bluuebunny/crossref_metadata_2025 huggingface dataset:
Some New Remarks about the Dynamics of an Automobile with Two Trailers
Authors: Petrişor Camelia
Published: June 2014

The goal of our paper is to complete some results presented by Craioveanu et al. (1998) concerning the nonlinear stability of the equilibrium states of the car with two trailers’ dynamics. In addition, the Lax formulation, numerical integration via Lie-Trotter, and Kahan’s integrator for these dynamics are presented.
Perspectives of Second-Order Blind Identification for Operational Modal Analysis of Civil Structures
Authors: Rainieri C.
Published: June 2014

Innovative methods for output-only estimation of the modal properties of civil structures are based on blind source separation techniques. In the present paper attention is focused on the second-order blind identification (SOBI) algorithm and the influence of its analysis parameters on computational time and accuracy of modal parameter estimates. These represent key issues in view of the automation of the algorithm and its integration within vibration-based monitoring systems. The herein reported analyses and results provide useful hints for reduction of computational time and control of accuracy of estimates. The latter topic is of interest in the case of single modal identification tests, too. A criterion for extraction of accurate modal parameter estimates is identified and applied to selected experimental case studies. They are representative of the different levels of complexity that can be encountered during real modal tests. The obtained results point out that SOBI can provide accurate estimates and it can also be automated, confirming that it represents a profitable alternative for output-only modal analysis and vibration-based monitoring of civil structures.
Design and Characterization of Electrospun Polyamide Nanofiber Media for Air Filtration Applications
Authors: Matulevicius Jonas , Kliucininkas Linas , Martuzevicius Dainius , Krugly Edvinas , Tichonovas Martynas , Baltrusaitis Jonas
Published: June 2014

Electrospun polyamide 6 (PA 6) and polyamide 6/6 (PA 6/6) nanofibers were produced in order to investigate their experimental characteristics with the goal of obtaining filtration relevant fiber media. The experimental design model of each PA nanofibers contained the following variables: polymer concentration, ratio of solvents, nanofiber media collection time, tip‐to‐collector distance, and the deposition voltage. The average diameter of the fibers, their morphology, basis weight, thickness, and resulting media solidity were investigated. Effects of each variable on the essential characteristics of PA 6/6 and PA 6 nanofiber media were studied. The comparative analysis of the obtained PA 6/6 and PA 6 nanofiber characteristics revealed that PA 6/6 had higher potential to be used in filtration applications. Based on the experimental results, the graphical representation—response surfaces—for obtaining nanofiber media with the desirable fiber diameter and basis weight characteristics were derived. Based on the modelling results the nanofiber filter media (mats) were fabricated. Filtration results revealed that nanofiber filter media electrospun from PA6/6 8% (w/vol) solutions with the smallest fiber diameters (62–66 nm) had the highest filtration efficiency (PA6/6_30 = 84.9–90.9%) and the highest quality factor (PA6/6_10 = 0.0486–0.0749 Pa−1).
Awareness and Attitude of Healthcare Workers to Cosmetic Surgery in Osogbo, Nigeria
Authors: Adedeji Opeyemi Adeniyi , Oseni Ganiyu Oladiran , Olaitan Peter Babatunde
Published: June 2014

This study aimed at understanding the level of awareness and elucidates the attitude and disposition of healthcare workers to cosmetic surgery in Osogbo, Nigeria. A questionnaire-based survey was done at LAUTECH Teaching Hospital, Osogbo, in 2012. Questionnaires were administered to 213 workers and students in the hospital. These were then analysed using SPSS version 16.0 with frequencies, means, and so forth. Respondents were 33 doctors, 32 nurses, 79 medical students, 60 nursing students, 4 administrative staff, 1 pharmacist, and 4 ward maids. There is fair awareness about cosmetic surgery generally with 94.5% and its availability in Nigeria with 67.0%. A fewer proportion of the respondents (44.5%) were aware of the facility for cosmetic surgery in their locality. A large percentage (86.5%) favorably considers facilities outside Nigeria when making choice of facility to have cosmetic surgery done. 85.5% considered the information about cosmetic surgery reliable while 19.0% objected going for cosmetic surgery of their choice even if done free. Only 34.0% consider cosmetic surgery socially acceptable. Although the awareness of health workers about cosmetic surgery is high, their disposition to it is low. There is a need to increase the awareness in order to increase cosmetic surgery practice in Nigeria.
PET Radiopharmaceuticals for Imaging Integrin Expression: Tracers in Clinical Studies and Recent Developments
Authors: Haubner Roland , Maschauer Simone , Prante Olaf
Published: June 2014

Noninvasive determination of integrin expression has become an interesting approach in nuclear medicine. Since the discovery of the first18F-labeled cyclic RGD peptide as radiotracer for imaging integrinαvβ3expression in vivo, there have been carried out enormous efforts to develop RGD peptides for PET imaging. Moreover, in recent years, additional integrins, includingα5β1andαvβ6, came into the focus of pharmaceutical radiochemistry. This review will discuss the tracers already evaluated in clinical trials and summarize the preliminary outcome. It will also give an overview on recent developments to further optimize the first-generation compounds such as [18F]Galacto-RGD. This includes recently developed18F-labeling strategies and also new approaches in68Ga-complex chemistry. Furthermore, the approaches to develop radiopharmaceuticals targeting integrinα5β1andαvβ6will be summarized and discussed.
A Mathematical Model of Skeletal Muscle Disease and Immune Response in themdxMouse
Authors: Jarrah Abdul Salam , Castiglione Filippo , Evans Nicholas P. , Grange Robert W. , Laubenbacher Reinhard
Published: June 2014

