, G + D450). On PND90, general morphometry (body weight, AGD, organ weight, and organ coefficient), testicular redox state, and testicular histology were studied. Our results indicated that DEHP could significantly decrease sex organs weight, organ coefficient, and testicular antioxidative ability, which largely depended on the dose of DEHP. However, coadministration of GEN could partially alleviate DEHP-induced reproductive injuries via enhancement of testicular antioxidative enzymes activities, which indicates that GEN has protective effects on DEHP-induced male reproductive system damage after prepubertal exposure and GEN may have promising future in its curative antioxidative role for reproductive disorders caused by other environmental endocrine disruptors. Lian-Dong Zhang, He-Cheng Li, Tie Chong, Ming Gao, Jian Yin, De-Lai Fu, Qian Deng, and Zi-Ming Wang Copyright © 2014 Lian-Dong Zhang et al. All rights reserved. Changing Interdigestive Migrating Motor Complex in Rats under Acute Liver Injury Tue, 28 Oct 2014 09:38:50 +0000 Gastrointestinal motility disorder is a major clinical manifestation of acute liver injury, and interdigestive migrating motor complex (MMC) is an important indicator. We investigated the changes and characteristics of MMC in rats with acute liver injury. Acute liver injury was created by D-galactosamine, and we recorded the interdigestive MMC using a multichannel physiological recorder and compared the indexes of interdigestive MMC. Compared with normal controls, antral MMC Phase I duration was significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The duodenal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The jejunal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury compared with normal controls. Compared with the normal controls, rats with acute liver injury had a significantly prolonged interdigestive MMC cycle, related mainly to longer MMC Phases I and IV, shortened MMC Phase III, and MMC Phase II characterized by increased migrating clustered contractions, which were probably major contributors to the gastrointestinal motility disorders. Mei Liu, Su-Jun Zheng, Weihong Xu, Jianying Zhang, Yu Chen, and Zhongping Duan Copyright © 2014 Mei Liu et al. All rights reserved. Type 2C Phosphatase 1 of Artemisia annua L. Is a Negative Regulator of ABA Signaling Tue, 28 Oct 2014 09:02:12 +0000 The phytohormone abscisic acid (ABA) plays an important role in plant development and environmental stress response. Additionally, ABA also regulates secondary metabolism such as artemisinin in the medicinal plant Artemisia annua L. Although an earlier study showed that ABA receptor, AaPYL9, plays a positive role in ABA-induced artemisinin content improvement, many components in the ABA signaling pathway remain to be elucidated in Artemisia annua L. To get insight of the function of AaPYL9, we isolated and characterized an AaPYL9-interacting partner, AaPP2C1. The coding sequence of AaPP2C1 encodes a deduced protein of 464 amino acids, with all the features of plant type clade A PP2C. Transcriptional analysis showed that the expression level of AaPP2C1 is increased after ABA, salt, and drought treatments. Yeast two-hybrid and bimolecular fluorescence complementation assays (BiFC) showed that AaPYL9 interacted with AaPP2C1. The P89S, H116A substitution in AaPYL9 as well as G199D substitution or deletion of the third phosphorylation site-like motif in AaPP2C1 abolished this interaction. Furthermore, constitutive expression of AaPP2C1 conferred ABA insensitivity compared with the wild type. In summary, our data reveals that AaPP2C1 is an AaPYL9-interacting partner and involved in the negative modulation of the ABA signaling pathway in A. annua L. Fangyuan Zhang, Xueqing Fu, Zongyou Lv, Qian Shen, Tingxian Yan, Weiming Jiang, Guofeng Wang, Xiaofen Sun, and Kexuan Tang Copyright © 2014 Fangyuan Zhang et al. All rights reserved. Effects of Various Antibiotics Alone or in Combination with Doripenem against Klebsiella pneumoniae Strains Isolated in an Intensive Care Unit Tue, 28 Oct 2014 07:54:59 +0000 Colistin, tigecycline, levofloxacin, tobramycin, and rifampin alone and in combination with doripenem were investigated for their in vitro activities and postantibiotic effects (PAEs) on Klebsiella pneumoniae. The in vitro activities of tested antibiotics in combination with doripenem were determined using a microbroth checkerboard technique. To determine the PAEs, K. pneumoniae