bluuebunny/crossref_metadata_2025 huggingface dataset:
Breadth of Neutralizing Antibody Response to Human Immunodeficiency Virus Type 1 Is Affected by Factors Early in Infection but Does Not Influence Disease Progression
Authors: Piantadosi Anne , Panteleeff Dana , Blish Catherine A. , Baeten Jared M. , Jaoko Walter , McClelland R. Scott , Overbaugh Julie
Published: July 2009

The determinants of a broad neutralizing antibody (NAb) response and its effect on human immunodeficiency virus type 1 (HIV-1) disease progression are not well defined, partly because most prior studies of a broad NAb response were cross-sectional. We examined correlates of NAb response breadth among 70 HIV-infected, antiretroviral-naïve Kenyan women from a longitudinal seroincident cohort. NAb response breadth was measured 5 years after infection against five subtype A viruses and one subtype B virus. Greater NAb response breadth was associated with a higher viral load set point and greater HIV-1
env
diversity early in infection. However, greater NAb response breadth was not associated with a delayed time to a CD4
+
T-cell count of <200, antiretroviral therapy, or death. Thus, a broad NAb response results from a high level of antigenic stimulation early in infection, which likely accounts for prior observations that greater NAb response breadth is associated with a higher viral load later in infection.
Detection of EGFR and KRAS mutations on trans-thoracic needle aspiration of lung nodules by high resolution melting analysis
Authors: Fassina A , Gazziero A , Zardo D , Corradin M , Aldighieri E , Rossi G P
Published: July 2009

Background:

EGFRandKRASare the target genes for tumour response to epidermal growth factor receptor (EGFR) inhibitors.

Aims:

To investigateEGFRandKRASmutational status with high resolution melting (HRM) analysis applied to cytological material obtained from trans-thoracic needle aspiration (TTNA) in order to better select patients for targeted therapy.

Methods:

DNA was extracted from fixed material of 108 TTNAs under CT guidance, from 108 consecutive patients. In 77 TTNAs (71.3.%) that were positive for non-small cell lung cancer, the variant in exon 21 (the missense mutation at codon 858, L858R) and the deletion in exon 19 (in frame deletion at codons 747–749) of theEGFRgene, and the point mutation in exon 2 ofKRASwere investigated with HRM assay using sequencing as the reference “gold standard”.

Results:

Nine (11.7%) samples were positive forKRASexon 2 mutations, and two (2.6%) samples were positive for theEGFRexon 21 missense mutation by HRM assay. No deletion at exon 19 forEGFRwas detected by HRM analysis. All HRM results were confirmed by direct DNA sequencing.

Conclusions:

HRM analysis of cytological material was accurate for the detection of two majorEGFRmutations andKRASmutations in exon 2. HRM analysis was fast, easy to apply, cheap, highly reproducible, and could be used with small amounts of material, such as is obtainable with needle lavage. Therefore, it may be useful as an adjunct to the cytological report that yields valuable molecular information.
“One man’s trash is another man’s treasure”: exploring economic and moral subtexts of the “organ shortage” problem in public views on organ donation
Authors: Schicktanz S , Schweda M
Published: July 2009

The debate over financial incentives and market models for organ procurement represents a key trend in recent bioethics. In this paper, we wish to reassess one of its central premises—the idea of organ shortage. While the problem is often presented as an objective statistical fact that can be taken for granted, we will take a closer look at the underlying framework expressed in the common rhetoric of “scarcity”, “shortage” or “unfulfilled demand”. On the basis of theoretical considerations as well as a socioempirical examination of public attitudes, we will argue that this rhetoric has an economic subtext that imbues the debate with normative premises that have far-reaching social and ethical consequences and need to be made explicit and discussed.
The principle of justice in patient priorities in the intensive care unit: the role of significant others: Table 1
Authors: Halvorsen K , Førde R , Nortvedt P
Published: July 2009

Background:

Theoretically, the principle of justice is strong in healthcare priorities both nationally and internationally. Research, however, has indicated that questions can be raised as to how this principle is dealt with in clinical intensive care.

Objective:

The objective of this article is to examine how significant others may affect the principle of justice in the medical treatment and nursing care of intensive care patients.