Duchenne muscular dystrophy (DMD) is a genetic disease that results in the death of affected boys by early adulthood. The genetic defect responsible for DMD has been known for over 25 years, yet at present there is neither cure nor effective treatment for DMD. During early disease onset, themdx mousehas been validated as an animal model for DMD and use of this model has led to valuable but incomplete insights into the disease process. For example, immune cells are thought to be responsible for a significant portion of muscle cell death in themdxmouse; however, the role and time course of the immune response in the dystrophic process have not been well described. In this paper we constructed a simple mathematical model to investigate the role of the immune response in muscle degeneration and subsequent regeneration in themdxmouse model of Duchenne muscular dystrophy. Our model suggests that the immune response contributes substantially to the muscle degeneration and regeneration processes. Furthermore, the analysis of the model predicts that the immune system response oscillates throughout the life of the mice, and the damaged fibers are never completely cleared.
Gingival Vitiligo: Report of a Case and Review of the Literature
Authors: Ashok Nipun , Karunakaran Anila , Singh Prabath , Rodrigues Jean , Ashok Navya , Tarakji Bassel , Saleh Azzeghaiby , Ibrahim Alzoghaibi
Published: June 2014

Rarely cases have been reported regarding depigmented lesions of the oral cavity. On reviewing the literature, only few cases of gingival vitiligo or similar lesions have been reported till date. These lesions pose a cosmetic challenge. We present here a case of vitiligo affecting gingiva. Vitiligo has been defined as an acquired, slowly progressive loss of cutaneous pigment which occurs as irregular, sharply defined patches which may or may not be surrounded by macroscopic hyperpigmentation. Differential diagnosis, detailed clinical history, histopathology, immunohistochemistry, and pathogenesis of this condition are discussed.
Effect of High-Fat Diet upon Inflammatory Markers and Aortic Stiffening in Mice
Authors: Santana Andre Bento Chaves , Souza Oliveira Thais Cristina de , Bianconi Barbara Lobo , Barauna Valerio Garrone , Santos Ed Wilson Cavalcante Oliveira , Alves Tatiana P. , Silva Juliane Cristina S. , Fiorino Patricia , Borelli Primavera , Irigoyen Maria Claudia Costa , Krieger José Eduardo , Lacchini Silvia
Published: June 2014

Changes in lifestyle such as increase in high-fat food consumption are an important cause for vascular diseases. The present study aimed to investigate the involvement of ACE and TGF-βin the aorta stiffness induced by high-fat diet. C57BL/6 male mice were divided in two groups according to their diet for 8 weeks: standard diet (ST) and high-fat diet (HF). At the end of the protocol, body weight gain, adipose tissue content, serum lipids and glucose levels, and aorta morphometric and biochemical measurements were performed. Analysis of collagen fibers by picrosirius staining of aorta slices showed that HF diet promoted increase of thin (55%) and thick (100%) collagen fibers deposition and concomitant disorganization of these fibers orientations in the aorta vascular wall (50%). To unravel the mechanism involved, myeloperoxidase (MPO) and angiotensin I converting enzyme (ACE) were evaluated by protein expression and enzyme activity. HF diet increased MPO (90%) and ACE (28%) activities, as well as protein expression of ACE. TGF-βwas also increased in aorta tissue of HF diet mice after 8 weeks. Altogether, we have observed that the HF diet-induced aortic stiffening may be associated with increased oxidative stress damage and activation of the RAS in vascular tissue.
EEG Oscillatory Phase-Dependent Markers of Corticospinal Excitability in the Resting Brain
Authors: Berger Barbara , Minarik Tamas , Liuzzi Gianpiero , Hummel Friedhelm C. , Sauseng Paul
Published: June 2014

Functional meaning of oscillatory brain activity in various frequency bands in the human electroencephalogram (EEG) is increasingly researched. While most research focuses on event-related changes of brain activity in response to external events there is also increasing interest in internal brain states influencing information processing. Several studies suggest amplitude changes of EEG oscillatory activity selectively influencing cortical excitability, and more recently it was shown that phase of EEG activity (instantaneous phase) conveys additional meaning. Here we review this field with many conflicting findings and further investigate whether corticospinal excitability in the resting brain is dependent on a specific spontaneously occurring brain state reflected by amplitude and instantaneous phase of EEG oscillations. We applied single pulse transcranial magnetic stimulation (TMS) over the left sensorimotor cortex, while simultaneously recording ongoing oscillatory activity with EEG. Results indicate that brain oscillations reflect rapid, spontaneous fluctuations of cortical excitability. Instantaneous phase but not amplitude of oscillations at various frequency bands at stimulation site at the time of TMS-pulse is indicative for brain states associated with different levels of excitability (defined by size of the elicited motor evoked potential). These results are further evidence that ongoing brain oscillations directly influence neural excitability which puts further emphasis on their role in orchestrating neuronal firing in the brain.
Reduction of Polymer Waste Pyrolysis Fractions over Pt/Al2O3with Methanol Decomposition Hydrogen to Obtain Fuel-Grade Hydrocarbons
Authors: Śmigiera Ewa , Osawaru Osazuwa , Kijeński Jacek , Migdał Antoni , Zgudka Anna
Published: June 2014