strains in the logarithmic phase of growth were exposed for 1 h to antibiotics, alone and in combination. Recovery periods of test cultures were evaluated using viable counting after centrifugation. Colistin, tobramycin, and levofloxacin produced strong PAEs ranging from 2.71 to 4.23 h, from 1.31 to 3.82 h, and from 1.35 to 4.72, respectively, in a concentration-dependent manner. Tigecycline and rifampin displayed modest PAEs ranging from 1.18 h to 1.55 h and 0.92 to 1.19, respectively. Because it is a beta-lactam, PAEs were not exactly induced by doripenem (ranging from 0.10 to 0.18 h). In combination, doripenem scarcely changed the duration of PAE of each tested antibiotic alone. The findings of this study may have important implications for the timing of doses during K. pneumoniae therapy with tested antibiotics. Berna Ozbek Celik, Emel Mataraci-Kara, and Mesut Yilmaz Copyright © 2014 Berna Ozbek Celik et al. All rights reserved. Application of Design of Experiment for Polyox and Xanthan Gum Coated Floating Pulsatile Delivery of Sumatriptan Succinate in Migraine Treatment Tue, 28 Oct 2014 06:59:07 +0000 Migraine follows circadian rhythm in which headache is more painful at the awakening time. This needs administration of dosage form at night time to release drug after lag period when pain gets worse. Sumatriptan succinate is a drug of choice for migraine. Sumatriptan succinate has bitter taste, low oral bioavailability, and shorter half-life. Present work deals with application of design of experiment for polyox and xanthan gum in development of press coated floating pulsatile tablet. Floating pulsatile concept was applied to increase gastric residence of the dosage form. Burst release was achieved through immediate release tablet using crospovidone as superdisintegrant (10%). Pulse lag time was achieved using swellable polymer polyox WSR205 and xanthan gum. 32 experimental design was applied. Optimized formulation was evaluated for physical characteristics and in-vitro and in-vivo study. From results, it can be concluded that optimized batch F8 containing polyox WSR205 (72.72%) and xanthan gum (27.27%) of total weight of polymer has shown floating lag time of 55 ± 2 sec, drug content of 100.35 ± 0.4%, hardness of 6 ± 0.1 Kg/cm2, and 98.69 ± 2% drug release in pulse manner with lag time of 7 ± 0.1 h. Optimized batch showed prolong gastric residence which was confirmed by in-vivo X-ray study. Swati C. Jagdale and Chandrakala R. Pawar Copyright © 2014 Swati C. Jagdale and Chandrakala R. Pawar. All rights reserved. Breast Cancer Risk in Rheumatoid Arthritis: An Update Meta-Analysis Mon, 27 Oct 2014 12:25:25 +0000 Background. The incidence of breast cancer in RA patients remains controversial. Thus we performed a meta-analysis to investigate the impact of RA on breast cancer. Methods. Published literature was available from PubMed, Embase, and Cochrane Library. Pooled standardized incidence rate (SIR) was computed by random-effect model analysis. Results. We identified 16 separate studies in the present study, in which the number of patients ranged from 458 to 84,475. We did not find the increased cancer risk in RA patients (, 95% –1.02). However, subgroup analysis showed that breast cancer risk in RA patients was positively different in Caucasians (, 95% –0.93) and non-Caucasians (, 95% –1.23), respectively. In subgroup analysis by style, a reduced incidence was found in hospital-based case subjects (, 95% –0.97). Similarly, subgroup analysis for adjusted factors indicated that in A3 (age and sex) and A4 (age, sex, and race/ethnicity) the risk was decreased (, 95% –0.99; , 95% –0.67). Conclusions. The meta-analysis revealed no increased breast cancer risk in RA patients. However, in the subgroup analysis, the risk of breast cancer is increased in non-Caucasians patients with RA while it decreased in Caucasian population, hospital-based case subjects, and A3 group. Such relationship may provide preference for risk of breast cancer in different population. Guo Tian, Jia-Ning Liang, Zhuo-Yun Wang, and Dian Zhou Copyright © 2014 Guo Tian et al. All rights reserved. CCR7 Regulates Cell Migration and Invasion through JAK2/STAT3 in Metastatic Squamous Cell Carcinoma of the Head and Neck Mon, 27 Oct 2014 11:51:38 +0000 Squamous cell carcinoma of the head and neck (SCCHN) frequently involves metastasis at diagnosis. Our previous research has demonstrated that CCR7 plays a key role in regulating SCCHN