bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative Erythrocyte Sedimentation Rate Independently Predicts Overall Survival in Localized Renal Cell Carcinoma following Radical Nephrectomy
Authors: Cross Brian W. , Johnson Timothy V. , DeRosa Austin B. , Ogan Kenneth , Pattaras John G. , Nieh Peter T. , Kucuk Omer , Harris Wayne B. , Master Viraj A.
Published: July 2012

Objectives. To determine the relationship between preoperative erythrocyte sedimentation rate (ESR) and overall survival in localized renal cell carcinoma (RCC) following nephrectomy.Methods. 167 patients undergoing nephrectomy for localized RCC had ESR levels measured preoperatively. Receiver Operating Characteristics curves were used to determine Area Under the Curve and relative sensitivity and specificity of preoperative ESR in predicting overall survival. Cut-offs for low (0.0–20.0 mm/hr), intermediate (20.1–50.0 mm/hr), and high risk (>50.0 mm/hr) groups were created. Kaplan-Meier analysis was conducted to assess the univariate impact of these ESR-based groups on overall survival. Univariate and multivariate Cox regression analysis was conducted to assess the potential of these groups to predict overall survival, adjusting for other patient and tumor characteristics.Results. Overall, 55.2% were low risk, while 27.0% and 17.8% were intermediate and high risk, respectively. Median (95% CI) survival was 44.1 (42.6–45.5) months, 35.5 (32.3–38.8) months, and 32.1 (25.5–38.6) months, respectively. After controlling for other patient and tumor characteristics, intermediate and high risk groups experienced a 4.5-fold (HR: 4.509, 95% CI: 0.735–27.649) and 18.5-fold (HR: 18.531, 95% CI: 2.117–162.228) increased risk of overall mortality, respectively.Conclusion. Preoperative ESR values represent a robust predictor of overall survival following nephrectomy in localized RCC.
Grounded Theory of Barriers and Facilitators to Mandated Implementation of Mental Health Care in the Primary Care Setting
Authors: Benzer Justin K. , Beehler Sarah , Miller Christopher , Burgess James F. , Sullivan Jennifer L. , Mohr David C. , Meterko Mark , Cramer Irene E.
Published: July 2012

Objective. There is limited theory regarding the real-world implementation of mental health care in the primary care setting: a type of organizational coordination intervention. The purpose of this study was to develop a theory to conceptualize the potential causes of barriers and facilitators to how local sites responded to this mandated intervention to achieve coordinated mental health care.Methods. Data from 65 primary care and mental health staff interviews across 16 sites were analyzed to identify how coordination was perceived one year after an organizational mandate to provide integrated mental health care in the primary care setting.Results. Standardized referral procedures and communication practices between primary care and mental health were influenced by the organizational factors of resources, training, and work design, as well as provider-experienced organizational boundaries between primary care and mental health, time pressures, and staff participation. Organizational factors and provider experiences were in turn influenced by leadership.Conclusions. Our emergent theory describes how leadership, organizational factors, and provider experiences affect the implementation of a mandated mental health coordination intervention. This framework provides a nuanced understanding of the potential barriers and facilitators to implementing interventions designed to improve coordination between professional groups.
Buried Object Detection by an Inexact Newton Method Applied to Nonlinear Inverse Scattering
Authors: Pastorino Matteo , Randazzo Andrea
Published: July 2012

An approach to reconstruct buried objects is proposed. It is based on the integral equations of the electromagnetic inverse scattering problem, written in terms of the Green’s function for half-space geometries. The full nonlinearity of the problem is exploited in order to inspect strong scatterers. After discretization of the continuous model, the resulting equations are solved in a regularization sense by means of a two-step inexact Newton algorithm. The capabilities and limitations of the method are evaluated by means of some numerical simulations.
Generalized Altering Distances and Common Fixed Points in Ordered Metric Spaces
Authors: Nashine Hemant Kumar , Aydi Hassen
Published: July 2012

Coincidence point and common fixed point results with the concept of generalized altering distance functions in complete ordered metric spaces are derived. These results generalize the existing fixed point results in the literature. To illustrate our results and to distinguish them from the existing ones, we equip the paper with examples. As an application, we study the existence of a common solution to a system of integral equations.
Theoretical Investigation of the Cooperativity in CH3CHO·2H2O, CH2FCHO·2H2O, and CH3CFO·2H2O Systems
Authors: Chandra Asit K. , Zeegers-Huyskens Thérèse
Published: July 2012

The hydrogen bond interaction between CH3CHO, CH2FCHO, and CH3CFO and two water molecules is investigated at the B3LYP/6-311++G(d,p) level. The results are compared with the complexes involving the same carbonyl derivatives and one water molecule. The calculations involve the optimization of the structure, the harmonic vibrational frequencies, and relevant NBO (natural bond orbital) parameters such as the NBO charges, the occupation of antibonding orbitals, and intra- and intermolecular hyperconjugation energies. Two stable cyclic structures are predicted. The two structures are stabilized by C=O⋯HO hydrogen bond. The A structures are further stabilized by CH⋯O bond involving the CH3 (CH2F) group. This bond results in an elongation of the CH bond and red shift of the ν(CH) vibration. The B structures are stabilized by CH⋯O interaction involving the aldehydic CH bond. The formation of this bond results in a marked contraction of the CH bond and blue shift of the ν(CH) vibration indicating the predominance of the lone pair effect in determining the CH distances. The total interaction energies range from −12.40 to −13.50 kcal mol−1. The cooperative energies calculated at the trimer geometry are comprised between −2.30 and −2.60 kcal mol−1.
Drift-Diffusion Analysis of Neutrophil Migration during Inflammation Resolution in a Zebrafish Model
Authors: Holmes Geoffrey R. , Dixon Giles , Anderson Sean R. , Reyes-Aldasoro Constantino Carlos , Elks Philip M. , Billings Stephen A. , Whyte Moira K. B. , Kadirkamanathan Visakan , Renshaw Stephen A.
Published: July 2012

