BioMed Research International: Pathology http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Tissue Biomarkers in Prognostication of Serous Ovarian Cancer following Neoadjuvant Chemotherapy Thu, 17 Apr 2014 10:04:19 +0000 http://www.hindawi.com/journals/bmri/2014/401245/ Serous ovarian cancer (SOC) is a significant cause of morbidity and mortality in females with poor prognosis because of advanced stage at presentation. Recently, neoadjuvant chemotherapy (NACT) is being used for management of advanced SOC, but role of tissue biomarkers in prognostication following NACT is not well established. The study was conducted on advanced stage SOC patients () that were treated either conventionally () or with NACT (), followed by surgery. In order to evaluate the expression of tissue biomarkers (p53, MIB1, estrogen and progesterone receptors, Her-2/neu, E-cadherin, and Bcl2), immunohistochemistry and semiquantitative scoring were done following morphological examination. Following NACT, significant differences in tumor histomorphology were observed as compared to the native neoplasms. MIB 1 was significantly lower in cases treated with NACT and survival outcome was significantly better in cases with low MIB 1. ER expression was associated with poor overall survival. No other marker displayed any significant difference in expression or correlation with survival between the two groups. Immunophenotype of SOC does not differ significantly in samples from cases treated with NACT, compared to upfront surgically treated cases. The proliferating capacity of the residual tumor cells is less, depicted by low mean MIB1 LI. MIB 1 and ER inversely correlate with survival. Binny Khandakar, Sandeep R. Mathur, Lalit Kumar, Sunesh Kumar, Siddhartha Datta Gupta, Venkateswaran K. Iyer, and M. Kalaivani Copyright © 2014 Binny Khandakar et al. All rights reserved. Predicting the Types of J-Proteins Using Clustered Amino Acids Wed, 02 Apr 2014 15:24:36 +0000 http://www.hindawi.com/journals/bmri/2014/935719/ J-proteins are molecular chaperones and present in a wide variety of organisms from prokaryote to eukaryote. Based on their domain organizations, J-proteins can be classified into 4 types, that is, Type I, Type II, Type III, and Type IV. Different types of J-proteins play distinct roles in influencing cancer properties and cell death. Thus, reliably annotating the types of J-proteins is essential to better understand their molecular functions. In the present work, a support vector machine based method was developed to identify the types of J-proteins using the tripeptide composition of reduced amino acid alphabet. In the jackknife cross-validation, the maximum overall accuracy of 94% was achieved on a stringent benchmark dataset. We also analyzed the amino acid compositions by using analysis of variance and found the distinct distributions of amino acids in each family of the J-proteins. To enhance the value of the practical applications of the proposed model, an online web server was developed and can be freely accessed. Pengmian Feng, Hao Lin, Wei Chen, and Yongchun Zuo Copyright © 2014 Pengmian Feng et al. All rights reserved. N-acetyl-seryl-aspartyl-lysyl-proline Inhibits Diabetes-Associated Kidney Fibrosis and Endothelial-Mesenchymal Transition Mon, 24 Mar 2014 08:25:13 +0000 http://www.hindawi.com/journals/bmri/2014/696475/ Endothelial-to-mesenchymal transition (EndMT) emerges as an important source of fibroblasts. MicroRNA let-7 exhibits anti-EndMT effects and fibroblast growth factor (FGF) receptor has been shown to be an important in microRNA let-7 expression. The endogenous antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a substrate of angiotensin-converting enzyme (ACE). Here, we found that AcSDKP inhibited the EndMT and exhibited fibrotic effects that were associated with FGF receptor-mediated anti-fibrotic program. Conventional ACE inhibitor plus AcSDKP ameliorated kidney fibrosis and inhibited EndMT compared to therapy with the ACE inhibitor alone in diabetic CD-1 mice. The endogenous AcSDKP levels were suppressed in diabetic animals. Cytokines induced cultured endothelial cells into EndMT; coincubation with AcSDKP inhibited EndMT. Expression of microRNA let-7 family was suppressed in the diabetic kidney; antifibrotic and anti-EndMT effects of AcSDKP were associated with the restoration of microRNA let-7 levels. AcSDKP restored diabetes- or cytokines-suppressed FGF receptor expression/phosphorylation into normal levels both in vivo and in vitro. These results suggest that AcSDKP is an endogenous antifibrotic molecule that has the potential to cure diabetic kidney fibrosis via an inhibition of the EndMT associated with the restoration of FGF receptor and microRNA let-7. Takako Nagai, Megumi Kanasaki, Swayam Prakash Srivastava, Yuka Nakamura, Yasuhito Ishigaki, Munehiro Kitada, Sen Shi, Keizo Kanasaki, and Daisuke Koya Copyright © 2014 Takako Nagai et al. All rights reserved. Evaluation of 12-Lipoxygenase (12-LOX) and Plasminogen Activator Inhibitor 1 (PAI-1) as Prognostic Markers in Prostate Cancer Mon, 24 Mar 2014 08:22:51 +0000 http://www.hindawi.com/journals/bmri/2014/102478/ In carcinoma of prostate, a causative role of platelet 12-lipoxygenase (12-LOX) and plasminogen activator inhibitor 1 (PAI-1) for tumor progression has been firmly established in tumor and/or adjacent tissue. Our goal was to investigate if 12-LOX and/or PAI-1 in patient’s plasma could be used to predict outcome of the disease. The study comprised 149 patients (age ) divided into two groups: a study group with carcinoma confirmed by positive biopsy of prostate () and a reference group () with benign prostatic hyperplasia (BPH). The following parameters were determined by the laboratory test in plasma or platelet-rich plasma: protein level of 12-LOX, PAI-1, thromboglobulin (TGB), prostate specific antigen (PSA), C-reactive protein (CRP), hemoglobin (HGB, and hematocrit (HCT), as well as red (RBC) and white blood cells (WBC), number of platelets (PLT), international normalized ratio of blood clotting (INR), and activated partial thromboplastin time (APTT). The only difference of significance was noticed in the concentration of 12-LOX in platelet rich plasma, which was lower in cancer than in BPH group. Standardization to TGB and platelet count increases the sensitivity of the test that might be used as a biomarker to assess risk for prostate cancer in periodically monitored patients. Tomasz Gondek, Mariusz Szajewski, Jarosław Szefel, Ewa Aleksandrowicz-Wrona, Ewa Skrzypczak-Jankun, Jerzy Jankun, and Wieslawa Lysiak-Szydlowska Copyright © 2014 Tomasz Gondek et al. All rights reserved. Image Guided Hypofractionated Radiotherapy by Helical Tomotherapy for Prostate Carcinoma: Toxicity and Impact on Nadir PSA Tue, 18 Mar 2014 09:53:23 +0000 http://www.hindawi.com/journals/bmri/2014/541847/ Aim. To evaluate the toxicity of a hypofractionated schedule for primary radiotherapy (RT) of prostate cancer as well as the value of the nadir PSA (nPSA) and time to nadir PSA (tnPSA) as surrogate efficacy of treatment. Material and Methods. Eighty patients underwent hypofractionated schedule by Helical Tomotherapy (HT). A dose of 70.2 Gy was administered in 27 daily fractions of 2.6 Gy. Acute and late toxicities were graded on the RTOG/EORTC scales. The nPSA and the tnPSA for patients treated with exclusive RT were compared to an equal cohort of 20 patients treated with conventional fractionation and standard conformal radiotherapy. Results. Most of patients (83%) did not develop acute gastrointestinal (GI) toxicity and 50% did not present genitourinary (GU) toxicity. After a median follow-up of 36 months only grade 1 of GU and GI was reported in 6 and 3 patients as late toxicity. Average tnPSA was 30 months. The median value of nPSA after exclusive RT with HT was 0.28 ng/mL and was significantly lower than the median nPSA (0.67 ng/mL) of the conventionally treated cohort (). Conclusions. Hypofractionated RT schedule with HT for prostate cancer treatment reports very low toxicity and reaches a low level of nPSA that might correlate with good outcomes. Salvina Barra, Stefano Vagge, Michela Marcenaro, Gladys Blandino, Giorgia Timon, Giulia Vidano, Dario Agnese, Marco Gusinu, Francesca Cavagnetto, and Renzo Corvò Copyright © 2014 Salvina Barra et al. All rights reserved. Chronic Wounds with Emphasis in Diabetic Foot Ulcers Mon, 17 Mar 2014 12:58:18 +0000 http://www.hindawi.com/journals/bmri/2014/890352/ Jorge Berlanga-Acosta, David G. Armstrong, Gregory S. Schultz, and Luis Herrera-Martinez Copyright © 2014 Jorge Berlanga-Acosta et al. All rights reserved. Low Temperature Plasma: A Novel Focal Therapy for Localized Prostate Cancer? Thu, 13 Mar 2014 16:14:17 +0000 http://www.hindawi.com/journals/bmri/2014/878319/ Despite considerable advances in recent years for the focal treatment of localized prostate cancer, high recurrence rates and detrimental side effects are still a cause for concern. In this review, we compare current focal therapies to a potentially novel approach for the treatment of early onset prostate cancer: low temperature plasma. The rapidly evolving plasma technology has the potential to deliver a wide range of promising medical applications via the delivery of plasma-induced reactive oxygen and nitrogen species. Studies assessing the effect of low temperature plasma on cell lines and xenografts have demonstrated DNA damage leading to apoptosis and reduction in cell viability. However, there have been no studies on prostate cancer, which is an obvious candidate for this novel therapy. We present here the potential of low temperature plasma as a focal therapy for prostate cancer. Adam M. Hirst, Fiona M. Frame, Norman J. Maitland, and Deborah O’Connell Copyright © 2014 Adam M. Hirst et al. All rights reserved. Advanced Imaging for the Early Diagnosis of Local Recurrence Prostate Cancer after Radical Prostatectomy Thu, 13 Mar 2014 13:40:37 +0000 http://www.hindawi.com/journals/bmri/2014/827265/ Currently the diagnosis of local recurrence of prostate cancer (PCa) after radical prostatectomy (RT) is based on the onset of biochemical failure which is defined by two consecutive values of prostate-specific antigen (PSA) higher than 0.2 ng/mL. The aim of this paper was to review the current roles of advanced imaging in the detection of locoregional recurrence. A nonsystematic literature search using the Medline and Cochrane Library databases was performed up to November 2013. Bibliographies of retrieved and review articles were also examined. Only those articles reporting complete data with clinical relevance for the present review were selected. This review article is divided into two major parts: the first one considers the role of PET/CT in the restaging of PCa after RP; the second part is intended to provide the impact of multiparametric-MRI (mp-MRI) in the depiction of locoregional recurrence. Published data indicate an emerging role for mp-MRI in the depiction of locoregional recurrence, while the performance of PET/CT still remains unclear. Moreover Mp-MRI, thanks to functional techniques, allows to distinguish between residual glandular healthy tissue, scar/fibrotic tissue, granulation tissue, and tumour recurrence and it may also be able to assess the aggressiveness of nodule recurrence. Valeria Panebianco, Flavio Barchetti, Daniela Musio, Francesca De Felice, Camilla Proietti, Elena Lucia Indino, Valentina Megna, Orazio Schillaci, Carlo Catalano, and Vincenzo Tombolini Copyright © 2014 Valeria Panebianco et al. All rights reserved. The Role of M1 and M2 Macrophages in Prostate Cancer in relation to Extracapsular Tumor Extension and Biochemical Recurrence after Radical Prostatectomy Tue, 11 Mar 2014 09:32:44 +0000 http://www.hindawi.com/journals/bmri/2014/486798/ Introduction. The aim of our work was to investigate the causal connection between M1 and M2 macrophage phenotypes occurrence and prostate cancer, their correlation with tumor extension (ECE), and biochemical recurrence (BR). Patient and Methods. Clinical and pathological data were prospectively gathered from 93 patients treated with radical prostatectomy. Correlations of commonly used variables were evaluated with uni- and multivariate analysis. The relationship between M1 and M2 occurrence and BR was also assessed with Kaplan-Meier survival analysis. Results. Above all in 63.4% there was a M2 prevalence. M1 occurred more frequently in OC disease, while M2 was more represented in ECE. At univariate analysis biopsy and pathologic GS and M2 were statistically correlated with ECE. Only pathologic GS and M2 confirmed to be correlated with ECE. According to macrophage density BCR free survival curves presented a statistically significant difference. When we stratified our population for M1 and M2,we did not find any statistical difference among curves. At univariate analysis GS, pTNM, and positive margins resulted to be significant predictors of BCR, while M1 and M2 did not achieve the statistical significance. At multivariate analysis, only GS and pathologic stage were independent predictors of BR. Conclusion. In our study patients with higher density of M count were associated with poor prognosis; M2 phenotype was significantly associated with ECE. M. Lanciotti, L. Masieri, M. R. Raspollini, A. Minervini, A. Mari, G. Comito, E. Giannoni, M. Carini, P. Chiarugi, and S. Serni Copyright © 2014 M. Lanciotti et al. All rights reserved. Erratum to “Strategies for Imaging Androgen Receptor Signaling Pathway in Prostate Cancer: Implications for Hormonal Manipulation and Radiation Treatment” Sun, 09 Mar 2014 12:53:09 +0000 http://www.hindawi.com/journals/bmri/2014/437910/ Giovanni L. Gravina, Claudio Festuccia, Pierluigi Bonfili, Mario Di Staso, Pietro Franzese, Valeria Ruggieri, Vladimir M. Popov, Vincenzo Tombolini, Carlo Masciocchi, Eleonora Carosa, Andrea Lenzi, Emmanuele A. Jannini, and Ernesto Di Cesare Copyright © 2014 Giovanni L. Gravina et al. All rights reserved. Extracellular Vesicles in Prostate Cancer: New Future Clinical Strategies? Sun, 23 Feb 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/561571/ Prostate cancer (PCa) is the most common cancer—excluding skin tumors—in men older than 50 years of age. Over time, the ability to diagnose PCa has improved considerably, mainly due to the introduction of prostate-specific antigen (PSA) in the clinical routine. However, it is important to take into account that although PSA is a highly organ-specific marker, it is not cancer-specific. This shortcoming suggests the need to find new and more specific molecular markers. Several emerging PCa biomarkers have been evaluated or are being assessed for their potential use. There is increasing interest in the prospective use of extracellular vesicles as specific markers; it is well known that the content of vesicles is dependent on their cellular origin and is strongly related to the stimulus that triggers the release of the vesicles. Consequently, the identification of a disease-specific molecule (protein, lipid or RNA) associated with vesicles could facilitate their use as novel biological markers. The present review describes several in vitro studies that demonstrate the role of vesicles in PCa progression and several in vivo studies that highlight the potential use of vesicles as PCa biomarkers. Ilaria Giusti and Vincenza Dolo Copyright © 2014 Ilaria Giusti and Vincenza Dolo. All rights reserved. Animal Models of Human Pathology 2013 Thu, 20 Feb 2014 13:32:22 +0000 http://www.hindawi.com/journals/bmri/2014/861424/ Monica Fedele, Oreste Gualillo, and Andrea Vecchione Copyright © 2014 Monica Fedele et al. All rights reserved. The Role of Single Nucleotide Polymorphisms in Predicting Prostate Cancer Risk and Therapeutic Decision Making Wed, 19 Feb 2014 10:02:26 +0000 http://www.hindawi.com/journals/bmri/2014/627510/ Prostate cancer (PCa) is a major health care problem because of its high prevalence, health-related costs, and mortality. Epidemiological studies have suggested an important role of genetics in PCa development. Because of this, an increasing number of single nucleotide polymorphisms (SNPs) had been suggested to be implicated in the development and progression of PCa. While individual SNPs are only moderately associated with PCa risk, in combination, they have a stronger, dose-dependent association, currently explaining 30% of PCa familial risk. This review aims to give a brief overview of studies in which the possible role of genetic variants was investigated in clinical settings. We will highlight the major research questions in the translation of SNP identification into clinical practice. Thomas Van den Broeck, Steven Joniau, Liesbeth Clinckemalie, Christine Helsen, Stefan Prekovic, Lien Spans, Lorenzo Tosco, Hendrik Van Poppel, and Frank Claessens Copyright © 2014 Thomas Van den Broeck et al. All rights reserved. Animal Models in Studies of Cardiotoxicity Side Effects from Antiblastic Drugs in Patients and Occupational Exposed Workers Wed, 19 Feb 2014 09:45:28 +0000 http://www.hindawi.com/journals/bmri/2014/240642/ Cardiotoxicity is an important side effect of cytotoxic drugs and may be a risk factor of long-term morbidity for both patients during therapy and also for staff exposed during the phases of manipulation of antiblastic drugs. The mechanism of cardiotoxicity studied in vitro and in vivo essentially concerns the formation of free radicals leading to oxidative stress, with apoptosis of cardiac cells or immunologic reactions, but other mechanisms may play a role in antiblastic-induced cardiotoxicity. Actually, some new cytotoxic drugs like trastuzumab and cyclopentenyl cytosine show cardiotoxic effects. In this report we discuss the different mechanisms of cardiotoxicity induced by antiblastic drugs assessed using animal models. Monica Lamberti, Giancarlo Giovane, Elpidio M. Garzillo, Franca Avino, Antonia Feola, Stefania Porto, Vincenzo Tombolini, and Marina Di Domenico Copyright © 2014 Monica Lamberti et al. All rights reserved. Diffusion-Weighted Magnetic Resonance Diagnosis of Local Recurrences of Prostate Cancer after Radical Prostatectomy: Preliminary Evaluation on Twenty-Seven Cases Sun, 16 Feb 2014 13:52:35 +0000 http://www.hindawi.com/journals/bmri/2014/780816/ Objectives. To assess the diagnostic performance of diffusion-weighted MR imaging (DWI) in patients affected by prostatic fossa (PF) relapse after radical prostatectomy (RP) for prostatic carcinoma (PC). Methods. Twenty-seven patients showing a nodular lesion in the PF at T2-weighted MR imaging after RP, with diagnosis of PC relapse established by biopsy or PSA determinations, were investigated by DWI. Two readers evaluated the DWI results in consensus and the apparent diffusion coefficient (ADC) of the nodules, separately; a mean value was obtained (ADCm). Results. Relapses did not significantly differ in size in respect of postsurgical benign nodules. The DWI qualitative evaluation showed sensitivity, specificity, accuracy, ppv, and npv values, respectively, of 83.3%, 88.9%, 85.2%, 93.7%, and 72.7% (100%, 87.5%, 95.6%, 93.7%, and 100%, for nodules >6 mm). The intraclass correlation coefficient (ICC) for ADC evaluation between the two readers was 0.852 (95% CI 0.661–0.935; ). The ADCm values for relapses and benign nodules were, respectively,  mm2/sec and  mm2/sec (). Sensitivity, specificity, accuracy, ppv and npv of ADCm were, respectively, 77.8%, 88.9%, 81.8%, 93.3%, and 66.7% (93.3%, 87.5%, 85.4%, 93.3%, and 87.5% for nodules >6 mm). Conclusions. Diffusion-weighted MR imaging is a promising tool in the management of a hyperintense nodule detected by T2-weighted sequences. This might have a relevant importance in contouring radiotherapy treatment volumes. Salvatore Francesco Carbone, Luigi Pirtoli, Veronica Ricci, Tommaso Carfagno, Paolo Tini, Augusto La Penna, Eleonora Cacchiarelli, and Luca Volterrani Copyright © 2014 Salvatore Francesco Carbone et al. All rights reserved. Renal Overexpression of Atrial Natriuretic Peptide and Hypoxia Inducible Factor-1 as Adaptive Response to a High Salt Diet Thu, 13 Feb 2014 13:35:08 +0000 http://www.hindawi.com/journals/bmri/2014/936978/ In the kidney, a high salt intake favors oxidative stress and hypoxia and causes the development of fibrosis. Both atrial natriuretic peptide (ANP) and hypoxia inducible factor (HIF-1) exert cytoprotective effects. We tested the hypothesis that renal expression of ANP and HIF-1 is involved in a mechanism responding to the oxidative stress produced in the kidneys of rats chronically fed a high sodium diet. Sprague-Dawley rats were fed with a normal salt (0.4% NaCl) (NS) or a high salt (8% NaCl) (HS) diet for 3 weeks, with or without the administration of tempol (T), an inhibitor of oxidative stress, in the drinking water. We measured the mean arterial pressure (MAP), glomerular filtration rate (GFR), and urinary sodium excretion (). We evaluated the expression of ANP, HIF-1, and transforming growth factor (TGF-1) in renal tissues by western blot and immunohistochemistry. The animals fed a high salt diet showed increased MAP and levels and enhanced renal immunostaining of ANP, HIF-1, and TGF-1. The administration of tempol together with the sodium overload increased the natriuresis further and prevented the elevation of blood pressure and the increased expression of ANP, TGF-1, and HIF-1 compared to their control. These findings suggest that HIF-1 and ANP, synthesized by the kidney, are involved in an adaptive mechanism in response to a sodium overload to prevent or attenuate the deleterious effects of the oxidative stress and the hypoxia on the development of fibrosis. Silvana Lorena Della Penna, Gabriel Cao, Andrea Carranza, Elsa Zotta, Susana Gorzalczany, Carolina Susana Cerrudo, Natalia Lucía Rukavina Mikusic, Alicia Correa, Verónica Trida, Jorge Eduardo Toblli, María Inés Rosón, and Belisario Enrique Fernández Copyright © 2014 Silvana Lorena Della Penna et al. All rights reserved. A Novel Role for Raloxifene Nanomicelles in Management of Castrate Resistant Prostate Cancer Thu, 06 Feb 2014 16:28:16 +0000 http://www.hindawi.com/journals/bmri/2014/323594/ Of patients with castrate resistant prostate cancer (CRPC), less than 25–33% survive more than five years. Recent studies have implicated estrogen, acting either alone or synergistically with androgens in the development of castrate resistant prostate cancer. Several in vitro and in vivo studies, as well as a limited number of clinical trials, have highlighted the potential of selective estrogen receptor modulators, such as raloxifene (Ral) for the treatment of castrate resistant prostate cancer. However, the poor oral bioavailability and metabolism of selective estrogen receptor modulators limit their efficiency in clinical application. To overcome these limitations, we have used styrene co-maleic acid (SMA) micelle to encapsulate raloxifene. Compared to free drug, SMA-Ral micelles had 132 and 140% higher cytotoxicity against PC3 and DU 145 prostate cell lines, respectively. SMA-Ral effectively inhibits cell cycle progression, increases apoptosis, and alters the integrity of tumor spheroid models. In addition, the micellar system induced changes in expression and localization of estrogen receptors, epidermal growth factor receptor (EGFR), and downstream effectors associated with cell proliferation and survival. Finally, SMA-Ral treatment decreased migration and invasion of castrate resistant prostate cancer cell lines. In conclusion, SMA-Ral micelles can potentially benefit new strategies for clinical management of castrate resistant prostate cancer. Sebastien Taurin, Hayley Nehoff, Thalita van Aswegen, Rhonda J. Rosengren, and Khaled Greish Copyright © 2014 Sebastien Taurin et al. All rights reserved. High Expression of Leucine Zipper-EF-Hand Containing Transmembrane Protein 1 Predicts Poor Prognosis in Head and Neck Squamous Cell Carcinoma Wed, 05 Feb 2014 14:04:46 +0000 http://www.hindawi.com/journals/bmri/2014/850316/ Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is a mitochondrial inner membrane protein and plays an important role in mitochondrial ATP production and biogenesis. High expression levels of LETM1 have been correlated with numerous human malignancies. This study explored the clinicopathological significance of LETM1 expression as a prognostic determinant in head and neck squamous cell carcinoma (HNSCC). HNSCC samples from 176 patients were selected for immunohistochemical staining of LETM1 protein. Correlations between LETM1 overexpression and clinicopathological features of HNSCC were evaluated by Chi-squared tests and Fisher’s exact tests, and relationships between prognostic factors and patient survival were analyzed using Cox proportional hazards models. Our results demonstrated that the strongly positive rate of LETM1 protein was 65.3% in HNSCC, which was significantly higher than in either adjacent nontumor tissue (25.0%) or normal squamous epithelia (6.7%). LETM1 overexpression correlated with poor differentiation, presence of lymph node metastasis, advanced stage, absence of chemoradiotherapy, and 5-year disease-free survival and overall survival rates in HNSCC. Further analysis showed that high LETM1 expression, advanced stage, and nonchemoradiotherapy were significant independent risk factors for mortality in HNSCC. In conclusion, LETM1 plays an important role in the progression of HNSCC and is an independent poor prognostic factor for HNSCC. Liyan Chen, Yang Yang, Shuangping Liu, Longzhen Piao, Yuan Zhang, Zhenhua Lin, and Zhuhu Li Copyright © 2014 Liyan Chen et al. All rights reserved. A Role for T-Lymphocytes in Human Breast Cancer and in Canine Mammary Tumors Sun, 02 Feb 2014 11:53:50 +0000 http://www.hindawi.com/journals/bmri/2014/130894/ Chronic inflammation in the tumor microenvironment has a prominent role in carcinogenesis and benefits the proliferation and survival of malignant cells, promoting angiogenesis and metastasis. Mammary tumors are frequently infiltrated by a heterogeneous population of immune cells where T-lymphocytes have a great importance. Interestingly, similar inflammatory cell infiltrates, cytokine and chemokine expression in humans and canine mammary tumors were recently described. However, in both species, despite all the scientific evidences that appoint for a significant role of T-lymphocytes, a definitive conclusion concerning the effectiveness of T-cell dependent immune mechanisms has not been achieved yet. In the present review, we describe similarities between human breast cancer and canine mammary tumors regarding tumor T-lymphocyte infiltration, such as relationship of TILs and mammary tumors malignancy, association of ratio CD4+/ CD8+ T-cells with low survival rates, promotion of tumor progression by Th2 cells actions, and association of great amounts of Treg cells with poor prognostic factors. This apparent parallelism together with the fact that dogs develop spontaneous tumors in the context of a natural immune system highlight the dog as a possible useful biological model for studies in human breast cancer immunology. Maria Isabel Carvalho, Isabel Pires, Justina Prada, and Felisbina L. Queiroga Copyright © 2014 Maria Isabel Carvalho et al. All rights reserved. Glix 13, a New Drug Acting on Glutamatergic Pathways in Children and Animal Models of Autism Spectrum Disorders Thu, 30 Jan 2014 07:57:23 +0000 http://www.hindawi.com/journals/bmri/2014/234295/ Recently standardized diagnostic instruments have been developed in diagnostic and therapeutic procedures for Autism Spectrumv Disorders (ASD). According to the DSM-5 criteria, individuals with ASD must show symptoms from early childhood. These symptoms are communication deficits and restricted, repetitive patterns of behaviour. It was recently described by Bioinformatic analysis that 99 modified genes were associated with human autism. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes and the NMDA receptor gene family was identified among these. Using ultrasonic vocalizations, it was demonstrated that genetic variation has a direct impact on the expression of social interactions. It has been proposed that specific alleles interact with a social reward process in the adolescent mouse modifying their social interaction and their approach toward each other. In this review we report that the monoclonal antibody-derived tetrapeptide GLYX-13 was found to act as an N-methyl-D-aspartate receptor modulator and possesses the ability to readily cross the blood brain barrier. Treatment with the NMDAR glycine site partial agonist GLYX-13 rescued the deficit in the animal model. Thus, the NMDA receptor has been shown to play a functional role in autism, and GLYX-13 shows promise for the treatment of autism in autistic children. Annamaria Chiara Santini, Giovanna Maria Pierantoni, Raffaele Gerlini, Rosamaria Iorio, Yinka Olabinjo, Alfonso Giovane, Marina Di Domenico, and Carla Sogos Copyright © 2014 Annamaria Chiara Santini et al. All rights reserved. Evaluation of the PI-RADS Scoring System for Classifying mpMRI Findings in Men with Suspicion of Prostate Cancer Mon, 16 Dec 2013 08:44:41 +0000 http://www.hindawi.com/journals/bmri/2013/252939/ Purpose. To evaluate the ESUR scoring system (PI-RADS) for multiparametric MRI of the prostate in clinical routine and to define a reliable way to generate an overall PI-RADS score. Methods. Retrospective analysis of all patients with a history of negative prebiopsies, who underwent 3 Tesla multiparametric MRI from October 2011 to April 2013 (): PI-RADS scores for each single modality were defined. To generate the overall PI-RADS score, an algorithm based approach summing up each single-modality score to a sum-score was compared to a more subjective approach, weighting the single modalities dependent on the radiologist’s impression. Because of ongoing cancer suspicion 73 patients underwent targeted mpMRI-ultrasound image fusion rebiopsy. For this group thresholds for tumor incidences and malignancy were calculated. Results. 