Method:

Field observations and in-depth interviews with physicians and nurses in intensive care units (ICU). Emphasis was placed on eliciting the underlying rationale for prioritisations in clinical intensive care with particular focus on clinicians’ considerations when limiting ICU treatment.

Results:

Significant others could induce an unintentional discrimination of ICU patients. Family members who were demanding received more time and attention for both the patient and themselves. Patients’ and families’ status and position and/or an interesting medical diagnosis seemed to govern the clinicians’ priorities of patients and families—consciously as well as unconsciously. The clinicians emphasised that patient information given through families was important. However, patients’ preferences and values conveyed to clinicians through their families were not always taken seriously. This even applied in cases with very serious prognoses and an explicit patient wish to forego life-prolonging treatment.

Conclusion:

The principle of justice was violated when qualified attention was given to significant others, and through this also to patients. Attention given to significant others was influenced by the healthcare workers’ professional and personal values, attitudes and interests.
Survey on the function, structure and operation of hospital ethics committees in Shanghai
Authors: Zhou P , Xue D , Wang T , Tang Z L , Zhang S K , Wang J P , Mao P P , Xi Y Q , Wu R , Shi R
Published: July 2009

Objective:

The objectives of this study are to understand the current functions, structure and operation of hospital ethics committees (HECs) in Shanghai and to facilitate their improvement.

Methods:

(1) A questionnaire survey, (2) interviews with secretaries and (3) on-site document reviews of HECs in Shanghai were used in the study, which surveyed 33 hospitals.

Results:

In Shanghai, 57.56% of the surveyed hospitals established HECs from 1998 to 2005. Most HECs used bioethical review of research involving human subjects as well as bioethical review or consultation regarding medical care services and administrative decision- making. Of the surveyed HECs, 14.3% did not provide any formal bioethical training to the HECs’ members and many HECs had no standard operating procedures. Some HECs had no clear definition of what was “conflict of interest” that should be considered by the HECs, while 44.4% of the HECs did not perform continuing review.

Discussion:

After the issues of related national regulations, more and more hospitals established HECs in Shanghai, but the functions of HECs need to be further developed and formal training on bioethics should be provided to HEC members. To assure the independence and good performance of HECs, the conflict of interest procedure, the standard operating procedures and bioethical review should be improved.

Conclusion:

HECs in Shanghai had developed in the preceding 10 years and they played great roles in protecting the rights and welfare of human subjects and patients; some areas need improvement.
Judgement of suffering in the case of a euthanasia request in The Netherlands
Authors: Rietjens J A C , van Tol D G , Schermer M , van der Heide A
Published: July 2009

Introduction:

In The Netherlands, physicians have to be convinced that the patient suffers unbearably and hopelessly before granting a request for euthanasia. The extent to which general practitioners (GPs), consulted physicians and members of the euthanasia review committees judge this criterion similarly was evaluated.

Methods:

300 GPs, 150 consultants and 27 members of review committees were sent a questionnaire with patient descriptions. Besides a “standard case” of a patient with physical suffering and limited life expectancy, the descriptions included cases in which the request was mainly rooted in psychosocial or existential suffering, such as fear of future suffering or dependency. For each case, respondents were asked whether they recognised the case from their own practice and whether they considered the suffering to be unbearable.

Results:

The cases were recognisable for almost all respondents. For the “standard case” nearly all respondents were convinced that the patient suffered unbearably. For the other cases, GPs thought the suffering was unbearable less often (2–49%) than consultants (25–79%) and members of the euthanasia review committees (24–88%). In each group, the suffering of patients with early dementia and patients who were “tired of living” was least often considered to be unbearable.

Conclusions:

When non-physical aspects of suffering are central in a euthanasia request, there is variance between and within GPs, consultants and members of the euthanasia committees in their judgement of the patient’s suffering. Possible explanations could be differences in their roles in the decision-making process, differences in experience with evaluating a euthanasia request, or differences in views regarding the permissibility of euthanasia.
Functional neuroimaging and withdrawal of life-sustaining treatment from vegetative patients
Authors: Wilkinson D J , Kahane G , Horne M , Savulescu J
Published: July 2009

