bluuebunny/crossref_metadata_2025 huggingface dataset:
AFM STUDY OF THE EVOLUTION OF DOUBLE LAYER ON SiO2 SURFACE AND SELF-ASSEMBLY MONOLAYER INDUCED BY THE POLARIZATION WITH DC VOLTAGES
Authors: TIAN TIAN , ZHANG YONG , WANG HAITAO , HUANG NINGPING , XIAO ZHONGDANG
Published: March 2009

AFM was used to study the evolution of double layer on SiO 2 surface and self-assembly monolayer induced by the polarization with DC voltages. Approach force curves were recorded when external DC voltages were applied between solution and SiO 2 or aminopropyltriethoxysilane (APTES) modified SiO 2 surfaces in electrolyte solution. The results showed that the reversing of tip–surface interaction forces between attraction and repulsion could take place only by adjusting DC voltages. It is very useful for biotechnology because the adsorption of biomolecules could be controllable by DC voltages. A model was proposed to explain the behavior of double layer under DC voltages.
Equally Potent Inhibition of c-Src and Abl by Compounds that Recognize Inactive Kinase Conformations
Authors: Seeliger Markus A. , Ranjitkar Pratistha , Kasap Corynn , Shan Yibing , Shaw David E. , Shah Neil P. , Kuriyan John , Maly Dustin J.
Published: March 2009

Imatinib is an inhibitor of the Abl tyrosine kinase domain that is effective in the treatment of chronic myelogenic leukemia. Although imatinib binds tightly to the Abl kinase domain, its affinity for the closely related kinase domain of c-Src is at least 2,000-fold lower. Imatinib recognition requires a specific inactive conformation of the kinase domain, in which a conserved Asp-Phe-Gly (DFG) motif is flipped with respect to the active conformation. The inability of c-Src to readily adopt this flipped DFG conformation was thought to underlie the selectivity of imatinib for Abl over c-Src. Here, we present a series of inhibitors (DSA compounds) that are based on the core scaffold of imatinib but which bind with equally high potency to c-Src and Abl. The DSA compounds bind to c-Src in the DFG-flipped conformation, as confirmed by crystal structures and kinetic analysis. The origin of the high affinity of these compounds for c-Src is suggested by the fact that they also inhibit clinically relevant Abl variants bearing mutations in a structural element, the P-loop, that normally interacts with the phosphate groups of ATP but is folded over a substructure of imatinib in Abl. Importantly, several of the DSA compounds block the growth of Ba/F3 cells harboring imatinib-resistant BCR-ABL mutants, including the Thr315Ile “gatekeeper” mutation, but do not suppress the growth of parental Ba/F3 cells. [Cancer Res 2009;69(6):2384–92
A Phase II Study of Celecoxib in Combination with Paclitaxel, Carboplatin, and Radiotherapy for Patients with Inoperable Stage IIIA/B Non–Small Cell Lung Cancer
Authors: Mutter Robert , Lu Bo , Carbone David P. , Csiki Ildiko , Moretti Luigi , Johnson David H. , Morrow Jason D. , Sandler Alan B. , Shyr Yu , Ye Fei , Choy Hak
Published: March 2009

Purpose: Cyclooxygenase (COX)-2 up-regulation plays an important role in the pathogenesis of lung cancer. Selective COX-2 inhibitors have promoted chemosensitivity and radiosensitivity of tumor cells in preclinical trials.

Experimental Design: In a single-institution phase II study, we sought to determine the effectiveness of concurrent chemoradiation given with celecoxib and examined biomarkers to predict response to COX-2 inhibition.

Results: Seventeen patients with stage IIIA or IIIB non–small cell lung cancer (NSCLC) were enrolled in the study. All received 400 mg celecoxib twice daily continuously while on trial in addition to concurrent chemoradiation therapy with paclitaxel and carboplatin. Celecoxib was continued until disease progression. The overall objective response rate was 42.9%, and the median overall survival time was 203 days. In contrast to nonresponders, those patients with complete and partial responses had a significant decrease in the level of urinary 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of prostaglandin E2, after 1 week of celecoxib administration. Patients with very high levels of PGE-M before initiation of therapy also responded poorly to therapy. Serum vascular endothelial growth factor levels did not predict response or survival.

Conclusion: The trial was terminated because it did not meet the predetermined goal of 80% overall response rate. In unselected patients, the addition of celecoxib to concurrent chemoradiotherapy with inoperable stage IIIA/B NSCLC does not improve survival. Urinary PGE-M is a promising biomarker for predicting response to COX-2 inhibition in NSCLC.
Interaction between BCL2 and Interleukin-10 Gene Polymorphisms Alter Outcomes of Diffuse Large B-Cell Lymphoma following Rituximab Plus CHOP Chemotherapy
Authors: Park Yeon Hee , Sohn Sang Kyun , Kim Jong Gwang , Lee Myung-Hoon , Song Hong Suk , Kim Min Kyoung , Jung Joo Seop , Lee Je-Joong , Kim Hyeoung Joon , Kim Dong Hwan
Published: March 2009

Purpose: Rituximab may overcome bcl-2-mediated chemoresistance through the inhibition of interleukin-10 (IL-10)-mediated loops, thus down-regulating bcl-2 expression. We examined the effects of genetic variation in BCL2/IL10 gene loops on treatment outcomes of diffuse large B-cell lymphoma when treated with either CHOP or rituximab plus CHOP (R-CHOP) chemotherapy.

Experimental Design: Four genotypes were tested including BCL2 -938 C>A (rs2279115), +21 A>G (rs1801018), IL10 -819 T>C (rs1800871), and -592 A>C (rs1800872) in patients receiving either R-CHOP (n = 125) or CHOP (n = 110).

