bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality Assessment of Serially Ultradiluted and Agitated Drug Digitalis purpurea by Emission Spectroscopy and Clinical Analysis of Its Effect on the Heart Rate of Indian Bufo melanostictus
Authors: Sharma Anup , Purkait Bulbul
Published: December 2012

The investigation of ultradiluted (homeopathic) drugs is extremely interesting and challenging, and from that point of view this study shows novelty. A study of in vivo changes in heart rate of the Indian Bufo melanostictus caused by commercially available serially ultra-diluted and agitated extract of Digitalis purpurea has been tried in order to understand their pharmacological role. RR interval (of ECG) was compared after intraperitoneal administration of serially diluted and agitated Digitalis purpurea extract, diluent rectified spirit, and Digoxin in anesthetized animals. The study revealed statistically significant changes in the heart rate after application of these drugs except in case of Digoxin and the 200th serial dilution of Digitalis purpurea. The duration of RR intervals after application of the drugs was corroborative of the effect of Digoxin and Digitalis purpurea extract up to 30th dilution. Emission spectra were obtained for the experimental ultra-diluted Digitalis purpurea extract and Digoxin to identify and characterize them. The observed RR pattern and emission spectra show an association. The quality assessment of the commercial ultra-diluted organic drugs obtained from natural products may be initiated by monitoring in vivo studies on animal models.
Simultaneous Quantification of Flavonol Glycosides, Terpene Lactones, Biflavones, Proanthocyanidins, and Ginkgolic Acids inGinkgo bilobaLeaves from Fruit Cultivars by Ultrahigh-Performance Liquid Chromatography Coupled with Triple Quadrupole Mass Spectrometry
Authors: Yao Xin , Zhou Gui-Sheng , Tang Yu-Ping , Qian Ye-Fei , Guan Han-Liang , Pang Hanqing , Zhu Shaoqing , Mo Xuan , Su Shu-Lan , Jin Chun , Qin Yong , Qian Da-Wei , Duan Jin-Ao
Published: December 2012

On the basis of liquid chromatography coupled with triple quadrupole mass spectrometry working in multiple reaction monitoring mode, an analytical method has been established to simultaneously determine flavonol glycosides, terpene lactones, biflavones, proanthocyanidins, and ginkgolic acids inGinkgo bilobaleaves. Chromatographic separation was carried out on an Acquity BEH C18column (100 mm × 2.1 mm, 1.7 μm) with gradient elution of acetonitrile and 0.10% formic acid (v/v) at a flow rate of 0.4 mL/min, and column temperature 30°C. The developed method was validated in terms of linearity, accuracy, precision, stability, and sensitivity. The optimized method was successfully applied to analyze twenty-twoG. bilobaleaf samples of fruit cultivars collected from different places in China. Furthermore, hierarchical clustering analysis (HCA) was performed to evaluate and classify the samples according to the contents of the twenty-four chemical constituents. All of the results demonstrated that the developed method was useful for the overall evaluation of the quality ofG. bilobaleaves, and this study was also helpful for the comprehensive utilization and development ofG. bilobaresources.
Milan PM1 Induces Adverse Effects on Mice Lungs and Cardiovascular System
Authors: Farina Francesca , Sancini Giulio , Longhin Eleonora , Mantecca Paride , Camatini Marina , Palestini Paola
Published: December 2012

Recent studies have suggested a link between inhaled particulate matter (PM) exposure and increased mortality and morbidity associated with cardiorespiratory diseases. Since the response to PM1 has not yet been deeply investigated, its impact on mice lungs and cardiovascular system is here examined. A repeated exposure to Milan PM1 was performed on BALB/c mice. The bronchoalveolar lavage fluid (BALf) and the lung parenchyma were screened for markers of inflammation (cell counts, tumor necrosis factor-α(TNF-α); macrophage inflammatory protein-2 (MIP-2); heme oxygenase-1 (HO-1); nuclear factor kappa-light-chain-enhancer of activated B cells p50 subunit (NFκB-p50); inducible nitric oxide synthetase (iNOS); endothelial-selectin (E-selectin)), cytotoxicity (lactate dehydrogenase (LDH); alkaline phosphatase (ALP); heat shock protein 70 (Hsp70); caspase-8-p18), and a putative pro-carcinogenic marker (cytochrome 1B1 (Cyp1B1)). Heart tissue was tested for HO-1, caspase-8-p18, NFκB-p50, iNOS, E-selectin, and myeloperoxidase (MPO); plasma was screened for markers of platelet activation and clot formation (soluble platelet-selectin (sP-selectin); fibrinogen; plasminogen activator inhibitor 1 (PAI-1)). PM1 triggers inflammation and cytotoxicity in lungs. A similar cytotoxic effect was observed on heart tissues, while plasma analyses suggest blood-endothelium interface activation. These data highlight the importance of lung inflammation in mediating adverse cardiovascular events following increase in ambient PM1 levels, providing evidences of a positive correlation between PM1 exposure and cardiovascular morbidity.
Hormonal Receptors in Skeletal Muscles of Dystrophic Mdx Mice
Authors: Feder David , Rodrigues Barros Godoy Ivan , Guimarães Pereira Maira Lazzarini , Silva Cledson Silveira , Nogueira Silvestre Diego , Fonseca Fernando Luiz Affonso , Alves de Siqueira Carvalho Alzira , Aparecida dos Santos Rosangela , Catteli Carvalho Maria Helena
Published: December 2012