39 (53%) out of 73 targeted rebiopsies were cancer positive. The PI-RADS score correlated well with tumor incidence (AUC of 0.86, 95% CI 0.78 to 0.94) and malignancy (AUC 0.84, 95% CI 0.68 to 0.99). Regarding the sum-score a threshold of ≥10 turned out to be reliable for cancer detection (sensitivity 90%, specificity 62%) and for ≥13 for indicating higher malignancy (Gleason ) (sensitivity 80%, specificity 86%). To generate the overall PI-RADS score, the use of an algorithm based approach was more reliable than that of the approach based on the radiologist’s impression. Conclusion. The presented scoring system correlates well with tumor incidence and malignancy. To generate the overall PI-RADS score, it seems to be advisable to use an algorithm based instead of a subjective approach. Daniel Junker, Georg Schäfer, Michael Edlinger, Christian Kremser, Jasmin Bektic, Wolfgang Horninger, Werner Jaschke, and Friedrich Aigner Copyright © 2013 Daniel Junker et al. All rights reserved. Obesity, Insulin Resistance, and Metabolic Syndrome: A Study in WNIN/Ob Rats from a Pancreatic Perspective Sun, 15 Dec 2013 17:31:22 +0000 http://www.hindawi.com/journals/bmri/2013/617569/ Alterations in pancreatic milieu to adapt to physiological shifts occurring in conditions of obesity and metabolic syndrome (MS) have been documented, though mechanisms leading to such a state have remained elusive so far. The data presented here tries to look at the gravity of metabolic insult during the early and prolonged phases of obesity/insulin resistance (IR) depicted in WNIN/Ob strain of rats—an obese euglycemic mutant rat model developed indigenously at our institute which is highly vulnerable for a variety of degenerative diseases. The present results in situ show the participation of several confounding factors in the pancreatic milieu that collectively coprecipitates for a state of profound inflammation in the pancreas (among Mutant compared to Lean/Control) which gets worsened with age. These include hypertrophy, macrophage infiltration (CD11b/TNF/IL6), apoptosis, -cell vacuolation, hyperinsulinemia (HI), and stress markers (RL-77/HSP104/TBARS) all of which correlated well with indices for obesity (2-3 fold), IR (1.5-3 fold), and HI (2-3 fold). Further, supportive data was also obtained from in vitro studies using islet cell cultures amongst phenotypes. Taken together, these results advocate that inflammation was the major precipitating factor to cause islet cell dysfunctions (in situ and in vitro) in these Mutant rats compared to their Lean littermates and parental Control. Vijayalakshmi Venkatesan, Soundarya L. Madhira, Venkata M. Malakapalli, Maniprabha Chalasani, Sarfaraz N. Shaik, Vasudevan Seshadri, Venkaiah Kodavalla, Ramesh R. Bhonde, and Giridharan Nappanveettil Copyright © 2013 Vijayalakshmi Venkatesan et al. All rights reserved. Hsa-miR-15a and Hsa-miR-16-1 Expression Is Not Related to Proliferation Centers Abundance and Other Prognostic Factors in Chronic Lymphocytic Leukemia Thu, 12 Dec 2013 10:51:43 +0000 http://www.hindawi.com/journals/bmri/2013/715391/ Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is the commonest leukemia in adults. Here, we aimed to evaluate hsa-miR-15a/hsa-miR-16-1 expression in CLL tissues by qPCR and correlate it with the other clinicopathological features and clinical outcome. 40 formalin-fixed paraffin-embedded (FFPE) lymph node samples obtained from CLL/SLL patients were classified into two categories, “PCs rich” and “typical.” We found a significant common expression level of 4 miRNAs; however, we did not find any significant relationship between PCs presence and miRNAs expression. Moreover, neither the presence of 13q deletion nor the percentage of cells carrying the deletion strictly correlated with miRNAs expression levels, although a significant number of patients with 13q deletion presented hsa-miR-16-1-3p levels below the median value in normal samples (). Finally, although no correlation was found between the expression of each miRNA and other clinicopathological features (Ki67, CD38, ZAP70, and IGVH@ hypermutations), the OS curves showed a positive trend in patients with miRNAs downregulation, though not statistically significant. In conclusion, we showed for the first time that all miRNAs can be successfully studied in FFPE CLL tissues and that del13q and PCs richness do not strictly correspond to miRNAs downregulation; therefore, a specific evaluation may be envisaged at least in patients enrolled in clinical trials. Maura Rossi, Fabio Fuligni, Maria Ciccone, Claudio Agostinelli, Simona Righi, Marco Luciani, Maria Antonella Laginestra, Gian Matteo Rigolin, Maria Rosaria Sapienza, Anna Gazzola, Claudia Mannu, Antonio Cuneo, Stefano Pileri, and Pier Paolo Piccaluga Copyright © 2013 Maura Rossi et al. All rights reserved. A Nonthoracotomy Myocardial Infarction Model in an Ovine Using Autologous Platelets Tue, 03 Dec 2013 10:14:03 +0000 http://www.hindawi.com/journals/bmri/2013/938047/ Objective. There is a paucity of a biological large animal model of myocardial infarction (MI). We hypothesized that, using autologous-aggregated platelets, we could create an ovine model that was reproducible and more closely mimicked the pathophysiology of MI. Methods. Mepacrine stained autologous platelets from male sheep () were used to create a myocardial infarction via catheter injection into the mid-left anterior descending (LAD) coronary artery. Serial daily serum troponin measurements were taken and tissue harvested on post-embolization day three. Immunofluorescence microscopy was used to detect the mepacrine-stained platelet-induced thrombus, and histology performed to identify three distinct myocardial (infarct, peri-ischemic “border zone,” and remote) zones. Results. Serial serum troponin levels (μg/mL) measured at baseline and peaked at on post-embolization day 1, followed by on day 2 and on day 3. Staining confirmed distinct myocardial regions of inflammation and fibrosis as well as mepacrine-stained platelets as the cause of intravascular thrombosis. Conclusion. We report a reproducible, unique model of a biological myocardial infarction in a large animal model. This technique can be used to study acute, regional myocardial changes following a thrombotic injury. Tyler Spata, Daniel Bobek, Bryan A. Whitson, Sampath Parthasarathy, Peter J. Mohler, Robert S. D. Higgins, and Ahmet Kilic Copyright © 2013 Tyler Spata et al. All rights reserved. Immunohistochemical Analysis of P63 Expression in Odontogenic Lesions Sun, 24 Nov 2013 16:03:29 +0000 http://www.hindawi.com/journals/bmri/2013/624176/ P63 may have a role in tumorigenesis and cytodifferentiation of odontogenic lesions. We investigated the immunohistochemical expression of P63 in a total of 30 cases of odontogenic cysts and tumors. The percentage of positive cells was calculated in the lining of odontogenic cysts and islands of ameloblastoma. P63 expression was evident in all types of odontogenic lesions. P63 was expressed throughout the lining epithelium of odontogenic keratocyst except surface parakeratinized layer. In addition, calcifying odontogenic cyst showed P63 expression in all layers. In almost all radicular and dentigerous cysts, the basal and parabasal layers were immunoreactive. Peripheral cells of ameloblastoma expressed P63; however, stellate reticulum had weaker immunostaining. No significant difference in P63 expression was observed between studied lesions (). Expression of P63 in odontogenic lesions suggests that this protein is important in differentiation and proliferation of odontogenic epithelial cells. However, it seems that it could not be a useful marker to differentiate between aggressive and nonaggressive lesions. P63 also represents a progenitor or basal cell marker, and it is not expressed in mature differentiated cells. Saede Atarbashi Moghadam, Fazele Atarbashi Moghadam, Sepideh Mokhtari, and Ebrahim Eini Copyright © 2013 Saede Atarbashi Moghadam et al. All rights reserved. The Roles of Genetic Polymorphisms and Human Immunodeficiency Virus Infection in Lipid Metabolism Tue, 12 Nov 2013 13:41:11 +0000 http://www.hindawi.com/journals/bmri/2013/836790/ Dyslipidemia has been frequently observed among individuals infected with human immunodeficiency virus type 1 (HIV-1), and factors related to HIV-1, the host, and antiretroviral therapy (ART) are involved in this phenomenon. This study reviews the roles of genetic polymorphisms, HIV-1 infection, and highly active antiretroviral therapy (HAART) in lipid metabolism. Lipid abnormalities can vary according to the HAART regimen, such as those with protease inhibitors (PIs). However, genetic factors may also be involved in dyslipidemia because not all patients receiving the same HAART regimen and with comparable demographic, virological, and immunological characteristics develop variations in the lipid profile. Polymorphisms in a large number of genes are involved in the synthesis of structural proteins, and enzymes related to lipid metabolism account for variations in the lipid profile of each individual. As some genetic polymorphisms may cause dyslipidemia, these allele variants should be investigated in HIV-1-infected patients to identify individuals with an increased risk of developing dyslipidemia during treatment with HAART, particularly during therapy with PIs. This knowledge may guide individualized treatment decisions and lead to the development of new therapeutic targets for the treatment of dyslipidemia in these patients. Elaine Regina Delicato de Almeida, Edna Maria Vissoci Reiche, Ana Paula Kallaur, Tamires Flauzino, and Maria Angelica Ehara Watanabe Copyright © 2013 Elaine Regina Delicato de Almeida et al. All rights reserved. Curcumin Inhibits Tumor Growth and Angiogenesis in an Orthotopic Mouse Model of Human Pancreatic Cancer Sun, 10 Nov 2013 10:05:26 +0000 http://www.hindawi.com/journals/bmri/2013/810423/ Pancreatic cancer is a malignant neoplasm originating from transformed cells arising in tissues forming the pancreas. The best chemotherapeutic agent used to treat pancreatic cancer is the gemcitabine. However, gemcitabine treatment is associated with many side effects. Thus novel strategies involving less toxic agents for treatment of pancreatic cancer are necessary. Curcumin is one such agent that inhibits the proliferation and angiogenesis of a wide variety of tumor cells, through the modulation of many cell signalling pathways. In this study, we investigated whether curcumin plays antitumor effects in MIA PaCa-2 cells. In vitro studies showed that curcumin inhibits the proliferation and enhances apoptosis of MIA PaCa-2 cells. To test whether the antitumor activity of curcumin is also observed in vivo, we generated an orthotopic mouse model of pancreatic cancer by injection of MIA PaCa-2 cells in nude mice. We placed mice on diet containing curcumin at 0.6% for 6 weeks. In these treated mice tumors were smaller with respect to controls and showed a downregulation of the transcription nuclear factor NF-κB and NF-κB-regulated gene products. Overall, our data indicate that curcumin has a great potential in treatment of human pancreatic cancer through the modulation of NF-κB pathway. Sabrina Bimonte, Antonio Barbieri, Giuseppe Palma, Antonio Luciano, Domenica Rea, and Claudio Arra Copyright © 2013 Sabrina Bimonte et al. All rights reserved. 17β-Estradiol Attenuates Poststroke Depression and Increases Neurogenesis in Female Ovariectomized Rats Thu, 07 Nov 2013 11:59:07 +0000 http://www.hindawi.com/journals/bmri/2013/392434/ Studies have linked neurogenesis to the beneficial actions of specific antidepressants. However, whether 17β-estradiol (E2), an antidepressant, can ameliorate poststroke depression (PSD) and whether E2-mediated improvement of PSD is associated with neurogenesis are largely unexplored. In the present study, we found that depressive-like behaviors were observed at the first week after focal ischemic stroke in female ovariectomized (OVX) rats, as measured by sucrose preference and open field test, suggesting that focal cerebral ischemia could induce PSD. Three weeks after middle cerebral artery occlusion (MCAO), rats were treated with E2 for consecutive 14 days. We found that E2-treated rats had significantly improving ischemia-induced depression-like behaviors in the forced-swimming test and sucrose preference test, compared to vehicle-treated group. In addition, we also found that BrdU- and doublecortin (DCX)-positive cells in the dentate gyrus of the hippocampus and the subventricular zone (SVZ) were significantly increased in ischemic rats after E2 treatment, compared to vehicle-treated group. Our data suggest that focal cerebral ischemia can induce PSD, and E2 can ameliorate PSD. In addition, newborn neurons in the hippocampus may play an important role in E2-mediated antidepressant like effect after ischemic stroke. Yifan Cheng, Qiaoer Su, Bei Shao, Jianhua Cheng, Hong Wang, Liuqing Wang, Zhenzhen Lin, Linhui Ruan, Qichuan ZhuGe, and Kunlin Jin Copyright © 2013 Yifan Cheng et al. All rights reserved. A Posteriori Comparison of Natural and Surgical Destabilization Models of Canine Osteoarthritis Thu, 31 Oct 2013 15:06:31 +0000 http://www.hindawi.com/journals/bmri/2013/180453/ For many years Canis familiaris, the domestic dog, has drawn particular interest as a model of osteoarthritis (OA). Here, we optimized the dog model of experimental OA induced by cranial cruciate ligament sectioning. The usefulness of noninvasive complementary outcome measures, such as gait analysis for the limb function and magnetic resonance imaging for structural changes, was demonstrated in this model. Relationships were established between the functional impairment and the severity of structural changes including the measurement of cartilage thinning. In the dog model of naturally occurring OA, excellent test-retest reliability was denoted for the measurement of the limb function. A criterion to identify clinically meaningful responders to therapy was determined for privately owned dogs undergoing clinical trials. In addition, the recording of accelerometer-based duration of locomotor activity showed strong and complementary agreement with the biomechanical limb function. The translation potential of these models to the human OA condition is underlined. A preclinical testing protocol which combines the dog model of experimental OA induced by cranial cruciate ligament transection and the Dog model of naturally occurring OA offers the opportunity to further investigate the structural and functional benefits of disease-modifying strategies. Ultimately, a better prediction of outcomes for human clinical trials would be brought. Maxim Moreau, Jean-Pierre Pelletier, Bertrand Lussier, Marc-André d’Anjou, Laurent Blond, Johanne-Martel Pelletier, Jérôme R. E. del Castillo, and Eric Troncy Copyright © 2013 Maxim Moreau et al. All rights reserved. Modification of a Rodent Hindlimb Model of Secondary Lymphedema: Surgical Radicality versus Radiotherapeutic Ablation Wed, 30 Oct 2013 11:57:02 +0000 http://www.hindawi.com/journals/bmri/2013/208912/ Secondary lymphedema is an intractable disease mainly caused by damage of the lymphatic system during surgery, yet studies are limited by the lack of suitable animal models. The purpose of this study was to create an improved model of secondary lymphedema in the hindlimbs of rodents with sustained effects and able to mimic human lymphedema. This was achieved by combining previously reported surgical methods and radiation to induce chronic lymphedema. Despite more radical surgical destruction of superficial and deep lymphatic vessels, surgery alone was not enough to sustain increased hindlimb volume. Radiotherapy was necessary to prolong these effects, with decreased lymphatic flow on lymphoscintigraphy, but hindlimb necrosis occurred after 4 weeks due to radiation toxicity. The applicability of this model for studies of therapeutic lymphangiogenesis was subsequently tested by injecting muscle-derived stem cells previously cocultured with the supernatant of human lymphatic endothelial cells in vitro. There was a tendency for increased lymphatic flow which significantly increased lymphatic vessel formation after cell injection, but attenuation of hindlimb volume was not observed. These results suggest that further refinement of the rodent hindlimb model is needed by titration of adequate radiation dosage, while stem cell lymphangiogenesis seems to be a promising approach. Hyung Sub Park, In Mok Jung, Geum Hee Choi, Soli Hahn, Young Sun Yoo, and Taeseung Lee Copyright © 2013 Hyung Sub Park et al. All rights reserved. Strategies for Imaging Androgen Receptor Signaling Pathway in Prostate Cancer: Implications for Hormonal Manipulation and Radiation Treatment Tue, 29 Oct 2013 11:51:00 +0000 http://www.hindawi.com/journals/bmri/2013/460546/ Prostate cancer (Pca) is a heterogeneous disease; its etiology appears to be related to genetic and epigenetic factors. Radiotherapy and hormone manipulation are effective treatments, but many tumors will progress despite these treatments. Molecular imaging provides novel opportunities for image-guided optimization and management of these treatment modalities. Here we reviewed the advances in targeted imaging of key biomarkers of androgen receptor signaling pathways. A computerized search was performed to identify all relevant studies in Medline up to 2013. There are well-known limitations and inaccuracies of current imaging approaches for monitoring biological changes governing tumor progression. The close integration of molecular biology and clinical imaging could ease the development of new molecular imaging agents providing novel tools to monitor a number of biological events that, until a few years ago, were studied by conventional molecular assays. Advances in translational research may represent the next step in improving the oncological outcome of men with Pca who remain at high risk for systemic failure. This aim may be obtained by combining the anatomical properties of conventional imaging modalities with biological information to better predict tumor response to conventional treatments. Gravina Giovanni Luca, Claudio Festuccia, Pierluigi Bonfili, Mario Di Staso, Pietro Franzese, Valeria Ruggieri, Vladimir M. Popov, Vincenzo Tombolini, Carlo Masciocchi, Eleonora Carosa, Andrea Lenzi, Emmanuele A. Jannini, and Ernesto Di Cesare Copyright © 2013 Gravina Giovanni Luca et al. All rights reserved. Differentially Methylated Loci Distinguish Ovarian Carcinoma Histological Types: Evaluation of a DNA Methylation Assay in FFPE Tissue Tue, 24 Sep 2013 09:54:42 +0000 http://www.hindawi.com/journals/bmri/2013/815894/ Epigenomic markers can identify tumor subtypes, but few platforms can accommodate formalin-fixed paraffin-embedded (FFPE) tumor tissue. We tested different amounts of bisulfite-converted (bs) DNA from six FFPE ovarian carcinomas (OC) of serous, endometrioid, and clear cell histologies and two HapMap constitutional genomes to evaluate the performance of the GoldenGate methylation assay. Methylation status at each 1,505 CpG site was expressed as β-values. Comparing 400 ng versus 250 ng bsDNA, reproducibility of the assay ranged from Spearman to 0.90, indicating that β-values obtained with a lower DNA amount did not always correlate well with the higher amount. Average methylation for the six samples was higher using 250 ng (β-value = 0.45, ) than with 400 ng (β-value = 0.36, ). Reproducibility between duplicate HapMap samples ( to 0.92) was also variable. Using 400 ng input bsDNA, THBS2 and ERG were differentially methylated across all histologic types and between endometrioid and clear cell types at <0.1% false discovery rate. Methylation did not always correlate with gene expression ( to 0.15). We found that lower bsDNA overestimates methylation, and, using higher bsDNA amounts, we confirmed a previous report of higher methylation of THBS2 in clear cell OC, which could provide new insight into biological pathways that distinguish OC histological types. Linda E. Kelemen, Martin Köbel, Angela Chan, Soreh Taghaddos, and Irina Dinu Copyright © 2013 Linda E. Kelemen et al. All rights reserved. A Novel Closed-Chest Porcine Model of Chronic Ischemic Heart Failure Suitable for Experimental Research in Cardiovascular Disease Sun, 15 Sep 2013 14:43:04 +0000 http://www.hindawi.com/journals/bmri/2013/410631/ Cardiac pathologies are among the leading causes of mortality and morbidity in industrialized countries, with myocardial infarction (MI) representing one of the major conditions leading to heart failure (HF). Hitherto, the development of consistent, stable, and reproducible models of closed-chest MI in large animals, meeting the clinical realism of a patient with HF subsequent to chronic ischemic necrosis, has not been successful. We hereby report the design and ensuing application of a novel porcine experimental model of closed-chest chronic ischemia suitable for biomedical research, mimicking post-MI HF. We also emphasize the key procedural steps involved in replicating this unprecedented model, from femoral artery and vein catheterization to MI induction by permanent occlusion of the left anterior descending coronary artery through superselective deployment of platinum-nylon coils, as well as endomyocardial biopsy sampling for histologic analysis and cell harvesting. Our model could indeed represent a valuable contribution and tool for translational research, providing precious insights to understand and overcome the many hurdles concerning, and currently quenching, the preclinical steps mandatory for the clinical translation of new cardiovascular technologies for personalized HF treatments. Giuseppe Biondi-Zoccai, Elena De Falco, Mariangela Peruzzi, Elena Cavarretta, Massimo Mancone, Omar Leoni, Maria Emiliana Caristo, Marzia Lotrionte, Antonino G. M. Marullo, Antonio Amodeo, Luca Pacini, Antonella Calogero, Vincenzo Petrozza, Isotta Chimenti, Fabrizio D'Ascenzo, and Giacomo Frati Copyright © 2013 Giuseppe Biondi-Zoccai et al. All rights reserved. Proliferative Activity in Libyan Breast Cancer with Comparison to European and Central African Patients Wed, 11 Sep 2013 17:02:28 +0000 http://www.hindawi.com/journals/bmri/2013/831714/ Background. We evaluated the relation of proliferative indices with clinicopathological features and prognosis in breast cancer (BC) of Libyan female patients. The data were compared with corresponding results in Finland and Nigeria. Patients and Methods. Histological samples of breast cancer from 130 patients were retrospectively studied. Mitotic activity index (MAI) and standardized mitotic index (SMI) were estimated. Results. There were statistically significant correlations between the proliferative indices and most clinicopathological features, with the strongest association observed for histological grade ( for SMI and for MAI). The proliferative differences between Libyan, Nigerian, and Finnish population were prominent. The mean values of SMI and MAI in Libyan BC patients were 32.1 mitotic figures per square millimeter and 27.3 mitotic figures per 10 high-power fields, respectively. This is clearly lower than those in Nigeria but much higher than those in Finland. The differences between countries are seen in whole material and are also present in subgroups. The results indicated that mitotic activities can be reliable prognostic indicators in Libyan BCs, as they were among Finnish and Nigerian females. Univariate and multivariate analyses found at cut-offs of 19 and 44 mitosis/mm2 of SMI were the most significant prognostic factors. Conclusions. Proliferative indices with careful estimation of the MAI and SMI could be applied as quantitative criteria for Libyan BC to separate the patients into good, moderate, and bad prognosis groups. Jamela Boder, Fathi Abdalla, Mohamed Elfagieh, Abdelbaset Buhmeida, and Yrjö Collan Copyright © 2013 Jamela Boder et al. All rights reserved. Molecular Diagnostics Tue, 03 Sep 2013 14:22:11 +0000 http://www.hindawi.com/journals/bmri/2013/387486/ Akanchha Kesari, Ashwin Dalal, Girdhari Lal, and Sachchida Nand Pandey Copyright © 2013 Akanchha Kesari et al. All rights reserved. Models of Abnormal Scarring Tue, 03 Sep 2013 09:03:53 +0000 http://www.hindawi.com/journals/bmri/2013/423147/ Keloids and hypertrophic scars are thick, raised dermal scars, caused by derailing of the normal scarring process. Extensive research on such abnormal scarring has been done; however, these being refractory disorders specific to humans, it has been difficult to establish a universal animal model. A wide variety of animal models have been used. These include the athymic mouse, rats, rabbits, and pigs. Although these models have provided valuable insight into abnormal scarring, there is currently still no ideal model. This paper reviews the models that have been developed. Bommie F. Seo, Jun Yong Lee, and Sung-No Jung Copyright © 2013 Bommie F. Seo et al. All rights reserved. The Ehrlich Tumor Induces Pain-Like Behavior in Mice: A Novel Model of Cancer Pain for Pathophysiological Studies and Pharmacological Screening Thu, 29 Aug 2013 15:20:22 +0000 http://www.hindawi.com/journals/bmri/2013/624815/ The Ehrlich tumor is a mammary adenocarcinoma of mice that can be developed in solid and ascitic forms depending on its administration in tissues or cavities, respectively. The present study investigates whether the subcutaneous plantar administration of the Ehrlich tumor cells induces pain-like behavior and initial pharmacological susceptibility characteristics. The Ehrlich tumor cells (1 × 104–107 cells) induced dose-dependent mechanical hyperalgesia (electronic version of the von Frey filaments), paw edema/tumor growth (caliper), and flinches compared with the saline group between days 2 and 12. There was no difference between doses of cells regarding thermal hyperalgesia in the hot-plate test. Indomethacin (a cyclooxygenase inhibitor) and amitriptyline hydrochloride (a tricyclic antidepressant) treatments did not affect flinches or thermal and mechanical hyperalgesia. On the other hand, morphine (an opioid) inhibited the flinch behavior and the thermal and mechanical hyperalgesia. These effects of morphine on pain-like behavior were prevented by naloxone (an opioid receptor antagonist) treatment. None of the treatments affected paw edema/tumor growth. The results showed that, in addition to tumor growth, administration of the Ehrlich tumor cells may represent a novel model for the study of cancer pain, specially the pain that is susceptible to treatment with opioids, but not to cyclooxygenase inhibitor or to tricyclic antidepressant. Cassia Calixto-Campos, Ana C. Zarpelon, Mab Corrêa, Renato D. R. Cardoso, Felipe A. Pinho-Ribeiro, Rubens Cecchini, Estefania G. Moreira, Jefferson Crespigio, Catia C. F. Bernardy, Rubia Casagrande, and Waldiceu A. Verri Jr. Copyright © 2013 Cassia Calixto-Campos et al. All rights reserved. Difference of Morphology and Immunophenotype between Central and Peripheral Squamous Cell Carcinomas of the Lung Thu, 29 Aug 2013 14:00:21 +0000 http://www.hindawi.com/journals/bmri/2013/157838/ Background. Recent agents, that is, pemetrexed and bevacizumab, have shown reproductive negative association between squamous histology. According to these agents' effectiveness, ruling out of the squamous histology is a significant issue for surgical pathologists. Several articles have proposed the distinction of peripheral type from central type of squamous cell carcinoma (SqCC) due to its similarity to adenocarcinoma, although little evidence to support the difference between these two types was published. In this study, we compared the clinicopathologic findings of central and peripheral pulmonary SqCCs. Material and Methods. 