Results: IL10 SNPs, -819 TT/TC or -592 AA/AC genotypes correlated with improved CHOP response rates (P = 0.04). Neither polymorphism separately influenced the failure-free survival (FFS) or overall survival in patients, but the IL10 haplotype was associated with treatment outcomes after R-CHOP for FFS (P = 0.03) or progression (P = 0.007), whereas the -938 AA BCL2 genotype significantly affected overall survival (P = 0.04). An interactive effect between BCL2 and IL10 SNPs was significant in the group with both -938 AA BCL2 genotype and 1 to 2 copies of CC IL10 haplotype. This group showed a better FFS (P = 0.01) and a lower probability of progression (P = 0.004) compared with other genotype groups when treated with R-CHOP chemotherapy.

Conclusions: These data indicated that R-CHOP chemotherapy resistance in diffuse large B-cell lymphoma may involve interactions between the BCL2 and IL10 genes.
Novel Dithiolethione-Modified Nonsteroidal Anti-Inflammatory Drugs in Human Hepatoma HepG2 and Colon LS180 Cells
Authors: Bass Sara E. , Sienkiewicz Pawel , MacDonald Christopher J. , Cheng Robert Y.S. , Sparatore Anna , Del Soldato Piero , Roberts David D. , Moody Terry W. , Wink David A. , Yeh Grace Chao
Published: March 2009

Purpose: Nonsteroidal anti-inflammatory drugs (NSAID) are promising chemopreventive agents against colon and other cancers. However, the molecular basis mediated by NSAIDs for chemoprevention has not been fully elucidated. Environmental carcinogens induce DNA mutation and cellular transformation; therefore, we examined the effect of NSAIDs on carcinogenesis mediated by the aryl hydrocarbon receptor signaling pathway. In this study, we investigated the activities of a new class of NSAIDs containing dithiolethione moieties (S-NSAID) on both arms of carcinogenesis.

Experimental Design: We investigated the effects of the S-NSAIDs, S-diclofenac and S-sulindac, on carcinogen activation and detoxification mechanisms in human hepatoma HepG2 and human colonic adenocarcinoma LS180 cells.

Results: We found that S-diclofenac and S-sulindac inhibited the activity and expression of the carcinogen activating enzymes, cytochromes P-450 (CYP) CYP1A1, CYP1B1, and CYP1A2. Inhibition was mediated by transcriptional regulation of the aryl hydrocarbon receptor (AhR) pathway. The S-NSAIDs down-regulated carcinogen-induced expression of CYP1A1 heterogeneous nuclear RNA, a measure of transcription rate. Both compounds blocked carcinogen-activated AhR from binding to the xenobiotic responsive element as shown by chromatin immunoprecipitation. S-diclofenac and S-sulindac inhibited carcinogen-induced CYP enzyme activity through direct inhibition as well as through decreased transcriptional activation of the AhR. S-sulindac induced expression of several carcinogen detoxification enzymes of the glutathione cycle including glutathione S-transferase A2, glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione reductase.

Conclusions: These results indicate that S-diclofenac and S-sulindac may serve as effective chemoprevention agents by favorably balancing the equation of carcinogen activation and detoxification mechanisms.
Quantitative Ultrasound Characterization of Responses to Radiotherapy in Cancer Mouse Models
Authors: Vlad Roxana M. , Brand Sebastian , Giles Anoja , Kolios Michael C. , Czarnota Gregory J.
Published: March 2009

Purpose: Currently, no imaging modality is used routinely to assess tumor responses to radiotherapy within hours to days after the delivery of treatment. In this study, we show the application of quantitative ultrasound methods to characterize tumor responses to cancer radiotherapy in vivo, as early as 24 hours after treatment administration.

Experimental Design: Three mouse models of head and neck cancer were exposed to radiation doses of 0, 2, 4, and 8 Gray. Data were collected with an ultrasound scanner using frequencies of 10 to 30 MHz. Ultrasound estimates calculated from normalized power spectra and parametric images (spatial maps of local estimates of ultrasound parameters) were used as indicators of response.

Results: Two of the mouse models (FaDu and C666-1) exhibited large hyperechoic regions at 24 hours after radiotherapy. The ultrasound integrated backscatter increased by 6.5 to 8.2 dB (P < 0.001) and the spectral slopes increased from 0.77 to 0.90 dB/MHz for the C666-1 tumors and from 0.54 to 0.78 dB/MHz for the FaDu tumors (P < 0.05), in these regions compared with preirradiated tumors. The hyperechoic regions in the ultrasound images corresponded in histology to areas of cell death. Parametric images could discern the tumor regions that responded to treatment. The other cancer mouse model (Hep-2) was resistant to radiotherapy.

Conclusions: The results indicate that cell structural changes after radiotherapy have a significant influence on ultrasound spectral parameters. This provides a foundation for future investigations regarding the use of ultrasound in cancer patients to individualize treatments noninvasively based on their responses to specific interventions.
Apo2L/TRAIL Inhibits Tumor Growth and Bone Destruction in a Murine Model of Multiple Myeloma
Authors: Labrinidis Agatha , Diamond Peter , Martin Sally , Hay Shelley , Liapis Vasilios , Zinonos Irene , Sims Natalie A. , Atkins Gerald J. , Vincent Cristina , Ponomarev Vladimir , Findlay David M. , Zannettino Andrew C.W. , Evdokiou Andreas
Published: March 2009

Purpose: Multiple myeloma is an incurable disease, for which the development of new therapeutic approaches is required. Here, we report on the efficacy of recombinant soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to inhibit tumor progression and bone destruction in a xenogeneic model of human multiple myeloma.