Introduction. Several evidences show that muscles have an endocrine function. Glucocorticoid, estrogen, progesterone, and testosterone receptors have already been found in normal skeletal muscles, but not in dystrophic muscles.Methods. The gene expression of hormone receptors was compared between dystrophic and healthy muscles in mdx and C57BL6 mice strains.Results. The mdx mice showed a significant increase in the steroid receptors mRNA when compared to the C57BL6 mice: levels of androgen(s) receptors in the heart, estrogen receptors alpha in the EDL, and estrogen receptors beta in the quadriceps were increased. In addition, significant lowered levels of some other hormone receptors were found: corticosteroid receptors in the EDL and estrogen receptors alpha in the quadriceps.Conclusion. Dystrophic muscles bear significant differences in the expression of hormone receptors when compared to the C57BL6 mice strain. The importance of such differences is yet to be better understood.
Chemical Composition and Antibacterial and Cytotoxic Activities ofAllium hirtifoliumBoiss
Authors: Ismail Salmiah , Jalilian Farid Azizi , Talebpour Amir Hossein , Zargar Mohsen , Shameli Kamyar , Sekawi Zamberi , Jahanshiri Fatemeh
Published: December 2012

Allium hirtifoliumBoiss. known as Persian shallot, is a spice used as a traditional medicine in Iran and, Mediterranean region. In this study, the chemical composition of the hydromethanolic extract of this plant was analyzed using GC/MS. The result showed that 9-hexadecenoic acid, 11,14-eicosadienoic acid, and n-hexadecanoic acid are the main constituents. The antibacterial activity of the shallot extract was also examined by disk diffusion and microdilution broth assays. It was demonstrated that Persian shallot hydromethanolic extract was effective against 10 different species of pathogenic bacteria including methicillin resistantStaphylococcus aureus(MRSA), methicillin sensitiveStaphylococcus aureus(MSSA),Staphylococcus aureus,Staphylococcus epidermidis,Streptococcus pneumoniae,Escherichia coli, Escherichia coliO157:H7,Salmonella typhimurium, Proteus mirabilis, andKlebsiella pneumoniae. Specifically, the minimum concentration of the extract which inhibited bacterial growth (MIC values) was 1.88 mg/mL for most of the gram-positive bacteria. This concentration was not much different from the concentration that was safe for mammalian cells (1.50 mg/mL) suggesting that the hydromethanolic extract of Persian shallot may be a safe and strong antibacterial agent.
In VivoHealthy Knee Kinematics during Dynamic Full Flexion
Authors: Hamai Satoshi , Moro-oka Taka-aki , Dunbar Nicholas J. , Miura Hiromasa , Iwamoto Yukihide , Banks Scott A.
Published: December 2012

Healthy knee kinematics during dynamic full flexion were evaluated using 3D-to-2D model registration techniques. Continuous knee motions were recorded during full flexion in a lunge from 85° to 150°. Medial and lateral tibiofemoral contacts and femoral internal-external and varus-valgus rotations were analyzed as a function of knee flexion angle. The medial tibiofemoral contact translated anteroposteriorly, but remained on the center of the medial compartment. On the other hand, the lateral tibiofemoral contact translated posteriorly to the edge of the tibial surface at 150° flexion. The femur exhibited external and valgus rotation relative to the tibia over the entire activity and reached 30° external and 5° valgus rotations at 150° flexion. Kinematics’ data during dynamic full flexion may provide important insight as to the designing of high-flexion total knee prostheses.
Thioxopyrimidine in Heterocyclic Synthesis I: Synthesis of Some Novel 6‐(Heteroatom‐substituted)‐(thio)pyrimidine Derivatives
Authors: Ho Yuh-Wen , Suen Maw Cherng
Published: December 2012

A series of novel N‐cycloalkanes, morpholine, piperazines, pyrazole, pyrimidine, benzimidazolo[1,2‐a]pyrimidine, 1,2,3,4‐tetrazolo[1,5‐a]pyrimidine, azopyrazolo[1,5‐ a]pyrimidine, pyrimido[4′, 5′
:3,4]pyrazolo[1,5‐a]pyrimidines and pyridine derivatives incorporating a 5‐cyano‐4‐methyl‐2‐phenyl‐(thio)pyrimidine moiety were obtained by the intramolecular cyclization of 6‐methylthio‐pyrimidine, 6‐(benzoylmethyl)thio‐ pyrimidine and 2‐[(5‐cyano‐4‐methyl‐2‐phenylpyrimidin‐6‐yl)thio]‐3‐dimethyl‐ amino‐1‐phenyl‐prop‐2‐en‐1‐one with appropriate amines and enaminone compounds, respectively. The structure of all new synthesized compounds was established from their spectral data, elemental analysis and the X‐ray crystal analysis.
Increased Toll-Like Receptor Signaling Pathways Characterize CD8+ Cells in Rapidly Progressive SIV Infection
Authors: Marcondes Maria Cecilia Garibaldi , Spina Celsa , Bustamante Eduardo , Fox Howard
Published: December 2012

Similar to HIV infection in humans, SIV infection in macaques induces progressive loss of immune cell components and function, resulting in immune deficiency in nearly all untreated infected subjects. In SIV-infected macaques, 25% of animals develop terminal AIDS within 6 months of infection. The factors responsible for the development of such rapid progression are unknown. We have previously found that defects in CD8+ T cells detectable from early infection correlate to rapid progression to simian AIDS. The transcriptional screening of molecular fingerprints on different steps along the activation/effector process of splenic CD8+ cells at termination revealed a distinction in rapid compared to regular progressors, which was characterized by a decrease in classic T cell receptor (TCR) components, and an increase in Toll-like receptor (TLR) and apoptotic pathways. A TLR pathway screening in lymphoid and myeloid cells from both the spleen and from the central nervous system of infected macaques revealed that the upregulation of TLR is not in the innate immune compartment, but rather in lymphoid cells that contain adaptive immune cells. Our findings suggest that opposing effects of TCR specific signaling and TLR engagement may drive the CD8 phenotypic failure that determines a rapid disease course in HIV infection.
Effect of Nanoparticles and Environmental Particles on a Cocultures Model of the Air-Blood Barrier
Authors: Bengalli Rossella , Mantecca Paride , Camatini Marina , Gualtieri Maurizio
Published: December 2012