Recent studies using functional magnetic resonance imaging of patients in a vegetative state have raised the possibility that such patients retain some degree of consciousness. In this paper, the ethical implications of such findings are outlined, in particular in relation to decisions about withdrawing life-sustaining treatment. It is sometimes assumed that if there is evidence of consciousness, treatment should not be withdrawn. But, paradoxically, the discovery of consciousness in very severely brain-damaged patients may provide more reason to let them die. Although functional neuroimaging is likely to play an increasing role in the assessment of patients in a vegetative state, caution is needed in the interpretation of neuroimaging findings.
CLOUDS: A NEW PLAYGROUND FOR THE XTREEMOS GRID OPERATING SYSTEM
Authors: MORIN CHRISTINE , JÉGOU YVON , GALLARD JÉRÔME , RITEAU PIERRE
Published: July 2009

The emerging cloud computing model has recently gained a lot of interest both from commercial companies and from the research community. XtreemOS is a distributed operating system for large-scale wide-area dynamic infrastructures spanning multiple administrative domains. XtreemOS, which is based on the Linux operating system, has been designed as a Grid operating system providing native support for virtual organizations. In this paper, we discuss the positioning of XtreemOS technologies with regard to cloud computing. More specifically, we investigate a scenario where XtreemOS could help users take full advantage of clouds in a global environment including their own resources and cloud resources. We also discuss how the XtreemOS system could be used by cloud service providers to manage their underlying infrastructure. This study shows that the XtreemOS distributed operating system is a highly relevant technology in the new era of cloud computing where future clouds seamlessly span multiple bare hardware providers and where customers extend their IT infrastructure by provisioning resources from different cloud service providers.
EXACT ALGORITHMS FOR A TASK ASSIGNMENT PROBLEM
Authors: KAYA KAMER , UÇAR BORA
Published: July 2009

We consider the following task assignment problem. Communicating tasks are to be assigned to heterogeneous processors interconnected with a heterogeneous network. The objective is to minimize the total sum of the execution and communication costs. The problem is NP-hard. We present an exact algorithm based on the well-known A* search. We report simulation results over a wide range of parameters where the largest solved instance contains about three hundred tasks to be assigned to eight processors.
A SIMPLE PARALLEL ADAPTIVE MESH CFD METHOD SUITABLE FOR SMALL ENGINEERING WORKSTATIONS
Authors: TANG JOSEPH
Published: July 2009

This paper describes a simple shared-memory parallel implementation of an octree adaptive mesh Computational Fluid Dynamics (CFD) code with an explicit time discretization scheme. The parallel performance of the code when running a realistic simulation gives a serial code fraction of no more than 13%. This should be suitable for small multicore engineering workstations where a simple code is desired and medium-sized simulations are sufficient.
A MODIFIED SYMMETRY REDUCTION METHOD AND ITS APPLICATION IN NONLINEAR VARIABLE COEFFICIENT EVOLUTION EQUATION(S)
Authors: BAI CHENG-JIE , ZHAO HONG , ZHANG XIA , XU HENG-YING
Published: July 2009

Based on the one-parameter Lie group theory, we established a modified symmetry reduction method in solving nonlinear variable coefficient equations. Our study shows that the modified method can be applied in solving or reducing various nonlinear variable coefficient equations. In our initial applications, we have successfully obtained some exact solutions to the equations of nonlinear variable coefficients KdV and KP.
EFFECT OF SINTERING TEMPERATURE ON THE MICROSTRUCTURE AND THERMOELECTRIC PROPERTIES OF Ca2.7Bi0.3Co4O9
Authors: HAO HAOSHAN , LI SHAOFENG , ZHAO LIMIN , HU XING
Published: July 2009

Ca 2.7 Bi 0.3 Co 4 O 9 samples have been sintered in temperature range of 1183–1243 K by conventional solid-state reaction method. XRD and SEM investigations show that c-axis-oriented structure could be formed in these samples and Lotgering factors increase with the increase of sintering temperature when it is below 1223 K, from 52% for the sample sintered at 1183 K to 86% for the sample sintered at 1223 K. Due to decomposition of Ca 2.7 Bi 0.3 Co 4 O 9, however, the c-axis-oriented structure was destroyed in the sample sintered at 1243 K although Ca 2.7 Bi 0.3 Co 4 O 9 phase could be recovered at the cooling stage. The size of grains in all samples increases with the increase of sintering temperature, but the relative densities are almost kept unchanged for the samples sintered at the temperature higher than 1183 K. Due to the highly textured structure, the transport properties of the sample sintered at 1223 K are anisotropic and its ZT values in the ab plane are obviously larger than those along the c-axis.
ORDERING FROM FRUSTRATION IN A STRONGLY CORRELATED ONE-DIMENSIONAL SYSTEM
Authors: LAL SIDDHARTHA , LAAD MUKUL S.
Published: July 2009