Experimental Design: We established a mouse model of myeloma, in which Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells, tagged with a triple reporter gene construct (NES-HSV-TK/GFP/Luc), were transplanted directly into the tibial marrow cavity of nude mice. Tumor burden was monitored progressively by bioluminescence imaging and the development of myeloma-induced osteolysis was measured using high resolution in vivo micro-computed tomography.

Results: Tumor burden increased progressively in the tibial marrow cavity of mice transplanted with Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells associated with extensive osteolysis directly in the area of cancer cell transplantation. Treatment of mice with recombinant soluble Apo2L/TRAIL reduced myeloma burden in the bone marrow cavity and significantly protected against myeloma-induced osteolysis. The protective effects of Apo2L/TRAIL treatment on bone were mediated by the direct apoptotic actions of Apo2L/TRAIL on myeloma cells within the bone microenvironment.

Conclusions: This is the first in vivo study that investigates the efficacy of recombinant Apo2L/TRAIL on myeloma burden within the bone microenvironment and associated myeloma-induced bone destruction. Our findings that recombinant soluble Apo2L/TRAIL reduces myeloma burden within the bone microenvironment and protects the bone from myeloma-induced bone destruction argue against an inhibitory role of osteoprotegerin in Apo2L/TRAIL-induced apoptosis in vivo and highlight the need to clinically evaluate Apo2L/TRAIL in patients with multiple myeloma.
Single-Molecule Detection of Epidermal Growth Factor Receptor Mutations in Plasma by Microfluidics Digital PCR in Non–Small Cell Lung Cancer Patients
Authors: Yung Tony K.F. , Chan K.C. Allen , Mok Tony S.K. , Tong Joanna , To Ka-Fai , Lo Y.M. Dennis
Published: March 2009

Purpose: We aim to develop a digital PCR-based method for the quantitative detection of the two common epidermal growth factor receptor (EGFR) mutations (in-frame deletion at exon 19 and L858R at exon 21) in the plasma and tumor tissues of patients suffering from non-small cell lung cancers. These two mutations account for >85% of clinically important EGFR mutations associated with responsiveness to tyrosine kinase inhibitors.

Experimental Design: DNA samples were analyzed using a microfluidics system that simultaneously performed 9,180 PCRs at nanoliter scale. A single-mutant DNA molecule in a clinical specimen could be detected and the quantities of mutant and wild-type sequences were precisely determined.

Results: Exon 19 deletion and L858R mutation were detectable in 6 (17%) and 9 (26%) of 35 pretreatment plasma samples, respectively. When compared with the sequencing results of the tumor samples, the sensitivity and specificity of plasma EGFR mutation analysis were 92% and 100%, respectively. The plasma concentration of the mutant sequences correlated well with the clinical response. Decreased concentration was observed in all patients with partial or complete clinical remission, whereas persistence of mutation was observed in a patient with cancer progression. In one patient, tyrosine kinase inhibitor was stopped after an initial response and the tumor-associated EGFR mutation reemerged 4 weeks after stopping treatment.

Conclusion: The sensitive detection and accurate quantification of low abundance EGFR mutations in tumor tissues and plasma by microfluidics digital PCR would be useful for predicting treatment response, monitoring disease progression and early detection of treatment failure associated with acquired drug resistance.
NY-ESO-1 DNA Vaccine Induces T-Cell Responses That Are Suppressed by Regulatory T Cells
Authors: Gnjatic Sacha , Altorki Nasser K. , Tang Derek Ng , Tu Shi-Ming , Kundra Vikas , Ritter Gerd , Old Lloyd J. , Logothetis Christopher J. , Sharma Padmanee
Published: March 2009

Purpose: Different vaccination strategies against the NY-ESO-1 antigen have been employed in an attempt to induce antitumor immune responses. Antigen-specific effector T-cell responses have been reported in a subset of vaccinated patients; however, these responses have not consistently correlated with disease regression. Here, we report for the first time clinical and immune responses generated by the NY-ESO-1 DNA vaccine administered by particle-mediated epidermal delivery to cancer patients.

Experimental Design: Eligible patients received treatment with the NY-ESO-1 DNA vaccine. Clinical outcomes and immune responses were assessed.

Results: The NY-ESO-1 DNA vaccine was safely administered and induced both antigen-specific effector CD4 and/or CD8 T-cell responses in 93% (14 of 15) of patients who did not have detectable pre-vaccine immune responses. Despite the induction of antigen-specific T-cell responses, clinical outcomes consisted predominantly of progressive disease. Detectable effector T-cell responses were inconsistent and did not persist in all patients after completion of the scheduled vaccinations. However, high-avidity CD4 T-cell responses that were either undetectable pre-vaccine or found to be diminished at a later time during the clinical trial were detected in certain patients' samples after in vitro depletion of regulatory T cells.

Conclusions: Regulatory T cells play a role in diminishing vaccine-induced antigen-specific effector T-cell responses in cancer patients. The NY-ESO-1 DNA vaccine represents a feasible immunotherapeutic strategy to induce antigen-specific T-cell responses. Counteracting regulatory T-cell activity before vaccination may lead to prolonged effector T-cell responses and possibly antitumor responses in cancer patients.
A Six-Nucleotide Insertion-Deletion Polymorphism in the CASP8 Promoter Associated with Risk and Progression of Bladder Cancer
Authors: Wang Meilin , Zhang Zhizhong , Tian Yuanyuan , Shao Jianfeng , Zhang Zhengdong
Published: March 2009

Purpose: Caspase-8 (CASP8) is a key regulator of apoptosis or programmed cell death, an essential defense mechanism against hyperproliferation and malignancy. We hypothesized that the variants in the CASP8 gene are associated with risk of bladder cancer.