The hydrogenation under atmospheric pressure of waste polymer pyrolysis fractions over 5% Pt/γ-Al2O3with hydrogen from the catalytic decomposition of methanol over 5% CoO/SiO2has been performed. A 97–100% C=C bond hydrogenation selectivity was achieved at 300°C. The obtained saturated C6–C20and C20–C30fractions can be applied as blending material for fuels and lubricants, respectively, or as hydrocarbon feed. The applied coupled catalytic system exhibited high efficiency at 300°C for at least 5 hours.
Ventral Prostate Fibrosis in the Akita Mouse Is Associated with Macrophage and Fibrocyte Infiltration
Authors: Lee Sanghee , Yang Guang , Mulligan William , Gipp Jerry , Bushman Wade
Published: June 2014

A higher incidence of lower urinary tract symptoms (LUTS) among diabetic men is unexplained. Recently, prostate inflammation and fibrosis have been implicated as major contributing factors to bladder outlet obstruction and LUTS. We characterized the inflammatory cell infiltrate and collagen content of the anterior, dorsal, and ventral lobes of 18-week-old DBA2J.Ins2-Akita mice (Akita) and age-matched control mice. We performed hematoxylin and eosin staining to score tissue injury and inflammation, picrosirius red staining to quantitate collagen content, and immunostaining to identify monocytes/macrophages and infiltrating fibrocytes. We observed significantly greater numbers of monocytes/macrophages and fibrocytes specifically in the ventral prostate of the Akita mice and found that this was associated with significant greater collagen content specifically in the ventral prostate of the Akita mice. These observations support the inference that diabetes elicits monocyte/macrophage infiltration and collagen accumulation in the prostate and suggest that further study of Akita mice may inform translational studies of diabetes in the genesis prostatic inflammation, prostatic fibrosis, and LUTS.
Self-Passivation by Fluorine Plasma Treatment and Low-Temperature Annealing in SiGe Nanowires for Biochemical Sensors
Authors: Chang Kow-Ming , Lai Chiung-Hui , Chen Chu-Feng , Kuo Po-Shen , Chen Yi-Ming , Chang Tai-Yuan , Whang Allen Jong-Woei , Lai Yi-Lung , Chen Huai-Yi , Hsieh Ing-Jar
Published: June 2014

Nanowires are widely used as highly sensitive sensors for electrical detection of biological and chemical species. Modifying the band structure of strained-Si metal-oxide-semiconductor field-effect transistors by applying the in-plane tensile strain reportedly improves electron and hole mobility. The oxidation-induced Ge condensation increases the Ge fraction in a SiGe-on-insulator (SGOI) and substantially increases hole mobility. However, oxidation increases the number of surface states, resulting in hole mobility degradation. In this work, 3-aminopropyltrimethoxysilane (APTMS) was used as a biochemical reagent. The hydroxyl molecule on the oxide surface was replaced by the methoxy groups of the APTMS molecule. We proposed a surface plasma treatment to improve the electrical properties of SiGe nanowires. Fluorine plasma treatment can result in enhanced rates of thermal oxidation and speed up the formation of a self-passivation oxide layer. Like a capping oxide layer, the self-passivation oxide layer reduces the rate of follow-up oxidation. Preoxidation treatment also improved the sensitivity of SiGe nanowires because the Si-F binding was held at a more stable interface state compared to bare nanowire on the SiGe surface. Additionally, the sensitivity can be further improved by either the N2 plasma posttreatment or the low-temperature postannealing due to the suppression of outdiffusion of Ge and F atoms from the SiGe nanowire surface.
Fetal Tachycardia Treated Successfully with Maternally Administered Propylthiouracil
Authors: Parilla Barbara V. , Hanif Farhan , Hasbani Keren , Iannucci Thomas
Published: June 2014

Background. Fetal tachycardia may result from the transplacental passage of thyroid stimulating immunoglobulins in a patient with hypothyroidism secondary to ablation of Graves’ disease.Case. A 32-year-old woman, gravida 4, para 2, and abortus 1, with hypothyroidism and a history of Graves’ disease, presented at 23 6/7 weeks of gestation with a persistent fetal tachycardia. The treatment of the fetal tachycardia with maternally administered digoxin and Sotalol was unsuccessful. Maternal thyroid stimulating immunoglobulins were elevated, and treatment with maternally administered propylthiouracil (PTU) resulted in a normal sinus rhythm for the remainder of the pregnancy. An induction of labor was performed at 37 weeks. Four to five days after delivery, the neonate exhibited clinical signs of hyperthyroidism necessitating treatment.Conclusion. Fetal tachycardia resulting from the transplacental passage of thyroid stimulating immunoglobulins can be successfully treated with maternally administered PTU. The neonate needs to be followed up closely as clinical signs of hyperthyroidism may occur as thyroid stimulating immunoglobulins continue to circulate in the neonate, while the serum levels of PTU decline.
Exposure of a 23F Serotype Strain ofStreptococcus pneumoniaeto Cigarette Smoke Condensate Is Associated with Selective Upregulation of Genes Encoding the Two-Component Regulatory System 11 (TCS11)
Authors: Cockeran Riana , Herbert Jenny A. , Mitchell Timothy J. , Dix-Peek Thérèse , Dickens Caroline , Anderson Ronald , Feldman Charles
Published: June 2014

Alterations in whole genome expression profiles following exposure of the pneumococcus (strain 172, serotype 23F) to cigarette smoke condensate (160 μg/mL) for 15 and 60 min have been determined using the TIGR4 DNA microarray chip. Exposure to CSC resulted in the significant (P<0.014–0.0006) upregulation of the genes encoding the two-component regulatory system 11 (TCS11), consisting of the sensor kinase,hk11, and its cognate response regulator,rr11, in the setting of increased biofilm formation. These effects of cigarette smoke on the pneumococcus may contribute to colonization of the airways by this microbial pathogen.
Effect of Flow Rate of Side-Type Orifice Intake on Withdrawn Water Temperature
Authors: Gao Xueping , Li Guangning , Han Yunpeng
Published: June 2014