15 central and 35 peripheral types of SqCC from 2005 to 2010 were examined. Twelve morphological features were scored based on their intensity in the original H&E slides, and then, tissue microarray holding triplicated cores from 43 cases was immunohistochemically examined for cytokeratin (CK)7, CK14, TTF-1, Napsin A, p63, CK34βE12, CK5/6, and p53. Result. Most of the histological findings did not separate central and peripheral SqCCs; only the presence of emphysema, interstitial fibrosis, and entrapped pneumocytes inside the tumor showed statistic predominance in peripheral SqCC. This is the first immunophenotypic research in the central and peripheral types of SqCC. Tomayoshi Hayashi, Hisao Sano, Ryoko Egashira, Kazuhiro Tabata, Tomonori Tanaka, Toshiyuki Nakayama, Yukio Kashima, Takashi Hori, Sayuri Nunomura, and Junya Fukuoka Copyright © 2013 Tomayoshi Hayashi et al. All rights reserved. The Role of Morphine in Animal Models of Human Cancer: Does Morphine Promote or Inhibit the Tumor Growth? Wed, 28 Aug 2013 09:02:41 +0000 http://www.hindawi.com/journals/bmri/2013/258141/ Morphine, a highly potent analgesic agent, is widely used to relieve pain and suffering of patients with cancer. Additionally, it has been reported that morphine is important in the regulation of cancerous tissue. Morphine relieves pain by acting directly on the central nervous system, although its activities on peripheral tissues are responsible for many adverse side effects. For these reasons, it is very important also to understand the role of morphine in cancer treatment. The published literature reporting the effect of morphine on tumor growth presents some discrepancies, with reports suggesting that morphine may either promote or inhibit the tumor growth. It has been also demonstrated that morphine modulates angiogenesis which is important for primary tumour growth, invasiveness, and the development of metastasis. This review will focus on the latest findings on the role of morphine in the regulation of cancer cell growth and angiogenesis. Sabrina Bimonte, Antonio Barbieri, Giuseppe Palma, and Claudio Arra Copyright © 2013 Sabrina Bimonte et al. All rights reserved. Brain Tumor Classification Using AFM in Combination with Data Mining Techniques Sun, 25 Aug 2013 08:58:09 +0000 http://www.hindawi.com/journals/bmri/2013/176519/ Although classification of astrocytic tumors is standardized by the WHO grading system, which is mainly based on microscopy-derived, histomorphological features, there is great interobserver variability. The main causes are thought to be the complexity of morphological details varying from tumor to tumor and from patient to patient, variations in the technical histopathological procedures like staining protocols, and finally the individual experience of the diagnosing pathologist. Thus, to raise astrocytoma grading to a more objective standard, this paper proposes a methodology based on atomic force microscopy (AFM) derived images made from histopathological samples in combination with data mining techniques. By comparing AFM images with corresponding light microscopy images of the same area, the progressive formation of cavities due to cell necrosis was identified as a typical morphological marker for a computer-assisted analysis. Using genetic programming as a tool for feature analysis, a best model was created that achieved 94.74% classification accuracy in distinguishing grade II tumors from grade IV ones. While utilizing modern image analysis techniques, AFM may become an important tool in astrocytic tumor diagnosis. By this way patients suffering from grade II tumors are identified unambiguously, having a less risk for malignant transformation. They would benefit from early adjuvant therapies. Marlene Huml, René Silye, Gerald Zauner, Stephan Hutterer, and Kurt Schilcher Copyright © 2013 Marlene Huml et al. All rights reserved. PSCA and Oct-4 Expression in the Benign and Malignant Lesions of Gallbladder: Implication for Carcinogenesis, Progression, and Prognosis of Gallbladder Adenocarcinoma Thu, 01 Aug 2013 13:51:33 +0000 http://www.hindawi.com/journals/bmri/2013/648420/ PSCA and Oct-4 have been thought as markers of cancer stem cells. Although overexpression of PSCA and Oct-4 in cancer has been reported, little is known about the clinical and pathological significance with PSCA and Oct-4 expression in gallbladder adenocarcinoma. In this study, overexpression of PSCA and Oct-4 was detected in gallbladder adenocarcinoma (54.6% and 55.6%). Less expression of PSCA and Oct-4 was detected in the pericancerous tissues (19.6% and 21.7%), gallbladder polyps (13.3% and 13.3%), and gallbladder epithelium with chronic cholecystitis (14.3% and 14.3%). The overexpression of PSCA and Oct-4 was significantly associated with differentiation, tumor mass, lymph node metastasis, invasion of gallbladder adenocarcinoma, and decreased overall survival. Our study suggested that overexpression of PSCA and Oct-4 might be closely related to the carcinogenesis, progression, metastasis, or invasive potential and prognosis of gallbladder carcinoma. Qiong Zou, Leping Yang, Zhulin Yang, Jiangsheng Huang, and Xi Fu Copyright © 2013 Qiong Zou et al. All rights reserved. Development of Multiexon Skipping Antisense Oligonucleotide Therapy for Duchenne Muscular Dystrophy Wed, 31 Jul 2013 12:57:35 +0000 http://www.hindawi.com/journals/bmri/2013/402369/ Duchenne muscular dystrophy (DMD) is an incurable, X-linked progressive muscle degenerative disorder that results from the absence of dystrophin protein and leads to premature death in affected individuals due to respiratory and/or cardiac failure typically by age of 30. Very recently the exciting prospect of an effective oligonucleotide therapy has emerged which restores dystrophin protein expression to affected tissues in DMD patients with highly promising data from a series of clinical trials. This therapeutic approach is highly mutation specific and thus is personalised. Therefore DMD has emerged as a model genetic disorder for understanding and overcoming of the challenges of developing personalised genetic medicines. One of the greatest weaknesses of the current oligonucleotide approach is that it is a mutation-specific therapy. To address this limitation, we have recently demonstrated that exons 45–55 skipping therapy has the potential to treat clusters of mutations that cause DMD, which could significantly reduce the number of compounds that would need to be developed in order to successfully treat all DMD patients. Here we discuss and review the latest preclinical work in this area as well as a variety of accompanying issues, including efficacy and potential toxicity of antisense oligonucleotides, prior to human clinical trials. Yoshitsugu Aoki, Toshifumi Yokota, and Matthew J. A. Wood Copyright © 2013 Yoshitsugu Aoki et al. All rights reserved. Hematological Disorders following Gastric Bypass Surgery: Emerging Concepts of the Interplay between Nutritional Deficiency and Inflammation Thu, 25 Jul 2013 11:01:07 +0000 http://www.hindawi.com/journals/bmri/2013/205467/ Obesity and the associated metabolic syndrome are among the most common and detrimental metabolic diseases of the modern era, affecting over 50% of the adult population in the United States. Surgeries designed to promote weight loss, known as bariatric surgery, typically involve a gastric bypass procedure and have shown high success rates for treating morbid obesity. However, following gastric bypass surgery, many patients develop chronic anemia, most commonly due to iron deficiency. Deficiencies of vitamins B1, B12, folate, A, K, D, and E and copper have also been reported after surgery. Copper deficiency can cause hematological abnormalities with or without neurological complications. Despite oral supplementation and normal serum concentrations of iron, copper, folate, and vitamin B12, some patients present with persistent anemia after surgery. The evaluation of hematologic disorders after gastric bypass surgery must take into account issues unique to the postsurgery setting that influence the development of anemia and other cytopenias. In this paper, the clinical characteristics and differential diagnosis of the hematological disorders associated with gastric bypass surgery are reviewed, and the underlying molecular mechanisms are discussed. Mingyi Chen, Amrita Krishnamurthy, Ali R. Mohamed, and Ralph Green Copyright © 2013 Mingyi Chen et al. All rights reserved. The Prognostic Significance of CD44V6, CDH11, and -Catenin Expression in Patients with Osteosarcoma Thu, 18 Jul 2013 10:43:24 +0000 http://www.hindawi.com/journals/bmri/2013/496193/ This study aimed to examine the expression of and the relationship between CD44V6, CDH11, and β-catenin. The expression of these cell adhesion molecules was detected in 90 osteosarcoma and 20 osteochondroma specimens using immunohistochemistry. Associations between these parameters and clinicopathological data were also examined. The expression rates of CD44V6, CDH11, and β-catenin were 25.0% (5/20), 70.0% (14/20), and 20.0% (4/20) in osteochondroma specimens, respectively. Compared to osteochondromas, the proportions of expression of CD44V6 and β-catenin in osteosarcoma specimens increased to 65.6% (59/90) and 60.0% (54/90), respectively. However, the expression rate of CDH11 in osteosarcomas was reduced to 40.0% (36/90). The expression of these markers was significantly associated with metastasis and overall survival (). Survival analysis revealed that patients with increased expression of CD44V6 and β-catenin as well as decreased expression of CDH11 were correlated with a shorter survival time. Multivariate analysis indicated that clinical stage, metastasis status, and the expression of CD44V6, CDH11, and β-catenin were found to be associated with overall survival. Further, the expression of β-catenin and that of CD44V6 were positively correlated with each other. Thus, our results indicated abnormal expression of CD44V6, CDH11, and β-catenin in osteosarcomas and osteochondromas, which may provide important indicators for further research. Zhouming Deng, Guangfeng Niu, Lin Cai, Renxiong Wei, and Xiaolei Zhao Copyright © 2013 Zhouming Deng et al. All rights reserved. Whole Blood Platelet Aggregation and Release Reaction Testing in Uremic Patients Wed, 26 Jun 2013 11:28:45 +0000 http://www.hindawi.com/journals/bmri/2013/486290/ Background. Platelet function analysis utilizing platelet-rich plasma and optical density based aggregometry fails to identify patients at risk for uremia associated complications. Methods. We employed whole blood platelet aggregation analysis based on impedance as well as determination of ATP release from platelet granules detected by a chemiluminescence method. Ten chronic kidney disease (CKD) stage 4 or 5 predialysis patients underwent platelet evaluation. Our study aims to evaluate this platform in this patient population to determine if abnormalities could be detected. Results. Analysis revealed normal aggregation and ATP release to collagen, ADP, and high-dose ristocetin. ATP release had a low response to arachidonic acid (0.37 ± 0.26 nmoles, reference range: 0.6–1.4 nmoles). Platelet aggregation to low-dose ristocetin revealed an exaggerated response (20.9 ± 18.7 ohms, reference range: 0–5 ohms). Conclusions. Whole blood platelet analysis detected platelet dysfunction which may be associated with bleeding and thrombotic risks in uremia. Diminished ATP release to arachidonic acid (an aspirin-like defect) in uremic patients may result in platelet associated bleeding. An increased aggregation response to low-dose ristocetin (a type IIb von Willebrand disease-like defect) is associated with thrombus formation. This platelet hyperreactivity may be associated with a thrombotic diathesis as seen in some uremic patients. Jay Zeck, Jason Schallheim, Susie Q. Lew, and Louis DePalma Copyright © 2013 Jay Zeck et al. All rights reserved. Expression of Multidrug Resistance-Associated Protein 2 in Human Gallbladder Carcinoma Sun, 16 Jun 2013 15:40:01 +0000 http://www.hindawi.com/journals/bmri/2013/527534/ Gallbladder carcinoma (GBCA) is one of the most aggressive malignancies. It is usually diagnosed at an advanced stage, and prognosis remains poor despite advances in imaging techniques and aggressive surgical treatment. Overexpression of multidrug resistance-associated proteins (MRPs) in tumor cells is a major cause of the intrinsic multidrug resistance phenotype. Despite the documented importance of MRP expression in many carcinomas, the prognostic significance of MRP2 expression in primary GBCA is not known. Immunostaining for MRP2 was performed on tissue samples obtained from 143 patients with GBCA. We examined the association between MRP expression and clinicopathological characteristics and outcome of patients with GBCA. GBCA demonstrated MRP2 immunoreactivity in the apicolateral membranes of epithelial cells. MRP2 expression was positive in 53.1% (76/143) of GBCA samples. Positive MRP2 expression was significantly associated with the presence of local recurrence (), lymphatic invasion (), vascular invasion (), and perineural invasion (). In addition, the median survival time of patients with MRP2-positive GBCA (15 months) was significantly shorter than that of patients with MRP2-negative GBCA (85 months, ). We found that the expression of MRP2 in GBCA contributed to aggressive tumor behavior and poor prognosis, suggesting that MRP2 expression can be used as a potential prognostic biomarker of GBCA. Hyun-Soo Kim, Nam Chul Kim, Kyu Hee Chae, Gun Kim, Won Seo Park, Yong-Koo Park, and Youn Wha Kim Copyright © 2013 Hyun-Soo Kim et al. All rights reserved. Gastric Tissue Damage Analysis Generated by Ischemia: Bioimpedance, Confocal Endomicroscopy, and Light Microscopy Sat, 15 Jun 2013 17:42:19 +0000 http://www.hindawi.com/journals/bmri/2013/824682/ The gastric mucosa ischemic tissular damage plays an important role in critical care patients’ outcome, because it is the first damaged tissue by compensatory mechanism during shock. The aim of the study is to relate bioimpedance changes with tissular damage level generated by ischemia by means of confocal endomicroscopy and light microscopy. Bioimpedance of the gastric mucosa and confocal images were obtained from Wistar male rats during basal and ischemia conditions. They were anesthetized, and stain was applied (fluorescein and/or acriflavine). The impedance spectroscopy catheter was inserted and then confocal endomicroscopy probe. After basal measurements and biopsy, hepatic and gastric arteries clamping induced ischemia. Finally, pyloric antrum tissue was preserved in buffered formaldehyde (10%) for histology processing using light microscopy. Confocal images were equalized, binarized, and boundary defined, and infiltrations were quantified. Impedance and infiltrations increased with ischemia showing significant changes between basal and ischemia conditions (). Light microscopy analysis allows detection of general alterations in cellular and tissular integrity, confirming gastric reactance and confocal images quantification increments obtained during ischemia. Nohra E. Beltran, Laura E. Garcia, and Mario Garcia-Lorenzana Copyright © 2013 Nohra E. Beltran et al. All rights reserved. Molecular Characterization and Clinical Impact of TMPRSS2-ERG Rearrangement on Prostate Cancer: Comparison between FISH and RT-PCR Tue, 28 May 2013 07:50:13 +0000 http://www.hindawi.com/journals/bmri/2013/465179/ Prostate cancer (PCa) is a very heterogeneous disease, and there are constraints in its current diagnosis. Serum PSA levels, digital rectal examination (DRE), and histopathologic analysis often drive to overdiagnosis and overtreatment. Since 2005, the presence of the genetic rearrangement between transmembrane-serine protease gene (TMPRSS2) and the erythroblast transformation-specific (ETS) member ERG (v-ets erythroblastosis virus E26 oncogene homolog avian) has been demonstrated in almost half of PCa cases. Both FISH and RT-PCR are useful tools for detecting these rearrangements, but very few comparatives between both techniques have been published. In this study, we included FFPE tumors from 294 PCa patients treated with radical prostatectomy with more than 5 years of followup. We constructed a total of 20 tissue microarrays in order to perform break-apart and tricolor probe FISH approaches that were compared with RT-PCR, showing a concordance of 80.6% (). The presence of TMPRSS2-ERG rearrangement was observed in 56.6% of cases. No association between TMPRSS2-ERG status and clinicopathological parameters nor biochemical progression and clinical progression free survival was found. In conclusion, this study demonstrates that both FISH and RT-PCR are useful tools in the assessment of the TMPRSS2-ERG fusion gene status in PCa patients and that this genetic feature per se lacks prognostic value. A. Fernández-Serra, L. Rubio, A. Calatrava, J. Rubio-Briones, R. Salgado, R. Gil-Benso, B. Espinet, Z. García-Casado, and J. A. López-Guerrero Copyright © 2013 A. Fernández-Serra et al. All rights reserved. Revealing the Mechanism of In Vitro Wound Healing Properties of Citrus tamurana Extract Thu, 02 May 2013 10:00:35 +0000 http://www.hindawi.com/journals/bmri/2013/963457/ In the present investigation, we examined the effect of Hyuganatsu (Citrus tamurana) extract (HE) on skin fibroblast (TIG-119) proliferation and migration during in vitro wound healing. HE selectively inhibited proliferation of TIG-119 cells at higher concentration (>1.0 mg/mL); at lower concentrations (0.1, 0.25, 0.5, and 0.75 mg/mL), it exhibited linear and time-dependent cell proliferation. In vitro scratch wound healing studies showed that the HE also accelerated the migration of cells towards the wounded region. Cytometric analysis demonstrated that HE extract did not alter G1/0 and S phases of cell cycle in any concentration studied; however, G2/M phases of cell cycle were significantly () accelerated at 0.75 mg/mL dose. RT-PCR and Western blotting analysis indicated that HE markedly overexpressed levels of Rac-1, Rho-A, and Cdc-42 mRNA and the respective proteins. Cyclin-dependent kinases (Cdk-1 and -2) gene expression activity was significantly () increased, but protein content decreased during treatment with HE. The induction of Cdk-1 and -2 by HE was abolished by inhibitors, transcription (DRB), and translation (CHX), implying transcriptional regulation that required de novo protein synthesis. Madhyastha Harishkumar, Yamaguchi Masatoshi, Sameshima Hiroshi, Ikenoue Tsuyomu, and Maruyama Masugi Copyright © 2013 Madhyastha Harishkumar et al. All rights reserved. Current Aspects in the Pathophysiology and Treatment of Chronic Wounds in Diabetes Mellitus Sun, 07 Apr 2013 15:06:38 +0000 http://www.hindawi.com/journals/bmri/2013/385641/ Impaired wound healing is a frequent and very severe problem in patients with diabetes mellitus, yet little is known about the underlying pathomechanisms. In this paper we review the biology of wound healing with particular attention to the pathophysiology of chronic wounds in diabetic patients. The standard treatment of diabetic ulcers includes measures to optimize glycemic control as well as extensive debridement, infection elimination by antibiotic therapy based on wound pathogen cultures, the use of moisture dressings, and offloading high pressure from the wound bed. In this paper we discuss novel adjuvant therapies with particular reference to the use of autologous skin transplants for the treatment of diabetic foot ulcers which do not respond to standard care. Elena Tsourdi, Andreas Barthel, Hannes Rietzsch, Andreas Reichel, and Stefan R. Bornstein Copyright © 2013 Elena Tsourdi et al. All rights reserved. Treatment of Nonhealing Diabetic Lower Extremity Ulcers with Skin Graft and Autologous Platelet Gel: A Case Series Sun, 31 Mar 2013 17:39:30 +0000 http://www.hindawi.com/journals/bmri/2013/837620/ Lower extremity ulcers in diabetic patients are difficult to treat. Recently, the use of human blood platelet-derived components in this indication has been raising interest. In this study, we have evaluated the safety and efficacy of the combination of autologous platelet gel (PG) and skin graft for treating large size recalcitrant ulcers. Eight consecutive diabetic patients aged 25 to 82 with nine nonhealing lower extremity ulcers (median size of 50 cm2; range 15–150 cm2) were treated. Skin ulcer was debrided, and the wound was sprayed after 7 to 10 days with autologous platelet-rich plasma and thrombin. Thin split-thickness skin graft with multiple slits was then applied on the wound bed and fixed with staples or cat-gut sutures. There were no adverse reactions observed during the study. Eight out of 9 skin grafts took well. The interval between skin graft and complete wound healing ranged from 2 to 3 weeks in the 8 successful cases. No ulcer recurrence was noted in those patients during the follow-up period of 2 to 19 months. In this study, the combination of autologous platelet gel and skin grafting has proven beneficial to heal large-size recalcitrant ulcers. Yuan-Sheng Tzeng, Shou-Cheng Deng, Chih-Hsing Wang, Jui-Che Tsai, Tim-Mo Chen, and Thierry Burnouf Copyright © 2013 Yuan-Sheng Tzeng et al. All rights reserved. Mass Spectrometry-Based Proteomics in Molecular Diagnostics: Discovery of Cancer Biomarkers Using Tissue Culture Sun, 17 Mar 2013 15:31:19 +0000 http://www.hindawi.com/journals/bmri/2013/783131/ Accurate diagnosis and proper monitoring of cancer patients remain a key obstacle for successful cancer treatment and prevention. Therein comes the need for biomarker discovery, which is crucial to the current oncological and other clinical practices having the potential to impact the diagnosis and prognosis. In fact, most of the biomarkers have been discovered utilizing the proteomics-based approaches. Although high-throughput mass spectrometry-based proteomic approaches like SILAC, 2D-DIGE, and iTRAQ are filling up the pitfalls of the conventional techniques, still serum proteomics importunately poses hurdle in overcoming a wide range of protein concentrations, and also the availability of patient tissue samples is a limitation for the biomarker discovery. Thus, researchers have looked for alternatives, and profiling of candidate biomarkers through tissue culture of tumor cell lines comes up as a promising option. It is a rich source of tumor cell-derived proteins, thereby, representing a wide array of potential biomarkers. Interestingly, most of the clinical biomarkers in use today (CA 125, CA 15.3, CA 19.9, and PSA) were discovered through tissue culture-based system and tissue extracts. This paper tries to emphasize the tissue culture-based discovery of candidate biomarkers through various mass spectrometry-based proteomic approaches. Debasish Paul, Avinash Kumar, Akshada Gajbhiye, Manas K. Santra, and Rapole Srikanth Copyright © 2013 Debasish Paul et al. All rights reserved. Antimicrobial Photodynamic Therapy for Methicillin-Resistant Staphylococcus aureus Infection Thu, 28 Feb 2013 16:04:05 +0000 http://www.hindawi.com/journals/bmri/2013/159157/ Nowadays methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common multidrug resistant bacteria both in hospitals and in the community. In the last two decades, there has been growing concern about the increasing resistance to MRSA of the most potent antibiotic glycopeptides. MRSA infection poses a serious problem for physicians and their patients. Photosensitizer-mediated antimicrobial photodynamic therapy (PDT) appears to be a promising and innovative approach for treating multidrug resistant infection. In spite of encouraging reports of the use of antimicrobial PDT to inactivate MRSA in large in vitro studies, there are only few in vivo studies. Therefore, applying PDT in the clinic for MRSA infection is still a long way off. Xiu-jun Fu, Yong Fang, and Min Yao Copyright © 2013 Xiu-jun Fu et al. All rights reserved. Detection of Intracellular Factor VIII Protein in Peripheral Blood Mononuclear Cells by Flow Cytometry Thu, 28 Feb 2013 15:55:32 +0000 http://www.hindawi.com/journals/bmri/2013/793502/ Flow cytometry is widely used in cancer research for diagnosis, detection of minimal residual disease, as well as immune monitoring and profiling following immunotherapy. Detection of specific host proteins for diagnosis predominantly uses quantitative PCR and western blotting assays. In this study, we optimized a flow cytometry-based detection assay for Factor VIII protein in peripheral blood mononuclear cells (PBMCs). An indirect intracellular staining (ICS) method was standardized using monoclonal antibodies to different domains of human Factor VIII protein. The FVIII protein expression level was estimated by calculating the mean and median fluorescence intensities (MFI) values for each monoclonal antibody. ICS staining of transiently transfected cell lines supported the method's specificity. Intracellular FVIII protein expression was also detected by the monoclonal antibodies used in the study in PBMCs of five blood donors. In summary, our data suggest that intracellular FVIII detection in PBMCs of hemophilia A patients can be a rapid and reliable method to detect intracellular FVIII levels. Gouri Shankar Pandey, Sandra C. Tseng, Tom E. Howard, and Zuben E. Sauna Copyright © 2013 Gouri Shankar Pandey et al. All rights reserved. Vasculogenic Cytokines in Wound Healing Thu, 28 Feb 2013 10:39:50 +0000 http://www.hindawi.com/journals/bmri/2013/190486/ Chronic wounds represent a growing healthcare burden that particularly afflicts aged, diabetic, vasculopathic, and obese patients. Studies have shown that nonhealing wounds are characterized by dysregulated cytokine networks that impair blood vessel formation. Two distinct forms of neovascularization have been described: vasculogenesis (driven by bone-marrow-derived circulating endothelial progenitor cells) and angiogenesis (local endothelial cell sprouting from existing vasculature). Researchers have traditionally focused on angiogenesis but defects in vasculogenesis are increasingly recognized to impact diseases including wound healing. A more comprehensive understanding of vasculogenic cytokine networks may facilitate the development of novel strategies to treat recalcitrant wounds. Further, the clinical success of endothelial progenitor cell-based therapies will depend not only on the delivery of the cells themselves but also on the appropriate cytokine milieu to promote tissue regeneration. This paper will highlight major cytokines involved in vasculogenesis within the context of cutaneous wound healing. Victor W. Wong and Jeffrey D. Crawford Copyright © 2013 Victor W. Wong and Jeffrey D. Crawford. All rights reserved. The Influence of Flightless I on Toll-Like-Receptor-Mediated Inflammation in a Murine Model of Diabetic Wound Healing Mon, 18 Feb 2013 09:46:30 +0000 http://www.hindawi.com/journals/bmri/2013/389792/ Impaired wound healing and ulceration represent a serious complication of both type 1 and type 2 diabetes. Cytoskeletal protein Flightless I (Flii) is an important inhibitor of wound repair, and reduced Flii gene expression in fibroblasts increased migration, proliferation, and adhesion. As such it has the ability to influence all phases of wound healing including inflammation, remodelling and angiogenesis. Flii has the potential to modulate inflammation through its interaction with MyD88 which it an adaptor protein for TLR4. To assess the effect of Flii on the inflammatory response of diabetic wounds, we used a murine model of streptozocin-induced diabetes and Flii genetic mice. Increased levels of Flii were detected in Flii transgenic murine wounds resulting in impaired healing which was exacerbated when diabetes was induced. When Flii levels were reduced in diabetic wounds of Flii-deficient mice, healing was improved and decreased levels of TLR4 were observed. In contrast, increasing the level of Flii in diabetic mouse wounds led to increased TLR4 and NF-κB production. Treatment of murine diabetic wounds with neutralising antibodies to Flii led to an improvement in healing with decreased expression of TLR4. Decreasing the level of Flii in diabetic wounds may therefore reduce the inflammatory response and improve healing. Nadira Ruzehaji, Stuart J. Mills, Elizabeth Melville, Ruth Arkell, Robert Fitridge, and Allison J. Cowin Copyright © 2013 Nadira Ruzehaji et al. All rights reserved. Prescription Surveillance and Polymerase Chain Reaction Testing to Identify Pathogens during Outbreaks of Infection Thu, 07 Feb 2013 11:16:57 +0000 http://www.hindawi.com/journals/bmri/2013/746053/ Syndromic surveillance, including prescription surveillance, offers a rapid method for the early detection of agents of bioterrorism and emerging infectious diseases. However, it has the disadvantage of not considering definitive diagnoses. Here, we attempted to definitively diagnose pathogens using polymerase chain reaction (PCR) immediately after the prescription surveillance system detected an outbreak. Specimens were collected from 50 patients with respiratory infections. PCR was used to identify the pathogens, which included 14 types of common respiratory viruses and Mycoplasma pneumoniae. Infectious agents including M. pneumoniae, respiratory syncytial virus (RSV), rhinovirus, enterovirus, and parainfluenza virus were detected in 54% of patients. For the rapid RSV diagnosis kit, sensitivity was 80% and specificity was 85%. For the rapid adenovirus diagnosis kit, no positive results were obtained; therefore, sensitivity could not be calculated and specificity was 100%. Many patients were found to be treated for upper respiratory tract infections without the diagnosis of a specific pathogen. In Japan, an outbreak of M. pneumoniae infection began in 2011, and our results suggested that this outbreak may have included false-positive cases. By combining syndromic surveillance and PCR, we were able to rapidly and accurately identify causative pathogens during a recent respiratory infection outbreak. Hiroaki Sugiura, Tsuguto Fujimoto, Tamie Sugawara, Nozomu Hanaoka, Masami Konagaya, Kiyoshi Kikuchi, Eisuke Hanada, Nobuhiko Okabe, and Yasushi Ohkusa Copyright © 2013 Hiroaki Sugiura et al. All rights reserved. Targeted Resequencing Reveals ALK Fusions in Non-Small Cell Lung Carcinomas Detected by FISH, Immunohistochemistry, and Real-Time RT-PCR: A Comparison of Four Methods Sun, 20 Jan 2013 11:03:03 +0000 http://www.hindawi.com/journals/bmri/2013/757490/ Anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements occur in a subgroup of non-small cell lung carcinomas (NSCLCs). The identification of these rearrangements is important for guiding treatment decisions. The aim of our study was to screen ALK gene fusions in NSCLCs and to compare the results detected by targeted resequencing with results detected by commonly used methods, including fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and real-time reverse transcription-PCR (RT-PCR). Furthermore, we aimed to ascertain the potential of targeted resequencing in detection of ALK-rearranged lung carcinomas. We assessed ALK fusion status for 95 formalin-fixed paraffin-embedded tumor tissue specimens from 87 patients with NSCLC by FISH and real-time RT-PCR, for 57 specimens from 56 patients by targeted resequencing, and for 14 specimens from 14 patients by IHC. All methods were performed successfully on formalin-fixed paraffin-embedded tumor tissue material. We detected ALK fusion in 5.7% (5 out of 87) of patients examined. The results obtained from resequencing correlated significantly with those from FISH, real-time RT-PCR, and IHC. Targeted resequencing proved to be a promising method for ALK gene fusion detection in NSCLC. Means to reduce the material and turnaround time required for analysis are, however, needed. Katja Tuononen, Virinder Kaur Sarhadi, Aino Wirtanen, Mikko Rönty, Kaisa Salmenkivi, Aija Knuuttila, Satu Remes, Aino I. Telaranta-Keerie, Stuart Bloor, Pekka Ellonen, and Sakari Knuutila Copyright © 2013 Katja Tuononen et al. All rights reserved. Abnormal Cell Responses and Role of TNF- in Impaired Diabetic Wound Healing Sun, 20 Jan 2013 10:18:38 +0000 http://www.hindawi.com/journals/bmri/2013/754802/ Impaired diabetic wound healing constitutes a major health problem. The impaired healing is caused by complex factors such as