Exposure to engineered nanoparticles (NPs) and to ambient particles (PM) has increased significantly. During the last decades the application of nano-objects to daily-life goods and the emissions produced in highly urbanized cities have considerably augmented. As a consequence, the understanding of the possible effects of NPs and PM on human respiratory system and particularly on the air-blood barrier (ABB) has become of primary interest. The crosstalk between lung epithelial cells and underlying endothelial cells is indeed essential in determining the effects of inhaled particles. Here we report the effects of metal oxides NPs (CuO and TiO2) and of PM on anin vitromodel of the ABB constituted by the type II epithelial cell line (NCI-H441) and the endothelial one (HPMEC-ST1.6R). The results demonstrate that apical exposure of alveolar cells induces significant modulation of proinflammatory proteins also in endothelial cells.
Dynamical Analysis of a Modified Lorenz System
Authors: Tee Loong Soon , Salleh Zabidin
Published: December 2012

This paper presents another new modified Lorenz system which is chaotic in a certain range of parameters. Besides that, this paper also presents explanations to solve the new modified Lorenz system. Furthermore, some of the dynamical properties of the system are shown and stated. Basically, this paper shows the finding that led to the discovery of fixed points for the system, dynamical analysis using complementary-cluster energy-barrier criterion (CCEBC), finding the Jacobian matrix, finding eigenvalues for stability, finding the Lyapunov functions, and finding the Lyapunov exponents to investigate some of the dynamical behaviours of the system. Pictures and diagrams will be shown for the chaotic systems using the aide of MAPLE in 2D and 3D views. Nevertheless, this paper is to introduce the new modified Lorenz system.
Transcriptional Profiling of Canker-Resistant Transgenic Sweet Orange (Citrus sinensisOsbeck) Constitutively Overexpressing a Spermidine Synthase Gene
Authors: Fu Xing-Zheng , Liu Ji-Hong
Published: December 2012

Citrus canker disease caused byXanthomonas citrisubsp.citri(Xcc) is one of the most devastating diseases affecting the citrus industry worldwide. In our previous study, the canker-resistant transgenic sweet orange (Citrus sinensisOsbeck) plants were producedviaconstitutively overexpressing a spermidine synthase. To unravel the molecular mechanisms underlying Xcc resistance of the transgenic plants, in the present study global transcriptional profiling was compared between untransformed line (WT) and the transgenic line (TG9) by hybridizing with Affymetrix Citrus GeneChip. In total, 666 differentially expressed genes (DEGs) were identified, 448 upregulated, and 218 downregulated. The DEGs were classified into 33 categories after Gene ontology (GO) annotation, in which 68 genes are in response to stimulus and involved in immune system process, 12 genes are related to cell wall, and 13 genes belong to transcription factors. These genes and those related to starch and sucrose metabolism, glutathione metabolism, biosynthesis of phenylpropanoids, and plant hormones were hypothesized to play major roles in the canker resistance of TG9. Semiquantitative RT-PCR analysis showed that the transcript levels of several candidate genes in TG9 were significantly higher than in WT both before and after Xcc inoculation, indicating their potential association with canker disease.
Recovery of Glucose from Residual Starch of Sago Hampas for Bioethanol Production
Authors: Awg-Adeni D. S. , Bujang K. B. , Hassan M. A. , Abd-Aziz S.
Published: December 2012

Lower concentration of glucose was often obtained from enzymatic hydrolysis process of agricultural residue due to complexity of the biomass structure and properties. High substrate load feed into the hydrolysis system might solve this problem but has several other drawbacks such as low rate of reaction. In the present study, we have attempted to enhance glucose recovery from agricultural waste, namely, “sago hampas,” through three cycles of enzymatic hydrolysis process. The substrate load at 7% (w/v) was seen to be suitable for the hydrolysis process with respect to the gelatinization reaction as well as sufficient mixture of the suspension for saccharification process. However, this study was focused on hydrolyzing starch of sago hampas, and thus to enhance concentration of glucose from 7% substrate load would be impossible. Thus, an alternative method termed as cycles I, II, and III which involved reusing the hydrolysate for subsequent enzymatic hydrolysis process was introduced. Greater improvement of glucose concentration (138.45 g/L) and better conversion yield (52.72%) were achieved with the completion of three cycles of hydrolysis. In comparison, cycle I and cycle II had glucose concentration of 27.79 g/L and 73.00 g/L, respectively. The glucose obtained was subsequently tested as substrate for bioethanol production using commercial baker’s yeast. The fermentation process produced 40.30 g/L of ethanol after 16 h, which was equivalent to 93.29% of theoretical yield based on total glucose existing in fermentation media.
ADSPPMutation Causing Dentinogenesis Imperfecta and Characterization of the Mutational Effect
Authors: Lee Sook-Kyung , Lee Kyung-Eun , Song Su Jeong , Hyun Hong-Keun , Lee Sang-Hoon , Kim Jung-Wook
Published: December 2012