We study a one-dimensional extended Hubbard model with longer-range Coulomb interactions at quarter-filling in the strong coupling limit. We find two different charge-ordered (CO) ground states (Wigner and Peierls) as the strength of the longer range interactions is varied. At lower energies, the two CO states drive different spin-ordered ground states (Heisenberg antiferromagnet and dimerised respectively), reminiscent of the phase diagram of the TMTTF and TMTSF organic charge transfer salts. Several response functions computed in the quantum critical regime bear a remarkable resemblance to recent experimental observations related to CO in the organic TMTTF systems. RPA studies of coupled chains reveal a phase diagram with the ordered phase extended to finite temperatures and a phase boundary ending at a quantum critical point (QCP). Critical quantum fluctuations at the QCP enhance the transverse dispersion, leading to a dimensional crossover and a T = 0 deconfinement transition from insulating chains to anisotropic metallic planar behavior. Numerical estimates for the hierarchy of energy scales associated with charge and spin order and the dimensional crossover compare well with the values obtained experimentally. This leads us to propose that the TMTTF and TMTSF systems are proximate to a QCP associated with T = 0 charge order.
The role of the neural sympathetic and parasympathetic systems in diurnal and sleep state-related cardiovascular rhythms in the late-gestation ovine fetus
Authors: Jensen Ellen C. , Bennet Laura , Guild Sarah-Jane , Booth Lindsea C. , Stewart Joanna , Gunn Alistair J.
Published: July 2009

The efferent mechanisms mediating the well-known diurnal cardiovascular rhythms in the late-gestation fetus are only partially understood. In the present study, we evaluated the contribution of the parasympathetic and sympathetic nervous systems (SNS) to these rhythms. Chronically instrumented fetal sheep at a mean (SE) of 122 ( 1 ) days gestation (term is 147 days) underwent either chemical sympathectomy with 6-hydroxydopamine the day after surgery ( n = 8), vagotomy at surgery ( n = 8), or were sham controls ( n = 8). Fetal heart rate (HR), fetal HR variability (HRV), mean arterial blood pressure (MAP), carotid blood flow (CaBF), electrocorticogram (ECoG) activity, and nuchal activity were measured continuously for 24 h. Changes between sleep states were determined in a 6-h interval. Control fetal sheep showed consistent diurnal rhythms in fetal HR, HRV, MAP, and CaBF, with maximal activity in the evening, but not in nuchal activity. Sympathectomy was associated with a significant reduction of both fetal HR and HRV, while vagotomy was associated with a fall in fetal HRV ( P < 0.05) but no change in HR. Despite this, most animals in the two intervention groups still showed diurnal rhythms for fetal HR, HRV, MAP, and CaBF, although peak HR may have been delayed in the sympathectomy group (mean 02:22 vs. 23:54 h in controls, P = 0.06). There was no effect of either intervention on sleep state cycling, although state-related cardiovascular rhythms were significantly modulated. These data indicate that, neither the SNS nor vagal activity, in isolation at least, is essential for generating cardiovascular diurnal rhythms in the late-gestation fetus.
Glomerular epithelial cell injury associated with mutant α-actinin-4
Authors: Cybulsky Andrey V. , Takano Tomoko , Papillon Joan , Bijian Krikor , Guillemette Julie , Kennedy Chris R. J.
Published: July 2009