Side-type orifice intake is a type of selective withdrawal facility used in managing reservoirs to mitigate the negative effects of low-temperature water. Based on the temperature data of a thermal stratified reservoir in China, an experiment was conducted in flume to study the influence of intake flow rate on withdrawn water temperature with different temperature distributions. Results indicated that withdrawn water temperature changed with different flow rates. The temperature change was determined by the water temperature gradients above and below the intake, whereas the change trend of temperature depended on the difference between the water temperature gradient above and below the intake. We likewise proposed a new equation with which the withdrawn water temperature of a thermal stratified reservoir using a side-type orifice could be calculated. These findings could be directly applied to the design and operation of side-type orifice intake in thermal stratified reservoirs.
The Colorectal Cancer Screening Process in Community Settings: A Conceptual Model for the Population-Based Research Optimizing Screening through Personalized Regimens Consortium
Authors: Tiro Jasmin A. , Kamineni Aruna , Levin Theodore R. , Zheng Yingye , Schottinger Joanne S. , Rutter Carolyn M. , Corley Douglas A. , Skinner Celette S. , Chubak Jessica , Doubeni Chyke A. , Halm Ethan A. , Gupta Samir , Wernli Karen J. , Klabunde Carrie
Published: June 2014

Reducing colorectal cancer mortality by promoting screening has been a national goal for two decades. The NCI's Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium is the first federal initiative to foster coordinated, transdisciplinary research evaluating the entire cancer screening process in community settings. PROSPR is creating a central data repository to facilitate research evaluating the breast, cervical, and colorectal cancer screening process across different patient populations, provider types, and delivery systems. Data are being collected and organized at the multiple levels in which individuals are nested (e.g., healthcare systems, facilities, providers, and patients). Here, we describe a conceptual model of the colorectal cancer screening process guiding data collection and highlight critical research questions that will be addressed through pooled data. We also describe the three research centers focused on colorectal cancer screening with respect to study populations, practice settings, and screening policies. PROSPR comprehensively elucidates the complex screening process through observational study, and has potential to improve care delivery beyond the healthcare systems studied. Findings will inform intervention designs and policies to optimize colorectal cancer screening delivery and advance the Institute of Medicine's goals of effective, efficient, coordinated, timely, and safe health care with respect to evidence-based cancer screening. Cancer Epidemiol Biomarkers Prev; 23(7); 1147–58. ©2014 AACR.
Prediagnostic Intake of Dairy Products and Dietary Calcium and Colorectal Cancer Survival—Results from the EPIC Cohort Study
Authors: Dik Vincent K. , Murphy Neil , Siersema Peter D. , Fedirko Veronika , Jenab Mazda , Kong So Y. , Hansen Camilla P. , Overvad Kim , Tjønneland Anne , Olsen Anja , Dossus Laure , Racine Antoine , Bastide Nadia , Li Kuanrong , Kühn Tilman , Boeing Heiner , Aleksandrova Krasimira , Trichopoulou Antonia , Trichopoulos Dimitrios , Barbitsioti Antonia , Palli Domenico , Contiero Paolo , Vineis Paolo , Tumino Rosaria , Panico Salvatore , Peeters Petra H.M. , Weiderpass Elisabete , Skeie Guri , Hjartåker Anette , Amiano Pilar , Sánchez María-José , Fonseca-Nunes Ana , Barricarte Aurelio , Chirlaque María-Dolores , Redondo Maria-Luisa , Jirström Karin , Manjer Jonas , Nilsson Lena M. , Wennberg Maria , Bradbury Kathryn E. , Khaw Kay-Tee , Wareham Nicholas , Cross Amanda J. , Riboli Elio , Bueno-de-Mesquita H. Bas
Published: June 2014

Background: We investigated whether prediagnostic reported intake of dairy products and dietary calcium is associated with colorectal cancer survival.

Methods: Data from 3,859 subjects with colorectal cancer (42.1% male; mean age at diagnosis, 64.2 ± 8.1 years) in the European Investigation into Cancer and Nutrition cohort were analyzed. Intake of dairy products and dietary calcium was assessed at baseline (1992–2000) using validated, country-specific dietary questionnaires. Multivariable Cox regression models were used to calculate HR and corresponding 95% confidence intervals (CI) for colorectal cancer–specific death (n = 1,028) and all-cause death (n = 1,525) for different quartiles of intake.

Results: The consumption of total dairy products was not statistically significantly associated with risk of colorectal cancer–specific death (adjusted HR Q4 vs. Q1, 1.17; 95% CI, 0.97–1.43) nor that of all-cause death (Q4 vs. Q1, 1.16; 95% CI, 0.98–1.36). Multivariable-adjusted HRs for colorectal cancer–specific death (Q4 vs. Q1) were 1.21 (95% CI, 0.99–1.48) for milk, 1.09 (95% CI, 0.88–1.34) for yoghurt, and 0.93 (95% CI, 0.76–1.14) for cheese. The intake of dietary calcium was not associated with the risk of colorectal cancer–specific death (adjusted HR Q4 vs. Q1, 1.01; 95% CI, 0.81–1.26) nor that of all-cause death (Q4 vs. Q1, 1.01; 95% CI, 0.84–1.21).

Conclusions: The prediagnostic reported intake of dairy products and dietary calcium is not associated with disease-specific or all-cause risk of death in patients diagnosed with colorectal cancer.