Mutations in theDSPPgene have been identified in nonsyndromic hereditary dentin defects, but the genotype-phenotype correlations are not fully understood. Recently, it has been demonstrated that the mutations ofDSPPaffecting the IPV leader sequence result in mutant DSPP retention in rough endoplasmic reticulum (ER). In this study, we identified a Korean family with dentinogenesis imperfecta type III. To identify the disease causing mutation in this family, we performed mutational analysis based on candidate gene sequencing. Exons and exon-intron boundaries ofDSPPgene were sequenced, and the effects of the identified mutation on the pre-mRNA splicing and protein secretion were investigated. Candidate gene sequencing revealed a mutation (c.50C > T, p.P17L) in exon 2 of theDSPPgene. The splicing assay showed that the mutation did not influence pre-mRNA splicing. However, the mutation interfered with protein secretion and resulted in the mutant protein remaining largely in the ER. These results suggest that the mutation affects ER-to-Golgi apparatus export and results in the reduction of secreted DSPP and ER overload. This may induce cell stress and damage processing and/or transport of dentin matrix proteins or other critical proteins.
Evaluation of Acidity Constants and Evolution of Electronic Features of Phenol Derivatives in Different Compositions of Methanol/Water Mixture
Authors: Sanchooli Mahmood
Published: December 2012

This work was devoted to evaluation of acidity constants of 28 phenol derivatives in 11 different compositions of methanol/water solvent mixtures. The Onsager reaction field model was applied to any molecule of phenol derivatives dissolved in binary mixture of methanol/water, and the quantum chemical descriptors of the solute were calculated. Multiple linear regression was used to perform the reliable QSPR models in order to predict the acidity constants of the solutes. It was explored that the solvation of phenol derivatives in solvent of binary mixture of methanol/water shows a different behavior as the composition of methanol varies. Four different mechanisms proposed for solvation in 0–100 volume percent of methanol solvent. It was seen that the dipole‐dipole interactions increase as the amount of methanol increases in solvent mixture, which implies the contribution of highly negative oxygens of methanol on hydrogen bondings between solute and solvent cavity. The orbital energies are a major electronic descriptor on solvation processes. This proposes that the charge exchange between frontier orbital energies of anions and the solvent molecules is the major event occurring in solution in order to stabilize the produced anions.
FoxA1 Specifies Unique Androgen and Glucocorticoid Receptor Binding Events in Prostate Cancer Cells
Authors: Sahu Biswajyoti , Laakso Marko , Pihlajamaa Päivi , Ovaska Kristian , Sinielnikov Ievgenii , Hautaniemi Sampsa , Jänne Olli A.
Published: December 2012

The forkhead protein FoxA1 has functions other than a pioneer factor, in that its depletion brings about a significant redistribution in the androgen receptor (AR) and glucocorticoid receptor (GR) cistromes. In this study, we found a novel function for FoxA1 in defining the cell-type specificity of AR- and GR-binding events in a distinct fashion, namely, for AR in LNCaP-1F5 cells and for GR in VCaP cells. We also found different, cell-type and receptor-specific compilations of cis-elements enriched adjacent to the AR- and GR-binding sites. The AR pathway is central in prostate cancer biology, but the role of GR is poorly known. We find that AR and GR cistromes and transcription programs exhibit significant overlap, and GR regulates a large number of genes considered to be AR pathway-specific. This raises questions about the role of GR in maintaining the AR pathway under androgen-deprived conditions in castration-resistant prostate cancer patients. However, in the presence of androgen, ligand-occupied GR acts as a partial antiandrogen and attenuates the AR-dependent transcription program. Cancer Res; 73(5); 1570–80. ©2012 AACR.
Unconventional Role of the Inwardly Rectifying Potassium Channel Kir2.2 as a Constitutive Activator of RelA in Cancer
Authors: Lee Inkyoung , Lee Sook-Ja , Kang Tong Mook , Kang Won Ki , Park Chaehwa
Published: December 2012

The constitutive activation of NF-κB is a major event leading to the initiation, development, and progression of cancer. Recently, we showed that the size of preestablished tumors was reduced after the depletion of Kir2.2, an inwardly rectifying potassium channel. To determine the precise mechanism of action of Kir2.2 in the control of tumor growth, we searched for interacting proteins. Notably, NF-κB p65/RelA was identified as a binding partner of Kir2.2 in a yeast two-hybrid analysis. Further analyses revealed that Kir2.2 directly interacted with RelA in vitro and coimmunoprecipitated with RelA from cell lysates. Kir2.2 increased RelA phosphorylation at S536 and facilitated its translocation from the cytoplasm to the nucleus, thereby activating the transcription factor and increasing the expression level of NF-κB targets, including cyclin D1, matrix metalloproteinase (MMP)9, and VEGF. Kir2.2 was overexpressed in human cancer and the expression level was correlated with increased colony formation and tumor growth in mouse tumor models. On the basis of these findings, we propose an unconventional role for Kir2.2 as a constitutive RelA-activating protein, which is likely to contribute to tumor progression in vivo. Cancer Res; 73(3); 1056–62. ©2012 AACR.
Autoantibody Signatures Involving Glycolysis and Splicesome Proteins Precede a Diagnosis of Breast Cancer among Postmenopausal Women
Authors: Ladd Jon J. , Chao Timothy , Johnson Melissa M. , Qiu Ji , Chin Alice , Israel Rebecca , Pitteri Sharon J. , Mao Jianning , Wu Mei , Amon Lynn M. , McIntosh Martin , Li Christopher , Prentice Ross , Disis Nora , Hanash Samir
Published: December 2012