Neutrophils must be removed from inflammatory sites for inflammation to resolve. Recent work in zebrafish has shown neutrophils can migrate away from inflammatory sites, as well as die in situ. The signals regulating the process of reverse migration are of considerable interest, but remain unknown. We wished to study the behaviour of neutrophils during reverse migration, to see whether they moved away from inflamed sites in a directed fashion in the same way as they are recruited or whether the inherent random component of their migration was enough to account for this behaviour. Using neutrophil-driven photoconvertible Kaede protein in transgenic zebrafish larvae, we were able to specifically label neutrophils at an inflammatory site generated by tailfin transection. The locations of these neutrophils over time were observed and fitted using regression methods with two separate models: pure-diffusion and drift-diffusion equations. While a model hypothesis test (theF-test) suggested that the datapoints could be fitted by the drift-diffusion model, implying a fugetaxis process, dynamic simulation of the models suggested that migration of neutrophils away from a wound is better described by a zero-drift, “diffusion” process. This has implications for understanding the mechanisms of reverse migration and, by extension, neutrophil retention at inflammatory sites.
Can Estragole in Fennel Seed Decoctions Really Be Considered a Danger for Human Health? A Fennel Safety Update
Authors: Gori L. , Gallo E. , Mascherini V. , Mugelli A. , Vannacci A. , Firenzuoli F.
Published: July 2012

Fennel (Foeniculum vulgareMill.) mature fruit (commonly known as seeds) and essential oil of fennel are widely used as flavoring agents in food products such as liqueurs, bread, cheese, and an ingredient of cosmetics and pharmaceutical products. Moreover fennel infusions are the classical decoction for nursing babies to prevent flatulence and colic spasm. Traditionally in Europe and Mediterranean areas fennel is used as antispasmodic, diuretic, anti-inflammatory, analgesic, secretomotor, secretolytic, galactagogue, eye lotion, and antioxidant remedy and integrator. Topically, fennel powder is used as a poultice for snake bites. In Asian cultures fennel was ingested to speed the elimination of poisons. As one of the ancient Saxon people's nine sacred herbs, fennel was credited with the power to cure. Fennel was also valued as a magic herb: in the Middle Ages it was draped over doorways on Midsummer's Eve to protect the household from evil spirits. Recently because of estragole carcinogenicity, fennel has been charged to be dangerous for humans especially if used as decoction for babies. But this allegation do not consider the remedy is prepared as a matrix of substances, and recent researches confirm that pure estragole is inactivated by many substance contained in the decoction.
Anti-Inflammatory Effects of Bangpungtongsung-San, a Traditional Herbal Prescription
Authors: Lee Chul Won , Kim Sang Chan , Kwak Tae Won , Lee Jong Rok , Jo Mi Jeong , Ahn Yong-Tae , Kim Jong Myoung , An Won G.
Published: July 2012

Bangpungtongsung-san (BPTS), a traditional oriental herbal prescription, is widely used for expelling wind, draining heat, and providing general improvement to the immune system. In this study, we investigated the effects of BPTS on induction of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), proinflammatory cytokines, nuclear factor-kappa B (NF-κB), and mitogen-activated protein kinases (MAPKs) in lipopolysaccharide- (LPS- ) stimulated Raw 264.7 cells, and on paw edema in rats. At concentrations of 0.5, 0.75, and 1 mg/mL, treatment with BPTS inhibited levels of expression of LPS-induced NF-κB and MAPKs (ERK, JNK, and p38) as well as production of proinflammatory mediators, such as nitric oxide (NO), prostaglandin E2(PGE2), tumor necrosis factor-α(TNF-α), and interleukin-6 (IL-6) by LPS. These results suggest that BPTS may exert anti-inflammatory effects via reduction of proinflammatory mediators, including NO, PGE2, TNF-α, and IL-6 through suppression of the signaling pathways of NF-κB and MAPKs in LPS-induced macrophages. In addition, using the carrageenan-induced paw edema assay, an antiedema effect of BPTS was observed in rats. These findings may provide scientific evidence validating the use of BPTS in treatment of patients with heat syndrome in Korean oriental medicine.
System-on-Package MHMIC Milimeter-Wave Frequency Synthesizer for 60 GHz WPANs
Authors: Spokoinyi Boris , Amaya Rony E. , Haroun Ibrahim , Wight Jim
Published: July 2012