Focal segmental glomerulosclerosis (FSGS) may be associated with glomerular epithelial cell (GEC; podocyte) apoptosis due to acquired injury or mutations in α-actinin-4. This study addresses how FSGS-associated mutant α-actinin-4 may induce GEC injury, focusing on endoplasmic reticulum (ER) stress and metabolism of mutant α-actinin-4 via the ubiquitin-proteasome system. In a model of experimental FSGS induced by expression of an α-actinin-4 K256E transgene in podocytes, we show induction of ER stress, including upregulation of ER chaperones (bip, grp94), phosphorylation of the eukaryotic translation initiation factor-2α subunit, and induction of the proapop totic gene C/EBP homologous protein-10 (CHOP). To address mechanisms of ER stress, we studied signaling in cultured GEC and COS cells expressing α-actinin-4 K256E. Previously, we showed that expression of this α-actinin-4 mutant in GEC increased apoptosis. In the present study, we show that α-actinin-4 K256E upregulates grp94 and CHOP expression in COS cells and significantly exacerbates induction of bip and CHOP in GEC in the presence of tunicamycin. ER stress was associated with aggregation and ubiquitination of α-actinin-4 K256E and impairment of the ubiquitin-proteasome system. In addition, α-actinin-4 K256E exacerbated apoptosis in the context of mild proteasome inhibition. Thus α-actinin-4 K256E triggers several metabolic abnormalities, which may lead to GEC injury and glomerulosclerosis.
A test of the hypothesis that the collecting duct calcium-sensing receptor limits rise of urine calcium molarity in hypercalciuric calcium kidney stone formers
Authors: Bergsland Kristin J. , Coe Fredric L. , Gillen Daniel L. , Worcester Elaine M.
Published: July 2009

The process of kidney stone formation depends on an imbalance between excretion of water and insoluble stone-forming salts, leading to high concentrations that supersaturate urine and inner medullary collecting duct (IMCD) fluid. For common calcium-containing stones, a critical mechanism that has been proposed for integrating water and calcium salt excretions is activation of the cell surface calcium-sensing receptor (CaSR) on the apical membranes of IMCD cells. High deliveries of calcium into the IMCD would be predicted to activate CaSR, leading to reduced membrane abundance of aquaporin-2, thereby limiting water conservation and protecting against stone formation. We have tested this hypothesis in 16 idiopathic hypercalciuric calcium stone formers and 14 matched normal men and women in the General Clinical Research Center. Subjects were fed identical diets; we collected 14 urine samples at 1-h intervals during a single study day, and one sample overnight. Hypercalciuria did not increase urine volume, so urine calcium molarity and supersaturation with respect to calcium oxalate and calcium phosphate rose proportionately to calcium excretion. Thus CaSR modulation of urine volume via IMCD CaSR activation does not appear to be an important mechanism of protection against stone formation. The overnight period, one of maximal water conservation, was a time of maximal stone risk and perhaps a target of specific clinical intervention.
Role of spinal serotonergic pathways in sneeze-induced urethral continence reflex in rats
Authors: Miyazato Minoru , Kaiho Yasuhiro , Kamo Izumi , Kitta Takeya , Chancellor Michael B. , Sugaya Kimio , Arai Yoichi , de Groat William C. , Yoshimura Naoki
Published: July 2009

To clarify the role of spinal serotonergic mechanisms in preventing stress urinary incontinence (SUI) during sneezing, we investigated the effect of intrathecal (it) application of 8-OH-DPAT (a 5-HT1Aagonist), mCPP (a 5-HT2B/2Cagonist), and fluoxetine (a serotonin reuptake inhibitor) using a rat model that can examine the neurally evoked continence reflex during sneezing. Amplitudes of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats and rats with SUI induced by vaginal distention (VD). In normal rats, 8-OH-DPAT decreased A-URS by 48.9%, whereas mCPP increased A-URS by 33.6%. However, A-URS was not changed after fluoxetine. 8-OH-DPAT, mCPP, or fluoxetine did not alter UBP. The effect of 8-OH-DPAT and mCPP was antagonized by WAY-100635 (it), a selective 5-HT1Aantagonist, and RS-102221 (it), a selective 5-HT2Cantagonist, respectively. Fluoxetine in the presence of WAY-100635 did not change either A-URS or UBP, but fluoxetine in the presence of RS-102221 decreased A-URS. In VD rats, S-LPP was decreased by 14.6 cmH2O after 8-OH-DPAT, whereas it was increased by 12.8 cmH2O after mCPP. However, S-LPP was not changed after fluoxetine. These results indicate that activation of 5-HT2Creceptors enhances the active urethral closure reflex during sneezing at the spinal level, whereas 5-HT1Ainhibits it and that no apparent changes in the sneeze-induced continence reflex after fluoxetine treatment are due to coactivation of excitatory 5-HT2Creceptors and inhibitory 5-HT receptors other than the 5-HT1Asubtype. Thus, activation of excitatory 5-HT receptor subtypes such as 5-HT2Ccould be effective for the treatment of SUI.
Breath-by-breath measurement of particle deposition in the lung of spontaneously breathing rats
Authors: Karrasch S. , Eder G. , Bolle I. , Tsuda A. , Schulz H.
Published: July 2009