Experimental Design: In a hospital-based case-control study of 365 case patients with newly diagnosed bladder transitional cell carcinoma and 368 cancer-free controls frequency-matched by age and sex, we genotyped the functional -652 6N ins/del polymorphism (rs3834129) in the promoter of CASP8 and assessed its associations with risk of bladder cancer and interaction with tobacco smoking.

Results: A significant decreased risk of bladder cancer was found for the CASP8 -652 6N ins/del (adjusted odds ratio, 0.72; 95% confidence interval, 0.53-0.99) and del/del (odds ratio, 0.37; 95% confidence interval, 0.18-0.77) genotypes. Furthermore, a significant additive interaction between CASP8 polymorphism and tobacco smoking on bladder cancer risk was observed.

Conclusions: These results suggested that the CASP8 -652 6N ins/del polymorphism is involved in etiology of bladder cancer and thus may be a marker for genetic susceptibility to bladder cancer in Chinese populations. Larger studies are warranted to validate our findings.
Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy
Authors: Yang Jinming , Zaja-Milatovic Snjezana , Thu Yee-Mon , Lee Francis , Smykla Richard , Richmond Ann
Published: March 2009

The BRAFV600E mutation is common in human melanoma. This mutation enhances IκB kinase (IKK)/nuclear factor-κB (NF-κB) and extracellular signal-regulated kinase/activator protein signaling cascades. In this study, we evaluated the efficacy of targeting either B-Raf or IKKβ in combination with the DNA alkylating agent temozolomide for treatment of advanced metastatic melanoma. Xenografts of Hs294T human metastatic melanoma cells exhibiting the BRAFV600E mutation were treated with inhibitors of IKKβ (BMS-345541), B-Raf (BAY 54-9085), and/or temozolomide. Drug response was mechanistically analyzed in vitro and in vivo. In this study, we determined that the antitumor activity of all three drugs depends on inhibition of NF-κB. BMS-345541 inhibits IKKβ-mediated phosphorylation of IκBα and thus blocks the nuclear localization of NF-κB, whereas BAY 54-9085 inhibits activation of NF-κB through a mechanism that does not involve stabilization of IκBα. Moreover, BMS-345541, but not BAY 54-9085, activates the death pathways of p53 and c-Jun-NH2-kinase, contributing to the killing of melanoma cells. Temozolomide inhibits both NF-κB and extracellular signal-regulated kinase activity, conferring effective in vivo antitumor activity. Thus, temozolomide, but not BAY 54-9085, has a synergistic in vivo antitumor effect with BMS-345541. We conclude that the efficacy of antimelanoma therapy depends on inhibition of expression of antiapoptotic genes transcriptionally regulated by NF-κB. In contrast, drug targeting of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway alone in melanoma cells is ineffective for melanoma therapy in cases where NF-κB is not also targeted. [Mol Cancer Ther 2009;8(3):OF636–12]
Aldehyde Dehydrogenase 1 Is a Tumor Stem Cell-Associated Marker in Lung Cancer
Authors: Jiang Feng , Qiu Qi , Khanna Abha , Todd Nevins W. , Deepak Janaki , Xing Lingxiao , Wang Huijun , Liu Zhenqiu , Su Yun , Stass Sanford A. , Katz Ruth L.
Published: March 2009

Tumor contains small population of cancer stem cells (CSC) that are responsible for its maintenance and relapse. Analysis of these CSCs may lead to effective prognostic and therapeutic strategies for the treatment of cancer patients. We report here the identification of CSCs from human lung cancer cells using Aldefluor assay followed by fluorescence-activated cell sorting analysis. Isolated cancer cells with relatively high aldehyde dehydrogenase 1 (ALDH1) activity display in vitro features of CSCs, including capacities for proliferation, self-renewal, and differentiation, resistance to chemotherapy, and expressing CSC surface marker CD133. In vivo experiments show that the ALDH1-positive cells could generate tumors that recapitulate the heterogeneity of the parental cancer cells. Immunohistochemical analysis of 303 clinical specimens from three independent cohorts of lung cancer patients and controls show that expression of ALDH1 is positively correlated with the stage and grade of lung tumors and related to a poor prognosis for the patients with early-stage lung cancer. ALDH1 is therefore a lung tumor stem cell-associated marker. These findings offer an important new tool for the study of lung CSCs and provide a potential prognostic factor and therapeutic target for treatment of the patients with lung cancer. (Mol Cancer Res 2009;7(3):330–8)
Establishment of a Predominantly African-American Cohort for the Study of Alzheimer’s Disease
Authors: Bachman David L. , Stuckey Marilyn , Ebeling Myla , Wagner Mark T. , Evans W. James , Hirth Victor , Walker Aljoeson , Memon Mohammed , Joglekar Rajiv , Faison Warachal , Mintzer Jacobo E.
Published: March 2009

Background/Aims: The recruitment of culturally diverse subject populations into research studies, particularly African-Americans (AA), has been the focus of intense interest by many groups. Methods: In this paper, we present the methodology utilized to create a predominantly AA cohort for the longitudinal study of risk factors in Alzheimer’s disease (AD). The underlying strategy was that of identifying geographically diverse clinical venues within South Carolina (SC) where large numbers of AA patients already come to seek medical care. Results: This strategy was successful, although recruitment rates for AA subjects (43.4%) still fell below those for white subjects (70.3%; p = 0.0025). Subject characteristics of AA subjects that chose to enroll were not substantially different from those that declined to participate. The demographic characteristics of this cohort were largely similar to those of the SC Alzheimer Disease Registry, a population-based database. The problems of standardization of subject recruitment and assessment across diverse clinical venues are also addressed. Conclusion: The utilization of geographically diverse sites for research recruitment where minorities already receive medical care is one practical solution to the problem of minority participation in research. Multi-site recruitment to improve minority recruitment can be accomplished with acceptable standardization and inter-rater reliability.
Tropical Cyclone Activity in the Fiji Region: Spatial Patterns and Relationship to Large-Scale Circulation
Authors: Chand Savin S. , Walsh Kevin J. E.
Published: March 2009