We assessed the autoantibody repertoire of a mouse model engineered to develop breast cancer and the repertoire of autoantibodies in human plasmas collected at a preclinical time point and at the time of clinical diagnosis of breast cancer. In seeking to identify common pathways, networks, and protein families associated with the humoral response, we elucidated the dynamic nature of tumor antigens and autoantibody interactions. Lysate proteins from an immortalized cell line from a MMTV-neu mouse model and from MCF7 human breast cancers were spotted onto nitrocellulose microarrays and hybridized with mouse and human plasma samples, respectively. Immunoglobulin-based plasma immunoreactivity against glycolysis and spliceosome proteins was a predominant feature observed both in tumor-bearing mice and in prediagnostic human samples. Interestingly, autoantibody reactivity was more pronounced further away than closer to diagnosis. We provide evidence for dynamic changes in autoantibody reactivity with tumor development and progression that may depend, in part, on the extent of antigen–antibody interactions. Cancer Res; 73(5); 1502–13. ©2012 AACR.
Epigenetic Regulator Smchd1 Functions as a Tumor Suppressor
Authors: Leong Huei San , Chen Kelan , Hu Yifang , Lee Stanley , Corbin Jason , Pakusch Miha , Murphy James M. , Majewski Ian J. , Smyth Gordon K. , Alexander Warren S. , Hilton Douglas J. , Blewitt Marnie E.
Published: December 2012

SMCHD1 is an epigenetic modifier of gene expression that is critical to maintain X chromosome inactivation. Here, we show in mouse that genetic inactivation of Smchd1 accelerates tumorigenesis in male mice. Loss of Smchd1 in transformed mouse embryonic fibroblasts increased tumor growth upon transplantation into immunodeficient nude mice. In addition, loss of Smchd1 in Eμ-Myc transgenic mice that undergo lymphomagenesis reduced disease latency by 50% relative to control animals. In premalignant Eμ-Myc transgenic mice deficient in Smchd1, there was an increase in the number of pre-B cells in the periphery, likely accounting for the accelerated disease in these animals. Global gene expression profiling suggested that Smchd1 normally represses genes activated by MLL chimeric fusion proteins in leukemia, implying that Smchd1 loss may work through the same pathways as overexpressed MLL fusion proteins do in leukemia and lymphoma. Notably, we found that SMCHD1 is underexpressed in many types of human hematopoietic malignancy. Together, our observations collectively highlight a hitherto uncharacterized role for SMCHD1 as a candidate tumor suppressor gene in hematopoietic cancers. Cancer Res; 73(5); 1591–9. ©2012 AACR.
Current Preclinical Models for the Advancement of Translational Bladder Cancer Research
Authors: DeGraff David J. , Robinson Victoria L. , Shah Jay B. , Brandt William D. , Sonpavde Guru , Kang Yibin , Liebert Monica , Wu Xue-Ru , Taylor John A.
Published: December 2012

Bladder cancer is a common disease representing the fifth most diagnosed solid tumor in the United States. Despite this, advances in our understanding of the molecular etiology and treatment of bladder cancer have been relatively lacking. This is especially apparent when recent advances in other cancers, such as breast and prostate, are taken into consideration. The field of bladder cancer research is ready and poised for a series of paradigm-shifting discoveries that will greatly impact the way this disease is clinically managed. Future preclinical discoveries with translational potential will require investigators to take full advantage of recent advances in molecular and animal modeling methodologies. We present an overview of current preclinical models and their potential roles in advancing our understanding of this deadly disease and for advancing care. Mol Cancer Ther; 12(2); 121–30. ©2012 AACR.
Biomechanical Properties of Vaginal Tissue in Women with Pelvic Organ Prolapse
Authors: Martins Pedro , Lopes Silva-Filho Agnaldo , Rodrigues Maciel da Fonseca Andrea Moura , Santos Agostinho , Santos Liliana , Mascarenhas Teresa , Natal Jorge Renato M. , Ferreira António J.M.
Published: December 2012

Background/Aims: To compare biomechanical properties of vaginal tissues between women with and without pelvic organ prolapse (POP) and investigate factors that may influence these properties. Methods: Forty patients submitted to POP surgery and 15 non-POP cadavers were evaluated. The tissue was excised from anterior and posterior middle third vagina. The biomechanical properties considered were stiffness (E) and maximum stress (Smax), and they were evaluated by means of uniaxial tension tests. Results: POP patients were associated with higher values of E (13.1 ± 0.8 vs. 9.5 ± 0.7 MPa; p < 0.001) and Smax (5.3 ± 0.5 vs. 3.2 ± 0.9 MPa; p < 0.001) in the anterior vaginal wall compared to the posterior wall. In contrast, non-POP women presented lower values of E (6.9 ± 1.1 vs. 10.5 ± 1.0 MPa; p = 0.01) and Smax (2.6 ± 0.4 vs. 3.5 ± 0.4 MPa; p = 0.043) in the anterior wall. The occurrence of POP was the only independent predictor of higher values of E and Smax in anterior vaginal samples (p = 0.003 and p = 0.008, respectively). Women with severe anterior vaginal prolapse presented higher levels of E and Smax in the anterior sample compared to those with lower POP stages (p = 0.001 and p = 0.01; respectively). Conclusion: Women with POP present significant changes of biomechanical properties in the vagina.
Intrauterine Growth Restriction and the Innate Immune System in Preterm Infants of ≤32 Weeks Gestation
Authors: Tröger Birte , Müller Thilo , Faust Kirstin , Bendiks Meike , Bohlmann Michael K. , Thonnissen Susanne , Herting Egbert , Göpel Wolfgang , Härtel Christoph
Published: December 2012