We present a low-cost millimeter-wave frequency synthesizer with ultralow phase noise, implemented using system-on-package (SoP) techniques for high-data-rate wireless personal area network (WPAN) systems operating in the unlicensed 60 GHz ISM band (57–64 GHz). The phase noise specification of the proposed frequency synthesizer is derived for a worst case scenario of an 802.11.3c system, which uses a 64-QAM 512-carrier-OFDM modulation, and a data rate of 5.775 Gbps. Our design approach adopts commercial-of-the-shelf (COTS) components integrated in a low-cost alumina-based miniature hybrid microwave integrated circuit (MHMIC) package. The proposed design approach reduces not only the system cost and time-to-market, but also enhances the system performance in comparison with system-on-chip (SoC) designs. The synthesizer has measured phase noise of -111.5 dBc/Hz at 1 MHz offset and integrated phase noise of 2.8° (simulated: 2.5°) measured at 57.6 GHz with output power of +1 dBm.
Corn-Soybean Rotation Systems in the Mississippi Delta: Implications on Mycotoxin Contamination and Soil Populations ofAspergillus flavus
Authors: Abbas Hamed K. , Bellaloui Nacer , Zablotowicz Robert M. , Bruns H. Arnold , Gillen Anne M.
Published: July 2012

The effect of corn-soybean rotation on mycotoxin contamination in corn (Zea maysL.) and soybean (Glycine maxL. Merrill.) grains has not been fully evaluated. Therefore, this research investigated the effect of corn-soybean rotation on aflatoxin and fumonisin contamination in respective grains. The results showed that aflatoxin levels in soybean averaged 2.3,<0.5, 0.6, and 6.8 ng/g in 2005, 2006, 2007, and 2008, while corn aflatoxin levels were 16.7, 37.1, 2.4, and 54.8 ng/g, respectively.Aspergillus flavuscolonization was significantly greater (P≤0.05) in corn (log 1.9, 2.9, and 4.0 cfu/g) compared to soybean (<1.3, 2.6, and 2.7 cfu/g) in 2005, 2007, and 2008, respectively. AflatoxigenicA. flavusisolates were more frequent in corn than in soybean in all four years. Higher fumonisin levels were found in corn (0.2 to 3.6 μg/g) than in soybean (<0.2 μg/g). Rotating soybean with corn reduces the potential for aflatoxin contamination in corn by reducingA. flavuspropagules in soil and grain and reducing aflatoxigenicA. flavuscolonization. These results demonstrated that soybean grain is less susceptible to aflatoxin contamination compared to corn due to a lower level of colonization byA. flavuswith a greater occurrence of non-aflatoxigenic isolates.
Colonic Diffuse Large B-Cell Lymphoma in a Liver Transplant Patient with Historically Very Low Tacrolimus Levels
Authors: Moore Christopher M. , Lamzabi Ihab , Bartels Anne K. , Jakate Shriram , Van Thiel David H.
Published: July 2012

Posttransplant lymphoproliferative disorders (PTLDs) comprise a wide spectrum of hematologic malignancies that are found increasingly in orthotopic liver transplant (OLT) patients given the rising frequency of these surgeries and their long-term success. PTLDs are highly correlated with both the Epstein-Barr virus (EBV) infection and the degree of immunosuppression involved. Herein is reported a case of a 53-year-old male with successfully treated hepatitis C virus genotype 4 and hepatocellular carcinoma who underwent OLT and developed symptoms of weakness and poor appetite 4 years later while on tacrolimus 3 mg b.i.d. with historically very low plasma levels. He was found to be anemic and colonoscopy revealed a 4.5 cm cecal diffuse large B-cell lymphoma (DLBCL). Further workup revealed mesenteric lymph node enlargement consistent and nodal DLBCL dissemination. He was treated with cyclophosphamide-hydroxyldaunorubicin-oncovin-prednisone-rituximab (CHOP-R) chemotherapy and his tacrolimus dose was lowered. Additionally, he manifested PTLD-associated cryoglobulinemia leading to acute kidney injury. After a prolonged hospitalization he was discharged with close followup.
Near-Field Diffraction from a Binary Microaxicon
Authors: Kotlyar Victor V. , Stafeev Sergey S. , Skidanov Roman V. , Soifer Victor A.
Published: July 2012

We study binary axicons of period 4, 6, and 8 μm fabricated by photolithography with a 1 μm resolution, 500 nm depth, and 4 mm diameter. Near-field diffraction focal spots varying in diameter from 3.5λ to 4.5λ (for the axicon of period T=4 μm) and from 5λ to 8λ (for the axicon with T=8 μm) are experimentally found on the optical axis at a distance of up to 40 μm from the axicon for the wavelength λ=0.532 μm. The first focal spot is found at distance 2 μm (T=4 μm), with the period of the focal spots being 2 μm (T=4 μm) and 4 μm (T=8 μm). Diffraction of linearly polarized plane and diverging waves is simulated using FullWAVE (RSoft) and a proprietary program BOR-FDTD, which implement finite-difference schemes to solve three-dimensional Maxwell's equations in the Cartesian and cylindrical coordinates. The numerically simulated values for diameters of the near-field focal spots for the axicon of period T=4 μm are in good agreement with the experimental values.
The Influence of the Local Neighbourhood Environment on Walking Levels during the Walking for Wellbeing in the West Pedometer-Based Community Intervention
Authors: Robertson L. B. , Ward Thompson C. , Aspinall P. , Millington C. , McAdam C. , Mutrie N.
Published: July 2012