Impact: The impact of diet on cancer survival is largely unknown. This study shows that despite its inverse association with colorectal cancer risk, the prediagnostic intake of dairy and dietary calcium does not affect colorectal cancer survival. Cancer Epidemiol Biomarkers Prev; 23(9); 1813–23. ©2014 AACR.
microRNAome Expression in Chronic Lymphocytic Leukemia: Comparison with Normal B-cell Subsets and Correlations with Prognostic and Clinical Parameters
Authors: Negrini Massimo , Cutrona Giovanna , Bassi Cristian , Fabris Sonia , Zagatti Barbara , Colombo Monica , Ferracin Manuela , D'Abundo Lucilla , Saccenti Elena , Matis Serena , Lionetti Marta , Agnelli Luca , Gentile Massimo , Recchia Anna Grazia , Bossio Sabrina , Reverberi Daniele , Rigolin Gianmatteo , Calin George A. , Sabbioni Silvia , Russo Giandomenico , Tassone Pierfrancesco , Morabito Fortunato , Ferrarini Manlio , Neri Antonino
Published: June 2014

Purpose: Despite its indolent nature, chronic lymphocytic leukemia (CLL) remains an incurable disease. To establish the potential pathogenic role of miRNAs, the identification of deregulated miRNAs in CLL is crucial.

Experimental Design: We analyzed the expression of 723 mature miRNAs in 217 early-stage CLL cases and in various different normal B-cell subpopulations from tonsils and peripheral blood.

Results: Our analyses indicated that CLL cells exhibited a miRNA expression pattern that was most similar to the subsets of antigen-experienced and marginal zone–like B cells. These normal subpopulations were used as reference to identify differentially expressed miRNAs in comparison with CLL. Differences related to the expression of 25 miRNAs were found to be independent from IGHV mutation status or cytogenetic aberrations. These differences, confirmed in an independent validation set, led to a novel comprehensive description of miRNAs potentially involved in CLL. We also identified miRNAs whose expression was distinctive of cases with mutated versus unmutated IGHV genes or cases with 13q, 11q, and 17p deletions and trisomy 12. Finally, analysis of clinical data in relation to miRNA expression revealed that miR26a, miR532-3p, miR146-5p, and miR29c* were strongly associated with progression-free survival.

Conclusion: This study provides novel information on miRNAs expressed by CLL and normal B-cell subtypes, with implication on the cell of origin of CLL. In addition, our findings indicate a number of deregulated miRNAs in CLL, which may play a pathogenic role and promote disease progression. Collectively, this information can be used for developing miRNA-based therapeutic strategies in CLL. Clin Cancer Res; 20(15); 4141–53. ©2014 AACR.
Cisplatin-Induced Renal Injury Is Independently Mediated by OCT2 and p53
Authors: Sprowl Jason A. , Lancaster Cynthia S. , Pabla Navjotsingh , Hermann Edwin , Kosloske Ashley M. , Gibson Alice A. , Li Lie , Zeeh Dorothea , Schlatter Eberhard , Janke Laura J. , Ciarimboli Giuliano , Sparreboom Alex
Published: June 2014

Purpose: Tubular secretion of cisplatin is abolished in mice deficient for the organic cation transporters Oct1 and Oct2 (Oct1/2−/−mice), and these animals are protected from severe cisplatin-induced kidney damage. Since tubular necrosis is not completely absent in Oct1/2−/−mice, we hypothesized that alternate pathways are involved in the observed injury.

Experimental Design: Studies were done in wild-type, Oct1/2−/−, or p53-deficient animals, all on an FVB background, receiving cisplatin intraperitoneally at 15 mg/kg. Cisplatin metabolites were analyzed using mass spectrometry, and gene expression was assessed using Affymetrix microarrays and RT-PCR arrays.

Results: KEGG pathway analyses on kidneys from mice exposed to cisplatin revealed that the most significantly altered genes were associated with the p53 signaling network, including Cdnk1a and Mdm2, in both wild-type (P = 2.40 × 10−11) and Oct1/2−/−mice (P = 1.92 × 10−8). This was confirmed by demonstrating that homozygosity for a p53-null allele partially reduced renal tubular damage, whereas loss of p53 in Oct1/2−/−mice (p53−/−/Oct1/2−/−) completely abolished nephrotoxicity. We found that pifithrin-α, an inhibitor of p53-dependent transcriptional activation, inhibits Oct2 and can mimic the lack of nephrotoxicity observed in p53−/−/Oct1/2−/−mice.

Conclusions: These findings indicate that (i) the p53 pathway plays a crucial role in the kidney in response to cisplatin treatment and (ii) clinical exploration of OCT2 inhibitors may not lead to complete nephroprotection unless the p53 pathway is simultaneously antagonized. Clin Cancer Res; 20(15); 4026–35. ©2014 AACR.
TGFα and Amphiregulin Paracrine Network Promotes Resistance to EGFR Blockade in Colorectal Cancer Cells
Authors: Hobor Sebastijan , Van Emburgh Beth O. , Crowley Emily , Misale Sandra , Di Nicolantonio Federica , Bardelli Alberto
Published: June 2014

Purpose: Targeted inhibition of EGFR with the mAbs cetuximab or panitumumab is a valuable treatment for RAS wild-type colorectal cancers. The efficacy of EGFR blockade is limited by the emergence of acquired resistance often attributed to secondary KRAS mutations. Remarkably, tumor biopsies from resistant patients show that only a fraction of the resilient cells carry KRAS mutations. We hypothesized that a paracrine cross-talk driven by the resistant subpopulation may provide in trans protection of surrounding sensitive cells.