abnormal keratinocyte and fibroblast migration, proliferation, differentiation, and apoptosis, abnormal macrophage polarization, impaired recruitment of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs), and decreased vascularization. Diabetes-enhanced and prolonged expression of TNF-α also contributes to impaired healing. In this paper, we discuss the abnormal cell responses in diabetic wound healing and the contribution of TNF-α. Fanxing Xu, Chenying Zhang, and Dana T. Graves Copyright © 2013 Fanxing Xu et al. All rights reserved. Low Circulating Protein C Levels Are Associated with Lower Leg Ulcers in Patients with Diabetes Wed, 02 Jan 2013 15:48:52 +0000 http://www.hindawi.com/journals/bmri/2013/719570/ Activated protein C (APC) promotes angiogenesis and reepithelialisation and accelerates healing of diabetic ulcers. The aim of this study was to determine the relationship between the incidence of lower leg ulcers and plasma levels of APC's precursor, protein C (PC), in diabetic patients. Patients with diabetes who had a lower leg ulcer(s) for >6 months () were compared with age-, type of diabetes-, and sex-matched subjects with diabetes but without an ulcer (, controls). Total PC was assessed using a routine PC colorimetric assay. There was a significantly () lower level of plasma PC in patients with ulcers (103.3 ± 22.7, mean ± SD) compared with control () subjects, when corrected for age and matched for gender and type of diabetes. Ulcer type (neuropathic, ischaemic, or mixed) was not a significant covariate for plasma PC levels (). There was no correlation between PC levels and gender, type of diabetes, , or C-reactive protein in either group. In summary, decreased circulating PC levels are associated with, and may predispose to, lower leg ulceration in patients with diabetes. K. Whitmont, G. Fulcher, I. Reid, M. Xue, K. McKelvey, Y. Xie, M. Aboud, C. Ward, M. M. Smith, A. Cooper, L. March, and C. J. Jackson Copyright © 2013 K. Whitmont et al. All rights reserved. Glucose Toxic Effects on Granulation Tissue Productive Cells: The Diabetics’ Impaired Healing Wed, 26 Dec 2012 09:06:50 +0000 http://www.hindawi.com/journals/bmri/2013/256043/ Type 2 diabetes mellitus is a metabolic noncommunicable disease with an expanding pandemic magnitude. Diabetes predisposes to lower extremities ulceration and impairs the healing process leading to wound chronification. Diabetes also dismantles innate immunity favoring wound infection. Amputation is therefore acknowledged as one of the disease’s complications. Hyperglycemia is the proximal detonator of systemic and local toxic effectors including proinflammation, acute-phase proteins elevation, and spillover of reactive oxygen and nitrogen species. Insulin axis deficiency weakens wounds’ anabolism and predisposes to inflammation. The systemic accumulation of advanced glycation end-products irreversibly impairs the entire physiology from cells-to-organs. These factors in concert hamper fibroblasts and endothelial cells proliferation, migration, homing, secretion, and organization of a productive granulation tissue. Diabetic wound bed may turn chronically inflammed, procatabolic, and an additional source of circulating pro-inflammatory cytokines, establishing a self-perpetuating loop. Diabetic fibroblasts and endothelial cells may bear mitochondrial damages becoming prone to apoptosis, which impairs granulation tissue cellularity and perfusion. Endothelial progenitor cells recruitment and tubulogenesis are also impaired. Failure of wound reepithelialization remains a clinical challenge while it appears to be biologically multifactorial. Ulcer prevention by primary care surveillance, education, and attention programs is of outmost importance to reduce worldwide amputation figures. Jorge Berlanga-Acosta, Gregory S. Schultz, Ernesto López-Mola, Gerardo Guillen-Nieto, Marianela García-Siverio, and Luis Herrera-Martínez Copyright © 2013 Jorge Berlanga-Acosta et al. All rights reserved. Hyperglycemia Increases Susceptibility to Ischemic Necrosis Sun, 23 Dec 2012 09:37:17 +0000 http://www.hindawi.com/journals/bmri/2013/490964/ Diabetic patients are at risk for spontaneous foot ulcers, chronic wounds, infections, and tissue necrosis. Current theories suggest that the development and progression of diabetic foot ulcers are mainly caused by arteriosclerosis and peripheral neuropathy. Tissue necrosis plays a primordial role in the progression of diabetic foot ulcers but the underlying mechanisms are poorly understood. The aim of the present study was to investigate the effects of hyperglycemia per se on the susceptibility of ischemic tissue to necrosis, using a critical ischemic hind limb animal model. We inflicted the same degree of ischemia in both euglycemic and streptozotocin-induced hyperglycemic rats by resecting the external iliac, the femoral, and the saphenous arteries. Postoperative laser Doppler flowmetry of the ischemic feet showed the same degree of reduction in skin perfusion in both hyperglycemic and euglycemic animals. Nevertheless, we found a significantly higher rate of limb necrosis in hyperglycemic rats compared to euglycemic rats (71% versus 29%, resp.). In this study, we revealed that hyperglycemia per se increases the susceptibility to limb necrosis in ischemic conditions. Our results may help to better understand the physiopathology of progressive diabetic wounds and underline the importance of strict glycemic control in patients with critical limb ischemia. D. Lévigne, M. Tobalem, A. Modarressi, and B. Pittet-Cuénod Copyright © 2013 D. Lévigne et al. All rights reserved. Animal Models of Human Pathology 2012 Thu, 30 Aug 2012 08:34:25 +0000 http://www.hindawi.com/journals/bmri/2012/404130/ Monica Fedele, Oreste Gualillo, and Andrea Vecchione Copyright © 2012 Monica Fedele et al. All rights reserved. An In Vivo Rabbit Model for the Evaluation of Antimicrobial Peripherally Inserted Central Catheter to Reduce Microbial Migration and Colonization as Compared to an Uncoated PICC Sun, 26 Aug 2012 15:16:13 +0000 http://www.hindawi.com/journals/bmri/2012/921617/ Infection is the leading complication associated with intravascular devices, and these infections develop when a catheter becomes colonized by microorganisms. To combat this issue, medical device manufacturers seek to provide healthcare facilities with antimicrobial medical devices to prevent or reduce the colonization. In order to adequately evaluate these devices, an in vivo model is required to accurately assess the performance of the antimicrobial devices in a clinical setting. The model presented herein was designed to provide a simulation of the subcutaneous tunnel environment to evaluate the ability of an antimicrobial peripherally inserted central catheter (PICC), coated with chlorhexidine based technology, to reduce microbial migration and colonization compared to an uncoated PICC. Three samples of control, uncoated PICCs and three samples of coated PICCs were surgically tunneled into the backs of female New Zealand White rabbits. The insertion sites were then challenged with Staphylococcus aureus at the time of implantation. Animals were evaluated out to thirty days and sacrificed. Complete en bloc dissection and evaluation of the catheter and surrounding tissue demonstrated that the chlorhexidine coated catheter was able to significantly reduce microbial colonization and prevent microbial migration as compared to the standard, un-treated catheter. Nicholas D. Allan, Kamna Giare-Patel, and Merle E. Olson Copyright © 2012 Nicholas D. Allan et al. All rights reserved. Sleep Deprivation Alters Rat Ventral Prostate Morphology, Leading to Glandular Atrophy: A Microscopic Study Contrasted with the Hormonal Assays Wed, 08 Aug 2012 08:35:49 +0000 http://www.hindawi.com/journals/bmri/2012/285938/ We investigated the effect of 96 h paradoxical sleep deprivation (PSD) and 21-day sleep restriction (SR) on prostate morphology using stereological assays in male rats. After euthanasia, the rat ventral prostate was removed, weighed, and prepared for conventional light microscopy. Microscopic analysis of the prostate reveals that morphology of this gland was altered after 96 h of PSD and 21 days of SR, with the most important alterations occurring in the epithelium and stroma in the course of both procedures compared with the control group. Both 96 h PSD and 21-day SR rats showed lower serum testosterone and higher corticosterone levels than control rats. The significance of our result referring to the sleep deprivation was responsible for deep morphological alterations in ventral prostate tissue, like to castration microscopic modifications. This result is due to the marked alterations in hormonal status caused by PSD and SR. Daniel P. Venâncio, Monica L. Andersen, Patricia S. L. Vilamaior, Fernanda C. Santos, Adriano Zager, Sérgio Tufik, Sebastião R. Taboga, and Marco T. De Mello Copyright © 2012 Daniel P. Venâncio et al. All rights reserved. Involvement of the Intrarenal Renin-Angiotensin System in Experimental Models of Glomerulonephritis Mon, 02 Jul 2012 10:42:00 +0000 http://www.hindawi.com/journals/bmri/2012/601786/ The intrarenal renin-angiotensin system (RAS) has several pathophysiologic functions not only in blood pressure regulation but also in the development of glomerulonephritis (GN). Angiotensin II (Ang II) is the biologically active product of the RAS. Locally produced Ang II induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation, regulates the gene expression of bioactive substances, and activates multiple intracellular signaling pathways, leading to tissue damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, cell proliferation, and extracellular matrix synthesis, which facilitates glomerular injury. Previous studies have shown that angiotensin-converting enzyme inhibitors and/or AT1 receptor blockers have beneficial effects in experimental GN models and humans with various types of GN, and that these effects are more significant than their suppressive effects on blood pressure. In this paper, we focus on intrarenal RAS activation in the pathophysiology of experimental models of GN. Maki Urushihara, Yukiko Kinoshita, Shuji Kondo, and Shoji Kagami Copyright © 2012 Maki Urushihara et al. All rights reserved. Nuclear Expression of a Mitochondrial DNA Gene: Mitochondrial Targeting of Allotopically Expressed Mutant ATP6 in Transgenic Mice Wed, 20 Jun 2012 11:58:25 +0000 http://www.hindawi.com/journals/bmri/2012/541245/ Nuclear encoding of mitochondrial DNA transgenes followed by mitochondrial targeting of the expressed proteins (allotopic expression; AE) represents a potentially powerful strategy for creating animal models of mtDNA disease. Mice were created that allotopically express either a mutant (A6M) or wildtype (A6W) mt-Atp6 transgene. Compared to non-transgenic controls, A6M mice displayed neuromuscular and motor deficiencies (wire hang, pole, and balance beam analyses; 𝑃<0.05), no locomotor differences (gait analysis; 𝑃<0.05) and enhanced endurance in Rota-Rod evaluations (𝑃<0.05). A6W mice exhibited inferior muscle strength (wire hang test; 𝑃<0.05), no difference in balance beam footsteps, accelerating Rota-Rod, pole test and gait analyses; (𝑃<0.05) and superior performance in balance beam time-to-cross and constant velocity Rota-Rod analyses (𝑃<0.05) in comparison to non-transgenic control mice. Mice of both transgenic lines did not differ from non-transgenic controls in a number of bioenergetic and biochemical tests including measurements of serum lactate and mitochondrial MnSOD protein levels, ATP synthesis rate, and oxygen consumption (𝑃>0.05). This study illustrates a mouse model capable of circumventing in vivo mitochondrial mutations. Moreover, it provides evidence supporting AE as a tool for mtDNA disease research with implications in development of DNA-based therapeutics. David A. Dunn and Carl A. Pinkert Copyright © 2012 David A. Dunn and Carl A. Pinkert. All rights reserved. Development of Animal Model for Studying Deep Second-Degree Thermal Burns Tue, 12 Jun 2012 08:04:53 +0000 http://www.hindawi.com/journals/bmri/2012/460841/ Thermal lesions were produced in 12 male Wistar rats, positioning a massive aluminum bar 10 mm in diameter (51 g), preheated to 99°C ± 2°C/10 min. on the back of each animal for 15 sec. After 7, 14, 21, and 28 days, animals were euthanized. The edema intensity was mild, with no bubble and formation of a thick and dry crust from the 3rd day. The percentage of tissue shrinkage at 28 days was 66.67 ± 1.66%. There was no sign of infection, bleeding, or secretion. Within 28 days reepithelialization was incomplete, with fibroblastic proliferation and moderate fibrosis and presence of modeled dense collagen fibers. It is concluded that the model established is applicable in obtaining deep second-degree thermal burns in order to evaluate the healing action of therapeutic agents of topical use. Danielle dos Santos Tavares Pereira, Maria Helena Madruga Lima-Ribeiro, Nicodemos Teles de Pontes-Filho, Ana Maria dos Anjos Carneiro-Leão, and Maria Tereza dos Santos Correia Copyright © 2012 Danielle dos Santos Tavares Pereira et al. All rights reserved. Think Small: Zebrafish as a Model System of Human Pathology Sun, 03 Jun 2012 10:13:45 +0000 http://www.hindawi.com/journals/bmri/2012/817341/ Although human pathologies have mostly been modeled using higher mammal systems such as mice, the lower vertebrate zebrafish has gained tremendous attention as a model system. The advantages of zebrafish over classical vertebrate models are multifactorial and include high genetic and organ system homology to humans, high fecundity, external fertilization, ease of genetic manipulation, and transparency through early adulthood that enables powerful imaging modalities. This paper focuses on four areas of human pathology that were developed and/or advanced significantly in zebrafish in the last decade. These areas are (1) wound healing/restitution, (2) gastrointestinal diseases, (3) microbe-host interactions, and (4) genetic diseases and drug screens. Important biological processes and pathologies explored include wound-healing responses, pancreatic cancer, inflammatory bowel diseases, nonalcoholic fatty liver disease, and mycobacterium infection. The utility of zebrafish in screening for novel genes important in various pathologies such as polycystic kidney disease is also discussed. J. R. Goldsmith and Christian Jobin Copyright © 2012 J. R. Goldsmith and Christian Jobin. All rights reserved. Advancement in the Development of Models for Hepatitis C Research Wed, 30 May 2012 09:25:51 +0000 http://www.hindawi.com/journals/bmri/2012/346761/ Hepatitis C virus (HCV) is a pandemic disease affecting an estimated 180 million individuals worldwide and infecting each year another ~3-4 million people making HCV a global public health issue. HCV is the main cause for chronic hepatitis, cirrhosis, and hepatocellular carcinoma. In the United States, HCV-related chronic liver disease is a leading cause of liver transplantation. Despite significant improvements in antiviral drugs, only ~50% of treated patients with HCV have viral clearance after treatment. Showing unique species specificity, HCV has a narrow range of potential hosts infecting only chimpanzees and humans. For decades, the chimpanzee model has been the only and instrumental primate for studying HCV infection; however, availability, economic, and ethical issues make the chimpanzee an unsuitable animal model today. Thus, significant research has been devoted to explore different models that are suitable in studying the biology of the virus and application in the clinical research for developing efficient and tolerable treatments for patients. This review focuses on experimental models that have been developed to date and their findings related to HCV. Wendy C. Carcamo and Cuong Q. Nguyen Copyright © 2012 Wendy C. Carcamo and Cuong Q. Nguyen. All rights reserved. Animal Models of Glaucoma Tue, 15 May 2012 10:40:48 +0000 http://www.hindawi.com/journals/bmri/2012/692609/ Glaucoma is a heterogeneous group of disorders that progressively lead to blindness due to loss of retinal ganglion cells and damage to the optic nerve. It is a leading cause of blindness and visual impairment worldwide. Although research in the field of glaucoma is substantial, the pathophysiologic mechanisms causing the disease are not completely understood. A wide variety of animal models have been used to study glaucoma. These include monkeys, dogs, cats, rodents, and several other species. Although these models have provided valuable information about the disease, there is still no ideal model for studying glaucoma due to its complexity. In this paper we present a summary of most of the animal models that have been developed and used for the study of the different types of glaucoma, the strengths and limitations associated with each species use, and some potential criteria to develop a suitable model. Rachida A. Bouhenni, Jeffrey Dunmire, Abby Sewell, and Deepak P. Edward Copyright © 2012 Rachida A. Bouhenni et al. All rights reserved. Dextran Sodium Sulphate Colitis Mouse Model: Traps and Tricks Mon, 14 May 2012 14:23:23 +0000 http://www.hindawi.com/journals/bmri/2012/718617/ Inflammatory bowel disease (IBD) is a complex multifactorial disease of unknown etiology. Thus, dozens of different animal models of IBD have been developed in past decades. Animal models of IBD are valuable and indispensable tools that provide a wide range of options for investigating involvement of various factors into the pathogenesis of IBD and to evaluate different therapeutic options. However, the dextran sulphate sodium (DSS-) induced colitis model has some advantages when compared to other animal models of colitis. It is well appreciated and widely used model of inflammatory bowel disease because of its simplicity. It has many similarities to human IBD, which are mentioned in the paper. In spite of its simplicity and wide applicability, there are also traps that need to be taken into account when using DSS model. As demonstrated in the present paper, various factors may affect susceptibility to DSS-induced lesions and modify results. Martina Perše and Anton Cerar Copyright © 2012 Martina Perše and Anton Cerar. All rights reserved. Posterior Circulation Stroke: Animal Models and Mechanism of Disease Mon, 14 May 2012 14:19:07 +0000 http://www.hindawi.com/journals/bmri/2012/587590/ Posterior circulation stroke refers to the vascular occlusion or bleeding, arising from the vertebrobasilar vasculature of the brain. Clinical studies show that individuals who experience posterior circulation stroke will develop significant brain injury, neurologic dysfunction, or death. Yet the therapeutic needs of this patient subpopulation remain largely unknown. Thus understanding the causative factors and the pathogenesis of brain damage is important, if posterior circulation stroke is to be prevented or treated. Appropriate animal models are necessary to achieve this understanding. This paper critically integrates the neurovascular and pathophysiological features gleaned from posterior circulation stroke animal models into clinical correlations. Tim Lekic and Chizobam Ani Copyright © 2012 Tim Lekic and Chizobam Ani. All rights reserved. Cytokines and VEGF Induction in Orthodontic Movement in Animal Models Mon, 14 May 2012 14:12:48 +0000 http://www.hindawi.com/journals/bmri/2012/201689/ Orthodontics is a branch of dentistry that aims at the resolution of dental malocclusions. The specialist carries out the treatment using intraoral or extraoral orthodontic appliances that require forces of a given load level to obtain a tooth movement in a certain direction in dental arches. Orthodontic tooth movement is dependent on efficient remodeling of periodontal ligament and alveolar bone, correlated with several biological and mechanical responses of the tissues surrounding the teeth. A periodontal ligament placed under pressure will result in bone resorption whereas a periodontal ligament under tension results in bone formation. In the primary stage of the application of orthodontic forces, an acute inflammation occurs in periodontium. Several proinflammatory cytokines are produced by immune-competent cells migrating by means of dilated capillaries. In this paper we summarize, also through the utilization of animal models, the role of some of these molecules, namely, interleukin-1β and vascular endothelial growth factor, that are some proliferation markers of osteoclasts and osteoblasts, and the macrophage colony stimulating factor. M. Di Domenico, F. D'apuzzo, A. Feola, L. Cito, A. Monsurrò, G. M. Pierantoni, L. Berrino, A. De Rosa, A. Polimeni, and L. Perillo Copyright © 2012 M. Di Domenico et al. All rights reserved. The Current State of Knowledge of Hepatic Ischemia-Reperfusion Injury Based on Its Study in Experimental Models Wed, 09 May 2012 09:44:49 +0000 http://www.hindawi.com/journals/bmri/2012/298657/ The present review focuses on the numerous experimental models used to study the complexity of hepatic ischemia/reperfusion (I/R) injury. Although experimental models of hepatic I/R injury represent a compromise between the clinical reality and experimental simplification, the clinical transfer of experimental results is problematic because of anatomical and physiological differences and the inevitable simplification of experimental work. In this review, the strengths and limitations of the various models of hepatic I/R are discussed. Several strategies to protect the liver from I/R injury have been developed in animal models and, some of these, might find their way into clinical practice. We also attempt to highlight the fact that the mechanisms responsible for hepatic I/R injury depend on the experimental model used, and therefore the therapeutic strategies also differ according to the model used. Thus, the choice of model must therefore be adapted to the clinical question being answered. M. Mendes-Braz, M. Elias-Miró, M. B. Jiménez-Castro, A. Casillas-Ramírez, F. S. Ramalho, and C. Peralta Copyright © 2012 M. Mendes-Braz et al. All rights reserved. Effect of Colic Vein Ligature in Rats with Loperamide-Induced Constipation Tue, 08 May 2012 14:01:24 +0000 http://www.hindawi.com/journals/bmri/2012/896162/ Introduction. Medical treatment in chronic constipation is not always successful. Surgery is indicated in unresponsive selected severe cases. This study presents the distal venous colic ligation in rat as a novel surgical approach. Materials and Methods. 16 rats (study group) were evaluated in 3 phases of 6 days each: A (normal conditions), B (loperamide-induced constipation), and C (colic vein legation) and compared with rats treated in phase C with PEG 4,000 (control group). Blood biochemical and physiological parameters, daily fecal water content (FWC), and histological analysis were performed in all study phases. Results. No biochemical and physiological parameters changes were observed. FWC decreased in phase B and increased in phase C in both groups with a grow up to 2.3-fold in study group compared to control (𝑃<0.0001). Moreover, in study group, a high number of colonic goblet cells were detected (phase C versus phase B: 𝑃<0.001) while no differences were registered in control. Conclusion. By ligature of the colic vein in constipated rats, an increase in FWC and goblet cells higher than in PEG treated rats was detected. The described surgical procedure appeared effective, simple, and safe; further studies in animal models, however, are necessary to assess its clinical applicability. Flavia Neri, Giuseppe Cavallari, Matvey Tsivian, Elisa Bianchi, Rita Aldini, Monica Cevenini, Elena Guidetti, Gian Luca Piras, Milena Pariali, and Bruno Nardo Copyright © 2012 Flavia Neri et al. All rights reserved. What Sequences on High-Field MR Best Depict Temporal Resolution of Experimental ICH and Edema Formation in Mice? Mon, 30 Apr 2012 18:44:53 +0000 http://www.hindawi.com/journals/bmri/2012/961461/ Background and Purpose. Pilot study to examine the use of T1-, T2-, and T2*-weighted images for evaluating hematoma size and extent of edema in mouse brain at high field. Methods. Following collagenase-induced intracerebral hemorrhage, nine mice were imaged at 4.7 T using T1-, T2-, and T2*-weighted images for hematoma and edema quantitation on days 1, 3, 10, and 21 after surgery. Values were compared with morphometric analysis of cryosections at the time of final MR imaging. Results. For hematoma quantitation, the Spearman correlation coefficient (𝑟) between T1 signal change and histology was 0.70 (𝑃<0.04) compared with 𝑟=0.61 (𝑃<0.09) for T2*. The extent of perihematomal edema formation on cryosections was well reflected on T2 with 𝑟=0.73 (𝑃<0.03). Conclusions. Within the limits of our pilot study, MR imaging on 4.7 T appears to approximate the temporal changes in hematoma and edema sizes in murine ICH well, thus laying the groundwork for longitudinal studies on hematoma resorption and edema formation. Mingchang Li, Reza M. Akhavan-Sharif, Robert M. Friedlander, Rose Du, and Ruth Thiex Copyright © 2012 Mingchang Li et al. All rights reserved. MicroRNAs and Induced Pluripotent Stem Cells for Human Disease Mouse Modeling Mon, 30 Apr 2012 09:12:00 +0000 http://www.hindawi.com/journals/bmri/2012/758169/ Human disease animal models are absolutely invaluable tools for our understanding of mechanisms involved in both physiological and pathological processes. By studying various genetic abnormalities in these organisms we can get a better insight into potential candidate genes responsible for human disease development. To this point a mouse represents one of the most used and convenient species for human disease modeling. Hundreds if not thousands of inbred, congenic, and transgenic mouse models have been created and are now extensively utilized in the research labs worldwide. Importantly, pluripotent stem cells play a significant role in developing new genetically engineered mice with the desired human disease-like phenotype. Induced pluripotent stem (iPS) cells which represent reprogramming of somatic cells into pluripotent stem cells represent a significant advancement in research armament. The novel application of microRNA manipulation both in the generation of iPS cells and subsequent lineage-directed differentiation is discussed. Potential applications of induced pluripotent stem cell—a relatively new type of pluripotent stem cells—for human disease modeling by employing human iPS cells derived from normal and diseased somatic cells and iPS cells derived from mouse models of human disease may lead to uncovering of disease mechanisms and novel therapies. Chingiz Underbayev, Siddha Kasar, Yao Yuan, and Elizabeth Raveche Copyright © 2012 Chingiz Underbayev et al. All rights reserved. Animal Model of Dermatophytosis Sun, 29 Apr 2012 14:43:39 +0000 http://www.hindawi.com/journals/bmri/2012/125384/ Dermatophytosis is superficial fungal infection caused by dermatophytes that invade the keratinized tissue of humans and animals. Lesions from dermatophytosis exhibit an inflammatory reaction induced to eliminate the invading fungi by using the host’s normal immune function. Many scientists have attempted to establish an experimental animal model to elucidate the pathogenesis of human dermatophytosis and evaluate drug efficacy. However, current animal models have several issues. In the present paper, we surveyed reports about the methodology of the dermatophytosis animal model for tinea corporis, tinea pedis, and tinea unguium and discussed future prospects. Tsuyoshi Shimamura, Nobuo Kubota, and Kazutoshi Shibuya Copyright © 2012 Tsuyoshi Shimamura et al. All rights reserved. Proteomic Characterization of a Mouse Model of Familial Danish Dementia Thu, 26 Apr 2012 13:48:37 +0000 http://www.hindawi.com/journals/bmri/2012/728178/ A dominant mutation in the ITM2B/BRI2 gene causes familial Danish dementia (FDD) in humans. To model FDD in animal systems, a knock-in approach was recently implemented in mice expressing a wild-type and mutant allele, which bears the FDD-associated mutation. Since these FDDKI mice show behavioural alterations and impaired synaptic function, we characterized their synaptosomal proteome via two-dimensional differential in-gel electrophoresis. After identification by nanoliquid chromatography coupled to electrospray-linear ion trap tandem mass spectrometry, the differentially expressed proteins were classified according to their gene ontology descriptions and their predicted functional interactions. The Dlg4/Psd95 scaffold protein and additional signalling proteins, including protein phosphatases, were revealed by STRING analysis as potential players in the altered synaptic function of FDDKI mice. Immunoblotting analysis finally demonstrated the actual downregulation of the synaptosomal scaffold protein Dlg4/Psd95 and of the dual-specificity phosphatase Dusp3 in the synaptosomes of FDDKI mice. Monica Vitale, Giovanni Renzone, Shuji Matsuda, Andrea Scaloni, Luciano D'Adamio, and Nicola Zambrano Copyright © 2012 Monica Vitale et al. All rights reserved. Patient-Derived Xenografts of Non Small Cell Lung Cancer: Resurgence of an Old Model for Investigation of Modern Concepts of Tailored Therapy and Cancer Stem Cells Wed, 04 Apr 2012 12:12:50 +0000 http://www.hindawi.com/journals/bmri/2012/568567/ Current chemotherapy regimens have unsatisfactory results in most advanced solid tumors. It is therefore imperative to devise novel therapeutic strategies and to optimize selection of patients, identifying early those who could benefit from available treatments. Mouse models are the most valuable tool for preclinical evaluation of novel therapeutic strategies in cancer and, among them, patient-derived xenografts models (PDX) have made a recent comeback in popularity. These models, obtained by direct implants of tissue fragments in immunocompromised mice, have great potential in drug development studies because they faithfully reproduce the patient’s original