We investigated the relationship between walking levels and the local neighbourhood physical environment during the Walking for Wellbeing in the West (WWW) randomised pedometer-based community intervention. Walking activity was recorded as step counts at baseline (n=76), and at 3 months (n=57), 6 months (n=54), and 12 months (n=45) post-intervention. Objective physical environment data were obtained from GIS datasets and street surveys conducted using the SWAT audit tool. Sixty-nine environment variables were reduced to eight environment factors using principal axis factoring, and the relationship between environment factors and (i) step counts, and (ii) the change in step counts relative to baseline, was examined using hierarchical multiple linear regression, controlling for age, gender, income, and deprivation. Five environment factors were significant predictors of step counts, but none were significant predictors of the change in step counts relative to baseline. None of the demographic variables included in the analysis were significant predictors at any stage of the study. Total variance explained by the environment ranged from 6% (P<0.05) to 34% (P<0.01), with lowest levels during the initial stages of the study. The physical environment appears to have influenced walking levels during the WWW intervention, and to have contributed to the maintenance of walking levels post-intervention.
Mechanisms of BRCA1 Tumor Suppression
Authors: Silver Daniel P. , Livingston David M.
Published: July 2012

The p220 BRCA1 tumor suppressor protein has been implicated in multiple biochemical and biologic functions since its molecular cloning 18 years ago. Here, we discuss those functions most relevant for its tumor-suppressing activities with an emphasis on new findings. In particular, this review focuses on what is known of the activities of those BRCA1-binding partners that have tumor suppressor functions, on the reversion of mutant BRCA1 alleles concomitant with therapy resistance, on insights gained from studies of BRCA1 structure–function relationships, recent findings from animal models, and the potential role of BRCA1 in some nonhereditary tumors. From this information, a more detailed and refined picture of BRCA1 tumor suppression is beginning to emerge. Although key mysteries remain—such as why BRCA1 tumor suppression is focused on carcinomas of the breast and ovary—the pace of discovery is increasing.

Significance: BRCA1 functions as a clinically important classical tumor suppressor in hereditary breast and ovarian cancer; here, we review progress in understanding how BRCA1 operates to suppress tumor formation. Cancer Discov; 2(8); 679–84. ©2012 AACR.
Redox-Sensitive Sulfenic Acid Modification Regulates Surface Expression of the Cardiovascular Voltage-Gated Potassium Channel Kv1.5
Authors: Svoboda Laurie K. , Reddie Khalilah G. , Zhang Lian , Vesely Eileen D. , Williams Elizabeth S. , Schumacher Sarah M. , O'Connell Ryan P. , Shaw Robin , Day Sharlene M. , Anumonwo Justus M. , Carroll Kate S. , Martens Jeffrey R.
Published: July 2012

Rationale:

Kv1.5 (KCNA5) is expressed in the heart, where it underlies the I
Kur
current that controls atrial repolarization, and in the pulmonary vasculature, where it regulates vessel contractility in response to changes in oxygen tension. Atrial fibrillation and hypoxic pulmonary hypertension are characterized by downregulation of Kv1.5 protein expression, as well as with oxidative stress. Formation of sulfenic acid on cysteine residues of proteins is an important, dynamic mechanism for protein regulation under oxidative stress. Kv1.5 is widely reported to be redox-sensitive, and the channel possesses 6 potentially redox-sensitive intracellular cysteines. We therefore hypothesized that sulfenic acid modification of the channel itself may regulate Kv1.5 in response to oxidative stress.

Objective:

To investigate how oxidative stress, via redox-sensitive modification of the channel with sulfenic acid, regulates trafficking and expression of Kv1.5.

Methods and Results:

Labeling studies with the sulfenic acid–specific probe DAz and horseradish peroxidase–streptavidin Western blotting demonstrated a global increase in sulfenic acid–modified proteins in human patients with atrial fibrillation, as well as sulfenic acid modification to Kv1.5 in the heart. Further studies showed that Kv1.5 is modified with sulfenic acid on a single COOH-terminal cysteine (C581), and the level of sulfenic acid increases in response to oxidant exposure. Using live-cell immunofluorescence and whole-cell voltage-clamping, we found that modification of this cysteine is necessary and sufficient to reduce channel surface expression, promote its internalization, and block channel recycling back to the cell surface. Moreover, Western blotting demonstrated that sulfenic acid modification is a trigger for channel degradation under prolonged oxidative stress.

Conclusions:

Sulfenic acid modification to proteins, which is elevated in diseased human heart, regulates Kv1.5 channel surface expression and stability under oxidative stress and diverts channel from a recycling pathway to degradation. This provides a molecular mechanism linking oxidative stress and downregulation of channel expression observed in cardiovascular diseases.
Patterns and architecture of genomic islands in marine bacteria
Authors: Fernández-Gómez Beatriz , Fernàndez-Guerra Antonio , Casamayor Emilio O , González José M , Pedrós-Alió Carlos , Acinas Silvia G
Published: July 2012

Background

Genomic Islands (GIs) have key roles since they modulate the structure and size of bacterial genomes displaying a diverse set of laterally transferred genes. Despite their importance, GIs in marine bacterial genomes have not been explored systematically to uncover possible trends and to analyze their putative ecological significance.

Results

We carried out a comprehensive analysis of GIs in 70 selected marine bacterial genomes detected with IslandViewer to explore the distribution, patterns and functional gene content in these genomic regions. We detected 438 GIs containing a total of 8152 genes. GI number per genome was strongly and positively correlated with the total GI size. In 50% of the genomes analyzed the GIs accounted for approximately 3% of the genome length, with a maximum of 12%. Interestingly, we found transposases particularly enriched within Alphaproteobacteria GIs, and site-specific recombinases in Gammaproteobacteria GIs. We described specific Homologous Recombination GIs (HR-GIs) in several genera of marine Bacteroidetes and inShewanellastrains among others. In these HR-GIs, we recurrently found conserved genes such as the β-subunit of DNA-directed RNA polymerase, regulatory sigma factors, the elongation factor Tu and ribosomal protein genes typically associated with the core genome.