Objective: Intrauterine growth restriction (IUGR) is a well-known cause of adverse neonatal outcomes. As it may have an impact on innate immune responses, we aimed to investigate several parameters of the innate immune response in preterm infants of ≤32 weeks gestation who were small for gestational age (SGA). Methods: We compared clinical data of SGA (n = 20) and appropriate for gestational age (AGA; n = 124) newborns with a gestational age of ≤32 weeks. We investigated full blood counts at birth and on days 3 and 7 of life and cytokine immune responses in a human whole cord blood assay. Results: SGA preterm infants had a higher risk of the combined outcome mortality or bronchopulmonary dysplasia. Numbers of white blood cells and neutrophils were diminished in SGA infants at birth and on day 3. At birth, platelet counts were also diminished while the number of nucleated red blood cells tended to be elevated in SGA infants. After stimulation of whole blood cell cultures with lipopolysaccharides, the concentrations of interleukin-6 and interleukin-10 were significantly lower in SGA preterm infants compared to AGA infants. Conclusions: SGA infants differ remarkably from AGA infants in full blood counts and in their ability to mount an immune response. Whether the quantitative deficiency in innate immunity plays a role for adverse outcomes needs to be investigated in larger future trials.
Amniotic Fluid Oxidative and Nitrosative Stress Biomarkers Correlate with Fetal Chronic Hypoxia in Diabetic Pregnancies
Authors: Escobar Javier , Teramo Kari , Stefanovic Vedran , Andersson Sture , Asensi Miguel A. , Arduini Alessandro , Cubells Elena , Sastre Juan , Vento Máximo
Published: December 2012

Background: In spite of improvement in obstetrical care, pregnancy in women with type 1 diabetes mellitus is associated with increased perinatal morbidity and mortality. Hyperglycemia during pregnancy causes excessive fetal growth and chronic fetal hypoxia as reflected in increased erythropoietin (EPO) levels in amniotic fluid (AF). Objectives: We hypothesized that the degree of fetal hypoxia would correlate with fetal oxidative and nitrosative stress as evidenced by the concentration of specific biomarkers in AF. Material and Methods: 19 pregnant women with type 1 or insulin-treated gestational diabetes mellitus were studied. AF samples were collected and processed for EPO, meta-tyrosine, nitro-tyrosine and 8-hydroxy-2-deoxiguanosine by chemiluminescent immunoassay and high-performance liquid chromatography coupled to tandem mass spectrometry methods, respectively. Results: The mean (SD) of the last HbA1c concentration before delivery was 7.7% (1.1). Median gestational age was 258 days (range 231–268). Birth weight was 3,868 ± 695 g with a z-score >2 SD in 47% of the cases. A significant correlation was found between the concentrations of AF EPO and meta-tyrosine/phenylalanine ratio (p < 0.001), nitro-tyrosine (p < 0.01) and 8-oxo-dG/2dG ratio (p < 0.001). Conclusions: We confirmed that fetuses of type 1 diabetes or insulin-treated gestational diabetes pregnancies experience chronic hypoxia as reflected by increased EPO concentrations in AF near term. Moreover, EPO levels significantly correlated with the concentration of oxidative and nitrosative stress biomarkers in AF. This pro-oxidant status may predispose newborn infants to poor postnatal adaptation and early neonatal complications.
Antiviral Innate Immunity Disturbs Podocyte Cell Function
Authors: Yamashita Michifumi , Millward Carrie A. , Inoshita Hiroyuki , Saikia Paramananda , Chattopadhyay Saurabh , Sen Ganes C. , Emancipator Steven N.
Published: December 2012

Immunoglobulin A nephropathy (IgAN) is the most common form of glomerulonephritis throughout the world. A majority (approx. 60%) of patients with IgAN experience disease exacerbations associated with an acute respiratory or gastrointestinal illness that appears to represent a viral infection. However, the exact mechanism of the disease exacerbation by viral infection is not understood, especially at the cellular and molecular levels. Here we report that glomerular podocytes express the major sensors for double-stranded RNA (dsRNA), a common byproduct of viral replication. In addition to these receptors, Toll-like receptor 3 (TLR3) and retinoic acid-inducible gene 1 (RIG-I)-like helicases (RLHs), podocytes express the collateral proteins required to support intracellular signaling. The pathways that mediate responses to dsRNA are fully functional in podocytes. The transcription factor interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-ĸB) are phosphorylated and translocate to the nucleus, and dsRNA increases synthesis of proteins driven by IRF3 (P54, P56 and P60) or NF-ĸB (interleukin 8 and A20). Furthermore, dsRNA suppresses podocyte cell migration, alters the expression of a panel of podocyte essential proteins (nephrin, podocin and CD2-associated protein or CD2AP) and changes transepithelial albumin flux. These effects are dsRNA sensor-specific: TLR3-/- podocytes do not respond to extracellular dsRNA, while intracellular dsRNA has no effect on podocytes bearing a dominant negative form of the major active RLH. These results demonstrate that innate responses to viruses can disturb podocyte cell function in vitro.
Bilistick: A Low-Cost Point-of-Care System to Measure Total Plasma Bilirubin
Authors: Coda Zabetta C.D. , Iskander I.F. , Greco C. , Bellarosa C. , Demarini S. , Tiribelli C. , Wennberg R.P.
Published: December 2012

Background: Severe neonatal hyperbilirubinemia, with consequent encephalopathy, remains a common cause of morbidity and death in many regions of the world. Poor access to clinical laboratory resources and screening programs to measure plasma bilirubin levels is a major contributor to delayed treatment in developing countries, and the cost of existing point-of-care screening instruments precludes their dissemination. Objectives: We are evaluating the accuracy of a low-cost, minimally invasive point-of-care system (Bilistick) requiring a 25-µl blood sample that could be used in low-resource environments to evaluate patients with neonatal jaundice. Methods: We compared plasma bilirubin levels in divided blood samples by clinical laboratories and by Bilistick at two medical centers serving term and near-term newborns from ethnically different populations. Results: 118 neonates with bilirubin levels ranging from 24.8 to 501.0 µmol/l were analyzed. The mean bilirubin concentration (±SD) was 215.6 ± 85.5 µmol/l for Bilistick and 226.1 ± 86.4 µmol/l by laboratory determination. Pearson’s correlation coefficient between all paired results was 0.961, and the Bland-Altman analysis showed a mean difference of 10.3 µmol/l with a 95% interval of agreement of –38.0 to 58.7 µmol/l. Conclusion: Bilistick is a minimally invasive method for measuring total bilirubin concentration over a wide range of values and should provide an affordable and accurate system for pre-discharge and follow-up screening of jaundiced infants, particularly in low-resource environments.
Reduced Retinoid Signaling in the Skin after Systemic Retinoid-X Receptor Ligand Treatment in Mice with Potential Relevance for Skin Disorders
Authors: Mihály Johanna , Gericke Janine , Aydemir Gamze , Weiss Kathrin , Carlsen Harald , Blomhoff Rune , Garcia Javier , Rühl Ralph
Published: December 2012