This study examines the variations in tropical cyclone (TC) genesis positions and their subsequent tracks for different phases of the El Niño–Southern Oscillation (ENSO) phenomenon in the Fiji, Samoa, and Tonga region (FST region) using Joint Typhoon Warning Center best-track data. Over the 36-yr period from 1970/71 to 2005/06, 122 cyclones are observed in the FST region. A large spread in the genesis positions is noted. During El Niño years, genesis is enhanced east of the date line, extending from north of Fiji to over Samoa, with the highest density centered around 10°S, 180°. During neutral years, maximum genesis occurs immediately north of Fiji with enhanced genesis south of Samoa. In La Niña years, there are fewer cyclones forming in the region than during El Niño and neutral years. During La Niña years, the genesis positions are displaced poleward of 12°S, with maximum density centered around 15°S, 170°E and south of Fiji. The cyclone tracks over the FST region are also investigated using cluster analysis. Tracks during the period 1970/71–2005/06 are conveniently described using three separate clusters, with distinct characteristics associated with different ENSO phases. Finally, the role of large-scale environmental factors affecting interannual variability of TC genesis positions and their subsequent tracks in the FST region are investigated. Favorable genesis positions are observed where large-scale environments have the following seasonal average thresholds: (i) 850-hPa cyclonic relative vorticity between −16 and −4 (×10−6 s−1), (ii) 200-hPa divergence between 2 and 8 (×10−6 s−1), and (iii) environmental vertical wind shear between 0 and 8 m s−1. The subsequent TC tracks are observed to be steered by mean 700–500-hPa winds.
Dynamics of the Northern Tsuchiya Jet*
Authors: Furue Ryo , McCreary Julian P. , Yu Zuojun
Published: March 2009

The Tsuchiya jets (TJs) are narrow eastward currents located along thermal fronts at the poleward edges of thermostad water in the Pacific Ocean. In this study, an oceanic general circulation model (OGCM) is used to explore the dynamics of the northern TJ. Solutions are found in a rectangular basin, extending 100° zonally and from 40°S to 40°N. They are forced by three idealized forcings: several patches of idealized wind fields, including one that simulates the strong Ekman pumping region in the vicinity of the Costa Rica Dome (CRD); surface heating that warms the ocean in the tropics; and a prescribed interocean circulation (IOC) that enters the basin through the southern boundary and exits through the western boundary from 2° to 6°N (the model’s Indonesian passages).

Solutions forced by all the aforementioned processes and with minimal diffusion resemble the observed flow field in the tropical North Pacific. A narrow eastward current, the model’s northern TJ, flows across the basin along the northern edge of a thick equatorial thermostad. Part of the TJ water upwells at the CRD upwelling region and the rest returns westward in the lower part of the North Equatorial Current. The deeper part of the TJ is supplied by water that leaves the western boundary current somewhat north of the equator. Its shallower part originates from water that diverges from the deep portion of the Equatorial Undercurrent (EUC); as a result, the TJ transport increases to the east and the TJ warms as it flows across the basin. These and other properties suggest that the dynamics of the model’s TJ are those of an arrested front, which in a 2½-layer model are generated when characteristics of the flow converge strongly or intersect.

Eddy form stress, due to instability waves generated at the CRD region, extends the TJ circulation to deeper levels. When diffusivity is increased to commonly used values, the thermostad is less well defined and the TJ is weak. In a solution without the IOC, the TJ is shifted to higher temperatures with its water supplied by the subtropical cell. When horizontal viscosity is reduced, the TJ becomes narrower and is flanked by a westward current on its equatorward side.
Assessment of Value Added for Surface Marine Wind Speed Obtained from Two Regional Climate Models
Authors: Winterfeldt Jörg , Weisse Ralf
Published: March 2009

Hindcasts with reanalysis-driven regional climate models (RCMs) are a common tool to assess weather statistics (i.e., climate) and recent changes and trends. The capability of different state-of-the-art RCMs (with and without spectral nudging applied) to add value for surface marine wind speed in comparison to the reanalysis wind speed forcing is assessed by the comparison with observations in the eastern North Atlantic in 1998. Added value is elaborated on instantaneous wind speeds and their frequency distribution. The observations are discriminated into groups according to their proximity to land and assimilation status, meaning whether they are assimilated into the reanalysis or not. For instantaneous wind speeds RCMs do not show added value both in “open ocean” areas and the German Bight. However, in the English Channel, where local topography and associated local wind regimes become important, the regional models show an added value for instantaneous wind speeds. Concerning the wind speed distribution there is a clear indication for an added value of the RCMs in coastal regions, especially for higher wind speed percentiles, while in open-ocean areas no added value is found. In comparison to the unnudged simulation, the spectrally nudged simulations better represent both instantaneous wind speeds and their frequency distribution. These results hold independently of the measurements’ assimilation status. Strictly the findings of this study only hold for hindcast studies, the results may differ for other areas and years.
Evaluation of Scalar Advection Schemes in the Advanced Research WRF Model Using Large-Eddy Simulations of Aerosol–Cloud Interactions
Authors: Wang Hailong , Skamarock William C. , Feingold Graham
Published: March 2009