Conclusions

Our results indicate that horizontal gene transfer mediated by phages, plasmids and other mobile genetic elements, and HR by site-specific recombinases play important roles in the mobility of clusters of genes between taxa and within closely related genomes, modulating the flexible pool of the genome. Our findings suggest that GIs may increase bacterial fitness under environmental changing conditions by acquiring novel foreign genes and/or modifying gene transcription and/or transduction.
Global transcriptome analysis reveals distinct expression among duplicated genes during sorghum-Bipolaris sorghicolainteraction
Authors: Mizuno Hiroshi , Kawahigashi Hiroyuki , Kawahara Yoshihiro , Kanamori Hiroyuki , Ogata Jun , Minami Hiroshi , Itoh Takeshi , Matsumoto Takashi
Published: July 2012

Background

Sorghum (Sorghum bicolor L. Moench) is a rich source of natural phytochemicals. We performed massive parallel sequencing of mRNA to identify differentially expressed genes after sorghum BTx623 had been infected with Bipolaris sorghicola, a necrotrophic fungus causing a sorghum disease called target leaf spot.

Result

Seventy-six-base-pair reads from mRNAs of mock- or pathogen-infected leaves were sequenced. Unannotated transcripts were predicted on the basis of the piling-up of mapped short reads. Differentially expressed genes were identified statistically; particular genes in tandemly duplicated putative paralogs were highly upregulated. Pathogen infection activated the glyoxylate shunt in the TCA cycle; this changes the role of the TCA cycle from energy production to synthesis of cell components. The secondary metabolic pathways of phytoalexin synthesis and of sulfur-dependent detoxification were activated by upregulation of the genes encoding amino acid metabolizing enzymes located at the branch point between primary and secondary metabolism. Coordinated gene expression could guide the metabolic pathway for accumulation of the sorghum-specific phytochemicals 3-deoxyanthocyanidin and dhurrin. Key enzymes for synthesizing these sorghum-specific phytochemicals were not found in the corresponding region of the rice genome.

Conclusion

Pathogen infection dramatically changed the expression of particular paralogs that putatively encode enzymes involved in the sorghum-specific metabolic network.
Net financial benefits of averting HIV infections among people who inject drugs in Urumqi, Xinjiang, Peoples Republic of China (2005–2010)
Authors: Ni Mingjian J , Fu Li Ping , Chen Xue Ling , Hu Xiao Yuan , Wheeler Kim
Published: July 2012

Background

To quantify the contribution of locally implemented prevention programmes in contributing to reductions in treatment and care costs by averting HIV infections among those who inject drugs this study calculates net financial benefit of providing harm reduction programmes using information from services being implemented in Urumqi, Xinjiang Uighur Autonomous Region of China ( between 2005 and 2010).

Methods

Information was collected to assess cost of providing methadone treatment (MMT) and needle and syringe programmes (NSP). HIV incidence was estimated among people who inject drugs (PWID). HIV infections averted were calculated. Net benefit was assessed by estimating costs of providing prevention programmes and comparing these to the costs of providing care.

Results

An estimated 5678 (range 3982–7599) HIV infections were averted between 2005 and 2010 and the net financial benefit of providing harm reduction programmes compared to treatment and care costs for HIV infections averted was USD 4.383 million during the same time period.

Conclusion

These results demonstrate the net and accumulating benefit of investing in harm reduction programmes for PWID in Urumqi. The return on investment progressively increased during the time period studied and it is clear that these cost savings will continue to accrue with the continued implementation of HIV prevention interventions in the community that include harm reduction programmes targeted at PWID.
Computational challenges and human factors influencing the design and use of clinical research participant eligibility pre-screening tools
Authors: Pressler Taylor R , Yen Po-Yin , Ding Jing , Liu Jianhua , Embi Peter J , Payne Philip R O
Published: July 2012

Background

Clinical trials are the primary mechanism for advancing clinical care and evidenced-based practice, yet challenges with the recruitment of participants for such trials are widely recognized as a major barrier to these types of studies. Data warehouses (DW) store large amounts of heterogenous clinical data that can be used to enhance recruitment practices, but multiple challenges exist when using a data warehouse for such activities, due to the manner of collection, management, integration, analysis, and dissemination of the data. A critical step in leveraging the DW for recruitment purposes is being able to match trial eligibility criteria to discrete and semi-structured data types in the data warehouse, though trial eligibility criteria tend to be written without concern for their computability. We present the multi-modal evaluation of a web-based tool that can be used for pre-screening patients for clinical trial eligibility and assess the ability of this tool to be practically used for clinical research pre-screening and recruitment.

Methods

The study used a validation study, usability testing, and a heuristic evaluation to evaluate and characterize the operational characteristics of the software as well as human factors affecting its use.

Results

Clinical trials from the Division of Cardiology and the Department of Family Medicine were used for this multi-modal evaluation, which included a validation study, usability study, and a heuristic evaluation. From the results of the validation study, the software demonstrated a positive predictive value (PPV) of 54.12% and 0.7%, respectively, and a negative predictive value (NPV) of 73.3% and 87.5%, respectively, for two types of clinical trials. Heuristic principles concerning error prevention and documentation were characterized as the major usability issues during the heuristic evaluation.