metastasis, and this process involves several molecules, such as PI3K/cdc42, pyk2, and Src. In this study, the goals are to identify whether JAK2/STAT3 also participates in CCR7’s signal network, its relationship with other signal pathways, and its role in SCCHN cell invasion and migration. The results showed that stimulation of CCL19 could induce JAK2/STAT3 phosphorylation, which can be blocked by Src and pyk2 inhibitors. After activation, STAT3 was able to promote low expression of E-cadherin and had no effect on vimentin. This JAk2/STAT3 pathway not only mediated CCR7-induced cell migration but also mediated invasion speed. The immunohistochemistry results also showed that the phosphorylation of STAT3 was correlated with CCR7 expression in SCCHN, and CCR7 and STAT3 phosphorylation were all associated with lymph node metastasis. In conclusion, JAk2/STAT3 plays a key role in CCR7 regulating SCCHN metastasis. Fa-Yu Liu, Jawad Safdar, Zhen-Ning Li, Qi-Gen Fang, Xu Zhang, Zhong-Fei Xu, and Chang-Fu Sun Copyright © 2014 Fa-Yu Liu et al. All rights reserved. Early Second-Trimester Serum MicroRNAs as Potential Biomarker for Nondiabetic Macrosomia Mon, 27 Oct 2014 11:14:40 +0000 Background. Macrosomia has become a worldwide problem with the rapid economic growth in the past few years. However, the detailed mechanism of how the macrosomia happened remains unknown. Growing evidence indicates that miRNAs are involved in maintaining metabolic homeostasis. We hypothesized that serum miRNAs are potential biomarkers for macrosomia. Methods. We performed miRNAs profiling using TLDA chips in the discovery phase in two pooled samples from 30 cases and 30 controls, respectively. Individual qRT-PCR was conducted for the discovery phase samples. To confirm the results, we detected the miRNAs which were differentially expressed in the microarray assays and individual qRT-PCR in external validation phase with another 30 cases and 30 controls. Results. In the discovery stage, miR-194 and miR-376a expression levels were significantly different between macrosomia group and controls ( for miR-194 and for miR-376a, resp.). Further evaluation of the two miRNAs on a total of 120 serum samples showed that the miR-376a remains significantly lower in macrosomia (). Receiver operating characteristic curve analyses showed that the area under curve for miR-376a was 67.8% (sensitivity = 96.7% and specificity = 40.0%). Conclusions. Serum miR-376a may serve as a potential noninvasive biomarker in detecting macrosomia. Lingmin Hu, Jing Han, Fangxiu Zheng, Hongxia Ma, Jiaping Chen, Yue Jiang, and Hua Jiang Copyright © 2014 Lingmin Hu et al. All rights reserved. Identification of Chemokines and Growth Factors in Proliferative Diabetic Retinopathy Vitreous Mon, 27 Oct 2014 06:53:24 +0000 Associations were investigated between levels of chemokines and growth factors in the vitreous and proliferative diabetic retinopathy (PDR). Enrolled were 58 patients (58 eyes) requiring pars plana vitrectomy (PPV), with PDR (, none with traction retinal detachment) or not (non-PDR). In the latter, 16 had macular hole (MH) and 10 had epiretinal membrane (ERM). With a multiplex bead immunoassay, levels of 11 chemokines and growth factors were measured from the undiluted vitreous sample from each patient. In the non-PDR eyes, the levels of the 11 chemokines and growth factors tested were similar between patients with MH and those with ERM. However, the levels of all 11 were significantly higher in the PDR eyes relative to the non-PDR; CCL17, CCL19, and TGFβ3 were markedly upregulated and have not been investigated in PDR previously. The significantly higher levels of CCL4 and CCL11 in PDR contradict the results of previous reports. Based on Spearman’s nonparametric test, moderate-to-strong correlations were found between VEGF and other mediators. Our results indicate that these chemokines and growth factors could be candidates for research into targeted therapies applied either singly or in combination with anti-VEGF drugs for the treatment of PDR. Ying Dai, Zhifeng Wu, Feng Wang, Zhengwei Zhang, and Mengxi Yu Copyright © 2014 Ying Dai et al. All rights reserved. Elastin-Coated Biodegradable Photopolymer Scaffolds for Tissue Engineering Applications Thu, 23 Oct 2014 12:45:58 +0000 One of the main open issues in modern vascular surgery is the nonbiodegradability of implants used for stent interventions, which can lead to small caliber-related thrombosis