Experimental design: Conditioned medium assays and three-dimensional cocultures were used to assess paracrine networks between cetuximab-sensitive and -resistant cells. Production of EGFR ligands by cells sensitive to cetuximab and panitumumab was measured. The ability of recombinant EGFR ligands to protect sensitive cells from cetuximab was assessed. Biochemical activation of the EGFR signaling pathway was measured by Western blotting.

Results: Colorectal cancer cells sensitive to EGFR blockade can successfully grow despite cetuximab treatment when in the company of their resistant derivatives. Media conditioned by resistant cells protect sensitive parental cells from cetuximab. EGFR blockade triggers increased secretion of TGFα and amphiregulin. Increased secretion of ligands by resistant cells can sustain EGFR/ERK signaling in sensitive cells.

Conclusions: Colorectal cancer cells that develop resistance to cetuximab and panitumumab secrete TGFα and amphiregulin, which protect the surrounding cells from EGFR blockade. This paracrine protective mechanism might be therapeutically exploitable. Clin Cancer Res; 20(24); 6429–38. ©2014 AACR.
Update on the Genetics of Bardet-Biedl Syndrome
Authors: M'hamdi O. , Ouertani I. , Chaabouni-Bouhamed H.
Published: June 2014

Bardet-Biedl syndrome (BBS) is an autosomal recessive disease characterized by retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, renal involvement, and male hypogenitalism. BBS is genetically heterogeneous, and to date 18 genes (BBS1-18) have been described. Mutations in known BBS genes account for approximately 70-80% of cases, and triallelic inheritance has been suggested in about 5%. Many minor features can be helpful in making the clinical diagnosis. Recently, the use of next-generation sequencing technologies has accelerated the identification of novel genes and causative disease mutations in known genes. This report presents a concise overview of the current knowledge on clinical data in BBS and the progress in molecular genetics research. A future objective will be the development of BBS diagnosis kits in order to offer genetic counseling for families at risk.
Update on the Diagnosis and Classification of Fetal Growth Restriction and Proposal of a Stage-Based Management Protocol
Authors: Figueras Francesc , Gratacós Eduard
Published: June 2014

Small fetuses are defined as those with an ultrasound estimated weight below a threshold, most commonly the 10th centile. The first clinically relevant step is the distinction of ‘true' fetal growth restriction (FGR), associated with signs of abnormal fetoplacental function and poorer perinatal outcome, from constitutional small-for-gestational age, with a near-normal perinatal outcome. Nowadays such a distinction should not be based solely on umbilical artery Doppler, since this index detects only early-onset severe forms. FGR should be diagnosed in the presence of any of the factors associated with a poorer perinatal outcome, including Doppler cerebroplacental ratio, uterine artery Doppler, a growth centile below the 3rd centile, and, possibly in the near future, maternal angiogenic factors. Once the diagnosis is established, differentiating into early- and late-onset FGR is useful mainly for research purposes, because it distinguishes two clear phenotypes with differences in severity, association with preeclampsia, and the natural history of fetal deterioration. As a second clinically relevant step, management of FGR and the decision to deliver aims at an optimal balance between minimizing fetal injury or death versus the risks of iatrogenic preterm delivery. We propose a protocol that integrates current evidence to classify stages of fetal deterioration and establishes follow-up intervals and optimal delivery timings, which may facilitate decisions and reduce practice variability in this complex clinical condition.
Assessment of Chimerism in Epithelial Cancers in Transplanted Patients
Authors: Leboeuf Christophe , Ratajczak Philippe , Vérine Jérôme , Elbouchtaoui Morad , Plassa François , Legrès Luc , Ferreira Irmine , Sandid Wissam , Varna Mariana , Bousquet Guilhem , Verneuil Laurence , Janin Anne
Published: June 2014

Cancer is now the most severe complication in the long term in transplant recipients. As most solid-organ or hematopoietic stem-cell transplantations are allogeneic, chimerism studies can be performed on cancers occurring in recipients. We summarize here the different methods used to study chimerism in cancers developing in allogeneic-transplant recipients, analyze their respective advantages and report the main results obtained from these studies. Chimerism analyses of cancers in transplant recipients require methods suited to tissue samples. In the case of gender-mismatched transplantation, the XY chromosomes can be explored using fluorescent in situ hybridization on whole-tissue sections or Y-sequence-specific PCR after the laser microdissection of tumor cells. For cancers occurring after gender-matched transplantation, laser microdissection of tumor cells enables studies of microsatellite markers and high-resolution melting analysis of mitochondrial DNA on genes with marked polymorphism, provided these are different in the donor and the recipient. The results of different studies address the cancers that develop in both recipients and in transplants. The presence of chimeric cells in these two types of cancer implies an exchange of progenitor/stem-cells between transplant and recipient, and the plasticity of these progenitor/stem-cells contributes to epithelial cancers. The presence of chimeric cells in concomitant cancers and preneoplastic lesions implies that the oncogenesis of these cancers progresses through a multistep process.
Managing Age-Related Hearing Loss: How to Use Hearing Aids Efficiently - A Mini-Review
Authors: Williger Bettina , Lang Frieder R.
Published: June 2014