tumor for both immunohistochemical markers and genetic alterations as well as in terms of response to common therapeutics They also maintain the original tumor heterogeneity, allowing studies of specific cellular subpopulations, including their modulation after drug treatment. Moreover PDXs maintain at least some aspects of the human microenvironment for weeks with the complete substitution with murine stroma occurring only after 2-3 passages in mouse and represent therefore a promising model for studies of tumor-microenvironment interaction. This review summarizes our present knowledge on mouse preclinical cancer models, with a particular attention on patient-derived xenografts of non small cell lung cancer and their relevance for preclinical and biological studies. Massimo Moro, Giulia Bertolini, Monica Tortoreto, Ugo Pastorino, Gabriella Sozzi, and Luca Roz Copyright © 2012 Massimo Moro et al. All rights reserved. Canine Liver Transplantation Model and the Intermediate Filaments of the Cytoskeleton of the Hepatocytes Wed, 28 Mar 2012 15:19:27 +0000 http://www.hindawi.com/journals/bmri/2012/131324/ Liver transplantation has been a successful therapy for liver failure. However, a significant number of recipients suffer from graft dysfunction. Considerably, ischemia and reperfusion (I/R) injury is the most important factor leading to organ dysfunction, although the pathogenesis has not been fully described. I/R injury have several established features that are accompanied by and/or linked to bile duct loss or ductopenia, cholestasis, and biliary ductular proliferations in the posttransplant liver biopsy. However, biliary marker levels increase usually only 5–7 days after transplantation. Intermediate filaments are one of the three cytoskeletal proteins that have a major role in liver protection and maintaining both cellular structure and integrity of eukaryotic cells. We reviewed the canine liver transplantation model as I/R injury model to delineate the intermediate filaments of the cytoskeleton that are probably the determinants in changing the phenotype of hepatocytes to cholangiocytes. Remarkably, this interesting feature seems to occur earlier than frank cholestasis. We speculate that I/R liver injury through a phenotypical switch of the hepatocytes may contribute to the poor outcome of the liver graft. Consolato Sergi, Reem Abdualmjid, and Yasser Abuetabh Copyright © 2012 Consolato Sergi et al. All rights reserved. Classic and New Animal Models of Parkinson's Disease Wed, 28 Mar 2012 14:53:08 +0000 http://www.hindawi.com/journals/bmri/2012/845618/ Neurological disorders can be modeled in animals so as to recreate specific pathogenic events and behavioral outcomes. Parkinson’s Disease (PD) is the second most common neurodegenerative disease of an aging population, and although there have been several significant findings about the PD disease process, much of this process still remains a mystery. Breakthroughs in the last two decades using animal models have offered insights into the understanding of the PD disease process, its etiology, pathology, and molecular mechanisms. Furthermore, while cellular models have helped to identify specific events, animal models, both toxic and genetic, have replicated almost all of the hallmarks of PD and are useful for testing new neuroprotective or neurorestorative strategies. Moreover, significant advances in the modeling of additional PD features have come to light in both classic and newer models. In this review, we try to provide an updated summary of the main characteristics of these models as well as the strengths and weaknesses of what we believe to be the most popular PD animal models. These models include those produced by 6-hydroxydopamine (6-OHDA), 1-methyl-1,2,3,6-tetrahydropiridine (MPTP), rotenone, and paraquat, as well as several genetic models like those related to alpha-synuclein, PINK1, Parkin and LRRK2 alterations. Javier Blesa, Sudarshan Phani, Vernice Jackson-Lewis, and Serge Przedborski Copyright © 2012 Javier Blesa et al. All rights reserved. PET/CT Imaging in Mouse Models of Myocardial Ischemia Tue, 13 Mar 2012 14:21:28 +0000 http://www.hindawi.com/journals/bmri/2012/541872/ Different species have been used to reproduce myocardial infarction models but in the last years mice became the animals of choice for the analysis of several diseases, due to their short life cycle and the possibility of genetic manipulation. Many techniques are currently used for cardiovascular imaging in mice, including X-ray computed tomography (CT), high-resolution ultrasound, magnetic resonance imaging, and nuclear medicine procedures. Cardiac positron emission tomography (PET) allows to examine noninvasively, on a molecular level and with high sensitivity, regional changes in myocardial perfusion, metabolism, apoptosis, inflammation, and gene expression or to measure changes in anatomical and functional parameters in heart diseases. Currently hybrid PET/CT scanners for small laboratory animals are available, where CT adds high-resolution anatomical information. This paper reviews mouse models of myocardial infarction and discusses the applications of dedicated PET/CT systems technology, including animal preparation, anesthesia, radiotracers, and images postprocessing. Sara Gargiulo, Adelaide Greco, Matteo Gramanzini, Maria Piera Petretta, Adele Ferro, Michele Larobina, Mariarosaria Panico, Arturo Brunetti, and Alberto Cuocolo Copyright © 2012 Sara Gargiulo et al. All rights reserved. Topical Application Effect of the Isolectin Hydrogel (Cramoll 1,4) on Second-Degree Burns: Experimental Model Tue, 14 Feb 2012 10:57:28 +0000 http://www.hindawi.com/journals/bmri/2012/184538/ This study aimed at evaluating the use of hydrogel isolectin in the treatment of second-degree burns. Twenty male rats were randomly divided into two groups (G1 = treatment with hydrogel containing 100 μg/mL Cramoll 1,4 and G2 = Control, hydrogel). After 7, 14, 21, 28, and 35 days, animals were euthanized. On the 7th day, G1 showed intense exudates, necrosis and edema. On the 14th day, G1 showed tissue reepithelialization and moderate autolysis. On the 21st day, G1 showed intense fibroblastic proliferation, presence of dense collagen, and moderate fibrosis. On the 28th day, G1 showed complete tissue epithelialization. On the 35th day, G1 showed modeled dense collagen. The significant wound contraction was initiated from day, 14 in the G1. There were no significant differences in biochemical and hematological parameters analyzed. These results extend the potential of therapeutic applications for Cramoll 1,4 in the treatment of thermal burns. Danielle dos Santos Tavares Pereira, Maria Helena Madruga Lima-Ribeiro, Ralph Santos-Oliveira, Carmelita de Lima Bezerra Cavalcanti, Nicodemos Teles de Pontes-Filho, Luana Cassandra Breitenbach Barroso Coelho, Ana Maria dos Anjos Carneiro-Leão, and Maria Tereza dos Santos Correia Copyright © 2012 Danielle dos Santos Tavares Pereira et al. All rights reserved. Ultrasound Biomicroscopy in Small Animal Research: Applications in Molecular and Preclinical Imaging Tue, 25 Oct 2011 08:45:13 +0000 http://www.hindawi.com/journals/bmri/2012/519238/ Ultrasound biomicroscopy (UBM) is a noninvasive multimodality technique that allows high-resolution imaging in mice. It is affordable, widely available, and portable. When it is coupled to Doppler ultrasound with color and power Doppler, it can be used to quantify blood flow and to image microcirculation as well as the response of tumor blood supply to cancer therapy. Target contrast ultrasound combines ultrasound with novel molecular targeted contrast agent to assess biological processes at molecular level. UBM is useful to investigate the growth and differentiation of tumors as well as to detect early molecular expression of cancer-related biomarkers in vivo and to monitor the effects of cancer therapies. It can be also used to visualize the embryological development of mice in uterus or to examine their cardiovascular development. The availability of real-time imaging of mice anatomy allows performing aspiration procedures under ultrasound guidance as well as the microinjection of cells, viruses, or other agents into precise locations. This paper will describe some basic principles of high-resolution imaging equipment, and the most important applications in molecular and preclinical imaging in small animal research. A. Greco, M. Mancini, S. Gargiulo, M. Gramanzini, P. P. Claudio, A. Brunetti, and M. Salvatore Copyright © 2012 A. Greco et al. All rights reserved. Animal Models of Human Pathology Thu, 30 Jun 2011 09:12:19 +0000 http://www.hindawi.com/journals/bmri/2011/764618/ Monica Fedele, Oreste Gualillo, and Andrea Vecchione Copyright © 2011 Monica Fedele et al. All rights reserved. Effects of a Tumor Necrosis Factor-α Antagonist on Experimentally Induced Rhinosinusitis Thu, 09 Jun 2011 16:40:48 +0000 http://www.hindawi.com/journals/bmri/2011/360457/ This prospective, randomized, and controlled study examined the effects of tumor necrosis factor soluble receptor type I (sTNFRI, a TNF-α antagonist) on experimentally induced rhinosinusitis in rats. The experimental groups received an instillation of lipopolysaccharide (LPS) plus an intramuscular injection of amoxicillin/clavulanate (antibiotic group), an instillation of sTNFRI (sTNFRI group), an instillation of sTNFRI and an injection of amoxicillin/clavulanate (sTNFRI/antibiotic group), or no additional treatment (LPS group). Histopathological changes were determined using hematoxylin-eosin and periodic acid-Schiff (PAS) staining. Leakage of exudate was determined using fluorescence microscopy. Vascular permeability was measured using the Evans blue dye technique. Expression of MUC5AC was measured using reverse transcriptase PCR. The sTNFRI, antibiotic, and sTNFRI/antibiotic groups had significantly less capillary permeability, mucosal edema, PAS staining, and expression of MUC5AC than the LPS group. There were no differences in capillary permeability, mucosal edema, PAS staining, and MUC5AC expression between the sTNFRI and sTNFRI/antibiotic groups. The antibiotic group had PAS staining similar to that of the sTNFRI and sTNFRI/antibiotic groups but had a greater increase in capillary permeability, mucosal edema, and MUC5AC expression. This study shows that sTNFRI reduces inflammatory activity and mucus hypersecretion in LPS-induced rhinosinusitis in rats. Dong-Hyun Kim, Eun-ju Jeon, Shi-Nae Park, Kyung-Ho Park, Yong-Soo Park, and Sang Won Yeo Copyright © 2011 Dong-Hyun Kim et al. All rights reserved. Dysfunction of Lacrimal and Salivary Glands in Sjögren's Syndrome: Nonimmunologic Injury in Preinflammatory Phase and Mouse Model Wed, 01 Jun 2011 09:48:57 +0000 http://www.hindawi.com/journals/bmri/2011/407031/ Sjögren's syndrome (SjS) is a chronic autoimmune disorder characterized by dry eyes and dry mouth due to dacryoadenitis and sialoadenitis with SS-A/Ro and/or SS-B/La autoantibodies in genetically predisposed individuals. Destruction of lacrimal and salivary glands by autoimmune reactions may lead to clinical manifestation. However, the mechanisms behind the decreased volume of secretions in tears and saliva are complex and are not fully understood. Exocrine gland dysfunction may precede autoimmunity (acquired immunity) or represent a process independent from inflammation in the pathogenesis of SjS. The preceded functional and morphologic changes of those tissues by nonimmunologic injury before the development of inflammation at the sites of target organs have been implicated. This paper focuses on the several factors and components relating to glandular dysfunction and morphologic changes by nonimmunologic injury during the preinflammatory phase in mouse model, including the factors which link between innate immunity and adaptive immunity. Toshiharu Hayashi Copyright © 2011 Toshiharu Hayashi. All rights reserved. Vanadium Inhalation in a Mouse Model for the Understanding of Air-Suspended Particle Systemic Repercussion Sun, 22 May 2011 10:41:56 +0000 http://www.hindawi.com/journals/bmri/2011/951043/ There is an increased concern about the health effects that air-suspended particles have on human health which have been dissected in animal models. Using CD-1 mouse, we explore the effects that vanadium inhalation produce in different tissues and organs. Our findings support the systemic effects of air pollution. In this paper, we describe our findings in different organs in our conditions and contrast our results with the literature. T. I. Fortoul, V. Rodriguez-Lara, A. Gonzalez-Villalva, M. Rojas-Lemus, G. Cano-Gutierrez, M. Ustarroz-Cano, L. Colin-Barenque, L. F. Montaño, I. García-Pelez, P. Bizarro-Nevares, N. Lopez-Valdez, C. I. Falcon-Rodriguez, R. S. Jimenez-Martínez, M. L. Ruiz-Guerrero, L. S. López-Zepeda, A. Morales-Rivero, and A. Muñiz-Rivera-Cambas Copyright © 2011 T. I. Fortoul et al. All rights reserved. Genetically Modified Mouse Models Used for Studying the Role of the AT2 Receptor in Cardiac Hypertrophy and Heart Failure Wed, 27 Apr 2011 15:09:37 +0000 http://www.hindawi.com/journals/bmri/2011/141039/ The actions of Angiotensin II have been implicated in many cardiovascular conditions. It is widely accepted that the cardiovascular effects of Angiotensin II are mediated by different subtypes of receptors: AT1 and AT2. These membrane-bound receptors share a part of their nucleic acid but seem to have different distribution and pathophysiological actions. AT1 mediates most of the Angiotensin II actions since it is ubiquitously expressed in the cardiovascular system of the normal adult. Moreover AT2 is highly expressed in the developing fetus but its expression in the cardiovascular system is low and declines after birth. However the expression of AT2 appears to be modulated by pathological states such as hypertension, myocardial infarction or any pathology associated to tissue remodeling or inflammation. The specific role of this receptor is still unclear and different studies involving in vivo and in vitro experiments have shown conflicting data. It is essential to clarify the role of the AT2 receptor in the different pathological states as it is a potential site for an effective therapeutic regimen that targets the Angiotensin II system. We will review the different genetically modified mouse models used to study the AT2 receptor and its association with cardiac hypertrophy and heart failure. Maria D. Avila, James P. Morgan, and Xinhua Yan Copyright © 2011 Maria D. Avila et al. All rights reserved. The Effects of Erythropoietin Dose Titration during High-Fat Diet-Induced Obesity Wed, 20 Apr 2011 15:24:09 +0000 http://www.hindawi.com/journals/bmri/2011/373781/ Erythropoietin (Epo) is a pleotropic cytokine with several nonhematopoietic tissue effects. High-dose Epo treatment-mediated effects on body weight, fat mass and glucose tolerance have recently been reported, thus extending its pleotropic effects to fat and glucose metabolism. However, the exact dose range of Epo treatment required for such effects remains unidentified to date. We investigated Epo dosage effect (up to 1000 U/kg) on hematocrit, body weight, body composition, glucose metabolism, food intake, and physical activity, during high-fat diet-induced obesity. We report that Epo doses (1000, 600, 300, and 150 U/kg) significantly reduced body weight gain and fat mass, while, only Epo doses of 300 U/kg and higher significantly affected glucose tolerance. None of the tested Epo doses showed any detectable effects on food intake, and only 1000 U/kg dose significantly increased physical activity, suggesting that these parameters may only be partially responsible for the metabolic effects of Epo treatment. Amanda Foskett, Mawadda Alnaeeli, Li Wang, Ruifeng Teng, and Constance T. Noguchi Copyright © 2011 Amanda Foskett et al. All rights reserved. Roles of the WHHL Rabbit in Translational Research on Hypercholesterolemia and Cardiovascular Diseases Tue, 19 Apr 2011 11:27:04 +0000 http://www.hindawi.com/journals/bmri/2011/406473/ Conquering cardiovascular diseases is one of the most important problems in human health. To overcome cardiovascular diseases, animal models have played important roles. Although the prevalence of genetically modified animals, particularly mice and rats, has contributed greatly to biomedical research, not all human diseases can be investigated in this way. In the study of cardiovascular diseases, mice and rats are inappropriate because of marked differences in lipoprotein metabolism, pathophysiological findings of atherosclerosis, and cardiac function. On the other hand, since lipoprotein metabolism and atherosclerotic lesions in rabbits closely resemble those in humans, several useful animal models for these diseases have been developed in rabbits. One of the most famous of these is the Watanabe heritable hyperlipidemic (WHHL) rabbit, which develops hypercholesterolemia and atherosclerosis spontaneously due to genetic and functional deficiencies of the low-density lipoprotein (LDL) receptor. The WHHL rabbit has been improved to develop myocardial infarction, and the new strain was designated the myocardial infarction-prone WHHL (WHHLMI) rabbit. This review summarizes the importance of selecting animal species for translational research in biomedical science, the development of WHHL and WHHLMI rabbits, their application to the development of hypocholesterolemic and/or antiatherosclerotic drugs, and future prospects regarding WHHL and WHHLMI rabbits. Tsutomu Kobayashi, Takashi Ito, and Masashi Shiomi Copyright © 2011 Tsutomu Kobayashi et al. All rights reserved. Animal Models of Middle Ear Cholesteatoma Wed, 06 Apr 2011 14:17:53 +0000 http://www.hindawi.com/journals/bmri/2011/394241/ Middle ear acquired cholesteatoma is a pathological condition associated with otitis media, which may be associated with temporal bone resorption, otorrhea and hearing loss, and occasionally various other complications. Cholesteatoma is characterized by the enhanced proliferation of epithelial cells with aberrant morphologic characteristics. Unfortunately, our understanding of the mechanism underlying its pathogenesis is limited. To investigate its pathogenesis, different animal models have been used. This paper provides a brief overview of the current status of research in the field of pathogenesis of middle ear acquired cholesteatoma, four types of animal models previously reported on, up-to-date cholesteatoma research using these animal models, our current studies of the local hybrid ear model, and the future prospect of new animal models of middle ear cholesteatoma. Tomomi Yamamoto-Fukuda, Haruo Takahashi, and Takehiko Koji Copyright © 2011 Tomomi Yamamoto-Fukuda et al. All rights reserved. Methotrexate Toxicity in Growing Long Bones of Young Rats: A Model for Studying Cancer Chemotherapy-Induced Bone Growth Defects in Children Thu, 17 Mar 2011 12:05:20 +0000 http://www.hindawi.com/journals/bmri/2011/903097/ 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. Chiaming Fan, Kristen R. Georgiou, Tristan J. King, and Cory J. Xian Copyright © 2011 Chiaming Fan et al. All rights reserved. A Novel Animal Model of Hippocampal Cognitive Deficits, Slow Neurodegeneration, and Neuroregeneration Tue, 15 Mar 2011 14:33:45 +0000 http://www.hindawi.com/journals/bmri/2011/527201/ Long-term adrenalectomy (ADX) results in an extensive and specific loss of dentate gyrus granule cells in the hippocampus of adult rats. This loss of granule cells extends over a period of weeks to months and ultimately results in cognitive deficits revealed in a number of tasks that depend on intact hippocampal function. The gradual nature of ADX-induced cell death and the ensuing deficits in cognition resemble in some important respects a variety of pathological conditions in humans. Here, we characterize behavioural and cellular processes, including adult neurogenesis, in the rat ADX model. We also provide experimental evidence for a neurogenic treatment strategy by which the lost hippocampal cells may be replaced, with the goal of functional recovery in mind. Simon C. Spanswick, Hugo Lehmann, and Robert J. Sutherland Copyright © 2011 Simon C. Spanswick et al. All rights reserved. The Animal Model of Spinal Cord Injury as an Experimental Pain Model Mon, 07 Mar 2011 14:51:07 +0000 http://www.hindawi.com/journals/bmri/2011/939023/ Pain, which remains largely unsolved, is one of the most crucial problems for spinal cord injury patients. Due to sensory problems, as well as motor dysfunctions, spinal cord injury research has proven to be complex and difficult. Furthermore, many types of pain are associated with spinal cord injury, such as neuropathic, visceral, and musculoskeletal pain. Many animal models of spinal cord injury exist to emulate clinical situations, which could help to determine common mechanisms of pathology. However, results can be easily misunderstood and falsely interpreted. Therefore, it is important to fully understand the symptoms of human spinal cord injury, as well as the various spinal cord injury models and the possible pathologies. The present paper summarizes results from animal models of spinal cord injury, as well as the most effective use of these models. Aya Nakae, Kunihiro Nakai, Kenji Yano, Ko Hosokawa, Masahiko Shibata, and Takashi Mashimo Copyright © 2011 Aya Nakae et al. All rights reserved. Joint Inflammation and Early Degeneration Induced by High-Force Reaching Are Attenuated by Ibuprofen in an Animal Model of Work-Related Musculoskeletal Disorder Thu, 03 Mar 2011 10:25:10 +0000 http://www.hindawi.com/journals/bmri/2011/691412/ We used our voluntary rat model of reaching and grasping to study the effect of performing a high-repetition and high-force (HRHF) task for 12 weeks on wrist joints. We also studied the effectiveness of ibuprofen, administered in the last 8 weeks, in attenuating HRHF-induced changes in these joints. With HRHF task performance, ED1+ and COX2+ cells were present in subchondral radius, carpal bones and synovium; IL-1alpha and TNF-alpha increased in distal radius/ulna/carpal bones; chondrocytes stained with Terminal deoxynucleotidyl Transferase- (TDT-) mediated dUTP-biotin nick end-labeling (TUNEL) increased in wrist articular cartilages; superficial structural changes (e.g., pannus) and reduced proteoglycan staining were observed in wrist articular cartilages. These changes were not present in normal controls or ibuprofen treated rats, although IL-1alpha was increased in reach limbs of trained controls. HRHF-induced increases in serum C1,2C (a biomarker of collagen I and II degradation), and the ratio of collagen degradation to synthesis (C1,2C/CPII; the latter a biomarker of collage type II synthesis) were also attenuated by ibuprofen. Thus, ibuprofen treatment was effective in attenuating HRHF-induced inflammation and early articular cartilage degeneration. Jeffrey B. Driban, Ann E. Barr, Mamta Amin, Michael R. Sitler, and Mary F. Barbe Copyright © 2011 Jeffrey B. Driban et al. All rights reserved. Laboratory Animal Models for Brucellosis Research Sun, 20 Feb 2011 14:05:49 +0000 http://www.hindawi.com/journals/bmri/2011/518323/ Brucellosis is a chronic infectious disease caused by Brucella spp., a Gram-negative facultative intracellular pathogen that affects humans and animals, leading to significant impact on public health and animal industry. Human brucellosis is considered the most prevalent bacterial zoonosis in the world and is characterized by fever, weight loss, depression, hepato/splenomegaly, osteoarticular, and genital infections. Relevant aspects of Brucella pathogenesis have been intensively investigated in culture cells and animal models. The mouse is the animal model more commonly used to study chronic infection caused by Brucella. This model is most frequently used to investigate specific pathogenic factors of Brucella spp., to characterize the host immune response, and to evaluate therapeutics and vaccines. Other animal species have been used as models for brucellosis including rats, guinea pigs, and monkeys. This paper discusses the murine and other laboratory animal models for human and animal brucellosis. Teane M. A. Silva, Erica A. Costa, Tatiane A. Paixão, Renée M. Tsolis, and Renato L. Santos Copyright © 2011 Teane M. A. Silva et al. All rights reserved. Animal Models of Cardiovascular Diseases Wed, 16 Feb 2011 09:27:54 +0000 http://www.hindawi.com/journals/bmri/2011/497841/ Cardiovascular diseases are the first leading cause of death and morbidity in developed countries. The use of animal models have contributed to increase our knowledge, providing new approaches focused to improve the diagnostic and the treatment of these pathologies. Several models have been developed to address cardiovascular complications, including atherothrombotic and cardiac diseases, and the same pathology have been successfully recreated in different species, including small and big animal models of disease. However, genetic and environmental factors play a significant role in cardiovascular pathophysiology, making difficult to match a particular disease, with a single experimental model. Therefore, no exclusive method perfectly recreates the human complication, and depending on the model, additional considerations of cost, infrastructure, and the requirement for specialized personnel, should also have in mind. Considering all these facts, and depending on the budgets available, models should be selected that best reproduce the disease being investigated. Here we will describe models of atherothrombotic diseases, including expanding and occlusive animal models, as well as models of heart failure. Given the wide range of models available, today it is possible to devise the best strategy, which may help us to find more efficient and reliable solutions against human cardiovascular diseases. Carlos Zaragoza, Carmen Gomez-Guerrero, Jose Luis Martin-Ventura, Luis Blanco-Colio, Begoña Lavin, Beñat Mallavia, Carlos Tarin, Sebastian Mas, Alberto Ortiz, and Jesus Egido Copyright © 2011 Carlos Zaragoza et al. All rights reserved. Murine Models of Systemic Lupus Erythematosus Mon, 14 Feb 2011 07:55:31 +0000 http://www.hindawi.com/journals/bmri/2011/271694/ Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder. The study of diverse mouse models of lupus has provided clues to the etiology of SLE. Spontaneous mouse models of lupus have led to identification of numerous susceptibility loci from which several candidate genes have emerged. Meanwhile, induced models of lupus have provided insight into the role of environmental factors in lupus pathogenesis as well as provided a better understanding of cellular mechanisms involved in the onset and progression of disease. The SLE-like phenotypes present in these models have also served to screen numerous potential SLE therapies. Due to the complex nature of SLE, it is necessary to understand the effect specific targeted therapies have on immune homeostasis. Furthermore, knowledge gained from mouse models will provide novel therapy targets for the treatment of SLE. Daniel Perry, Allison Sang, Yiming Yin, Ying-Yi Zheng, and Laurence Morel Copyright © 2011 Daniel Perry et al. All rights reserved. Animal Models for Periodontal Disease Thu, 10 Feb 2011 10:16:10 +0000 http://www.hindawi.com/journals/bmri/2011/754857/ Animal models and cell cultures have contributed new knowledge in biological sciences, including periodontology. Although cultured cells can be used to study physiological processes that occur during the pathogenesis of periodontitis, the complex host response fundamentally responsible for this disease cannot be reproduced in vitro. Among the animal kingdom, rodents, rabbits, pigs, dogs, and nonhuman primates have been used to model human periodontitis, each with advantages and disadvantages. Periodontitis commonly has been induced by placing a bacterial plaque retentive ligature in the gingival sulcus around the molar teeth. In addition, alveolar bone loss has been induced by inoculation or injection of human oral bacteria (e.g., Porphyromonas gingivalis) in different animal models. While animal models have provided a wide range of important data, it is sometimes difficult to determine whether the findings are applicable to humans. In addition, variability in host responses to bacterial infection among individuals contributes significantly to the expression of periodontal diseases. A practical and highly reproducible model that truly mimics the natural pathogenesis of human periodontal disease has yet to be developed. Helieh S. Oz and David A. Puleo Copyright © 2011 Helieh S. Oz and David A. Puleo. All rights reserved. The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus Thu, 10 Feb 2011 08:19:03 +0000 http://www.hindawi.com/journals/bmri/2011/207504/ To date, CNS disease and neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. In this review, we focus on a specific mouse model of lupus and the ways in which this model reflects some of the most common manifestations and potential mechanisms of human NP-SLE. The mouse MRL lymphoproliferation strain (a.k.a. MRL/lpr) spontaneously develops the hallmark serological markers and peripheral pathologies typifying lupus in addition to displaying the cognitive and affective dysfunction characteristic of NP-SLE, which may be among the earliest symptoms of lupus. We suggest that although NP-SLE may share common mechanisms with peripheral organ pathology in lupus, especially in the latter stages of the disease, the immunologically privileged nature of the CNS indicates that early manifestations of particularly mood disorders maybe derived from some unique mechanisms. These include altered cytokine profiles that can activate astrocytes, microglia, and alter neuronal function before dysregulation of the blood-brain barrier and development of clinical autoantibody titres. Maria Gulinello and Chaim Putterman Copyright © 2011 Maria Gulinello and Chaim Putterman. All rights reserved. Long-Term Type 1 Diabetes Enhances In-Stent Restenosis after Aortic Stenting in Diabetes-Prone BB Rats Wed, 09 Feb 2011 11:19:20 +0000 http://www.hindawi.com/journals/bmri/2011/396734/ Type 1 diabetic patients have increased risk of developing in-stent restenosis following endovascular stenting. Underlying pathogenetic mechanisms are not fully understood partly due to the lack of a relevant animal model to study the effect(s) of long-term autoimmune diabetes on development of in-stent restenosis. We here describe the development of in-stent restenosis in long-term (~7 months) spontaneously diabetic and age-matched, thymectomized, nondiabetic Diabetes Prone BioBreeding (BBDP) rats (𝑛=6-7 in each group). Diabetes was suboptimally treated with insulin and was characterized by significant hyperglycaemia, polyuria, proteinuria, and increased HbA1c levels. Stented abdominal aortas were harvested 28 days after stenting. Computerized morphometric analysis revealed significantly increased neointima formation in long-term diabetic rats compared with nondiabetic controls. In conclusion, long-term autoimmune diabetes in BBDP rats enhances in-stent restenosis. This model can be used to study the underlying pathogenetic mechanisms of diabetes-enhanced in-stent restenosis as well as to test new therapeutic modalities. Geanina Onuta, Hendrik C. Groenewegen, Flip A. Klatter, Mark Walther Boer, Maaike Goris, Harry van Goor, Anton J. M. Roks, Jan Rozing, Bart J. G. L. de Smet, and Jan-Luuk Hillebrands Copyright © 2011 Geanina Onuta et al. All rights reserved. Assessment of Elastase-Induced Murine Abdominal Aortic Aneurysms: Comparison of Ultrasound Imaging with In Situ Video Microscopy Sun, 06 Feb 2011 16:05:28 +0000 http://www.hindawi.com/journals/bmri/2011/252141/ Aims. The aim of this study was to definitively assess the validity of noninvasive high-frequency ultrasound (US) measurements of aortic luminal diameter (ALD) in a murine model of elastase-induced abdominal aortic aneurysm in comparison with in situ video microscopy (VM). Methods. C57BL/6 mice underwent transient perfusion of the aorta with either elastase (n=20: Elastase group) or saline (n=10: Sham). Unoperated mice (n=10) were also studied. Results. ALD measurements by US had excellent linear correlation and absolute agreement with that by VM in both Control (unoperated or sham-operated mice) and elastase groups (r=0.96, intraclass correlation coefficient (ICC)=0.88 and r=0.93, ICC=0.92, resp.). Bland-Altman analysis of US compared with VM measurements in both groups indicated good agreement, however US measurements were slightly but significantly higher than VM measurements in the control group (mean bias 0.039 mm, P<.05). Linear regression analysis revealed excellent correlation between US and VM measurements in both groups. (R2=0.91 in Control group, R2=0.85 in elastase group.) The reliability of US measurements was also confirmed by ex vivo histological measurements. Conclusions. High-frequency US provides reliable ALD measurements in developing murine abdominal aortic aneurysms. Junya Azuma, Lars Maegdefessel, Toshiro Kitagawa, Ronald L. Dalman, Michael V. McConnell, and Philip S. Tsao Copyright © 2011 Junya Azuma et al. All rights reserved. Blood-Oxygenation-Level-Dependent-(BOLD-) Based R2′ MRI Study in Monkey Model of Reversible Middle Cerebral Artery Occlusion Sun, 06 Feb 2011 08:55:26 +0000 http://www.hindawi.com/journals/bmri/2011/318346/ Objective. To investigate the value of BOLD-based reversible transverse relaxation rate (R2′) MRI in detecting ischemic penumbra (IP) in a monkey model of reversible middle cerebral artery occlusion (MCAO) and time evolution of relative R2′ (rR2′) in infarcted core, IP, and oligemia. Materials and Methods. 