and neointimal hyperplasia. Some new, resorbable polymeric materials have been proposed to substitute traditional stainless-steel stents, but so far they were affected by poor mechanical properties and low biocompatibility. In this respect, a new material, polypropylene fumarate (PPF), may be considered as a promising candidate to implement the development of next generation stents, due to its complete biodegradability, and excellent mechanical properties and the ease to be precisely patterned. Besides all these benefits, PPF has not been tested yet for vascular prosthesis, mainly because it proved to be almost inert, while the ability to elicit a specific biological function would be of paramount importance in such critical surgery applications. Here, we propose a biomimetic functionalization process, aimed at obtaining specific bioactivation and thus improved cell-polymer interaction. Porous PPF-based scaffolds produced by deep-UV photocuring were coated by elastin and the functionalized scaffolds were extensively characterized, revealing a stable bound between the protein and the polymer surface. Both 3T3 and HUVEC cell lines were used for in vitro tests displaying an enhancement of cells adhesion and proliferation on the functionalized scaffolds. Rossella Barenghi, Szabolcs Beke, Ilaria Romano, Paola Gavazzo, Balázs Farkas, Massimo Vassalli, Fernando Brandi, and Silvia Scaglione Copyright © 2014 Rossella Barenghi et al. All rights reserved. A Least Square Method Based Model for Identifying Protein Complexes in Protein-Protein Interaction Network Thu, 23 Oct 2014 12:45:40 +0000 Protein complex formed by a group of physical interacting proteins plays a crucial role in cell activities. Great effort has been made to computationally identify protein complexes from protein-protein interaction (PPI) network. However, the accuracy of the prediction is still far from being satisfactory, because the topological structures of protein complexes in the PPI network are too complicated. This paper proposes a novel optimization framework to detect complexes from PPI network, named PLSMC. The method is on the basis of the fact that if two proteins are in a common complex, they are likely to be interacting. PLSMC employs this relation to determine complexes by a penalized least squares method. PLSMC is applied to several public yeast PPI networks, and compared with several state-of-the-art methods. The results indicate that PLSMC outperforms other methods. In particular, complexes predicted by PLSMC can match known complexes with a higher accuracy than other methods. Furthermore, the predicted complexes have high functional homogeneity. Qiguo Dai, Maozu Guo, Yingjie Guo, Xiaoyan Liu, Yang Liu, and Zhixia Teng Copyright © 2014 Qiguo Dai et al. All rights reserved. Molecular, Phenotypic Aspects and Therapeutic Horizons of Rare Genetic Bone Disorders Wed, 22 Oct 2014 12:05:37 +0000 A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities. Taha Faruqi, Naveen Dhawan, Jaya Bahl, Vineet Gupta, Shivani Vohra, Khin Tu, and Samir M. Abdelmagid Copyright © 2014 Taha Faruqi et al. All rights reserved. Development of a Finite Element Head Model for the Study of Impact Head Injury Wed, 22 Oct 2014 10:49:26 +0000 This study is aimed at developing a high quality, validated finite element (FE) human head model for traumatic brain injuries (TBI) prediction and prevention during vehicle collisions. The geometry of the FE model was based on computed tomography (CT) and magnetic resonance imaging (MRI) scans of a volunteer close to the anthropometry of a 50th percentile male. The material and structural properties were selected based on a synthesis of current knowledge of the constitutive models for each tissue. The cerebrospinal fluid (CSF) was simulated explicitly as a hydrostatic fluid by using a surface-based fluid modeling method. The model was validated in the loading condition observed in frontal impact vehicle collision. These validations include the intracranial pressure (ICP), brain motion, impact force and intracranial acceleration response, maximum von Mises stress in the brain, and maximum principal stress in the skull. Overall results obtained in the validation indicated improved biofidelity relative to previous FE models, and the change in the maximum von Mises in the brain is mainly caused by the improvement of the CSF simulation. The model may be used for improving the current injury criteria of the