Conclusions

This software is intended to provide an initial list of eligible patients to a clinical study coordinators, which provides a starting point for further eligibility screening by the coordinator. Because this software has a high “rule in” ability, meaning that it is able to remove patients who are not eligible for the study, the use of an automated tool built to leverage an existing enterprise DW can be beneficial to determining eligibility and facilitating clinical trial recruitment through pre-screening. While the results of this study are promising, further refinement and study of this and related approaches to automated eligibility screening, including comparison to other approaches and stakeholder perceptions, are needed and future studies are planned to address these needs.
Artemisinin resistance containment project in Thailand. (I): Implementation of electronic-based malaria information system for early case detection and individual case management in provinces along the Thai-Cambodian border
Authors: Khamsiriwatchara Amnat , Sudathip Prayuth , Sawang Surasak , Vijakadge Saowanit , Potithavoranan Thanapon , Sangvichean Aumnuyphan , Satimai Wichai , Delacollette Charles , Singhasivanon Pratap , Lawpoolsri Saranath , Kaewkungwal Jaranit
Published: July 2012

Background

The Bureau of Vector-borne Diseases, Ministry of Public Health, Thailand, has implemented an electronic Malaria Information System (eMIS) as part of a strategy to contain artemisinin resistance. The attempt corresponds to the WHO initiative, funded by the Bill & Melinda Gates Foundation, to contain anti-malarial drug resistance in Southeast Asia. The main objective of this study was to demonstrate the eMIS’ functionality and outputs after implementation for use in the Thailand artemisinin-resistance containment project.

Methods

The eMIS had been functioning since 2009 in seven Thai-Cambodian border provinces. The eMIS has covered 61 malaria posts/clinics, 27 Vector-borne Disease Units covering 12,508 hamlets at risk of malaria infections. The eMIS was designed as an evidence-based and near real-time system to capture data for early case detection, intensive case investigation, monitoring drug compliance and on/off-site tracking of malarial patients, as well as collecting data indicating potential drug resistance among patients. Data captured by the eMIS in 2008–2011 were extracted and presented.

Results

The core functionalities of the eMIS have been utilized by malaria staff at all levels, from local operational units to ministerial management. The eMIS case detection module suggested decreasing trends during 2009–2011; the number of malaria cases detected in the project areas over the years studied were 3818, 2695, and 2566, with sero-positive rates of 1.24, 0.98, and 1.16%, respectively. The eMIS case investigation module revealed different trends in weekly Plasmodium falciparum case numbers, when classified by responsible operational unit, local and migrant status, and case-detection type. It was shown that most Thai patients were infected within their own residential district, while migrants were infected either at their working village or from across the border. The data mapped in the system suggested that P. falciparum-infected cases and potential drug-resistant cases were scattered mostly along the border villages. The mobile technology application has detected different follow-up rates, with particularly low rates among seasonal and cross-border migrants.

Conclusion

The eMIS demonstrated that it could capture essential data from individual malaria cases at local operational units, while effectively being used for situation and trend analysis at upper-management levels. The system provides evidence-based information that could contribute to the control and containment of resistant parasites. Currently, the eMIS is expanding beyond the Thai-Cambodian project areas to the provinces that lie along the Thai-Myanmar border.
Silencing of Apoptosis-Inducing factor and poly (ADP-ribose) glycohydrolase reveals novel roles in breast cancer cell death after chemotherapy
Authors: Feng Xiaoxing , Zhou Yiran , Proctor Alicia M , Hopkins Mandi M , Liu Mengwei , Koh David W
Published: July 2012

Background

Cell death induced by poly(ADP-ribose) (PAR) and mediated by apoptosis-inducing factor (AIF) is well-characterized in models of ischemic tissue injury, but their roles in cancer cell death after chemotherapy are less understood.

Methods

Here we investigated the roles of PAR and AIF by RNA interference (RNAi) in MDA-MB-231 and MCF-7 breast adenocarcinoma cells after chemotherapy. Differences in effects were statistically tested by analysis-of-variance and unpaired student’s t-test.

Results

Silencing of AIF by RNAi led to decreased MDA-MB-231 and MCF-7 breast cancer cell death after chemotherapy, which demonstrates a critical role for AIF. RNAi silencing of PAR glycohydrolase (PARG), the primary enzyme that catalyzes the hydrolysis of PAR, led to increased PAR levels but decreased cell death. Further investigation into the possible role of PAR in apoptosis revealed decreased caspase-3/7/8/9 activity in PARG-null cells. Interestingly, the pharmacologic inhibition of caspase activity in PARG-silenced breast cancer cells led to increased cell death after chemotherapy, which indicates that an alternative cell death pathway is activated due to elevated PAR levels and caspase inhibition. AIF silencing in these cells led to profound protection from chemotherapy, which demonstrates that the increased cell death after PARG silencing and caspase inhibition was mediated by AIF.