6 monkeys were used to make MCAO by the microcatheter method. MR scans were performed at 0 h (1 h after MCAO), 1 h, 3 h, 6 h, 12 h, 24 h, and 48 h after reperfusion. R2′ was calculated using quantitative T2 and T2∗ maps. Ischemic area was subdivided into infracted core, IP and oligemia. rR2′ was calculated respectively. Results. Reversible MCAO model for 4/6 monkeys was made successfully. rR2′ values were significantly different at each time point, being highest in oligemia followed by IP and infarcted core (𝑃<.05). With reperfusion time evolution, rR2′ in infarcted core showed a decreased trend: sharply decreased within 6 hours and maintained at 0 during 6–48 hours (𝑃<.05). rR2′ values in IP and oligemia showed similar increased trend: sharply increased within 6 hours, maintained a plateau during 6–24 hours, and slightly increased until 48 hours. Conclusion. BOLD-based R2′ MRI can be used to describe changes of cerebral oxygen extract in acute ischemic stroke, and it can provide additional information in detecting IP. The time evolution rR2′ in infarcted core, IP, and oligemia is in accordance with the underlying pathophysiology. Jing Zhang, Ying-min Chen, and Yun-ting Zhang Copyright © 2011 Jing Zhang et al. All rights reserved. Experimental Trauma Models: An Update Wed, 26 Jan 2011 10:20:02 +0000 http://www.hindawi.com/journals/bmri/2011/797383/ Treatment of polytrauma patients remains a medical as well as socioeconomic challenge. Although diagnostics and therapy improved during the last decades, multiple injuries are still the major cause of fatalities in patients below 45 years of age. Organ dysfunction and organ failure are major complications in patients with major injuries and contribute to mortality during the clinical course. Profound understanding of the systemic pathophysiological response is crucial for innovative therapeutic approaches. Therefore, experimental studies in various animal models are necessary. This review is aimed at providing detailed information of common trauma models in small as well as in large animals. Michael Frink, Hagen Andruszkow, Christian Zeckey, Christian Krettek, and Frank Hildebrand Copyright © 2011 Michael Frink et al. All rights reserved. Middle Cerebral Artery Occlusion Model in Rodents: Methods and Potential Pitfalls Sun, 23 Jan 2011 08:49:08 +0000 http://www.hindawi.com/journals/bmri/2011/464701/ A variety of animal models have been developed for modeling ischemic stroke. The middle cerebral artery occlusion (MCAO) model has been utilized extensively, especially in rodents. While the MCAO model provides stroke researchers with an excellent platform to investigate the disease, controversial or even paradoxical results are occasionally seen in the literature utilizing this model. Various factors exert important effects on the outcome in this stroke model, including the age and sex of the animal examined. This paper discusses emerging information on the effects of age and sex on ischemic outcomes after MCAO, with an emphasis on mouse models of stroke. Fudong Liu and Louise D. McCullough Copyright © 2011 Fudong Liu and Louise D. McCullough. All rights reserved. Glucose Tolerance and Left Ventricular Pressure-Volume Relationships in Frequently Used Mouse Strains Thu, 20 Jan 2011 10:23:23 +0000 http://www.hindawi.com/journals/bmri/2011/281312/ We investigated glucose tolerance and left ventricular contractile performance in 4 frequently used mouse strains (Swiss, C57BL/6J, DBA2, and BalbC) at 24 weeks. Glucose tolerance was tested by measuring blood glucose levels in time after intraperitoneal glucose injection (2 mg/g body weight). Left ventricular contractility was assessed by pressure-conductance analysis. Peak glucose levels and glucose area under the curve were higher (all 𝑃<.05) in C57BL/6J (418±65 mg/dL and 813±100 mg·h/dL) versus Swiss (237±66 mg/dL and 470±126 mg·h/dL), DBA2 (113±20 mg/dL and 304±49 mg·h/dL, 𝑃<.01), and BalbC mice (174±55 mg/dL and 416±70 mg·h/dL). Cardiac output was higher (all 𝑃<.05) in Swiss (14038±4530 μL/min) versus C57BL/6J (10405±2683 μL/min), DBA2 (10438±3251 μL/min), and BalbC mice (8466±3013 μL/min). Load-independent left ventricular contractility assessed as recruitable stroke work (PRSW) was comparable in all strains. In conclusion, glucose tolerance and load-dependent left ventricular performance parameters were different between 4 mice background strains, but PRSW was comparable. Wouter Oosterlinck, Annelies Vanderper, Willem Flameng, and Paul Herijgers Copyright © 2011 Wouter Oosterlinck et al. All rights reserved. Psychological Stress Induces Temporary Masticatory Muscle Mechanical Sensitivity in Rats Wed, 19 Jan 2011 10:03:27 +0000 http://www.hindawi.com/journals/bmri/2011/720603/ To explore the relationship between psychological stress and masticatory muscle pain, we created a communication stress animal model to determine whether psychological stress could induce increased mechanical sensitivity in masticatory muscles and to study the changes of mechanical nociceptive thresholds after stress removal. Forty-eight male Sprague-Dawley rats were divided into a control group (CON), a foot-shocked group (FS, including 3 subgroups recorded as FS-1, FS-2, and FS-3), a psychological stress group (PS), and a drug treatment group (DT). PS and DT rats were confined in a communication box for one hour a day to observe the psychological responses of neighboring FS rats.Measurements of the mechanical nociceptive thresholds of the bilateral temporal and masseter muscles showed a stimulus-response relationship between psychological stress and muscle mechanical sensitivity. The DT rats, who received a diazepam injection, showed almost the same mechanical sensitivity of the masticatory muscles to that of the control in response to psychological stress. Fourteen days after the psychological stressor was removed, the mechanical nociceptive thresholds returned to normal. These findings suggest that psychological stress is directly related to masticatory muscle pain. Removal of the stressor could be a useful method for relieving mechanical sensitivity increase induced by psychological stress. Fei Huang, Min Zhang, Yong-Jin Chen, Qiang Li, and An-Zhen Wu Copyright © 2011 Fei Huang et al. All rights reserved. Experimentally Approaching the ICU: Monitoring Outcome-Based Responses in the Two-Hit Mouse Model of Posttraumatic Sepsis Tue, 18 Jan 2011 11:51:36 +0000 http://www.hindawi.com/journals/bmri/2011/357926/ To simulate and monitor the evolution of posttraumatic sepsis in mice, we combined a two-hit model of trauma/hemorrhage (TH) followed by polymicrobial sepsis with repetitive blood sampling. Anesthetized mice underwent femur fracture/sublethal hemorrhage and cecal ligation and puncture (CLP) 48 h later. To monitor outcome-dependent changes in circulating cells/biomarkers, mice were sampled daily (facial vein) for 7 days and retrospectively divided into either dead (DIE) or surviving (SUR) by post-CLP day 7. Prior to CLP, AST was 3-fold higher in DIE, while all other post-TH changes were similar between groups. There was a significant post-CLP intergroup separation. In SUR, RBC and Hb were lower, platelets and neutrophils higher, and lymphocytes mixed compared to DIE. In DIE, all organ function markers except glucose (decrease) were few folds higher compared to SUR. In summary, the combination of daily monitoring with an adequate two-hit model simulates the ICU setting, allows insight into outcome-based responses, and can identify biomarkers indicative of death in the acute posttraumatic sepsis in mice. Susanne Drechsler, Katrin M. Weixelbaumer, Heinz Redl, Martijn van Griensven, Soheyl Bahrami, and Marcin F. Osuchowski Copyright © 2011 Susanne Drechsler et al. All rights reserved. Phosphocreatine Preconditioning Attenuates Apoptosis in Ischemia-Reperfusion Injury of Rat Brain Mon, 17 Jan 2011 15:31:07 +0000 http://www.hindawi.com/journals/bmri/2011/107091/ Phosphocreatine (PCr) is an endogenous compound containing high-energy phosphate bonds. It has been confirmed that PCr is effective in preventing and treating cardiac and renal ischemia-reperfusion injury. In this study, rat cerebral ischemia-reperfusion injury models were constructed. Apoptotic cells in the cortex region were measured by TUNEL method. Malondialdehyde (MDA) content was detected by chromatometry, and calmodulin (CaM) activity was detected by ELISA. Compared with sham-operated group (sham group), TUNEL-positive cells, MDA, and level of CaM activity increased in ischemia-reperfusion group (I/R group) and PCr preconditioning group (PCr group); compared with I/R group, TUNEL-positive cells, MDA content, and level of CaM activity decreased in PCr group. This study indicated that PCr can decrease the morphological damage and the neuron apoptosis of the ischemia-reperfusion injury brain through attenuating abnormalities of calcium balance and production of oxygen free radicals. Ling-Hua Tang, Zhong-Yuan Xia, Bo Zhao, Xiao-Dong Wei, Tao Luo, and Qing-Tao Meng Copyright © 2011 Ling-Hua Tang et al. All rights reserved. Gait Disturbances in Dystrophic Hamsters Thu, 13 Jan 2011 15:31:30 +0000 http://www.hindawi.com/journals/bmri/2011/235354/ The delta-sarcoglycan-deficient hamster is an excellent model to study muscular dystrophy. Gait disturbances, important clinically, have not been described in this animal model. We applied ventral plane videography (DigiGait) to analyze gait in BIO TO-2 dystrophic and BIO F1B control hamsters walking on a transparent treadmill belt. Stride length was ~13% shorter (𝑃<.05) in TO-2 hamsters at 9 months of age compared to F1B hamsters. Hindlimb propulsion duration, an indicator of muscle strength, was shorter in 9-month-old TO-2 (247±8 ms) compared to F1B hamsters (272±11 ms; 𝑃<.05). Braking duration, reflecting generation of ground reaction forces, was delayed in 9-month-old TO-2 (147±6 ms) compared to F1B hamsters (126±8 ms; 𝑃<.05). Hindpaw eversion, evidence of muscle weakness, was greater in 9-month-old TO-2 than in F1B hamsters (17.7±1.2∘ versus 8.7±1.6∘; 𝑃<.05). Incline and decline walking aggravated gait disturbances in TO-2 hamsters at 3 months of age. Several gait deficits were apparent in TO-2 hamsters at 1 month of age. Quantitative gait analysis demonstrates that dystrophic TO-2 hamsters recapitulate functional aspects of human muscular dystrophy. Early detection of gait abnormalities in a convenient animal model may accelerate the development of therapies for muscular dystrophy. Thomas G. Hampton, Ajit Kale, Ivo Amende, Wenlong Tang, Scott McCue, Hemmi N. Bhagavan, and Case G. VanDongen Copyright © 2011 Thomas G. Hampton et al. All rights reserved. Animal Models of Colitis-Associated Carcinogenesis Wed, 12 Jan 2011 13:03:17 +0000 http://www.hindawi.com/journals/bmri/2011/342637/ Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that affect individuals throughout life. Although the etiology and pathogenesis of IBD are largely unknown, studies with animal models of colitis indicate that dysregulation of host/microbial interactions are requisite for the development of IBD. Patients with long-standing IBD have an increased risk for developing colitis-associated cancer (CAC), especially 10 years after the initial diagnosis of colitis, although the absolute number of CAC cases is relatively small. The cancer risk seems to be not directly related to disease activity, but is related to disease duration/extent, complication of primary sclerosing cholangitis, and family history of colon cancer. In particular, high levels and continuous production of inflammatory mediators, including cytokines and chemokines, by colonic epithelial cells (CECs) and immune cells in lamina propria may be strongly associated with the pathogenesis of CAC. In this article, we have summarized animal models of CAC and have reviewed the cellular and molecular mechanisms underlining the development of carcinogenic changes in CECs secondary to the chronic inflammatory conditions in the intestine. It may provide us some clues in developing a new class of therapeutic agents for the treatment of IBD and CAC in the near future. Manasa Kanneganti, Mari Mino-Kenudson, and Emiko Mizoguchi Copyright © 2011 Manasa Kanneganti et al. All rights reserved. Aortocaval Fistula in Rat: A Unique Model of Volume-Overload Congestive Heart Failure and Cardiac Hypertrophy Tue, 11 Jan 2011 15:18:28 +0000 http://www.hindawi.com/journals/bmri/2011/729497/ Despite continuous progress in our understanding of the pathogenesis of congestive heart failure (CHF) and its management, mortality remains high. Therefore, development of reliable experimental models of CHF and cardiac hypertrophy is essential to better understand disease progression and allow new therapy developement. The aortocaval fistula (ACF) model, first described in dogs almost a century ago, has been adopted in rodents by several groups including ours. Although considered to be a model of high-output heart failure, its long-term renal and cardiac manifestations are similar to those seen in patients with low-output CHF. These include Na+-retention, cardiac hypertrophy and increased activity of both vasoconstrictor/antinatriureticneurohormonal systems and compensatory vasodilating/natriuretic systems. Previous data from our group and others suggest that progression of cardiorenal pathophysiology in this model is largely determined by balance between opposing hormonal forces, as reflected in states of CHF decompensation that are characterized by overactivation of vasoconstrictive/Na+-retaining systems. Thus, ACF serves as a simple, cheap, and reproducible platform to investigate the pathogenesis of CHF and to examine efficacy of new therapeutic approaches. Hereby, we will focus on the neurohormonal, renal, and cardiac manifestations of the ACF model in rats, with special emphasis on our own experience. Zaid Abassi, Ilia Goltsman, Tony Karram, Joseph Winaver, and Aaron Hoffman Copyright © 2011 Zaid Abassi et al. All rights reserved. Collagen-Based Films Containing Liposome-Loaded Usnic Acid as Dressing for Dermal Burn Healing Tue, 11 Jan 2011 15:16:24 +0000 http://www.hindawi.com/journals/bmri/2011/761593/ The aim of this study was assess the effect of collagen-based films containing usnic acid as a wound dressing for dermal burn healing. Second-degree burn wounds were performed in forty-five Wistar rats, assigned into nine groups: COL—animals treated with collagen-based films; PHO—animals treated with collagen films containing empty liposomes; UAL—animals treated with collagen-based films containing usnic acid incorporated into liposomes. After 7, 14, and 21 days the animals were euthanized. On 7th day there was a moderate infiltration of neutrophils, in UAL, distributed throughout the burn wounds, whereas in COL and PHO, the severity of the reaction was slighter and still limited to the margins of the burn wounds. On the 14th day, the inflammatory reaction was less intense in UAL, with remarkable plasma cells infiltration. On the 21st day, there was reduction of the inflammation, which was predominantly composed of plasma cells in all groups, particularly in UAL. The use of the usnic acid provided more rapid substitution of type-III for type-I collagen on the 14th day, and improved the collagenization density on the 21st day. It was concluded that the use of reconstituted bovine type-I collagen-based films containing usnic acid improved burn healing process in rats. Paula S. Nunes, Ricardo L. C. Albuquerque-Júnior, Danielle R. R. Cavalcante, Marx D. M. Dantas, Juliana C. Cardoso, Marília S. Bezerra, Jamille C. C. Souza, Mairim Russo Serafini, Lucindo J. Quitans-Jr, Leonardo R. Bonjardim, and Adriano A. S. Araújo Copyright © 2011 Paula S. Nunes et al. All rights reserved. Loss of the NHE2 Na+/H+ Exchanger in Mice Results in Dilation of Folliculo-Stellate Cell Canaliculi Mon, 10 Jan 2011 09:48:05 +0000 http://www.hindawi.com/journals/bmri/2011/510827/ Genetic ablation of the NHE2 Na+/H+ exchanger causes gastric achlorhydria, absorptive defects in kidney and colon, and low fertility. Here we show that NHE2 is expressed in the pituitary, with the highest mRNA expression in pars distalis and lower expression in pars intermedia. In pars distalis of NHE2-null mice, prominent cyst-like dilatations of folliculo-stellate (FS) cell canaliculi developed with age, and there were increased FS cell area, accumulation of lipid in FS cell cytoplasm, redundancies in FS cell basement membrane, and other changes. The expansion of the canaliculi indicates that NHE2 is a major absorptive Na+/H+ exchanger in the luminal membranes lining the extensive network of channels formed by FS cells, which may provide a means of intrapituitary communication. The results suggest that NHE2 contributes to homeostatic regulation of the volume and composition of the canalicular fluid and may counter the secretory activity of the CFTR Cl− channel, which is known to be expressed in pituitary. Marian L. Miller, Anastasia Andringa, Patrick J. Schultheis, and Gary E. Shull Copyright © 2011 Marian L. Miller et al. All rights reserved. Mammalian Models of Duchenne Muscular Dystrophy: Pathological Characteristics and Therapeutic Applications Wed, 05 Jan 2011 15:01:04 +0000 http://www.hindawi.com/journals/bmri/2011/184393/ Duchenne muscular dystrophy (DMD) is a devastating X-linked muscle disorder characterized by muscle wasting which is caused by mutations in the DMD gene. The DMD gene encodes the sarcolemmal protein dystrophin, and loss of dystrophin causes muscle degeneration and necrosis. Thus far, therapies for this disorder are unavailable. However, various therapeutic trials based on gene therapy, exon skipping, cell therapy, read through therapy, or pharmaceutical agents have been conducted extensively. In the development of therapy as well as elucidation of pathogenesis in DMD, appropriate animal models are needed. Various animal models of DMD have been identified, and mammalian (murine, canine, and feline) models are indispensable for the examination of the mechanisms of pathogenesis and the development of therapies. Here, we review the pathological features of DMD and therapeutic applications, especially of exon skipping using antisense oligonucleotides and gene therapies using viral vectors in murine and canine models of DMD. Akinori Nakamura and Shin'ichi Takeda Copyright © 2011 Akinori Nakamura and Shin'ichi Takeda. All rights reserved. Biology of Obesity: Lessons from Animal Models of Obesity Wed, 05 Jan 2011 13:31:45 +0000 http://www.hindawi.com/journals/bmri/2011/197636/ Obesity is an epidemic problem in the world and is associated with several health problems, including diabetes, cardiovascular disease, respiratory failure, muscle weakness, and cancer. The precise molecular mechanisms by which obesity induces these health problems are not yet clear. To better understand the pathomechanisms of human disease, good animal models are essential. In this paper, we will analyze animal models of obesity and their use in the research of obesity-associated human health conditions and diseases such as diabetes, cancer, and obstructive sleep apnea syndrome. Keizo Kanasaki and Daisuke Koya Copyright © 2011 Keizo Kanasaki and Daisuke Koya. All rights reserved. Animal Models of Bacterial Keratitis Tue, 04 Jan 2011 18:00:13 +0000 http://www.hindawi.com/journals/bmri/2011/680642/ Bacterial keratitis is a disease of the cornea characterized by pain, redness, inflammation, and opacity. Common causes of this disease are Pseudomonas aeruginosa and Staphylococcus aureus. Animal models of keratitis have been used to elucidate both the bacterial factors and the host inflammatory response involved in the disease. Reviewed herein are animal models of bacterial keratitis and some of the key findings in the last several decades. Mary E. Marquart Copyright © 2011 Mary E. Marquart. All rights reserved. Mouse Models of Escherichia coli O157:H7 Infection and Shiga Toxin Injection Mon, 03 Jan 2011 15:44:07 +0000 http://www.hindawi.com/journals/bmri/2011/258185/ Escherichia coli O157:H7 has been responsible for multiple food- and waterborne outbreaks of diarrhea and/or hemorrhagic colitis (HC) worldwide. More importantly, a portion of E. coli O157:H7-infected individuals, particularly young children, develop a life-threatening sequela of infection called hemolytic uremic syndrome (HUS). Shiga toxin (Stx), a potent cytotoxin, is the major virulence factor linked to the presentation of both HC and HUS. Currently, treatment of E. coli O157:H7 and other Stx-producing E. coli (STEC) infections is limited to supportive care. To facilitate development of therapeutic strategies and vaccines for humans against these agents, animal models that mimic one or more aspect of STEC infection and disease are needed. In this paper, we focus on the characteristics of various mouse models that have been developed and that can be used to monitor STEC colonization, disease, pathology, or combinations of these features as well as the impact of Stx alone. Krystle L. Mohawk and Alison D. O'Brien Copyright © 2011 Krystle L. Mohawk and Alison D. O'Brien. All rights reserved. Experimental Model of Zymosan-Induced Arthritis in the Rat Temporomandibular Joint: Role of Nitric Oxide and Neutrophils Mon, 03 Jan 2011 13:44:14 +0000 http://www.hindawi.com/journals/bmri/2011/707985/ Aims. To establish a new model of zymosan-induced temporomandibular joint (TMJ) arthritis in the rat and to investigate the role of nitric oxide. Methods. Inflammation was induced by an intra-articular injection of zymosan into the left TMJ. Mechanical hypernociception, cell influx, vascular permeability, myeloperoxidase activity, nitrite levels, and histological changes were measured in TMJ lavages or tissues at selected time points. These parameters were also evaluated after treatment with the nitric oxide synthase (NOS) inhibitors L-NAME or 1400 W. Results. Zymosan-induced TMJ arthritis caused a time-dependent leucocyte migration, plasma extravasation, mechanical hypernociception, and neutrophil accumulation between 4 and 24 h. TMJ immunohistochemical analyses showed increased inducible NOS expression. Treatment with L-NAME or 1400 W inhibited these parameters. Conclusion. Zymosan-induced TMJ arthritis is a reproducible model that may be used to assess both the mechanisms underlying TMJ inflammation and the potential tools for therapies. Nitric oxide may participate in the inflammatory temporomandibular dysfunction mechanisms. Hellíada Vasconcelos Chaves, Ronaldo de Albuquerque Ribeiro, André Mattos Brito de Souza, Antonio Alfredo Rodrigues e Silva, Antoniella Souza Gomes, Mariana Lima Vale, Mirna Marques Bezerra, and Gerly Anne de Castro Brito Copyright © 2011 Hellíada Vasconcelos Chaves et al. All rights reserved. Glycogen Storage Disease Type Ia in Canines: A Model for Human Metabolic and Genetic Liver Disease Mon, 03 Jan 2011 10:23:24 +0000 http://www.hindawi.com/journals/bmri/2011/646257/ A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases. Andrew Specht, Laurie Fiske, Kirsten Erger, Travis Cossette, John Verstegen, Martha Campbell-Thompson, Maggie B. Struck, Young Mok Lee, Janice Y. Chou, Barry J. Byrne, Catherine E. Correia, Cathryn S. Mah, David A. Weinstein, and Thomas J. Conlon Copyright © 2011 Andrew Specht et al. All rights reserved. Atherosclerosis and Thrombosis: Insights from Large Animal Models Sun, 02 Jan 2011 15:08:20 +0000 http://www.hindawi.com/journals/bmri/2011/907575/ Atherosclerosis and its thrombotic complications are responsible for remarkably high numbers of deaths. The combination of in vitro, ex vivo, and in vivo experimental approaches has largely contributed to a better understanding of the mechanisms underlying the atherothrombotic process. Indeed, different animal models have been implemented in atherosclerosis and thrombosis research in order to provide new insights into the mechanisms that have already been outlined in isolated cells and protein studies. Yet, although no model completely mimics the human pathology, large animal models have demonstrated better suitability for translation to humans. Indeed, direct translation from mice to humans should be taken with caution because of the well-reported species-related differences. This paper provides an overview of the available atherothrombotic-like animal models, with a particular focus on large animal models of thrombosis and atherosclerosis, and examines their applicability for translational research purposes as well as highlights species-related differences with humans. Gemma Vilahur, Teresa Padro, and Lina Badimon Copyright © 2011 Gemma Vilahur et al. All rights reserved. Genetic Rodent Models of Amyotrophic Lateral Sclerosis Sun, 02 Jan 2011 08:38:21 +0000 http://www.hindawi.com/journals/bmri/2011/348765/ Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. A large number of rodent models are available that show motor neuron death and a progressive motor phenotype that is more or less reminiscent of what occurs in patients. These rodent models contain genes with spontaneous or induced mutations or (over) express different (mutant) genes. Some of these models have been of great value to delineate potential pathogenic mechanisms that cause and/or modulate selective motor neuron degeneration. In addition, these genetic rodent models play a crucial role in testing and selecting potential therapeutics that can be used to treat ALS and/or other motor neuron disorders. In this paper, we give a systematic overview of the most important genetic rodent models that show motor neuron degeneration and/or develop a motor phenotype. In addition, we discuss the value and limitations of the different models and conclude that it remains a challenge to find more and better rodent models based on mutations in new genes causing ALS. L. Van Den Bosch Copyright © 2011 L. Van Den Bosch. All rights reserved. Current Concepts: Mouse Models of Sjögren's Syndrome Thu, 30 Dec 2010 14:49:16 +0000 http://www.hindawi.com/journals/bmri/2011/549107/ Sjögren's syndrome (SjS) is a complex chronic autoimmune disease of unknown etiology which primarily targets the exocrine glands, resulting in eventual loss of secretory function. The disease can present as either primary SjS or secondary SjS, the latter of which occurs concomitantly with another autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or primary