A number of deposition models for humans, as well as experimental animals, have been described. However, no breath-by-breath deposition measurement in rats has been reported to date. The objective of this study is to determine lung deposition of micrometer-sized particles as a function of breathing parameters in the adult rat lung. A new aerosol photometry system was designed to measure deposition of nonhygroscopic, 2-μm sebacate particles in anesthetized, intubated, and spontaneously breathing 90-day-old Wistar-Kyoto rats placed in a size-adjusted body plethysmograph box. Instrumental dead space of the system was minimized down to 310 μl (i.e., ∼20% of respiratory dead space). The system allows continuous monitoring of particle concentration in the respired volume. Breathing parameters, such as respiratory rate (f), tidal volume (Vt), as well as inspiration/expiration times, were also monitored at different levels of anesthesia. The results showed that Vt typically varied between 1.5 and 4.0 ml for regular breathing and between 4.0 and 10.0 ml for single-sigh breaths; f ranged from 40 to 200 breaths/min. Corresponding deposition values varied between 5 and 50%, depending on breath-by-breath breathing patterns. The best fit of deposition (D) was achieved by a bilinear function of Vt and f and found to be D = 11.0 − 0.09·f + 3.75·Vt. We conclude that our approach provides more realistic conditions for the measurement of deposition than conventional models using ventilated animals and allows us to analyze the correlation between breath-specific deposition and spontaneous breathing patterns.
PD Control for Vibration Attenuation in a Physical Pendulum with Moving Mass
Authors: Gutiérrez-Frias Oscar Octavio , Martínez-García Juan Carlos , Garrido Moctezuma Rubén A.
Published: July 2009

This paper proposes a Proportional Derivative controller plus gravity compensation to
damp out the oscillations of a frictionless physical pendulum with moving mass. A mass slides
along the pendulum main axis and operates as an active vibration‐damping element. The Lyapunov
method together with the LaSalle′s theorem allows concluding closed‐loop asymptotic
stability. The proposed approach only uses measurements of the moving mass position and velocity
and it does not require synchronization of the pendulum and moving mass movements.
Numerical simulations assess the performance of the closed‐loop system.
Waveguide Parameters of 19.8 kHz Signal Propagating over a Long Path
Authors: Kumar Sushil
Published: July 2009

The amplitude and phase of 19.8 kHz signal from navigational transmitter located in North West Cape, Australia, recorded at Suva, Fiji, have been utilized to determine the waveguide mode parameters. The propagation path is mixed over land and sea having Transmitter-Receiver Great Circle Path distance 6.7 Mm. The experimental values of the parameters were found to be consistent with the theoretical values calculated using the mode theory of VLF wave propagation in the waveguide.
A Combinatory Approach for Selecting Prognostic Genes in Microarray Studies of Tumour Survivals
Authors: Tan Qihua , Thomassen Mads , Jochumsen Kirsten M. , Mogensen Ole , Christensen Kaare , Kruse Torben A.
Published: July 2009

Different from significant gene expression analysis which looks for genes that are differentially regulated, feature selection in the microarray-based prognostic gene expression analysis aims at finding a subset of marker genes that are not only differentially expressed but also informative for prediction. Unfortunately feature selection in literature of microarray study is predominated by the simple heuristic univariate gene filter paradigm that selects differentially expressed genes according to their statistical significances. We introduce a combinatory feature selection strategy that integrates differential gene expression analysis with the Gram-Schmidt process to identify prognostic genes that are both statistically significant and highly informative for predicting tumour survival outcomes. Empirical application to leukemia and ovarian cancer survival data through-within- and cross-study validations shows that the feature space can be largely reduced while achieving improved testing performances.
High Levels of Proinflammatory Cytokines, but Not Markers of Tissue Injury, in Unaffected Intestinal Areas from Patients with IBD
Authors: León Alberto J. , Gómez Emma , Garrote Jose A. , Bernardo David , Barrera Asterio , Marcos Jose L. , Fernández-Salazar Luis , Velayos Benito , Blanco-Quirós Alfredo , Arranz Eduardo
Published: July 2009