Using hearing aids may contribute to better functioning in the everyday lives of hearing-impaired older individuals. We introduce an integrative concept for the efficient use of hearing aids that involves both satisfaction with, and behaviour towards, hearing aids. We review theoretical and empirical work on the predictors of the efficient use of hearing aids in everyday life. Furthermore, we contend that the use of hearing aids requires improved understanding of the variability of hearing demands within specific contexts of everyday life (e.g. conversation with family members, listening to music). The efficiency of hearing aid use thus depends on the fit of situational demands, personal resources, and the specific configuration of the hearing aid device. We propose an integrative person-environment-fit model that advances concepts of selection, optimisation, and compensation to hearing aid efficiency. We discuss the implications of this model for research and for practitioners in the field of gerontology.
The Role of Neurokinin B Signalling in Reproductive Neuroendocrinology
Authors: Grachev P. , Millar R.P. , O'Byrne K.T.
Published: June 2014

The KNDy neuropeptides, kisspeptin, neurokinin B (NKB) and dynorphin A (Dyn), have been implicated in regulating pulsatile luteinising hormone (LH) secretion. Studies of the interactions between KNDy signalling systems, however, are currently few. Although the stimulatory effect of kisspeptin and the inhibitory effect of Dyn on the gonadotropin-releasing hormone pulse generator are widely accepted, the effects of NKB in rodents are variable and sometimes controversial. Literature describing increased LH secretion in response to NKB receptor agonism predominates and is in line with human physiology, as well as the pathophysiology of pubertal failure associated with disruption of NKB signalling. However, the robust suppression of the LH pulse, induced by the same treatment under hypoestrogenic conditions, may hold clues as to the mechanisms of reproductive inhibition under pathological conditions. This review discusses the recent evidence for this paradox and outlines a revised working model incorporating the mechanisms by which KNDy neuropeptides modulate the reproductive axis.
The Increasing Prevalence of Multiple Sclerosis in New Zealand
Authors: Alla Sridhar , Pearson John , Debernard Laëtitia , Miller David , Mason Deborah
Published: June 2014

Background: New Zealand (NZ) has a high prevalence of multiple sclerosis (MS). Worldwide, the prevalence of MS appears to be increasing. Objectives: To review all published prevalence studies undertaken in NZ to determine whether the prevalence of MS in NZ is increasing. Methods: PubMed, Medline, Scopus, Web of Knowledge, EMBASE, AMED and CINAHL were searched to identify studies reporting the prevalence of MS in NZ. Prevalence rates from the National MS Prevalence study in 2006 were compared with earlier prevalence rates for the same regions using Poisson regression. Results: Prevalence rates reported in the earlier regional studies ranged from 23.6 to 68.5/100,000 population; in the same regions in 2006, the range was 47.6-134.2/100,000 population. Prevalence rates were significantly increased in all regions studied except for the Bay of Plenty. The increase in prevalence was seen in both sexes. The sex ratio remained constant over time. Conclusions: In studies spanning almost 40 years (1968-2006), the prevalence of MS within the same regions of NZ has significantly increased whereas the sex ratio and latitudinal gradient have remained stable.
Serum Levels of Sclerostin and Dickkopf-1: Effects of Age, Gender and Fracture Status
Authors: Dovjak Peter , Dorfer Sonja , Föger-Samwald Ursula , Kudlacek Stefan , Marculescu Rodrig , Pietschmann Peter
Published: June 2014

Background: Fragility fractures, especially hip fractures, are a very common complication of osteoporosis in elderly subjects. Sclerostin (SOST) and dickkopf-1 (DKK-1) are inhibitors of the canonical wnt signalling pathway and thus could be involved in the pathogenesis of age-related bone fragility. Objective: To investigate SOST and DKK-1 in a large group of geriatric patients with hip fractures and to relate the wnt inhibitors to age and gender. Methods: This was a cross-sectional study carried out in a department of acute geriatric care in a district hospital in Upper Austria and a hospital in Vienna, Austria. A total of 256 geriatric patients (172 women and 84 men) and 67 young control subjects were selected after exclusion. Medical history was obtained, a comprehensive geriatric assessment was performed and serum levels of SOST, DKK-1 and bone formation markers were analysed. Results: DKK-1 levels increased with age and in the presence of hip fractures. In contrast, SOST levels were lower in patients with hip fractures. When compared to women, men had higher SOST levels but lower DKK-1 levels. Conclusion: Serum levels of the inhibitors of the canonical wnt signalling pathway reflect different biological events and are useful for the study of bone fragility in geriatric patients.
Combination of Cross-Sectional and Molecular Imaging Studies in the Localization of Gastroenteropancreatic Neuroendocrine Tumors
Authors: Toumpanakis Christos , Kim Michelle K. , Rinke Anja , Bergestuen Deidi S. , Thirlwell Christina , Khan Mohid S. , Salazar Ramon , Oberg Kjell
Published: June 2014