biliary cirrhosis. Current advancements in therapeutic prevention and treatment for SjS are impeded by lack of understanding in the pathophysiological and clinical progression of the disease. Development of appropriate mouse models for both primary and secondary SjS is needed in order to advance knowledge of this disease. This paper details important features, advantages, and pitfalls of current animal models of SjS, including spontaneous, transgenic, knockout, immunization, and transplantation chimera mouse models, and emphasizes the need for a better model in representing the human SjS phenotype. Tegan N. Lavoie, Byung Ha Lee, and Cuong Q. Nguyen Copyright © 2011 Tegan N. Lavoie et al. All rights reserved. Approaching Biomarkers of Membranous Nephropathy from a Murine Model to Human Disease Thu, 30 Dec 2010 14:40:37 +0000 http://www.hindawi.com/journals/bmri/2011/581928/ Background. Membranous glomerulonephropathy (MN) is the most prevalent cause of nephrotic syndrome in adult humans. However, the specific biomarkers of MN have not been fully elucidated. We examined the alterations in gene expression associated with the development of MN. Methods. Murine MN was induced by cationic bovine serum albumin (cBSA). After full-blown MN, cDNA microarray analysis was performed to identify gene expression changes, and highly expressed genes were evaluated as markers both in mice and human kidney samples. Results. MN mice revealed clinical proteinuria and the characteristic diffuse thickening of the glomerular basement membrane. There were 175 genes with significantly different expressions in the MN kidneys compared with the normal kidneys. Four genes, metallothionein-1 (Mt1), cathepsin D (CtsD), lymphocyte 6 antigen complex (Ly6), and laminin receptor-1 (Lamr1), were chosen and quantified. Mt1 was detected mainly in tubules, Lamr1 was highly expressed in glomeruli, and CtsD was detected both in tubules and glomeruli. The high expressions of Lamr1 and CtsD were also confirmed in human kidney biopsies. Conclusion. The murine MN model resembled the clinical and pathological features of human MN and may provide a tool for investigating MN. Applying cDNA microarray analysis may help to identify biomarkers for human MN. Chia-Chao Wu, Jin-Shuen Chen, Ching-Feng Huang, Chun-Chi Chen, Kuo-Chen Lu, Pauling Chu, Huey-Kang Sytwu, and Yuh-Feng Lin Copyright © 2011 Chia-Chao Wu et al. All rights reserved. Bovine Model of Doxorubicin-Induced Cardiomyopathy Thu, 30 Dec 2010 14:25:04 +0000 http://www.hindawi.com/journals/bmri/2011/758736/ Left ventricular assist devices (LVADs) constitute a recent advance in heart failure (HF) therapeutics. As the rigorous experimental assessment of LVADs in HF requires large animal models, our objective was to develop a bovine model of cardiomyopathy. Male calves (𝑛=8) were used. Four animals received 1.2 mg/kg intravenous doxorubicin weekly for seven weeks and four separate animals were studied as controls. Doxorubicin-treated animals were followed with weekly echocardiography. Target LV dysfunction was defined as an ejection fraction ≤35%. Sixty days after initiating doxorubicin, a terminal study was performed to determine hemodynamic, histological, biochemical, and molecular parameters. All four doxorubicin-treated animals exhibited significant (𝑃<0.05) contractile dysfunction, with target LV dysfunction achieved in three animals. Doxorubicin-treated hearts exhibited significantly reduced coronary blood flow and interstitial fibrosis and significantly increased apoptosis and myocyte size. Gene expression of atrial natriuretic factor increased more than 3-fold. Plasma norepinephrine and epinephrine levels were significantly increased early and late during the development of cardiomyopathy, respectively. We conclude that sequential administration of intravenous doxorubicin in calves induces a cardiomyopathy with many phenotypic hallmarks of the failing human heart. This clinically-relevant model may be useful for testing pathophysiologic responses to LVADs in the context of HF. Carlo R. Bartoli, Kenneth R. Brittian, Guruprasad A. Giridharan, Steven C. Koenig, Tariq Hamid, and Sumanth D. Prabhu Copyright © 2011 Carlo R. Bartoli et al. All rights reserved. Rodent Models for Metabolic Syndrome Research Thu, 30 Dec 2010 14:18:36 +0000 http://www.hindawi.com/journals/bmri/2011/351982/ Rodents are widely used to mimic human diseases to improve understanding of the causes and progression of disease symptoms and to test potential therapeutic interventions. Chronic diseases such as obesity, diabetes and hypertension, together known as the metabolic syndrome, are causing increasing morbidity and mortality. To control these diseases, research in rodent models that closely mimic the changes in humans is essential. This review will examine the adequacy of the many rodent models of metabolic syndrome to mimic the causes and progression of the disease in humans. The primary criterion will be whether a rodent model initiates all of the signs, especially obesity, diabetes, hypertension and dysfunction of the heart, blood vessels, liver and kidney, primarily by diet since these are the diet-induced signs in humans with metabolic syndrome. We conclude that the model that comes closest to fulfilling this criterion is the high carbohydrate, high fat-fed male rodent. Sunil K. Panchal and Lindsay Brown Copyright © 2011 Sunil K. Panchal and Lindsay Brown. All rights reserved. Presenilin-2 Mutation Causes Early Amyloid Accumulation and Memory Impairment in a Transgenic Mouse Model of Alzheimer's Disease Wed, 29 Dec 2010 14:57:54 +0000 http://www.hindawi.com/journals/bmri/2011/617974/ In order to clarify the pathophysiological role of presenilin-2 (PS2) carrying the Volga German Kindred mutation (N141I) in a conventional mouse model of Alzheimer's disease (AD) expressing amyloid precursor protein (APP) with the Swedish mutation (Tg2576 line), we generated a double transgenic mouse (PS2Tg2576) by crossbreeding the PS2 mutant with Tg2576 mice. Here, we demonstrate that the PS2 mutation induced the early deposition of amyloid β-protein (Aβ) at 2-3 months of age and progressive accumulation at 4-5 months of age in the brains of the mutant mice. The PS2 mutation also accelerated learning and memory impairment associated with Aβ accumulation at 4-5 months of age in Tg2576 mice. These results suggest that the PS2 mutation causes early cerebral amyloid accumulation and memory dysfunction. PS2Tg2576 mice are a suitable mouse model for studying amyloid-lowering therapies. Toshihiko Toda, Yoshihiro Noda, Genzo Ito, Masahiro Maeda, and Takahiko Shimizu Copyright © 2011 Toshihiko Toda et al. All rights reserved. Common Fragile Site Tumor Suppressor Genes and Corresponding Mouse Models of Cancer Wed, 29 Dec 2010 09:30:01 +0000 http://www.hindawi.com/journals/bmri/2011/984505/ Chromosomal common fragile sites (CFSs) are specific mammalian genomic regions that show an increased frequency of gaps and breaks when cells are exposed to replication stress in vitro. CFSs are also consistently involved in chromosomal abnormalities in vivo related to cancer. Interestingly, several CFSs contain one or more tumor suppressor genes whose structure and function are often affected by chromosomal fragility. The two most active fragile sites in the human genome are FRA3B and FRA16D where the tumor suppressor genes FHIT and WWOX are located, respectively. The best approach to study tumorigenic effects of altered tumor suppressors located at CFSs in vivo is to generate mouse models in which these genes are inactivated. This paper summarizes our present knowledge on mouse models of cancer generated by knocking out tumor suppressors of CFS. Alessandra Drusco, Yuri Pekarsky, Stefan Costinean, Anna Antenucci, Laura Conti, Stefano Volinia, Rami I. Aqeilan, Kay Huebner, and Nicola Zanesi Copyright © 2011 Alessandra Drusco et al. All rights reserved. The Development and the Use of Experimental Animal Models to Study the Underlying Mechanisms of CA Formation Tue, 28 Dec 2010 18:42:27 +0000 http://www.hindawi.com/journals/bmri/2011/535921/ Cerebral aneurysms (CAs) have a high prevalence and can cause a lethal subarachnoid hemorrhage. Currently, CAs can only be treated with invasive surgical procedures. To unravel the underlying mechanisms of CA formation and to develop new therapeutic drugs for CAs, animal models of CA have been established, modified, and analyzed. Experimental findings from these models have clarified some of the potential mechanisms of CA formation, especially the relationship between hemodynamic stress and chronic inflammation. Increased hemodynamic stress acting at the site of bifurcation of cerebral arteries triggers an inflammatory response mediated by various proinflammatory molecules in arterial walls, inducing pathological changes in the models similar to those observed in the walls of human CAs. Findings from animal studies have provided new insights into CA formation and may contribute to the development of new therapeutic drugs for CAs. Tomohiro Aoki and Masaki Nishimura Copyright © 2011 Tomohiro Aoki and Masaki Nishimura. All rights reserved. Morphological and Molecular Alterations in 1,2 Dimethylhydrazine and Azoxymethane Induced Colon Carcinogenesis in Rats Tue, 28 Dec 2010 18:42:16 +0000 http://www.hindawi.com/journals/bmri/2011/473964/ The dimethyhydrazine (DMH) or azoxymethane (AOM) model is a well-established, well-appreciated, and widely used model of experimental colon carcinogenesis. It has many morphological as well as molecular similarities to human sporadic colorectal cancer (CC), which are summarized and discussed in this paper. In addition, the paper combines present knowledge of morphological and molecular features in the multistep development of CC recognized in the DMH/AOM rat model. This understanding is necessary in order to accurately identify and interpret alterations that occur in the colonic mucosa when evaluating natural or pharmacological compounds in DMH/AOM rat colon carcinogenesis. The DMH/AOM model provides a wide range of options for investigating various initiating and environmental factors, the role of specific dietary and genetic factors, and therapeutic options in CC. The limitations of this model and suggested areas in which more research is required are also discussed. Martina Perše and Anton Cerar Copyright © 2011 Martina Perše and Anton Cerar. All rights reserved. Novel Concept of Motor Functional Analysis for Spinal Cord Injury in Adult Mice Tue, 28 Dec 2010 18:42:05 +0000 http://www.hindawi.com/journals/bmri/2011/157458/ In basic research on spinal cord injury (SCI), behavioral evaluation of the SCI animal model is critical. However, it is difficult to accurately evaluate function in the mouse SCI model due to the small size of mice. Although the open-field scoring scale is an outstanding appraisal method, supplementary objective tests are required. Using a compact SCANET system, in which a mouse carries out free movement for 5 min, we developed a novel method to detect locomotor ability. A SCANET system samples the horizontal coordinates of a mouse every 0.1 s, and both the speed and acceleration of its motion are calculated at each moment. It was found that the maximum speed and acceleration of motion over 5 min varied by injury severity. Moreover, these values were significantly correlated with open-field scores. The maximum speed and acceleration of SCI model mice using a SCANET system are objective, easy to obtain, and reproducible for evaluating locomotive function. Munehisa Shinozaki, Yuichiro Takahashi, Masahiko Mukaino, Nobuhito Saito, Yoshiaki Toyama, Hideyuki Okano, and Masaya Nakamura Copyright © 2011 Munehisa Shinozaki et al. All rights reserved. Rodent Preclinical Models for Developing Novel Antiarthritic Molecules: Comparative Biology and Preferred Methods for Evaluating Efficacy Tue, 28 Dec 2010 14:33:50 +0000 http://www.hindawi.com/journals/bmri/2011/569068/ Rodent models of immune-mediated arthritis (RMIA) are the conventional approach to evaluating mechanisms of inflammatory joint disease and the comparative efficacy of antiarthritic agents. Rat adjuvant-induced (AIA), collagen-induced (CIA), and streptococcal cell wall-induced (SCW) arthritides are preferred models of the joint pathology that occurs in human rheumatoid arthritis (RA). Lesions of AIA are most severe and consistent; structural and immunological changes of CIA best resemble RA. Lesion extent and severity in RMIA depends on experimental methodology (inciting agent, adjuvant, etc.) and individual physiologic parameters (age, genetics, hormonal status, etc.). The effectiveness of antiarthritic molecules varies with the agent, therapeutic regimen, and choice of RMIA. All RMIA are driven by overactivity of proinflammatory pathways, but the dominant molecules differ among the models. Hence, as with the human clinical experience, the efficacy of various antiarthritic molecules differs among RMIA, especially when the agent is a specific cytokine inhibitor. Brad Bolon, Marina Stolina, Caroline King, Scot Middleton, Jill Gasser, Debra Zack, and Ulrich Feige Copyright © 2011 Brad Bolon et al. All rights reserved. Rabbit Model of Retinoblastoma Tue, 28 Dec 2010 14:32:41 +0000 http://www.hindawi.com/journals/bmri/2011/394730/ We created a rabbit model of retinoblastoma and confirmed the tumor clinically and histopathologically. Seventeen New Zealand rabbits were immunosuppressed with cyclosporin A at doses of 10–15 mg/kg. At day 3, the animals received a 30 μl subretinal injection of 1×106 cultured WERI retinoblastoma cells. Digital fundus images were captured before euthanasia, and the eyes were submitted for histopathology. Retinoblastoma cells grew in all the inoculated eyes and established a tumor under the retina and/or in the vitreous. New blood vessels in the tumor were observed starting at week 5. Cuffs of viable tumor cells surrounded the blood vessels with regions of necrosis present at 70–80 μm from nutrient vessels. Occasional tumor seeds in the vitreous histologically exhibited central necrosis. This rabbit model demonstrated similar fundus appearance and pathologic features to human retinoblastoma and may be used as a model to test various routes of drug delivery for retinoblastoma. Shin Jeong Kang and Hans E. Grossniklaus Copyright © 2011 Shin Jeong Kang and Hans E. Grossniklaus. All rights reserved. The Representative Porcine Model for Human Cardiovascular Disease Tue, 28 Dec 2010 14:29:54 +0000 http://www.hindawi.com/journals/bmri/2011/195483/ To improve human health, scientific discoveries must be translated into practical applications. Inherent in the development of these technologies is the role of preclinical testing using animal models. Although significant insight into the molecular and cellular basis has come from small animal models, significant differences exist with regard to cardiovascular characteristics between these models and humans. Therefore, large animal models are essential to develop the discoveries from murine models into clinical therapies and interventions. This paper will provide an overview of the more frequently used large animal models, especially porcine models for preclinical studies. Yoriyasu Suzuki, Alan C. Yeung, and Fumiaki Ikeno Copyright © 2011 Yoriyasu Suzuki et al. All rights reserved. Hydrodynamic Delivery of Chitosan-Folate-DNA Nanoparticles in Rats with Adjuvant-Induced Arthritis Tue, 28 Dec 2010 14:28:35 +0000 http://www.hindawi.com/journals/bmri/2011/148763/ 50 kDa chitosan was conjugated with folate, a specific tissue-targeting ligand. Nanoparticles such as chitosan-DNA and folate-chitosan-DNA were prepared by coacervation process. The hydrodynamic intravenous injection of nanoparticles was performed in the right posterior paw in normal and arthritic rats. Our results demonstrated that the fluorescence intensity of DsRed detected was 5 to 12 times more in the right soleus muscle and in the right gastro muscle than other tissue sections. β-galactosidase gene expression with X-gal substrate and folate-chitosan-plasmid nanoparticles showed best coloration in the soleus muscle. Treated arthritic animals also showed a significant decrease in paw swelling and IL-1β and PGE2 concentration in serum compared to untreated rats. This study demonstrated that a nonviral gene therapeutic approach using hydrodynamic delivery could help transfect more efficiently folate-chitosan-DNA nanoparticles in vitro/in vivo and could decrease inflammation in arthritic rats. Qin Shi, Huijie Wang, Covi Tran, Xingping Qiu, Françoise M. Winnik, Xiaoling Zhang, Kerong Dai, Mohamed Benderdour, and Julio C. Fernandes Copyright © 2011 Qin Shi et al. All rights reserved. A Rabbit Model of Thrombosis on Atherosclerotic Lesions Sun, 26 Dec 2010 15:10:33 +0000 http://www.hindawi.com/journals/bmri/2011/424929/ Thrombus formation on a disrupted atherosclerotic plaque is a key event that leads to atherothrombosis. Because thrombus is induced by chemical or physical injury of normal arteries in most animal models of thrombosis, the mechanisms of thrombogenesis and thrombus growth in atherosclerotic vessels should be investigated in diseased arteries of appropriate models. Pathological findings of human atherothrombosis suggest that tissue factor, an initiator of the coagulation cascade, significantly affects enhanced platelet aggregation and fibrin formation after plaque disruption. We established a rabbit model of atherothrombosis based on human pathology in which differences in thrombus formation between normal and atherosclerotic arteries, factors contributing to thrombus growth, and mechanisms of plaque erosion can be investigated. Emerging transgenic and stem cell technologies should also provide an invaluable rabbit experimental model in the near future. Atsushi Yamashita and Yujiro Asada Copyright © 2011 Atsushi Yamashita and Yujiro Asada. All rights reserved. A Missense Mutation in Canine CLN6 in an Australian Shepherd with Neuronal Ceroid Lipofuscinosis Wed, 22 Dec 2010 12:31:51 +0000 http://www.hindawi.com/journals/bmri/2011/198042/ The childhood neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases that are progressive and ultimately fatal. An Australian Shepherd that exhibited a progressive neurological disorder with signs similar to human NCL was evaluated. The cerebral cortex, cerebellum, and retina were found to contain massive accumulations of autofluorescent inclusions characteristic of the NCLs. Nucleotide sequence analysis of DNA from the affected dog identified a T to C variant (c.829T>C) in exon 7 of CLN6. Mutations in the human ortholog underlie a late-infantile form of NCL in humans. The T-to-C transition results in a tryptophan to arginine amino acid change in the predicted protein sequence. Tryptophans occur at homologous positions in the CLN6 proteins from all 13 other vertebrates evaluated. The c.829T>C transition is a strong candidate for the causative mutation in this NCL-affected dog. Dogs with this mutation could serve as a model for the analogous human disorder. Martin L. Katz, Fabiana H. Farias, Douglas N. Sanders, Rong Zeng, Shahnawaz Khan, Gary S. Johnson, and Dennis P. O'Brien Copyright © 2011 Martin L. Katz et al. All rights reserved. Guillain-Barré Syndrome Animal Model: The First Proof of Molecular Mimicry in Human Autoimmune Disorder Wed, 15 Dec 2010 15:12:13 +0000 http://www.hindawi.com/journals/bmri/2011/829129/ Molecular mimicry between self and microbial components has been proposed as the pathogenic mechanism of autoimmune diseases, and this hypothesis is proven in Guillain-Barré syndrome. Guillain-Barré syndrome, the most frequent cause of acute neuromuscular paralysis, sometimes occurs after Campylobacter jejuni enteritis. Gangliosides are predominantly cell-surface glycolipids highly expressed in nervous tissue, whilst lipo-oligosaccharides are major components of the Gram-negative bacterium C. jejuni outer membrane. IgG autoantibodies to GM1 ganglioside were found in the sera from patients with Guillain-Barré syndrome. Molecular mimicry was demonstrated between GM1 and lipo-oligosaccharide of C. jejuni isolated from the patients. Disease models by sensitization of rabbits with GM1 and C. jejuni lipo-oligosaccharide were established. Guillain-Barré syndrome provided the first verification that an autoimmune disease is triggered by molecular mimicry. Its disease models are helpful to further understand the molecular pathogenesis as well as to develop new treatments in Guillain-Barré syndrome. Nortina Shahrizaila and Nobuhiro Yuki Copyright © 2011 Nortina Shahrizaila and Nobuhiro Yuki. All rights reserved. Perinatal Hypoxic-Ischemic Encephalopathy Mon, 13 Dec 2010 09:03:11 +0000 http://www.hindawi.com/journals/bmri/2011/609813/ Perinatal hypoxic-ischemic encephalopathy (HIE) is an important cause of brain injury in the newborn and can result in long-term devastating consequences. Perinatal hypoxia is a vital cause of long-term neurologic complications varying from mild behavioural deficits to severe seizure, mental retardation, and/or cerebral palsy in the newborn. In the mammalian developing brain, ongoing research into pathophysiological mechanism of neuronal injury and therapeutic strategy after perinatal hypoxia is still limited. With the advent of promising therapy of hypothermia in HIE, this paper reviews the pathophysiology of HIE and the future potential neuroprotective strategies for clinical potential for hypoxia sufferers. Ming-Chi Lai and San-Nan Yang Copyright © 2011 Ming-Chi Lai and San-Nan Yang. All rights reserved. Evaluation of Itch by Using NC/NgaTnd Mice: A Model of Human Atopic Dermatitis Thu, 09 Dec 2010 18:21:34 +0000 http://www.hindawi.com/journals/bmri/2011/790436/ Atopic dermatitis (AD) is the extremely complicated syndrome that various abnormalities develop in a heap. There are various factors in patients for the onset and exacerbation of AD, including genetic cofactors of individuals, environmental factors, the failure of the skin barrier function, unfavorable regulation of the immune system, and the hypersensitivity of sensory nerves. In recent years, there have been many trials of the drug discovery that targets itch, because itch is one of the most serious clinical symptoms of AD. The selection of the suitable animal model that represents the condition of patients, as well as innovative analyzing protocols that can precisely evaluate itch, is indispensable for investigation of an effective drug for AD. In the paper, the unique spontaneous animal model for AD (NC/NgaTnd mice) and the novel quantification system of the laboratory animals that may bring a great progress in the future study of itch are outlined. Akane Tanaka and Hiroshi Matsuda Copyright © 2011 Akane Tanaka and Hiroshi Matsuda. All rights reserved. Placental Leucine Aminopeptidase- and Aminopeptidase A- Deficient Mice Offer Insight concerning the Mechanisms Underlying Preterm Labor and Preeclampsia Mon, 06 Dec 2010 11:34:57 +0000 http://www.hindawi.com/journals/bmri/2011/286947/ Preeclampsia and preterm delivery are important potential complications in pregnancy and represent the leading causes for maternal and perinatal morbidity and mortality. The mechanisms underlying both diseases remain unknown, thus available treatments (beta2-stimulants and magnesium sulfate) are essentially symptomatic. Both molecules have molecular weights less than 5–8 kDa, cross the placental barrier, and thus exert their effects on the fetus. The fetus produces peptides that are highly vasoactive and uterotonic and increase in response to maternal stress and with continued development. Fetal peptides are also small molecules that inevitably leak across into the maternal circulation. Aminopeptidases such as placental leucine aminopeptidase (P-LAP) and aminopeptidase A (APA) are large molecules that do not cross the placental barrier. We have shown that APA acts as an antihypertensive agent in the pregnant spontaneously hypertensive rat by degrading vasoactive peptides and as a result returns the animal to a normotensive state. P-LAP also acts as an antiuterotonic agent by degrading uterotonic peptides and thus prolongs gestation in the pregnant mouse. Given the ever increasing worldwide incidences of preeclampsia and preterm labor, it is imperative that new agents be developed to safely prolong gestation. We believe that the use of aminopeptidases hold promise in this regard. Shigehiko Mizutani, John W. Wright, and Hiroshi Kobayashi Copyright © 2011 Shigehiko Mizutani et al. All rights reserved. Cardiac Imaging Using Clinical 1.5 T MRI Scanners in a Murine Ischemia/Reperfusion Model Sun, 05 Dec 2010 10:04:00 +0000 http://www.hindawi.com/journals/bmri/2011/185683/ To perform cardiac imaging in mice without having to invest in expensive dedicated equipment, we adapted a clinical 1.5 Tesla (T) magnetic resonance imaging (MRI) scanner for use in a murine ischemia/reperfusion model. Phase-sensitive inversion recovery (PSIR) sequence facilitated the determination of infarct sizes in vivo by late gadolinium enhancement. Results were compared to histological infarct areas in mice after ischemia/reperfusion procedure with a good correlation (𝑟=0.807, 𝑃<.001). In addition, fractional area change (FAC) was assessed with single slice cine MRI and was matched to infarct size (𝑟=−0.837) and fractional shortening (FS) measured with echocardiography (𝑟=0.860); both 𝑃<.001. Here, we demonstrate the use of clinical 1.5 MRI scanners as a feasible method for basic phenotyping in mice. These widely available scanners are capable of investigating in vivo infarct dimensions as well as assessment of cardiac functional parameters in mice with reasonable throughput. Jakob G. J. Voelkl, Bernhard J. Haubner, Christian Kremser, Agnes Mayr, Gert Klug, Alexander Loizides, Silvana Müller, Otmar Pachinger, Michael Schocke, and Bernhard Metzler Copyright © 2011 Jakob G. J. Voelkl et al. All rights reserved. Surgical Approaches to Create Murine Models of Human Wound Healing Wed, 01 Dec 2010 11:54:52 +0000 http://www.hindawi.com/journals/bmri/2011/969618/ Wound repair is a complex biologic process which becomes abnormal in numerous disease states. Although in vitro models have been important in identifying critical repair pathways in specific cell populations, in vivo models are necessary to obtain a more comprehensive and pertinent understanding of human wound healing. The laboratory mouse has long been the most common animal research tool and numerous transgenic strains and models have been developed to help researchers study the molecular pathways involved in wound repair and regeneration. This paper aims to highlight common surgical mouse models of cutaneous disease and to provide investigators with a better understanding of the benefits and limitations of these models for translational applications. Victor W. Wong, Michael Sorkin, Jason P. Glotzbach, Michael T. Longaker, and Geoffrey C. Gurtner Copyright © 2011 Victor W. Wong et al. All rights reserved. Shen-Fu Injection Preconditioning Inhibits Myocardial Ischemia-Reperfusion Injury in Diabetic Rats: Activation of eNOS via the PI3K/Akt Pathway Mon, 29 Nov 2010 10:16:13 +0000 http://www.hindawi.com/journals/bmri/2011/384627/ The aim of this paper is to investigate whether Shen-fu injection (SFI), a traditional Chinese medicine, could attenuate myocardial ischemia-reperfusion (MI/R) injury in diabetes. Streptozotocin-induced diabetic rats were randomly assigned to the Sham, I/R, SFI preconditioning, and SFI plus wortmannin (a phosphatidylinositol 3-kinase inhibitor) groups. After the treatment, hearts were subjected to 30 min of coronary artery occlusion and 2 h reperfusion except the Sham group. Myocardial infarct size and cardiomyocytes apoptosis were increased significantly in MI/R group as compared with the Sham group. SFI preconditioning significantly decreased infarct size, apoptosis, caspase-3 protein expression, MDA level in myocardial tissues, and plasma level of CK and LDH but increased p-Akt, p-eNOS, bcl-2 protein expression, and SOD activity compared to I/R group. Moreover, SFI-induced cardioprotection was abolished by wortmannin. We conclude that SFI preconditioning protects diabetic hearts from I/R injury via PI3K/Akt-dependent pathway. Yang Wu, Zhong-yuan Xia, Qing-tao Meng, Jie Zhu, Shaoqing Lei, Jinjin Xu, and Juan Dou Copyright © 2011 Yang Wu et al. All rights reserved. Comparison of Myocardial Remodeling between Cryoinfarction and Reperfused Infarction in Mice Sun, 28 Nov 2010 13:59:25 +0000 http://www.hindawi.com/journals/bmri/2011/961298/ Myocardial infarction is associated with inflammatory reaction leading to tissue remodeling. We compared tissue remodeling between cryoinfarction (cMI) and reperfused myocardial infarction (MI) in order to better understand the local environment where we apply cell therapies. Models of closed-chest one-hour ischemia/reperfusion MI and cMI were used in C57/Bl6-mice. The reperfused MI showed rapid development of granulation tissue and compacted scar formation after 7 days. In contrast, cMI hearts showed persistent cardiomyocyte debris and cellular infiltration after 7 days and partially compacted scar formation accompanied by persistent macrophages and myofibroblasts after 14 days. The mRNA of proinflammatory mediators was transiently induced in MI and persistently upregulated in cMI. Tenascin C and osteopontin-1 showed delayed induction in cMI. In conclusion, the cryoinfarction was associated with prolonged inflammation and active myocardial remodeling when compared to the reperfused MI. These substantial differences in remodeling may influence cellular engraftment and should be considered in cell therapy studies. Georg D. Duerr, Naziha Elhafi, Toktam Bostani, Joerg Ellinger, Louay Swieny, Elvis Kolobara, Armin Welz, and Oliver Dewald Copyright © 2011 Georg D. Duerr et al. All rights reserved. Animal Models to Study the Role of Long-Term Hypergastrinemia in Gastric Carcinogenesis Wed, 24 Nov 2010 15:41:43 +0000 http://www.hindawi.com/journals/bmri/2011/975479/ Patients