Conclusions

The results show a role for AIF in breast cancer cell death after chemotherapy, the ability of PAR to regulate caspase activity, and the ability of AIF to substitute as a primary mediator of breast cancer cell death in the absence of caspases. Thus, the induction of cell death by PAR/AIF may represent a novel strategy to optimize the eradication of breast tumors by activating an alternative cell death pathway.
Neural Mobilization Reverses Behavioral and Cellular Changes That Characterize Neuropathic Pain in Rats
Authors: Santos Fabio M , Silva Joyce T , Giardini Aline C , Rocha Priscila A , Achermann Arnold PP , Alves Adilson S , Britto Luiz RG , Chacur Marucia
Published: July 2012

Background:

The neural mobilization technique is a noninvasive method that has proved clinically effective in reducing pain sensitivity and consequently in improving quality of life after neuropathic pain. The present study examined the effects of neural mobilization (NM) on pain sensitivity induced by chronic constriction injury (CCI) in rats. The CCI was performed on adult male rats, submitted thereafter to 10 sessions of NM, each other day, starting 14 days after the CCI injury. Over the treatment period, animals were evaluated for nociception using behavioral tests, such as tests for allodynia and thermal and mechanical hyperalgesia. At the end of the sessions, the dorsal root ganglion (DRG) and spinal cord were analyzed using immunohistochemistry and Western blot assays for neural growth factor (NGF) and glial fibrillary acidic protein (GFAP).

Results:

The NM treatment induced an early reduction (from the second session) of the hyperalgesia and allodynia in CCI-injured rats, which persisted until the end of the treatment. On the other hand, only after the 4th session we observed a blockade of thermal sensitivity. Regarding cellular changes, we observed a decrease of GFAP and NGF expression after NM in the ipsilateral DRG (68% and 111%, respectively) and the decrease of only GFAP expression after NM in the lumbar spinal cord (L3-L6) (108%).

Conclusions:

These data provide evidence that NM treatment reverses pain symptoms in CCI-injured rats and suggest the involvement of glial cells and NGF in such an effect.
Constitutive phosphorylation of the mTORC2/Akt/4E-BP1 pathway in newly derived canine hemangiosarcoma cell lines
Authors: Murai Atsuko , Asa Samah Abou , Kodama Atsushi , Hirata Akihiro , Yanai Tokuma , Sakai Hiroki
Published: July 2012

Background

Canine hemangiosarcoma (HSA) is a malignant tumor with poor long-term prognosis due to development of metastasis despite aggressive treatment. The phosphatidyl-inositol-3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is involved in its endothelial pathologies; however, it remains unknown how this pathway plays a role in canine HSA. Here, we characterized new canine HSA cell lines derived from nude mice-xenografted canine HSAs and investigated the deregulation of the signaling pathways in these cell lines.

Results

Seven canine HSA cell lines were established from 3 xenograft canine HSAs and showed characteristics of endothelial cells (ECs), that is, uptake of acetylated low-density lipoprotein and expression of canine-specific CD31 mRNA. They showed varied morphologies and mRNA expression levels for VEGF-A, bFGF, HGF, IGF-I, EGF, PDGF-B, and their receptors. Cell proliferation was stimulated by these growth factors and fetal bovine serum (FBS) in 1 cell line and by FBS alone in 3 cell lines. However, cell proliferation was not stimulated by growth factors and FBS in the remaining 3 cell lines. Phosphorylated p44/42 Erk1/2 was increased by FBS stimulation in 4 cell lines. In contrast, phosphorylation of Akt at Ser473, mTOR complex 1 (mTORC1) at Ser2448, and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) at Ser65 was high in serum-starved condition and not altered by FBS stimulation in 6 cell lines, despite increased phosphorylation of these residues in normal canine ECs. This suggested that the mTORC2/Akt/4E-BP1 pathway was constitutively activated in these 6 canine HSA cell lines. After cell inoculation into nude mice, canine HSA tumors were formed from 4 cell lines and showed Akt and 4E-BP1 phosphorylation identical to the parental cell lines.

Conclusions

Our findings suggest that the present cell lines may be useful tools for investigating the role of the mTORC2/Akt/4E-BP1 pathway in canine HSA formation both in vivo and in vitro.
The saw-tooth sign as a clinical clue for intrathoracic central airway obstruction
Authors: Nakajima Akira , Saraya Takeshi , Takata Saori , Ishii Haruyuki , Nakazato Yoko , Takei Hidefumi , Takizawa Hajime , Goto Hajime
Published: July 2012

Background

The saw-tooth sign was first described by Sanders et al in patients with obstructive sleep apnea syndrome as one cause of extrathoracic central airway obstruction. The mechanism of the saw-tooth sign has not been conclusively clarified. The sign has also been described in various extrathoracic central airway diseases, such as in burn victims with thermal injury to the upper airways, Parkinson’s disease, tracheobronchomalacia, laryngeal dyskinesia, and pedunculated tumors of the upper airway.

Case presentation

A 61-year-old man was referred to our hospital with a two-month history of persistent dry cough and dyspnea. He was diagnosed with lung cancer located in an intrathoracic central airway, which was accompanied by the saw-tooth sign on flow-volume loops. This peculiar sign repeatedly improved and deteriorated, in accordance with the waxing and waning of central airway stenosis by anti-cancer treatments.