brain and anthropometric test devices. Bin Yang, Kwong-Ming Tse, Ning Chen, Long-Bin Tan, Qing-Qian Zheng, Hui-Min Yang, Min Hu, Gang Pan, and Heow-Pueh Lee Copyright © 2014 Bin Yang et al. All rights reserved. Comparison of Structural Architecture of HCV NS3 Genotype 1 versus Pakistani Genotype 3a Tue, 21 Oct 2014 13:49:18 +0000 This study described the structural characterization of Pakistani HCV NS3 GT3a in parallel with genotypes 1a and 1b NS3. We investigated the role of amino acids and their interaction patterns in different HCV genotypes by crystallographic modeling. Different softwares were used to study the interaction pattern, for example, CLCBIO sequence viewer, MODELLER, NMRCLUST, ERRAT score, and MODELLER. Sixty models were produced and clustered into groups and the best model of PK-NCVI/Pk3a NS3 was selected and studied further to check the variability with other HCV NS3 genotypes. This study will help in future to understand the structural architecture of HCV genome variability and to further define the conserved targets for antiviral agents. Kaneez Fatima, Esam Azhar, Shilu Mathew, Ghazi Damanhouri, and Ishtiaq Qadri Copyright © 2014 Kaneez Fatima et al. All rights reserved. Antidiabetic Activity of Pterospermum acerifolium Flowers and Glucose Uptake Potential of Bioactive Fraction in L6 Muscle Cell Lines with Its HPLC Fingerprint Tue, 21 Oct 2014 08:43:33 +0000 The present study was designed to estimate the detailed antidiabetic activity of Pterospermum acerifolium (L.) Willd flowers. In vitro alpha amylase inhibition study was carried out on 50% ethanol extract of flowers (PAFEE) and its various fractions. The active ethyl acetate fraction (PAFEF) was subfractionated into three subfractions (PAFE1, PAFE2, and PAFE3) and subjected to acute toxicity studies followed by antidiabetic screening in vivo by streptozotocin-nicotinamide induced type II diabetes. Diabetic animals treated with PAFE2 (30 mg/kg) reduced the levels of fasting blood glucose, significantly () compared to that of diabetic control animals. Histological studies on drug treated groups did not show remarkable positive changes in β-cells. PAFE2 showed % glucose uptake over control and, in the presence of PI3K inhibitor wortmannin, declined to %. HPLC analysis of PAFE2 reveals the presence of quercetin and apigenin as major constituents and both are inhibiting the glycogen phosphorylase enzyme in molecular modelling studies. The study evidenced strongly that the probable glucose lowering mechanism of action of active subfraction PAFE2 is by increasing the glucose uptake in peripheral tissues and by inhibition of gluconeogenesis. Rathinavelusamy Paramaguru, Papiya Mitra Mazumder, Dinakar Sasmal, and Venkatesan Jayaprakash Copyright © 2014 Rathinavelusamy Paramaguru et al. All rights reserved. Identification of Endothelial Progenitor Cells in the Corpus Cavernosum in Rats Tue, 21 Oct 2014 00:00:00 +0000 The vascular wall resident progenitor cells seem to serve as a local reservoir of cells for vascular repair. It was hypothesized that the corpus cavernosum may contain vascular wall endothelial progenitor cells (EPCs). In this study, we investigated the identification and localization of EPCs in the corpus cavernosum in a rat model. Adult male Sprague-Dawley rats were used to isolate EPCs from corpora cavernosum. To verify the existence and localization of EPCs, EPC-specific markers (CD34, Flk-1, and VE-cadherin) were evaluated by flow cytometric analysis and confocal microscopy. The EPC markers were mainly expressed in the cavernosal sinusoidal endothelial space. EPC-marker-positive cells made up about 3.31% of the corpus cavernosum of normal rat by FACS analysis. As shown by confocal microscopy, CD34+/Flk-1+ and CD34+/VE-cadherin+ positive cells existed in the corpus cavernosum. Our findings imply that regulation of corpus cavernosal EPCs may be a new therapeutic strategy in the treatment of erectile dysfunction. Jun Sik Lee, In Sang Hwang, Hyun-Suk Lee, Mi Eun Kim, Young-Woo Seo, and Kwangsung Park Copyright © 2014 Jun Sik Lee et al. All rights reserved. Activation of the AT1R/HIF-1α/ACE Axis Mediates Angiotensin II-Induced VEGF Synthesis in Mesenchymal Stem Cells Mon, 20 Oct 2014 11:47:30 +0000 A local renin-angiotensin system (RAS) is expressed in mesenchymal stem cells (MSCs) and regulates stem cell function. The local RAS influences the survival and tissue repairing ability of transplanted stem cells. We have