Intestinal alterations in IBD are triggered and maintained by an overexpression of proinflammatory cytokines. Additionally, increased immune activation has been found in the adjacent intestinal areas without displaying any apparent histological alterations, however, the regulatory environment is not well established. Biopsy specimens from patients with ulcerative colitis (UC) and Crohn's disease (CD), from both affected and unaffected areas, and also from a group of colonic biopsies from healthy controls, were included in our study. Cytokines and markers of mucosal damage were analyzed by real-time PCR, and some of the results confirmed by western-blot and ELISA. Levels of IFNγ, TNFα, IL-6, IL-15, IL-18, and IL-23 were increased (above healthy controls) in both affected and unaffected areas from IBD. IL-1β, IL-6, IL-12, and IL-27 were higher in affected areas compared to unaffected ones in UC but not CD. In general, a correlation was observed between mRNA levels of these cytokines and both iNOS and Granzyme B. SOCS-2 and SOCS-3 were also increased in the affected areas. In conclusion, the unaffected areas from IBD show increased levels of a restricted set of cytokines that may exert immune activating roles in these areas without being able to trigger tissue damage.
Existence of Weak Solutions to a Class of Degenerate Semiconductor Equations Modeling Avalanche Generation
Authors: Wu Bin
Published: July 2009

We consider the drift‐diffusion model with avalanche generation for evolution
in time of electron and hole densities n, p coupled with the electrostatic potential ψ in a semiconductor device. We also assume that the diffusion term is degenerate. The existence of local weak solutions to this Dirichlet‐Neumann mixed boundary value problem is obtained.
Gene Expression Analysis of an EGFR Indirectly Related Pathway Identified PTEN and MMP9 as Reliable Diagnostic Markers for Human Glial Tumor Specimens
Authors: Comincini Sergio , Paolillo Mayra , Barbieri Giulia , Palumbo Silvia , Sbalchiero Elena , Azzalin Alberto , Russo Marika A. , Schinelli Sergio
Published: July 2009

In this study the mRNA levels of five EGFR indirectly related genes, EGFR, HB-EGF, ADAM17, PTEN, and MMP9, have been assessed by Real‐time PCR in a panel of 37 glioblastoma multiforme specimens and in 5 normal brain samples; as a result, in glioblastoma, ADAM17 and PTEN expression was significantly lower than in normal brain samples, and, in particular, a statistically significant inverse correlation was found between PTEN and MMP9 mRNA levels. To verify if this correlation was conserved in gliomas, PTEN and MMP9 expression was further investigated in an additional panel of 16 anaplastic astrocytoma specimens and, in parallel, in different human normal and astrocytic tumor cell lines. In anaplastic astrocytomas PTEN expression was significantly higher than in glioblastoma multiforme, but no significant correlation was found between PTEN and MMP9 expression. PTEN and MMP9 mRNA levels were also employed to identify subgroups of specimens within the different glioma malignancy grades and to define a gene expression‐based diagnostic classification scheme. In conclusion, this gene expression survey highlighted that the combined measurement of PTEN and MMP9 transcripts might represent a novel reliable tool for the differential diagnosis of high‐grade gliomas, and it also suggested a functional link involving these genes in glial tumors.
Optimal Inventory Policy Involving Ordering Cost Reduction, Back‐Order Discounts, and Variable Lead Time Demand by Minimax Criterion
Authors: Wu Jong-Wuu , Lee Wen-Chuan , Lei Chia-Ling
Published: July 2009