Conclusion

This report suggests that the so-called saw-tooth sign may be found even in intrathoracic central airway obstruction due to lung cancer.
Genome-wide DNA methylation profiling of non-small cell lung carcinomas
Authors: Carvalho Rejane Hughes , Haberle Vanja , Hou Jun , van Gent Teus , Thongjuea Supat , van IJcken Wilfred , Kockx Christel , Brouwer Rutger , Rijkers Erikjan , Sieuwerts Anieta , Foekens John , van Vroonhoven Mirjam , Aerts Joachim , Grosveld Frank , Lenhard Boris , Philipsen Sjaak
Published: July 2012

Background

Non-small cell lung carcinoma (NSCLC) is a complex malignancy that owing to its heterogeneity and poor prognosis poses many challenges to diagnosis, prognosis and patient treatment. DNA methylation is an important mechanism of epigenetic regulation involved in normal development and cancer. It is a very stable and specific modification and therefore in principle a very suitable marker for epigenetic phenotyping of tumors. Here we present a genome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, where we combine MethylCap and next generation sequencing (MethylCap-seq) to provide comprehensive DNA methylation maps of the tumor and paired lung samples. The MethylCap-seq data were validated by bisulfite sequencing and methyl-specific polymerase chain reaction of selected regions.

Results

Analysis of the MethylCap-seq data revealed a strong positive correlation between replicate experiments and between paired tumor/lung samples. We identified 57 differentially methylated regions (DMRs) present in all NSCLC tumors analyzed by MethylCap-seq. While hypomethylated DMRs did not correlate to any particular functional category of genes, the hypermethylated DMRs were strongly associated with genes encoding transcriptional regulators. Furthermore, subtelomeric regions and satellite repeats were hypomethylated in the NSCLC samples. We also identified DMRs that were specific to two of the major subtypes of NSCLC, adenocarcinomas and squamous cell carcinomas.

Conclusions

Collectively, we provide a resource containing genome-wide DNA methylation maps of NSCLC and their paired lung tissues, and comprehensive lists of known and novel DMRs and associated genes in NSCLC.
Contrast-enhanced peripheral MRA: technique and contrast agents
Authors: Nielsen Yousef W , Thomsen Henrik S
Published: July 2012

In the last decade contrast-enhanced magnetic resonance angiography (CE-MRA) has gained wide acceptance as a valuable tool in the diagnostic work-up of patients with peripheral arterial disease.

This review presents current concepts in peripheral CE-MRA with emphasis on MRI technique and contrast agents.

Peripheral CE-MRA is defined as an MR angiogram of the arteries from the aortic bifurcation to the feet. Advantages of CE-MRA include minimal invasiveness and lack of ionizing radiation. The basic technique employed for peripheral CE-MRA is the bolus-chase method. With this method a paramagnetic MRI contrast agent is injected intravenously and T1-weighted images are acquired in the subsequent arterial first-pass phase. In order to achieve high quality MR angiograms without interfering venous contamination or artifacts, a number of factors need to be taken into account. This includes magnetic field strength of the MRI system, receiver coil configuration, use of parallel imaging, contrast bolus timing technique, and k-space filling strategies. Furthermore, it is possible to optimize peripheral CE-MRA using venous compression techniques, hybrid scan protocols, time-resolved imaging, and steady-state MRA.

Gadolinium(Gd)-based contrast agents are used for CE-MRA of the peripheral arteries. Extracellular Gd agents have a pharmacokinetic profile similar to iodinated contrast media. Accordingly, these agents are employed for first-pass MRA. Blood-pool Gd-based agents are characterized by prolonged intravascular stay, due to macromolecular structure or protein binding. These agents can be used for first-pass, as well as steady-state MRA. Some Gd-based contrast agents with low thermodynamic stability have been linked to development of nephrogenic systemic fibrosis in patients with severe renal insufficiency.

Using optimized technique and a stable MRI contrast agent, peripheral CE-MRA is a safe procedure with diagnostic accuracy close to that of conventional catheter X-ray angiography.
Sclerosing angiomatoid nodular transformation of the spleen: clinical and radiologic characteristics
Authors: Kim Hyoung Jung , Kim Kyoung Won , Yu Eun Sil , Byun Jae Ho , Lee Seung Soo , Kim Jin Hee , Lee Jong Seok
Published: July 2012

Background

Sclerosing angiomatoid nodular transformation (SANT) is a rare benign primary vascular lesion of the spleen. Although there have been many reports about the pathology of SANTs of the spleen, there have been no comprehensive descriptions of the imaging findings of SANTs of the spleen.

Purpose

To determine the clinical characteristics and imaging findings of SANTs of the spleen.

Material and Methods

We retrospectively evaluated seven patients with pathologically confirmed SANT, who underwent CT ( n = 7), MRI ( n = 4), ultrasonography ( n = 4), and PET/CT ( n = 3). Follow-up CT examinations were obtained in five patients. Clinical characteristics such as symptoms and concurrent disease were assessed. CT and MRI findings were evaluated by two radiologists, including the number, border, signal intensity, enhancement pattern, hemorrhage, and cystic change or necrosis. The longest diameter of each tumor was measured on CT. Echogenicity on ultrasonography and standardized uptake value on PET/CT were also evaluated.

Results

No specific symptom was associated with SANT. Two patients had a history of malignancy, one with cervical cancer and the other with early gastric cancer. Tumor growth was observed in four of five patients. On CT, all seven SANTs appeared as single, well-demarcated masses. CT showed a heterogeneous enhancement in seven patients. MRI showed centripetal progressive enhancement and absence of cystic change or necrosis in four patients, with three of these patients showing evidence of old hemorrhage. Ultrasonography showed heterogeneous hypoechoic mass in four patients. PET/CT showed increased standardized uptake value, ranging from 2.0 to 2.8, in three patients.

Conclusion

SANT of the spleen is a single, well-demarcated solid mass without cystic change or necrosis. Increased FDG activity and tumor growth on follow-up imaging are common.