previously reported that angiotensin II (Ang II) pretreatment can significantly increase vascular endothelial growth factor (VEGF) synthesis in MSCs through the ERK1/2 and Akt pathways via the Ang II receptor type 1 (AT1R). However, the role of angiotensin-converting enzyme (ACE) has not been clarified. Furthermore, whether Ang II pretreatment activates hypoxia-inducible factor-1α (HIF-1α) in MSCs has not been elucidated. Our data show that both ACE and HIF-1α are involved in promoting VEGF expression in MSCs, and that both are upregulated by Ang II stimulation. The upregulation of ACE appeared after the rapid degradation of exogenous Ang II, and led to the formation of endogenous Ang II. On the other hand, the ACE inhibitor, captopril, attenuated Ang II-enhanced HIF-1α upregulation, while HIF-1α suppression markedly attenuated ACE expression. This interesting finding suggests an interaction between ACE and HIF-1α. We conclude that Ang II pretreatment, as a trigger, activated the AT1R/HIF-1α/ACE axis that then mediated Ang II-induced VEGF synthesis in MSCs. Chao Liu, Jing-Wen Zhang, Liang Hu, Yi-Chen Song, Lu Zhou, Yue Fan, Hong-Yi Zhu, Yu Wang, and Qing-Ping Li Copyright © 2014 Chao Liu et al. All rights reserved. Deregulation of Serum MicroRNA Expression Is Associated with Cigarette Smoking and Lung Cancer Mon, 20 Oct 2014 09:28:51 +0000 Lung cancer is the leading cause of cancer-related death and cigarette smoking is the main risk factor for lung cancer. Circulating microRNAs (miRNAs) are considered potential biomarkers of various cancers, including lung cancer. However, it is unclear whether changes in circulating miRNAs are associated with smoking and smoking-related lung cancer. In this study, we determined the serum miRNA profiles of 10 nonsmokers, 10 smokers, and 10 lung-cancer patients with miRCURY LNA microRNA arrays. The differentially expressed miRNAs were then confirmed in a larger sample. We found that let-7i-3p and miR-154-5p were significantly downregulated in the sera of smokers and lung-cancer patients, so the serum levels of let-7i-3p and miR-154-5p are associated with smoking and smoking-related lung cancer. The areas under receiver operating characteristic curves for let-7i-3p and miR-154-5p were approximately 0.892 and 0.957, respectively. In conclusion, our results indicate that changes in serum miRNAs are associated with cigarette smoking and lung cancer and that let-7i-3p and miR-154-5p are potential biomarkers of smoking-related lung cancer. Jinkun Huang, Jianjun Wu, Yuanqi Li, Xun Li, Ti Yang, Qiaoyuan Yang, and Yiguo Jiang Copyright © 2014 Jinkun Huang et al. All rights reserved. Genetic Diversity of SCN5A Gene and Its Possible Association with the Concealed Form of Brugada Syndrome Development in Polish Group of Patients Mon, 20 Oct 2014 09:14:39 +0000 Brugada Syndrome (BS) is an inherited channelopathy associated with a high incidence of sudden cardiac death. The paper presents the discovery of new genetic variants of SCN5A gene which might be associated with the development of a concealed form of Brugada Syndrome. The study involved a group of 59 patients (37 men) with suspected concealed form of Brugada Syndrome. Pharmacological provocation with intravenous ajmaline administration was performed. Six patients with positive test results were subjected to molecular analysis of SCN5A gene with MSSCP method. Additionally, MSSCP genotyping was performed for samples obtained from the family members with Brugada Syndrome, despite the fact that they had negative ajmaline challenge test results. Genetic examinations of the SCN5A gene at 6 positive patients showed 6 known polymorphisms, 8 new single nucleotide point (SNP) variants located at exons, and 12 new single nucleotide point variants located at introns. Among new SNPs localized in SCN5A gene exons three SNPs affected the protein sequence. Beata Uziębło-Życzkowska, Grzegorz Gielerak, Paweł Siedlecki, and Beata Pająk Copyright © 2014 Beata Uziębło-Życzkowska et al. All rights reserved. Genetic Multipartitions Based on D-Loop Sequences and Chromosomal Patterns in Brown Chromis, Chromis multilineata (Pomacentridae), in the Western Atlantic Sun, 19 Oct 2014 11:45:01 +0000 Connectivity levels among Brazilian reef fish fauna populations have attracted growing interest, mainly between mainland shores and oceanic islands. The Pomacentridae, whose phylogeographic patterns are largely unknown in the Atlantic, are a family of