In the Advanced Research Weather Research and Forecasting Model (ARW), versions 3.0 and earlier, advection of scalars was performed using the Runge–Kutta time-integration scheme with an option of using a positive-definite (PD) flux limiter. Large-eddy simulations of aerosol–cloud interactions using the ARW model are performed to evaluate the advection schemes. The basic Runge–Kutta scheme alone produces spurious oscillations and negative values in scalar mixing ratios because of numerical dispersion errors. The PD flux limiter assures positive definiteness but retains the oscillations with an amplification of local maxima by up to 20% in the tests. These numerical dispersion errors contaminate active scalars directly through the advection process and indirectly through physical and dynamical feedbacks, leading to a misrepresentation of cloud physical and dynamical processes. A monotonic flux limiter is introduced to correct the generally accurate but dispersive solutions given by high-order Runge–Kutta scheme. The monotonic limiter effectively minimizes the dispersion errors with little significant enhancement of numerical diffusion errors. The improvement in scalar advection using the monotonic limiter is discussed in the context of how the different advection schemes impact the quantification of aerosol–cloud interactions. The PD limiter results in 20% (10%) fewer cloud droplets and 22% (5%) smaller cloud albedo than the monotonic limiter under clean (polluted) conditions. Underprediction of cloud droplet number concentration by the PD limiter tends to trigger the early formation of precipitation in the clean case, leading to a potentially large impact on cloud albedo change.
The clinical usefulness of spirometric information
Authors: Calverley P.M.A.
Published: March 2009

Spirometry is a remarkably versatile and informative measurement with known between-test reproducibility. It can be used reliably by a range of practitioners and technologists and changes in spirometry indicate important changes in the patient's clinical condition, although the significance of a given change has to be calibrated against the disease context in which it occurs. Community-based spirometry can identify a range of diseases and exclude others while promoting significant changes in treatment.

Spirometry is a key part of bronchial challenge testing, which can be said to diagnose and monitor progress in asthma. Reductions in forced expiratory volume in one second (FEV1) are prognostically relevant in chronic obstructive pulmonary disease (COPD) as are decreases in vital capacity in neuromuscular disease. Determining disease progression as the rate of decline in FEV1 is not practical at an individual patient level, but documenting the loss of lung function over time is still a valuable outcome to monitor. Used together with other clinical features, spirometry can substantially improve our assessment of the patient and their long-term management [1].
Scientific highlights from the European Sleep Research Society Congress, 2008
Authors: Goff E.A. , Jackson M.L. , Shaikh Z.F. , Atalla A. , Hill C.M. , Morrell M.J.
Published: March 2009

You simply cannot go to Glasgow in Scotland and be a shrinking violet. Or at least this is what we were told when we attended the European Sleep Research Society (ESRS) Congress in Glasgow in 2008. This report aims to illustrate how collaboration and communication between specialists can help to facilitate breakthroughs in clinical practice. We leave it up to the reader to decide whether those who attended also made breakthroughs in learning local customs.
Heat shock proteins and immune system
Authors: Tsan Min-Fu , Gao Baochong
Published: March 2009

Heat shock proteins (HSPs) such as HSP 60 (Hsp60), Hsp70, Hsp90, and gp96, have been reported to play important roles in antigen presentation and cross-presentation, activation of macrophages and lymphocytes, and activation and maturation of dendritic cells. HSPs contain peptide-binding domains that bind exposed hydrophobic residues of substrate proteins. As part of their molecular chaperone functions, HSPs bind and deliver chaperoned, antigenic peptides to MHC class I molecules at the cell surface for presentation to lymphocytes. HSPs also bind nonprotein molecules with exposed hydrophobic residues including lipid-based TLR ligands. Recombinant HSP products may be contaminated with pathogen-associated molecules that contain exposed hydrophobic residues such as LPS (a TLR4 ligand), lipoprotein (a TLR2 ligand), and flagellin (a TLR5 ligand). These contaminants appear to be responsible for most, if not all, reported in vitro cytokine effects of HSPs, as highly purified HSPs do not show any cytokine effects. We propose that HSPs are molecular chaperones that bind protein and nonprotein molecules with exposed hydrophobic residues. The reported antigen presentation and cross-presentation and in vitro HSP cytokine functions are a result of molecules bound to or chaperoned by HSPs but not a result of HSPs themselves.
Carbonic Anhydrases CA4 and CA14 Both Enhance AE3-Mediated Cl−–HCO3−Exchange in Hippocampal Neurons
Authors: Svichar Nataliya , Waheed Abdul , Sly William S. , Hennings Jean C. , Hübner Christian A. , Chesler Mitchell
Published: March 2009