Retinoid-X receptor (RXR)- and retinoic acid receptor (RAR)-mediated signaling is induced by retinoic acids (RA), which are involved in the regulation of skin permeability, differentiation and immune response. Dysregulation of retinoid signaling is present in various skin disorders. Topically and systemically administered synthetic RAR or RXR agonists might influence retinoid-mediated signaling in the skin of RARE reporter animals and gene expression analysis for retinoid, skin homeostasis and skin inflammation marker genes and local retinoid concentrations. Mice were treated orally and topically with synthetic ligands and bioimaging, QRT-PCR and retinoid analysis were performed. Topical application of the synthetic RAR ligand AM580 significantly enhanced retinoid signaling in skin while topical application of the RXR ligand LG268 did not influence retinoic acid receptor re-sponse elements (RARE)-mediated signaling. Systemic treatments with LG268 decreased the expression of genes involved in skin homeostasis, RA synthesis and skin RA concentrations, while it increased various markers for skin inflammation and RA degradation, which corresponds to decreased skin RARE signaling. We conclude from these observations that increased systemic concentrations of an RXR -ligand may be one reason for reduced retinoid signaling, -reduced all-trans RA levels in the skin, reduced epidermal homeostasis and increased skin inflammation marker expression with potential relevance for various skin disorders, like atopic dermatitis.
Downregulation of Fumarate Hydratase Is Related to Tumorigenesis in Sporadic Renal Cell Cancer
Authors: Ha Yun-Sok , Chihara Yoshitomo , Yoon Hyung-Yoon , Kim Yong-June , Kim Tae-Hwan , Woo Seung Hyo , Yun Seok-Joong , Kim Isaac Yi , Hirao Yoshihiko , Kim Wun-Jae
Published: December 2012

Objective: Although germline mutations of fumarate hydratase (FH) are a useful molecular marker of hereditary leiomyomatosis and renal cell cancer (RCC) syndrome, their clinical significance in sporadic RCC has not been studied in detail. The aim of the present study was to investigate possible correlations between the expression of FH and the clinical implications of sporadic RCC. Materials and Methods:FH mRNA levels were evaluated in 140 tumor specimens from patients with primary RCC and in 62 specimens of corresponding normal-appearing kidney tissue using real-time quantitative polymerase chain reaction. Immunohistochemical staining was performed on 6 normal surrounding tissues and 71 RCC tissues. Results:FH mRNA levels were significantly lower in tumor tissues than in matched normal-appearing kidney tissues (p = 0.031). In all normal tissues, FH staining intensity was strong. However, the expression of FH showed no significant correlation with the pathological and clinical characteristics of patients with sporadic RCC. Conclusions: Our results showed that FH mRNA expression decreased significantly in correlation with the transition from normal renal parenchyma to RCC. FH may be an indicator or tumorigenesis in sporadic RCC and could be a potential target for therapies against RCC in the future.
Vesicoureteral Reflux and Urodynamic Dysfunction
Authors: Batinic Danica , Miloševic Danko , Topalovic-Grkovic Marija , Nizic Ljiljana , Vrljicak Kristina , Batinic Danko , Turudic Daniel
Published: December 2012

Introduction: The concept of vesicoureteral reflux (VUR) as a consequence of congenital anomaly of vesicoureteral junction has undergone changes owing to the finding that such children may have lower urinary tract dysfunction, which produces high intravesical pressure and consequently a predisposition for VUR. Patients and Methods: The urodynamics was investigated by pressure-flow-EMG study in 132 children with VUR and 162 refluxing units. Results: Only 33 (25.0%) patients had normal urodynamic finding. The most frequent pathological finding was overactive bladder (OAB), found in 59 (44.7%) children, followed by dysfunctional voiding (DV) in 25 (18.9%) children. Children with VUR grades I and II had a higher percentage of pathological urodynamic findings than children with VUR grades III and IV. OAB was more frequent in children under 5 years of age with unilateral and lower grade VUR. It was found equally in children with and without uroinfections. DV was more frequent in children older than 5 years, with bilateral VUR, higher grade VUR and uroinfections. Conclusions: Children with VUR have a high incidence of urodynamic disorders. The results of the study indicate the possible role of urodynamic dysfunction in the pathogenesis of VUR, especially mild one.
Complete Resolution of Erythrodermic Psoriasis in an HIV and HCV Patient Unresponsive to Antipsoriatic Treatments after Highly Active Antiretroviral Therapy (Ritonavir, Atazanavir, Emtricitabine, Tenofovir)
Authors: Chiricozzi Andrea , Saraceno Rosita , Cannizzaro Maria Vittoria , Nisticò Steven P. , Chimenti Sergio , Giunta Alessandro
Published: December 2012