dominant fish in reef regions. We present data on the variability and population structure of damselfish Chromis multilineata in different areas along the northeast coast of Brazil and in the waters around the oceanic islands of Fernando de Noronha (FNA) and Saint Peter and Saint Paul Archipelago (SPSPA) through analysis of the HVR1 mtDNA sequence of the control region. The remote SPSPA exhibits the highest level of genetic divergence among populations. Conventional and molecular cytogenetic analysis showed similar karyotype patterns (2n = 48 acrocentrics) between these insular areas. Our estimates reveal three genetically different population groups of C. multilineata on the Brazilian coast. The level of genetic structure is higher than previous data suggested, indicating complex panel of interactions between the oceanic island and coastal populations of Brazil. Inailson Márcio Costa da Cunha, Allyson Santos de Souza, Eurico Azevedo Dias Jr., Karlla Danielle Jorge Amorim, Rodrigo Xavier Soares, Gideão Wagner Werneck Félix da Costa, Erik García-Machado, Pedro Manoel Galetti Jr., and Wagner Franco Molina Copyright © 2014 Inailson Márcio Costa da Cunha et al. All rights reserved. Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin Sun, 19 Oct 2014 08:23:16 +0000 The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer’s disease, tauopathies, and Huntington’s diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell. Panchanan Maiti, Jayeeta Manna, Shobi Veleri, and Sally Frautschy Copyright © 2014 Panchanan Maiti et al. All rights reserved. Contribution of α,β-Amyrenone to the Anti-Inflammatory and Antihypersensitivity Effects of Aleurites moluccana (L.) Willd. Sun, 19 Oct 2014 07:26:25 +0000 The aim of the study was to analyze the constituents of the dichloromethane fraction obtained from A. moluccana and also to evaluate the anti-inflammatory and antinociceptive properties of α,β-amyrenone isolated from A. moluccana in mice. The dichloromethane fraction was evaluated by gas chromatography and submitted to purification. The mixture of α,β-amyrenone was isolated and then evaluated using the carrageenan-induced paw-oedema or pleurisy and CFA-induced arthritis models in mice. Five triterpenes, α,β-amyrenone, glutinol, and α,β-amyrin were isolated from dichloromethane fraction of A. moluccana leaf extract. The mixture of α,β-amyrenone, dosed orally, was able to reduce mechanical hypersensitivity and paw-oedema induced by carrageenan, interfering with neutrophil migration. Similar results were observed in the carrageenan-induced pleurisy model. Repeated administration of the compounds was also effective in reducing the mechanical sensitization and oedema developed in the arthritis model induced by CFA. In conclusion, the results demonstrate that α,β-amyrenone interferes in both acute and chronic inflammatory processes. We can infer that these effects involve, at least in part, a reduction in the neutrophil migration. Therefore, it seems reasonable to suggest that α,β-amyrenone could represent a new therapeutic tool for the management of painful and inflammatory diseases, especially those presenting a chronic profile. Nara Lins Meira Quintão, Lilian W. Rocha, Gislaine Franciele Silva, Simone Reichert, Vanessa D. Claudino, Ruth Meri Lucinda-Silva, Angela Malheiros, Márcia Maria De Souza, Valdir Cechinel Filho, Tania M. Bellé Bresolin, Marina da Silva Machado, Theodoro Marcel Wagner, and Christiane Meyre-Silva Copyright © 2014 Nara Lins Meira Quintão et al. All rights reserved. Serum Fetuin-A Levels in Patients with Cardiovascular Disease: A Meta-Analysis Thu, 16 Oct 2014 13:01:01 +0000 Background. Fetuin-A (FA) suppresses arterial calcification, promotes insulin resistance, and appears to be elevated in patients with cardiovascular diseases (CVD), but the data is still inconsistent. To clarify the correlation between serum FA levels and the presence and severity of CVDs, we performed this meta-analysis. Method. Potential relevant studies were identified covering the following databases: PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine (CBM), and China National Knowledge Infrastructure (CNKI) databases. Data from eligible studies were extracted and included in the meta-analysis using a random-effects model. Results. Ten case-control studies, including 1,281 patients with CVDs and 2,663 healthy controls, were included. The results showed significant differences in serum levels of FA between