Carbonic anhydrase (CA) activity in the brain extracellular space is attributable mainly to isoforms CA4 and CA14. In brain, these enzymes have been studied mostly in the context of buffering activity-dependent extracellular pH transients. Yet evidence from others has suggested that CA4 acts in a complex with anion exchangers (AEs) to facilitate Cl−–HCO3−exchange in cotransfected cells. To investigate whether CA4 or CA14 plays such a role in hippocampal neurons, we studied NH4+-induced alkalinization of the cytosol, which is mitigated by Cl−entry and HCO3−exit. The NH4+-induced alkalinization was enhanced when the extracellular CAs were inhibited by the poorly permeant CA blocker, benzolamide, or by inhibitory antibodies specific for either CA4 or CA14. The NH4+-induced alkalinization was also increased with inhibition of anion exchange by 4,4*-diisothiocyanostilbene-2,2*-disulfonic acid, or by eliminating Cl−from the medium. No effect of benzolamide was seen under these conditions, in which no Cl−–HCO3−exchange was possible. Quantitative PCR on RNA from the neuronal cultures indicated that AE3 was the predominant AE isoform. Single-cell PCR also showed that Slc4a3 (AE3) transcripts were abundant in isolated neurons. In hippocampal neurons dissociated from AE3-null mice, the NH4+-induced alkalinization was much larger than that seen in neurons from wild-type mice, suggesting little or no Cl−–HCO3−exchange in the absence of AE3. Benzolamide had no effect on the NH4+-induced alkalinization in the AE3 knock-out neurons. Our results indicate that CA4 and CA14 both play important roles in the regulation of intracellular pH in hippocampal neurons, by facilitating AE3-mediated Cl−–HCO3−exchange.
Direct Innervation of GnRH Neurons by Metabolic- and Sexual Odorant-Sensing Leptin Receptor Neurons in the Hypothalamic Ventral Premammillary Nucleus
Authors: Leshan Rebecca L. , Louis Gwendolyn W. , Jo Young-Hwan , Rhodes Christopher J. , Münzberg Heike , Myers Martin G.
Published: March 2009

Leptin acts via its receptor (LepRb) on specific CNS neurons to signal the adequacy of long-term energy stores, thereby permitting the expenditure of resources on energy-intensive processes such as reproduction. The ventral premammillary nucleus of the hypothalamus (PMv), which has been implicated in the stimulation of gonadotropin release by olfactory cues, contains numerous LepRb neurons, suggesting a potential role for LepRb PMv neurons in transmitting both metabolic and odorant signals to the neuroendocrine reproductive system. Indeed, Fos immunoreactivity and electrophysiologic recordings revealed the direct activation of LepRb PMv neurons by leptin, and exposure to odors from mice of the opposite sex promoted Fos immunoreactivity (Fos-IR) in many LepRb PMv neurons. To determine the regions innervated by the LepRb PMv neurons, we used two novel cre-activated tract-tracing systems inLeprcreanimals; data from these systems and from standard tracing techniques revealed that LepRb PMv neurons project to a subset of the regions, including the preoptic area, that are innervated by the PMv as a whole. Furthermore, the retrograde accumulation in LepRb PMv neurons of a trans-synaptic tracer from GnRH neurons revealed the direct innervation of GnRH neurons by many LepRb PMv neurons. Thus, LepRb PMv neurons sense metabolic and sexual odorant cues and project to the rostral hypothalamus to directly innervate GnRH neurons. These results are consistent with a role for LepRb PMv neurons in regulating the reproductive axis in response to metabolic and odorant stimuli.
Diffusion Tensor Magnetic Resonance Imaging of Wallerian Degeneration in Rat Spinal Cord after Dorsal Root Axotomy
Authors: Zhang Jiangyang , Jones Melina , DeBoy Cynthia A. , Reich Daniel S. , Farrell Jonathan A. D. , Hoffman Paul N. , Griffin John W. , Sheikh Kazim A. , Miller Michael I. , Mori Susumu , Calabresi Peter A.
Published: March 2009

Diffusion tensor imaging (DTI) and immunohistochemistry were used to examine axon injury in the rat spinal cord after unilateral L2–L4dorsal root axotomy at multiple time points (from 16 h to 30 d after surgery). Three days after axotomy, DTI revealed a lesion in the ipsilateral dorsal column extending from the lumbar to the cervical cord. The lesion showed significantly reduced parallel diffusivity and increased perpendicular diffusivity at day 3 compared with the contralateral unlesioned dorsal column. These findings coincided with loss of phosphorylated neurofilaments, accumulation of nonphosphorylated neurofilaments, swollen axons and formation of myelin ovoids, and no clear loss of myelin (stained by Luxol fast blue and 2′-3′-cyclic nucleotide 3′-phosphodiesterase). At day 30, DTI of the lesion continued to show significantly decreased parallel diffusivity. There was a slow but significant increase in perpendicular diffusivity between day 3 and day 30, which correlated with gradual clearance of myelin without further significant changes in neurofilament levels. These results show that parallel diffusivity can detect axon degeneration within 3 d after injury. The clearance of myelin at later stages may contribute to the late increase in perpendicular diffusivity, whereas the cause of its early increase at day 3 may be related to changes associated with primary axon injury. These data suggest that there is an early imaging signature associated with axon transections that could be used in a variety of neurological disease processes.
Persistent Inflammation Induces GluR2 Internalization via NMDA Receptor-Triggered PKC Activation in Dorsal Horn Neurons
Authors: Park Jang-Su , Voitenko Nana , Petralia Ronald S. , Guan Xiaowei , Xu Ji-Tian , Steinberg Jordan P. , Takamiya Kogo , Sotnik Andrij , Kopach Olga , Huganir Richard L. , Tao Yuan-Xiang
Published: March 2009

Spinal cord GluR2-lacking AMPA receptors (AMPARs) contribute to nociceptive hypersensitivity in persistent pain, but the molecular mechanisms underlying this event are not completely understood. We report that complete Freund's adjuvant (CFA)-induced peripheral inflammation induces synaptic GluR2 internalization in dorsal horn neurons during the maintenance of CFA-evoked nociceptive hypersensitivity. This internalization is initiated by GluR2 phosphorylation at Ser880and subsequent disruption of GluR2 binding to its synaptic anchoring protein (GRIP), resulting in a switch of GluR2-containing AMPARs to GluR2-lacking AMPARs and an increase of AMPAR Ca2+permeability at the synapses in dorsal horn neurons. Spinal cord NMDA receptor-mediated triggering of protein kinase C (PKC) activation is required for the induction and maintenance of CFA-induced dorsal horn GluR2 internalization. Moreover, preventing CFA-induced spinal GluR2 internalization through targeted mutation of the GluR2 PKC phosphorylation site impairs CFA-evoked nociceptive hypersensitivity during the maintenance period. These results suggest that dorsal horn GluR2 internalization might participate in the maintenance of NMDA receptor/PKC-dependent nociceptive hypersensitivity in persistent inflammatory pain.
Neural Suppression of Irrelevant Information Underlies Optimal Working Memory Performance
Authors: Zanto Theodore P. , Gazzaley Adam
Published: March 2009