Background: Psoriasis is a chronic, inflammatory disease affecting 2-3% of the worldwide population, and it may worsen with HIV or be detected as HIV cutaneous manifestation. HIV-related psoriasis shows a severe and prolonged clinical course with more frequent exacerbations. The management of this condition is challenging because im-munomodulating and immunosuppressant agents may have variable and partial efficacy, and therefore, antiretroviral treatment represents a potential adjunctive therapeutic option. Results: In the case we report, the HIV test was shown to be crucial for driving the therapeutic approach. Indeed, antiretroviral agents have been proven to be effective in the treatment of HIV+ psoriasis as first-line therapy. Conclusion: The HIV test should be considered in high-risk patients affected by severe psoriasis and resistant to conventional and biological treatments.
Clinical Correlates of Weight Loss and Attrition During a 10-Week Dietary Intervention Study: Results from the NUGENOB Project
Authors: Handjieva-Darlenska Teodora , Holst Claus , Grau Katrine , Blaak Ellen , Martinez J.Alfredo , Oppert Jean-Michel , Taylor Moira A. , Sørensen Thorkild I.A. , Astrup Arne
Published: December 2012

Objective: The aim of this study was to identify the pre-treatment subject characteristics and weight loss changes as determinants of weight loss and attrition during a 10-week dietary intervention study. Methods: A total of 771 obese subjects (BMI 35.6 kg/m2) of both genders were included from 8 clinical centres in 7 European countries, who underwent a 10-week dietary intervention study comparing two hypo-energetic (–600 kcal/day) diets varying in fat content. Results: The multiple regression model showed that weight loss at week 10 was predicted by: 6.55 + 1.27 × early weight loss (kg) at week 1 + 1.35 × gender (R2 = 0.28, p < 0.001). When performing the corresponding model with half-way weight loss (week 5) as covariate, the regression equation was: weight loss (kg) at week 10 = 1.88 + 1.38 × half-way weight loss (kg) (week 5) + 0.42 × gender (R2 = 0.77, p < 0.001). A cut-off target of ≥ 4 kg weight loss at week 5 emerged as an optimal predictor for reaching at least 10% weight loss at week 10. Greater attrition likelihood was predicted by high-fat diet, decreased early and half-way weight losses. Conclusion: Early and half-way weight losses are associated with and could contribute to prediction of the final weight loss and attrition.
Contingency Management for the Treatment of Antipsychotic-Induced Weight Gain: A Randomized Controlled Pilot Study
Authors: Ratliff Joseph C. , Palmese Laura B. , Tonizzo K.Melek , Chwastiak Lydia , Tek Cenk
Published: December 2012

Objective: Weight gain is common for individuals with serious mental illness (SMI) receiving antipsychotic drug therapy. Contingency management (CM) is a behavioral intervention that rewards positive performance and has demonstrated effectiveness in reducing drug use in SMI populations. This study evaluated the feasibility of using CM to promote weight loss in individuals with SMI over 8 weeks. Method: 30 individuals (BMI ≥ 28 kg/m2) were randomized to one of three conditions: i) The combination of a standardized lifestyle modification (LM) program for individuals with SMI and payment for group attendance (CMattendance), ii) The combination of LM and payment for weight loss (CMweight), and iii) waitlist control (CON). After the waitlist period, those participants joined a LM group and received payment for behavioral change (CMbehavior). Results: Subjects in the CMattendance and in the CMweight group lost a mean of 1.16 kg and 1.23 kg, respectively, while subjects in the CON gained a mean of 0.68 kg. Subjects receiving CMbehavior, lost a mean of 2.54 kg, which was a significant weight loss compared to the control period. Conclusion: LM supplemented with CM may facilitate weight loss in patients taking antipsychotic medications; financial reimbursement for behavioral change may be particularly effective in this population.
Diagnosis and Treatment of Obesity among Mexican Adults
Authors: Pérez-Salgado Diana , Valdés Flores Jesús , Janssen Ian , Ortiz-Hernández Luis
Published: December 2012

Objectives: To quantify the access to diagnosis and treatment of obesity and intentional weight loss among obese adults in Mexico and to identify the sociodemographic factors related to these events. Methods: The 2006 Mexican National Health and Nutrition Survey – representative of the adults aged 20 to 64 years – was analyzed. Whether people had received diagnosis and treatment from health professionals and whether they had intentional weight loss were explored. The independent variables were: sex, age, socioeconomic position, locality size, and body weight perception. Analyses were carried out for obese people only (BMI ≥ 30 kg/m2, N = 8,545). Results: Among obese people, just 20.2% were diagnosed with such condition, only 8.0% undertook treatment, and barely 5.6% had lost weight intentionally. Individuals with a higher BMI, older individuals, people with higher education, those living in wealthier households, and those living in metropolitan areas were more likely to receive diagnosis and treatment for obesity. Women and people who had been diagnosed as obese were more likely to lose weight. Conclusion: There is an urgent need to increase access to diagnosis and treatment of obesity in Mexico, particularly for men and for lower socioeconomic groups.
Geometric Differential Evolution for Combinatorial and Programs Spaces
Authors: Moraglio A. , Togelius J. , Silva S.
Published: December 2012

Geometric differential evolution (GDE) is a recently introduced formal generalization of traditional differential evolution (DE) that can be used to derive specific differential evolution algorithms for both continuous and combinatorial spaces retaining the same geometric interpretation of the dynamics of the DE search across representations. In this article, we first review the theory behind the GDE algorithm, then, we use this framework to formally derive specific GDE for search spaces associated with binary strings, permutations, vectors of permutations and genetic programs. The resulting algorithms are representation-specific differential evolution algorithms searching the target spaces by acting directly on their underlying representations. We present experimental results for each of the new algorithms on a number of well-known problems comprising NK-landscapes, TSP, and Sudoku, for binary strings, permutations, and vectors of permutations. We also present results for the regression, artificial ant, parity, and multiplexer problems within the genetic programming domain. Experiments show that overall the new DE algorithms are competitive with well-tuned standard search algorithms.