Molecular imaging modalities exploit aspects of neuroendocrine tumors (NET) pathophysiology for both diagnostic imaging and therapeutic purposes. The characteristic metabolic pathways of NET determine which tracers are useful for their visualization. In this review, we summarize the diagnostic value of all available molecular imaging studies, present data about their use in daily practice in NET centers globally, and finally make recommendations about the appropriate use of those modalities in specific clinical scenarios. Somatostatin receptor scintigraphy (SRS) continues to have a central role in the diagnostic workup of patients with NET, as it is also widely available. However, and despite the lack of prospective randomized studies, many NET experts predict that Gallium-68 (68Ga)-DOTA positron emission tomography (PET) techniques may replace SRS in the future, not only because of their technical advantages, but also because they are superior in patients with small-volume disease, in patients with skeletal metastases, and in those with occult primary tumors. Carbon-11 (11C)-5-hydroxy-L-tryptophan (5-HTP) PET and 18F-dihydroxyphenylalanine (18F-DOPA) PET are new molecular imaging techniques of limited availability, and based on retrospective data, their sensitivities seem to be inferior to that of 68Ga-DOTA PET. Glucagon-like-peptide-1 (GLP-1) receptor imaging seems promising for localization of the primary in benign insulinomas, but is currently available only in a few centers. Fluorine-18 (18F)-fluorodeoxyglucose (18F-FDG) PET was initially thought to be of limited value in NET, due to their usually slow-growing nature. However, according to subsequent data, 18F-FDG PET is particularly helpful for visualizing the more aggressive NET, such as poorly differentiated neuroendocrine carcinomas, and well-differentiated tumors with Ki67 values >10%. According to limited data, 18F-FDG-avid tumor lesions, even in slow-growing NET, may indicate a more aggressive disease course. When a secondary malignancy has already been established or is strongly suspected, combining molecular imaging techniques (e.g. 18F-FDG PET and 68Ga-DOTA PET) takes advantage of the diverse avidities of different tumor types to differentiate lesions of different origins. All the above-mentioned molecular imaging studies should always be reviewed and interpreted in a multidisciplinary (tumor board) meeting in combination with the conventional cross-sectional imaging, as the latter remains the imaging of choice for the evaluation of treatment response and disease follow-up.
The Global Epidemiology of Hereditary Ataxia and Spastic Paraplegia: A Systematic Review of Prevalence Studies
Authors: Ruano Luis , Melo Claudia , Silva M. Carolina , Coutinho Paula
Published: June 2014

Background: Hereditary cerebellar ataxias (HCA) and hereditary spastic paraplegias (HSP) are two groups of neurodegenerative disorders that usually present with progressive gait impairment, often leading to permanent disability. Advances in genetic research in the last decades have improved their diagnosis and brought new possibilities for prevention and future treatments. Still, there is great uncertainty regarding their global epidemiology. Summary: Our objective was to assess the global distribution and prevalence of HCA and HSP by a systematic review and meta-analysis of prevalence studies. The MEDLINE, ISI Web of Science and Scopus databases were searched (1983-2013) for studies performed in well-defined populations and geographical regions. Two independent reviewers assessed the studies and extracted data and predefined methodological parameters. Overall, 22 studies were included, reporting on 14,539 patients from 16 countries. Multisource population-based studies yielded higher prevalence values than studies based primarily on hospitals or genetic centres. The prevalence range of dominant HCA was 0.0-5.6/105, with an average of 2.7/105 (1.5-4.0/105). Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease was the most common dominant ataxia, followed by SCA2 and SCA6. The autosomal recessive (AR) HCA (AR-HCA) prevalence range was 0.0-7.2/105, the average being 3.3/105 (1.8-4.9/105). Friedreich ataxia was the most frequent AR-HCA, followed by ataxia with oculomotor apraxia or ataxia-telangiectasia. The prevalence of autosomal dominant (AD) HSP (AD-HSP) ranged from 0.5 to 5.5/105 and that of AR-HSP from 0.0 to 5.3/105, with pooled averages of 1.8/105 (95% CI: 1.0-2.7/105) and 1.8/105 (95% CI: 1.0-2.6/105), respectively. The most common AD-HSP form in every population was spastic paraplegia, autosomal dominant, type 4 (SPG4), followed by SPG3A, while SPG11 was the most frequent AR-HSP, followed by SPG15. In population-based studies, the number of families without genetic diagnosis after systematic testing ranged from 33 to 92% in the AD-HCA group, and was 40-46% in the AR-HCA, 45-67% in the AD-HSP and 71-82% in the AR-HSP groups. Key Messages: Highly variable prevalence values for HCA and HSP are reported across the world. This variation reflects the different genetic make-up of the populations, but also methodological heterogeneity. Large areas of the world remain without prevalence studies. From the available data, we estimated that around 1:10,000 people are affected by HCA or HSP. In spite of advances in genetic research, most families in population-based series remain without identified genetic mutation after extensive testing.
Predialysis Care and Dialysis Outcomes in Hemodialysis Patients with a Functioning Fistula
Authors: Ishani Areef , Gilbertson David T. , Kim Deborah , Bradbury Brian D. , Collins Allan J.
Published: June 2014

Background/Aims: Predialysis care has been associated with improved first-year outcomes. We investigated types of predialysis care associated with improved patient outcomes in patients initiating dialysis with a fistula and at least 2 years of predialysis care. Methods: In this retrospective cohort of incident hemodialysis patients with ≥2 years of Medicare coverage before dialysis initiation, care patterns and patients were determined using Medicare claims. Fistula use at initiation was ascertained from the Medical Evidence Report. Results: Patients aged ≥67 years who initiated hemodialysis with a fistula (n = 14,459) differed demographically and clinically from patients who initiated with other vascular access types; however, 55% had diabetes, 28% heart failure, and 40% ischemic heart disease. In the year preceding initiation, 88% of these patients visited a nephrologist, 66% a cardiologist, 9% an endocrinologist, and 3% a dietician; most underwent routine laboratory measurements. In the first year of dialysis, 50% were hospitalized and 1.3% underwent transplant; the mortality rate remained constant (∼20 per 100 patient-years). Of predialysis care factors evaluated, only fistula placement more than 1 month before dialysis initiation was associated with lower hospitalization and mortality risk and greater likelihood of transplant. Other potentially modifiable factors included more contact with cardiologists and endocrinologists. Conclusion: Patients initiating dialysis with a functioning fistula appear to receive substantial predialysis preparation. This selected population does not show the excess mortality risk often observed early in dialysis treatment. Earlier fistula placement and referral to cardiology and endocrinology appear to be important aspects of predialysis care.