the CVDs patients and the healthy controls (SMD = 1.36, 95%CI: 0.37–2.36, ). Ethnicity-subgroup analysis implied that low serum FA levels are related to CVDs in Caucasians (SMD = 1.73, 95%CI: 0.20–3.26, ), but not in Asians (SMD = 1.04, 95%CI: −0.33–2.40, ). Conclusion. The data indicated that decreased serum FA level is correlated with the development of CVDs. FA might be clinically valuable for reflecting the progression of CVDs. Ze-Lin Sun, Qi-Ying Xie, Gong-Liang Guo, Ke Ma, and Yuan-Yuan Huang Copyright © 2014 Ze-Lin Sun et al. All rights reserved. Downregulation of MDR1 Gene by Cepharanthine Hydrochloride Is Related to the Activation of c-Jun/JNK in K562/ADR Cells Thu, 16 Oct 2014 08:40:31 +0000 The purpose of the study was to determine the signal transduction mechanism of cepharanthine hydrochloride (CH) on reversing tumor multidrug resistance. RT-PCR and Western blot analysis were used to determine the effects of CH on the expression of MDR1 mRNA and P-glycoprotein in K562/ADR cells when CH was used alone and combined with SP600125, a JNK inhibitor, to explore the effects of CH on JNK pathway. Western blot analysis was used to determine the effects of CH on c-Jun protein expression and phosphorylation, to explore the regulating effects of CH on c-Jun and phosphorylated c-Jun (p-c-Jun) proteins. Our results showed that the inhibitory effect of CH on MDR1 mRNA increased with the concentrations of CH (5.0, 10.0, and 20.0 μM) and the inhibitory effects of CH on MDR1 mRNA and P-glycoprotein increased with the incubation time of CH (0, 12, 24, 36, and 48 hours). The inhibitory effect was weakened after CH combined with SP600125. The expressions of c-Jun and p-c-Jun proteins increased with the incubation time of CH (0, 6, 12, and 24 hours). These findings suggest that CH downregulated the expressions of MDR1 mRNA and P-glycoprotein in a time and concentration manner; the mechanism may be mediated via activating c-Jun/JNK pathway. Li Han, Yafeng Wang, Xiaojuan Guo, Yubing Zhou, Jingmin Zhang, Ning Wang, Jinhua Jiang, Fang Ma, and Qingduan Wang Copyright © 2014 Li Han et al. All rights reserved. Advanced Tracers in PET Imaging of Cardiovascular Disease Wed, 15 Oct 2014 11:59:43 +0000 Cardiovascular disease is the leading cause of death worldwide. Molecular imaging with targeted tracers by positron emission tomography (PET) allows for the noninvasive detection and characterization of biological changes at the molecular level, leading to earlier disease detection, objective monitoring of therapies, and better prognostication of cardiovascular diseases progression. Here we review, the current role of PET in cardiovascular disease, with emphasize on tracers developed for PET imaging of cardiovascular diseases. Yesen Li, Wei Zhang, Hua Wu, and Gang Liu Copyright © 2014 Yesen Li et al. All rights reserved. Speckle-Tracking and Tissue-Doppler Stress Echocardiography in Arterial Hypertension: A Sensitive Tool for Detection of Subclinical LV Impairment Wed, 15 Oct 2014 07:32:52 +0000 Early diagnosis of cardiac alterations in hypertensive heart disease is still challenging. Since such patients might have depressed global LV systolic strain or strain rate when EF is still normal, speckle-tracking echocardiography (STE) and tissue-Doppler imaging (TDI) combined with stress echocardiography might improve early diagnosis of cardiac alterations. In this prospective study standard 2D Doppler echocardiography, STE, and TDI were performed at rest and during bicycle exercise in 92 consecutive patients—46 hypertensive subjects with normal ejection fraction and 46 healthy controls. STE and TDI were used to measure global peak systolic LV circumferential strain (CS), longitudinal strain (LS), and longitudinal strain rate (SR). Mean arterial blood pressure was significantly higher in hypertensive patients at rest (100.8 mmHg SD 13.5 mmHg; ) and during physical exercise testing (124.2 mmHg SD 13.4 mmHg; ). Hypertensive patients had significantly reduced values of systolic CS (), LS (), and SR () at rest as well as during physical exercise—CS (), LS (), and SR (). Using STE and TDI, reduced LV systolic strain and strain rate consistent with early cardiac alterations can be detected in patients with arterial hypertension. These findings were evident at rest and markedly pronounced during exercise echocardiography. Kai O. Hensel, Andreas Jenke, and Roman Leischik Copyright © 2014 Kai O. Hensel et al. All rights reserved.