Our ability to focus attention on task-relevant information and ignore distractions is reflected by differential enhancement and suppression of neural activity in sensory cortex (i.e., top-down modulation). Such selective, goal-directed modulation of activity may be intimately related to memory, such that the focus of attention biases the likelihood of successfully maintaining relevant information by limiting interference from irrelevant stimuli. Despite recent studies elucidating the mechanistic overlap between attention and memory, the relationship between top-down modulation of visual processing during working memory (WM) encoding, and subsequent recognition performance has not yet been established. Here, we provide neurophysiological evidence in healthy, young adults that top-down modulation of early visual processing (< 200 ms from stimulus onset) is intimately related to subsequent WM performance, such that the likelihood of successfully remembering relevant information is associated with limiting interference from irrelevant stimuli. The consequences of a failure to ignore distractors on recognition performance was replicated for two types of feature-based memory, motion direction and color. Moreover, attention to irrelevant stimuli was reflected neurally during the WM maintenance period as an increased memory load. These results suggest that neural enhancement of relevant information is not the primary determinant of high-level performance, but rather optimal WM performance is dependent on effectively filtering irrelevant information through neural suppression to prevent overloading a limited memory capacity.
Processo de seleção na pós-graduação em enfermagem psiquiátrica: uma discussão
Authors: Labarte Renata Curi , Scatena Maria Cecília Moraes , Ornelas Maria Alice , Furegato Antônia Regina
Published: March 2009

Relata o processo de seleção dos últimos três anos, analisando a formação e a área de atuação dos candidatos inscritos no processo seletivo. Metodologia: estudo exploratório descritivo. Da análise de dados obtidos em fonte documental do Programa, inúmeras reflexões emergiram e destacamos a importância de adequarmos o Programa para a formação de profissionais que procuram a área sem conhecimento anterior ou delimitamos o Programa para profissionais que buscam aprofundamento em Saúde Mental.
Educação em saúde: objeto de estudo em dissertações e teses de enfermeiras no Brasil
Authors: Guedes Maria Vilaní Cavalcante , Silva Lucia de Fatima da , Freitas Maria Célia de
Published: March 2009

Objetivou-se levantar o quantitativo de dissertações e teses produzidas por enfermeiras sobre educação em saúde, identificando e analisando seus passos metodológicos. Pesquisou-se nos 17 Catálogos de Informações sobre Pesquisas e Pesquisadores do CEPEn/ABEn, publicados de 1979 a 1999. A amostra constituiu-se de 105 dissertações e 15 teses sobre a temática. Destacaram-se como objeto: doenças crônicas, ciclo gravídico-puerperal, educação em saúde, gerenciamento e situação perioperatória. Foram populações: adultos, profissionais de enfermagem, mulheres, crianças e adolescentes. A entrevista foi a técnica mais utilizada. Os autores apontam necessidade de melhoria das práticas educativas e consideraram que educação em saúde motiva mudanças no estilo de vida. Concluiu-se haver necessidade de fortalecerem-se pesquisas sobre o cotidiano da Enfermagem no contexto histórico-social.
O enfermeiro analista de risco institucional
Authors: Feldman Liliane Bauer
Published: March 2009

Este estudo descritivo relata o trabalho desenvolvido pelo enfermeiro analista de risco; que é um processo de identificação, avaliação e tratamento dos riscos profissionais e institucionais que qualquer hospital está exposto. Além da responsabilidade pela qualidade oferecida, há o compromisso com a Responsabilidade Civil Profissional, isto é, o desenvolvimento do trabalho realizado pelos profissionais dentro da instituição. A coleta de dados realiza-se com o preenchimento de um formulário, visita e; entrevista formal / informal com os responsáveis pelos serviços. O resultado obtido identifica os fatores potenciais de risco, que podem gerar danos profissionais e hospitalares. O enfermeiro elabora o relatório, e como estratégia preventiva enumera recomendações. Evidenciamos que examinando cuidadosamente cada risco é possível determinar a melhor forma de gerenciá-lo.
AIDS e Diabetes Mellitus versus justiça distributiva no sistema público de saúde
Authors: Oliveira Silvia Lucia de Castro , Lunardi Filho Wilson Danilo
Published: March 2009

Reflexão sobre a forma de distribuição dos recursos públicos na área de saúde e as conseqüências decorrentes. Questiona-se a eqüidade da justiça distributiva. Propõe-se uma leitura contextual dos números oficiais, através de inter-relações que possibilitem a compreensão do significado das cifras governamentais. AIDS e Diabetes, escolhidas como paradigmas, representam, respectivamente, os grupos das Doenças Transmissíveis e das Não Transmissíveis. Os números oficiais relativos às duas doenças estão correlacionados em alguns aspectos pontuais: gastos com medicamentos, prevalência, evolução de taxas de mortalidade. Alerta-se para as diferenças de atenção oficial marcantes entre as duas doenças e para as conseqüências sofridas por pessoas atingidas por Diabetes e por outras doenças não transmissíveis, decorrentes da insuficiência de recursos públicos destinados ao seu atendimento.