with chronic hypergastrinemia due to chronic atrophic gastritis or gastrinomas have an increased risk of developing gastric malignancy, and it has been questioned whether also patients with hypergastrinemia caused by long-term use of acid inhibiting drugs are at risk. Gastric carcinogenesis in humans is affected by numerous factors and progresses slowly over years. When using animal models with the possibility of intervention, a complex process can be dissected by studying the role of hypergastrinemia in carcinogenesis within a relatively short period of time. We have reviewed findings from relevant models where gastric changes in animal models of long-term hypergastrinemia have been investigated. In all species where long-term hypergastrinemia has been induced, there is an increased risk of gastric malignancy. There is evidence that hypergastrinemia is a common causative factor in carcinogenesis in the oxyntic mucosa, while other cofactors may vary in the different models. Reidar Fossmark, Gunnar Qvigstad, Tom Chr. Martinsen, ⌀yvind Hauso, and Helge L. Waldum Copyright © 2011 Reidar Fossmark et al. All rights reserved. Kainic Acid-Induced Neurodegenerative Model: Potentials and Limitations Wed, 24 Nov 2010 15:20:48 +0000 http://www.hindawi.com/journals/bmri/2011/457079/ Excitotoxicity is considered to be an important mechanism involved in various neurodegenerative diseases in the central nervous system (CNS) such as Alzheimer's disease (AD). However, the mechanism by which excitotoxicity is implicated in neurodegenerative disorders remains unclear. Kainic acid (KA) is an epileptogenic and neuroexcitotoxic agent by acting on specific kainate receptors (KARs) in the CNS. KA has been extensively used as a specific agonist for ionotrophic glutamate receptors (iGluRs), for example, KARs, to mimic glutamate excitotoxicity in neurodegenerative models as well as to distinguish other iGluRs such as α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors and N-methyl-D-aspartate receptors. Given the current knowledge of excitotoxicity in neurodegeneration, interventions targeted at modulating excitotoxicity are promising in terms of dealing with neurodegenerative disorders. This paper summarizes the up-to-date knowledge of neurodegenerative studies based on KA-induced animal model, with emphasis on its potentials and limitations. Xiang-Yu Zheng, Hong-Liang Zhang, Qi Luo, and Jie Zhu Copyright © 2011 Xiang-Yu Zheng et al. All rights reserved. Intravesical Dimethyl Sulfoxide Inhibits Acute and Chronic Bladder Inflammation in Transgenic Experimental Autoimmune Cystitis Models Thu, 11 Nov 2010 11:25:15 +0000 http://www.hindawi.com/journals/bmri/2011/937061/ New animal models are greatly needed in interstitial cystitis/painful bladder syndrome (IC/PBS) research. We recently developed a novel transgenic cystitis model (URO-OVA mice) that mimics certain key aspects of IC/PBS pathophysiology. This paper aimed to determine whether URO-OVA cystitis model was responsive to intravesical dimethyl sulfoxide (DMSO) and if so identify the mechanisms of DMSO action. URO-OVA mice developed acute cystitis upon adoptive transfer of OVA-specific OT-I splenocytes. Compared to PBS-treated bladders, the bladders treated with 50% DMSO exhibited markedly reduced bladder histopathology and expression of various inflammatory factor mRNAs. Intravesical DMSO treatment also effectively inhibited bladder inflammation in a spontaneous chronic cystitis model (URO-OVA/OT-I mice). Studies further revealed that DMSO could impair effector T cells in a dose-dependent manner in vitro. Taken together, our results suggest that intravesical DMSO improves the bladder histopathology of IC/PBS patients because of its ability to interfere with multiple inflammatory and bladder cell types. Ronald Kim, Wujiang Liu, Xiaohong Chen, Karl J. Kreder, and Yi Luo Copyright © 2011 Ronald Kim et al. All rights reserved. Anti-VEGF Therapy in Breast and Lung Mouse Models of Cancers Sun, 07 Nov 2010 17:05:41 +0000 http://www.hindawi.com/journals/bmri/2011/947928/ Cancer is the second leading cause of death in the world after cardiovascular diseases. Some types of cancer cells often travel to other parts of the body through blood circulation or lymph vessels, where they begin to grow. This process is recognized as metastasis. Angiogenesis is the formation of new blood vessels from existing vessel. Normally angiogenesis is a healthy process, that helps the body to heal wounds and repair damaged body tissues, whereas in cancerous condition this process supports new blood vessels formation that provide a tumor with its own blood supply, nutrients and allow it to grow. The most important proximal factor for angiogenesis is the vascular endothelial growth factor VEGF. Angioinhibition is a form of targeted therapy that uses drugs to stop tumors from making new blood vessels. Therefore, in this paper we analyse the importance of VEGF as target of cancer therapy, analysing murine models. Di Domenico Marina, Ricciardi Carmela, Fusco Alfredo, and Pierantoni Giovanna Maria Copyright © 2011 Di Domenico Marina et al. All rights reserved. The Fat-Fed Apolipoprotein E Knockout Mouse Brachiocephalic Artery in the Study of Atherosclerotic Plaque Rupture Sun, 07 Nov 2010 08:52:07 +0000 http://www.hindawi.com/journals/bmri/2011/379069/ Atherosclerosis has been studied in animals for almost a century, yet the events leading up to the rupture of an atherosclerotic plaque (the underlying cause of the majority of fatal thrombosis formation) have only been studied in the past decade, due in part to the development of a mouse model of spontaneous plaque rupture. Apolipoprotein E knockout mice, when fed a high-fat diet, consistently develop lesions in the brachiocephalic artery that rupture at a known time point. It is therefore now possible to observe the development of lesions to elucidate the mechanisms behind the rupture of plaques. Critics argue that the model does not replicate the appearance of human atherosclerotic plaque ruptures. The purpose of this review is to highlight the reasons why we should be looking to the apolipoprotein E knockout mouse to further our understanding of plaque rupture. Andrew R. Bond and Christopher L. Jackson Copyright © 2011 Andrew R. Bond and Christopher L. Jackson. All rights reserved. A Transgenic Mouse Model for Studying the Role of the Parathyroid Hormone-Related Protein System in Renal Injury Sun, 31 Oct 2010 08:35:34 +0000 http://www.hindawi.com/journals/bmri/2011/290874/ Parathyroid hormone- (PTH-) related protein (PTHrP) and its receptor, the PTH1 receptor (PTH1R), are widely expressed in the kidney, where PTHrP exerts a modulatory action on renal function. PTHrP is known to be upregulated in several experimental nephropathies such as acute renal failure (ARF), obstructive nephropathy (ON) as well as diabetic nephropathy (DN). In this paper, we will discuss the functional consequences of chronic PTHrP overexpression in the damaged kidney using a transgenic mouse strain overexpressing PTHrP in the renal proximal tubule. In both ARF and ON, PTHrP displays proinflammatory and profibrogenic actions including the induction of epithelia to mesenquima transition. Moreover, PTHrP participates in the mechanisms of renal hypertrophy as well as proteinuria in experimental DN. Angiotensin II (Ang II), a critical factor in the progression of renal injury, appears to be, at least in part, responsible for endogenous PTHrP upregulation in these pathophysiological settings. These findings provide novel insights into the well-known protective effects of Ang II antagonists in renal diseases, paving the way for new therapeutic approaches. Ricardo J. Bosch, Arantxa Ortega, Adriana Izquierdo, Ignacio Arribas, Jordi Bover, and Pedro Esbrit Copyright © 2011 Ricardo J. Bosch et al. All rights reserved. Analysis of the Pathogenesis of Experimental Autoimmune Optic Neuritis Mon, 25 Oct 2010 09:17:32 +0000 http://www.hindawi.com/journals/bmri/2011/294046/ Optic neuritis associated with multiple sclerosis has a strong association with organ-specific autoimmune disease. The goal of our research is to establish an optimal organ-specific animal model to elucidate the pathogenetic mechanisms of the disease and to develop therapeutic strategies using the model. This paper is divided into five sections: (1) clinical picture of optic neuritis associated with multiple sclerosis, (2) elucidation of pathogenesis using animal models with inflammation in optic nerve and spinal cord, (3) clinical relevance of concurrent encephalomyelitis in optic neuritis model, (4) retinal damage in a concurrent multiple sclerosis and optic neuritis model, and (5) development of novel therapies using mouse optic neuritis model. Advanced therapies using biologicals have succeeded to control intractable optic neuritis in animal models. This may ultimately lead to prevention of vision loss within a short period from acute onset of optic neuritis in human. By conducting research flexibly, ready to switch from the bench to the bedside and from the bedside to the bench as the opportunity arises, this strategy may help to guide the research of optic neuritis in the right direction. Takeshi Kezuka, Yoshihiko Usui, and Hiroshi Goto Copyright © 2011 Takeshi Kezuka et al. All rights reserved. Animal Models of Typical Heterotopic Ossification Tue, 19 Oct 2010 13:47:29 +0000 http://www.hindawi.com/journals/bmri/2011/309287/ Heterotopic ossification (HO) is the formation of marrow-containing bone outside of the normal skeleton. Acquired HO following traumatic events is a common and costly clinical complication. In contrast, hereditary HO is rarer, progressive, and life-threatening. Substantial effort has been directed towards understanding the mechanisms underlying HO and finding efficient treatments. However, one crucial limiting factor has been the lack of relevant animal models. This article reviews the major currently available animal models, summarizes some of the insights gained from these studies, and discusses the potential future challenges and directions in HO research. Lixin Kan and John A. Kessler Copyright © 2011 Lixin Kan and John A. Kessler. All rights reserved. Effects of Clofibrate on Salt Loading-Induced Hypertension in Rats Thu, 14 Oct 2010 18:44:00 +0000 http://www.hindawi.com/journals/bmri/2011/469481/ The effects of clofibrate on the hemodynamic and renal manifestations of increased saline intake were analyzed. Four groups of male Wistar rats were treated for five weeks: control, clofibrate (240 mg/kg/day), salt (2% via drinking water), and salt+clofibrate. Body weight, systolic blood pressure (SBP), and heart rate (HR) were recorded weekly. Finally, SBP, HR, and morphologic, metabolic, plasma, and renal variables were measured. Salt increased SBP, HR, urinary isoprostanes, NOx, ET, vasopressin and proteinuria and reduced plasma free T4 (FT4) and tissue FT4 and FT3 versus control rats. Clofibrate prevented the increase in SBP produced by salt administration, reduced the sodium balance, and further reduced plasma and tissue thyroid hormone levels. However, clofibrate did not modify the relative cardiac mass, NOx, urinary ET, and vasopressin of saline-loaded rats. In conclusion, chronic clofibrate administration prevented the blood pressure elevation of salt-loaded rats by decreasing sodium balance and reducing thyroid hormone levels. Antonio Cruz, Isabel Rodríguez-Gómez, Rocío Pérez-Abud, Miguel Ángel Vargas, Rosemary Wangensteen, Andrés Quesada, Antonio Osuna, and Juan Manuel Moreno Copyright © 2011 Antonio Cruz et al. All rights reserved. Role of PIR-B in Autoimmune Glomerulonephritis Mon, 04 Oct 2010 09:22:54 +0000 http://www.hindawi.com/journals/bmri/2011/275302/ PIR-B, an inhibitory receptor expressed on murine B cells and myeloid cells, regulates humoral and cellular immune responses via its constitutive binding to the ligand, MHC class I molecules, on the same cells (cis) or on different cells (trans). Although it has been speculated that PIR-B is important for maintaining peripheral tolerance, PIR-B single deficiency does not cause overt autoimmune diseases. Recently, however, the combination of its deficiency with the Fas lpr mutation was found to result in augmented production of autoantibodies such as IgG rheumatoid factor and anti-DNA IgG, leading to glomerulonephritis in mice. Although the precise molecular mechanism for the overall scenario is unclear, PIR-B was found to suppress TLR9-mediated production of naturally autoreactive antibodies by innate B cells or B-1 cells by inhibiting the activation of Bruton's tyrosine kinase. Thus, PIR-B is an important regulator of innate immunity mediated by TLR9 in B-1 cells, which can otherwise provoke autoimmunity when overactivated. Toshiyuki Takai, Akira Nakamura, and Shota Endo Copyright © 2011 Toshiyuki Takai et al. All rights reserved. Muscle Atrophy and Motor Neuron Degeneration in Human NEDL1 Transgenic Mice Sun, 03 Oct 2010 16:42:55 +0000 http://www.hindawi.com/journals/bmri/2011/831092/ Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease. Approximately 20% cases of familial ALS show the mutation in the superoxide dismutase-1 (SOD1) gene. We previously demonstrated that homologue to E6AP carboxyl terminus- (HECT-) type ubiquitin protein E3 ligase (NEDL1) physically bind to mutated SOD1 protein but not wild-type SOD1 and promote the degradation of mutated SOD1 protein through ubiquitin-mediated proteasome pathway. To further understand the role of NEDL1 involved in the pathogenesis of familial ALS, we generated transgenic mice with human NEDL1 cDNA. The transgenic mice with human NEDL1 expression showed motor dysfunctions in rotarod, hanging wire, and footprint pattern examination. Histological studies indicated degeneration of neurons in the lumbar spinal cord and muscle atrophy. The number of activated microglia in the spinal cord of transgenic mice was significantly higher than that of wild-type mice, suggesting that inflammation might be observed in the spinal cord of transgenic mice. In conclusion, these findings suggest that the human NEDL1 transgenic mice might develop ALS-like symptoms, showing signs of motor abnormalities, accompanied with significant reduction in muscle strength. Lin Zhang, Seiki Haraguchi, Tadayuki Koda, Kenji Hashimoto, and Akira Nakagawara Copyright © 2011 Lin Zhang et al. All rights reserved. Bronchiolitis Obliterans Organizing Pneumonia in Swine Associated with Porcine Circovirus Type 2 Infection Mon, 27 Sep 2010 14:17:49 +0000 http://www.hindawi.com/journals/bmri/2011/245728/ Bronchiolitis obliterans organizing pneumonia (BOOP) is a chronic respiratory disease. Although the pathogenesis of BOOP is still incompletely understood, BOOP is responsive to steroids and has a good prognosis. In our five pigs with chronic postweaning multisystemic wasting syndrome (PMWS), typical BOOP lesions were revealed. All five porcine lungs showed typical intraluminal plugs, and porcine circovirus type 2 (PCV2) was identified. They also exhibited similar pathologic findings such as proliferation of type II pneumocytes and myofibroblasts (MFBs), extracellular collagen matrix (ECM) deposition, and fragmentation of elastic fibers. MFBs migration correlative molecules, for instance, gelatinase A, B and osteopontin, appeared strongly in the progressing marginal area of polypoid intraluminal plugs of fibrotic lesion. These molecules colocalized with the active MFBs. Both gelatinase activity and intercellular level of active MFBs were significantly increased (𝑃<.05). Porcine chronic bronchopneumonia leads to BOOP and it is associated with PCV2 persistent infection. Swine BOOP demonstrates similar cellular constituents with human BOOP. Perhaps their molecular mechanisms of pathogenesis operate in a similar way. Thus we infer that the swine BOOP can be considered as a potential animal model for human BOOP associated with natural viral infection. Moreover, it is more convenient to obtain samples. Ching-Chang Cheng, Yen-Feng Lee, Nai-Nu Lin, Chieh-Liang Wu, Kwong-Chung Tung, and Yung-Tsung Chiu Copyright © 2011 Ching-Chang Cheng et al. All rights reserved. In Vivo Imaging of Particle-Induced Inflammation and Osteolysis in the Calvariae of NF𝜅B/Luciferase Transgenic Mice Tue, 21 Sep 2010 14:15:39 +0000 http://www.hindawi.com/journals/bmri/2011/727063/ Wear debris causes biological response which can result in periprosthetic osteolysis after total joint replacement surgery. Nuclear factor-kappa B (NF𝜅B), a representative transcription factor involved in inflammation, is believed to play an important role in this event by regulating the production of proinflammatory mediators and osteoclastogenesis. In this study, we sought to determine whether activation of NF𝜅B in response to stimulation by particles could be visualized by in vivo imaging. We loaded polyethylene (PE) particles onto the calvaria of NF𝜅B/luciferase transgenic mouse, and detected luminescence generated by activation of NF𝜅B. On day 7 after loading, the level of luminescence was maximal. Levels of luminescence were significantly correlated with the levels of luciferase activity, proinflammatory mediator mRNAs, and bone resorption parameters. This system, which enabled us to evaluate particle-induced inflammation and osteolysis without sacrificing mice, constitutes a useful tool for evaluating the efficacy of prophylaxis or treatments for particle-induced osteolysis. Kunihiko Takahashi, Shin Onodera, Harukazu Tohyama, Hyuck Joon Kwon, Ken-ichi Honma, and Kazunori Yasuda Copyright © 2011 Kunihiko Takahashi et al. All rights reserved. The Venturia Apple Pathosystem: Pathogenicity Mechanisms and Plant Defense Responses Thu, 28 Jan 2010 15:02:25 +0000 http://www.hindawi.com/journals/bmri/2009/680160/ Venturia inaequalis is the causal agent of apple scab, a devastating disease of apple. We outline several unique features of this pathogen which are useful for molecular genetics studies intended to understand plant-pathogen interactions. The pathogenicity mechanisms of the pathogen and overview of apple defense responses, monogenic and polygenic resistance, and their utilization in scab resistance breeding programs are also reviewed. Gopaljee Jha, Karnika Thakur, and Priyanka Thakur Copyright © 2009 Gopaljee Jha et al. All rights reserved. Immunology and Molecular Biology of Protozoan Infections Thu, 03 Jan 2008 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2007/067210/abs/ Ali Ouaissi Copyright © 2007 Ali Ouaissi. All rights reserved. Immune Response Regulation by Leishmania Secreted and Nonsecreted Antigens Tue, 26 Jun 2007 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2007/085154/abs/ Leishmania infection consists in two sequential events, the host cell colonization followed by the proliferation/dissemination of the parasite. In this review, we discuss the importance of two distinct sets of molecules, the secreted and/or surface and the nonsecreted antigens. The importance of the immune response against secreted and surface antigens is noted in the establishment of the infection and we dissect the contribution of the nonsecreted antigens in the immunopathology associated with leishmaniasis, showing the importance of these panantigens during the course of the infection. As a further example of proteins belonging to these two different groups, we include several laboratorial observations on Leishmania Sir2 and LicTXNPx as excreted/secreted proteins and LmS3arp and LimTXNPx as nonsecreted/panantigens. The role of these two groups of antigens in the immune response observed during the infection is discussed. Nuno Santarém, Ricardo Silvestre, Joana Tavares, Marta Silva, Sofia Cabral, Joana Maciel, and Anabela Cordeiro-da-Silva Copyright © 2007 Nuno Santarém et al. All rights reserved. DNA Vaccines against Protozoan Parasites: Advances and Challenges Thu, 21 Jun 2007 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2007/090520/abs/ Over the past 15 years, DNA vaccines have gone from a scientific curiosity to one of the most dynamic research field and may offer new alternatives for the control of parasitic diseases such as leishmaniasis and Chagas disease. We review here some of the advances and challenges for the development of DNA vaccines against these diseases. Many studies have validated the concept of using DNA vaccines for both protection and therapy against these protozoan parasites in a variety of mouse models. The challenge now is to translate what has been achieved in these models into veterinary or human vaccines of comparable efficacy. Also, genome-mining and new antigen discovery strategies may provide new tools for a more rational search of novel vaccine candidates. Eric Dumonteil Copyright © 2007 Eric Dumonteil. All rights reserved. Enhancement of a TH1 Immune Response in Amphotericin B-Treated Mucocutaneous Leishmaniasis Sun, 10 Jun 2007 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2007/096410/abs/ In an attempt to investigate the effects of treatment of human leishmaniasis, the cytokines produced by peripheral blood mononuclear cells (PBMCs) of patients with cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) under treatment with amphotericin B were determined during the active disease from cocultures of cells and Leishmania (Viannia) braziliensis antigens. PBMC of these patients exhibited a nonsignificant marginal increased production of TNF-α upon antigen stimulation. However, under the same antigenic stimulus, patients with active MCL presented higher IFN-γ production compared to patients with CL. This increased IFN-γ production was accompanied by a drastically augmented IL-12 synthesis from cells of MCL patients. The highlighted T cell responses could be relevant for sound control measures of protozoan infections with emphasis on the combined usage of immunoenhancing agents and antiprotozoal drugs. Washington R. Cuna, Rianed Velasquez, Janeth Riva, Ingrid Guachalla, and Celeste Rodríguez Copyright © 2007 Washington R. Cuna et al. All rights reserved. Molecular Aspects of Plasmodium falciparum Infection during Pregnancy Thu, 07 Jun 2007 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2007/043785/abs/ Cytoadherence of Plasmodium-falciparum-parasitized red blood cells (PRBCs) to host receptors is the key phenomenon in the pathological process of the malaria disease. Some of these interactions can originate poor outcomes responsible for 1 to 3 million annual deaths mostly occurring among children in sub-Saharan Africa. Pregnancy-associated malaria (PAM) represents an important exception of the disease occurring at adulthood in malaria endemic settings. Consequences of this are shared between the mother (maternal anemia) and the baby (low birth weight and infant mortality). Demonstrating that parasites causing PAM express specific variant surface antigens (VSAPAM), including the P. falciparum erythrocyte membrane protein 1 (PfEMP1) variant VAR2CSA, that are targets for protective immunity has strengthened the possibility for the development of PAM-specific vaccine. In this paper, we review the molecular basis of malaria pathogenesis attributable to the erythrocyte stages of the parasites, and findings supporting potential anti-PAM vaccine components evidenced in PAM. Nicaise Tuikue Ndam and Philippe Deloron Copyright © 2007 Nicaise Tuikue Ndam and Philippe Deloron. All rights reserved. Regulatory Cells and Immunosuppressive Cytokines: Parasite-Derived Factors Induce Immune Polarization Mon, 21 May 2007 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2007/094971/abs/ Parasitic infections are prevalent in both tropical and subtropical areas. Most of the affected and/or exposed populations are living in developing countries where control measures are lacking or inadequately applied. Although significant progress has been made in our understanding of the immune response to parasites, no definitive step has yet been successfully done in terms of operational vaccines against parasitic diseases. Evidence accumulated during the past few years suggests that the pathology observed during parasitic infections is in part due to deregulation of normal components of the immune system, mainly cytokines, antibodies, and immune effector cell populations. A large number of studies that illustrate how parasites can modify the host immune system for their own benefit have been reported in both metazoan and protozoan parasites. The first line of defense against foreign organisms is barrier tissue such as skin, humoral factors, for instance the complement system and pentraxin, which upon activation of the complement cascade facilitate pathogen recognition by cells of innate immunity such as macrophages and DC. However, all the major groups of parasites studied have been shown to contain and/or to release factors, which interfere with both arms of the host immune system. Even some astonishing observations relate to the production by some parasites of orthologues of mammalian cytokines. Furthermore, chronic parasitic infections have led to the immunosuppressive environment that correlates with increased levels of myeloid and T suppressor cells that may limit the success of immunotherapeutic strategies based on vaccination. This minireview briefly analyzes some of the current data related to the regulatory cells and molecules derived from parasites that affect cellular function and contribute to the polarization of the immune response of the host. Special attention is given to some of the data from our laboratory illustrating the role of immunomodulatory factors released by protozoan parasites, in the induction and perpetuation of chronic disease. Ali Ouaissi Copyright © 2007 Ali Ouaissi. All rights reserved. Regulation of Defense Responses against Protozoan Infection by Interleukin-27 and Related Cytokines Sun, 22 Apr 2007 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2007/079401/abs/ Cytokine-mediated immunity is crucial in the defense against pathogens. Recently, IL-23 and IL-27 were identified, which along with IL-12 belong to the IL-12 cytokine family. IL-27 is pivotal for the induction of helper T cell (Th) 1 responses while IL-23 is important for the proliferation of memory type Th1 cells. Recent studies revealed that IL-27 also has an anti-inflammatory property. In some protozoan infection, various proinflammatory cytokines were over produced causing lethal inflammatory responses in IL-27 receptor-deficient mice. The anti-inflammatory effect of IL-27 depends, at least partly, on inhibition of the development of Th17 cells, a newly identified Th population that is induced by IL-23 and is characterized by the production of the inflammatogenic cytokine, IL-17. IL-27 thus has a double identity as an initiator and as an attenuator of immune responses and inflammation. With the discoveries of the new IL-12-related cytokines and Th17 cells, Th development is facing a new paradigm. Hiroki Yoshida, Yoshiyuki Miyazaki, Sen Wang, and Shinjiro Hamano Copyright © 2007 Hiroki Yoshida et al. All rights reserved. CD40-CD40L Interaction in Immunity Against Protozoan Infections Thu, 05 Apr 2007 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2007/059430/abs/ Activation of the immune system against protozoan infections relies particularly on two specific signals provided by cognate interaction of T cells with antigen presenting cells (APCs). The first signal is attributed to binding of the T-cell receptor (TCR) to peptide/MHC complexes on the surface of APCs, whereas the second signal is triggered through binding of several costimulatory molecules on the surface of APCs with their corresponding receptors on T cells. Among these costimulatory signallings, CD40/CD40L interactions have been particularly investigated in protozoan infection models with regard to their potential to amplify cell-mediated immunity against intracellular parasites. This article reviews current studies of the potential role of CD40/CD40L interaction in the modulation of immune responses against some protozoan parasites and highlights recent developments regarding manipulation of this interaction for promoting control of parasite infections. Mustapha Chamekh Copyright © 2007 Mustapha Chamekh. All rights reserved. Host Cell Phenotypic Variability Induced by Trypanosomatid-Parasite-Released Immunomodulatory Factors: Physiopathological Implications Mon, 01 Jan 1900 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2004/280740/abs/ The parasitic protozoa Trypanosoma cruzi and Leishmania sp release a variety of molecules into their mammalian hosts (ESA: excretory-secretory products). The effects of these ESA on the host cell function may participate in the establishment of a successful infection, in which the parasite persists for a sufficient period of time to complete its life cycle. A number of regulatory components or processes originating from the parasite that control or regulate the metabolism and the growth of host cell have been identified. The purpose of the present review is to analyze some of the current data related to the parasite ESA that interfere with the host cell physiology. Special attention is given to members of conserved protein families demonstrating remarkable diversity and plasticity of function (ie, glutathione S-transferases and related molecules; members of the trans-sialidase and mucin family; and members of the ribosomal protein family). The identification of parasite target molecules and the elucidation of their mode of action toward the host cell represents a step forward in efforts aimed at an immunotherapeutic or pharmacological control of parasitic infection. Ali Ouaissi, Mehdi Ouaissi, Joana Tavares, and Anabela Cordeiro-Da-Silva Copyright © 2004 Hindawi Publishing Corporation. All rights reserved. Hypoperfusion, Mitochondria Failure, Oxidative Stress, and Alzheimer Disease Mon, 01 Jan 1900 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2003/470104/abs/ Gjumrakch Aliev, Mark E. Obrenovich, Mark A. Smith, and George Perry Copyright © 2003 Hindawi Publishing Corporation. All rights reserved.