This paper allows
the backorder rate as a control variable to
widen applications of a continuous review
inventory model. Moreover, we also consider the
backorder rate that is proposed by combining Ouyang
and Chuang (2001) (or Lee (2005) with Pan and Hsiao
(2001) to present a new form. Thus, the backorder
rate is dependent on the amount of shortages and
backorder price discounts. Besides, we also
treat the ordering cost as a decision variable.
Hence, we develop an algorithmic procedure to
find the optimal inventory policy by minimax
criterion. Finally, a numerical example is also
given to illustrate the results.
Androgen Receptor Inhibits Estrogen Receptor-α Activity and Is Prognostic in Breast Cancer
Authors: Peters Amelia A. , Buchanan Grant , Ricciardelli Carmela , Bianco-Miotto Tina , Centenera Margaret M. , Harris Jonathan M. , Jindal Shalini , Segara Davendra , Jia Li , Moore Nicole L. , Henshall Susan M. , Birrell Stephen N. , Coetzee Gerhard A. , Sutherland Robert L. , Butler Lisa M. , Tilley Wayne D.
Published: July 2009

There is emerging evidence that the balance between estrogen receptor-α (ERα) and androgen receptor (AR) signaling is a critical determinant of growth in the normal and malignant breast. In this study, we assessed AR status in a cohort of 215 invasive ductal breast carcinomas. AR and ERα were coexpressed in the majority (80-90%) of breast tumor cells. Kaplan-Meier product limit analysis and multivariate Cox regression showed that AR is an independent prognostic factor in ERα-positive disease, with a low level of AR (less than median of 75% positive cells) conferring a 4.6-fold increased risk of cancer-related death (P = 0.002). Consistent with a role for AR in breast cancer outcome, AR potently inhibited ERα transactivation activity and 17β-estradiol–stimulated growth of breast cancer cells. Transfection of MDA-MB-231 breast cancer cells with either functionally impaired AR variants or the DNA-binding domain of the AR indicated that the latter is both necessary and sufficient for inhibition of ERα signaling. Consistent with molecular modeling, electrophoretic mobility shift assays showed binding of the AR to an estrogen-responsive element (ERE). Evidence for a functional interaction of the AR with an ERE in vivo was provided by chromatin immunoprecipitation data, revealing recruitment of the AR to the progesterone receptor promoter in T-47D breast cancer cells. We conclude that, by binding to a subset of EREs, the AR can prevent activation of target genes that mediate the stimulatory effects of 17β-estradiol on breast cancer cells. [Cancer Res 2009;69(15):6131–40]
Paracrine Hedgehog Signaling in Cancer
Authors: Theunissen Jan-Willem , de Sauvage Frederic J.
Published: July 2009

Ligand-dependent and ligand-independent activation of the Hedgehog (Hh) signaling pathway is involved in tumorigenesis. The importance of mutations in Hh pathway components leading to constitutive signaling has been well established in basal cell carcinoma and medulloblastoma. However, the role of ligand-driven Hh pathway activation in cancer remains to be established. Three recent articles support a model in which, in the absence of mutations in the Hh pathway, Hh ligands expressed by a subset of epithelial cancers, including colon, pancreatic, and ovarian cancer, promote tumor growth indirectly by activating Hh signaling in the surrounding stroma, which, in turn, provides a more favorable environment for tumor growth. These data have important implications for the use of Hh pathway inhibitors currently in development and for selection of tumors likely to respond to such inhibitors. [Cancer Res 2009;69(15):6007–10]
Specific Targeting of Brain Tumors with an Optical/Magnetic Resonance Imaging Nanoprobe across the Blood-Brain Barrier
Authors: Veiseh Omid , Sun Conroy , Fang Chen , Bhattarai Narayan , Gunn Jonathan , Kievit Forrest , Du Kim , Pullar Barbara , Lee Donghoon , Ellenbogen Richard G. , Olson Jim , Zhang Miqin
Published: July 2009

Nanoparticle-based platforms have drawn considerable attention for their potential effect on oncology and other biomedical fields. However, their in vivo application is challenged by insufficient accumulation and retention within tumors due to limited specificity to the target, and an inability to traverse biological barriers. Here, we present a nanoprobe that shows an ability to cross the blood-brain barrier and specifically target brain tumors in a genetically engineered mouse model, as established through in vivo magnetic resonance and biophotonic imaging, and histologic and biodistribution analyses. The nanoprobe is comprised of an iron oxide nanoparticle coated with biocompatible polyethylene glycol–grafted chitosan copolymer, to which a tumor-targeting agent, chlorotoxin, and a near-IR fluorophore are conjugated. The nanoprobe shows an innocuous toxicity profile and sustained retention in tumors. With the versatile affinity of the targeting ligand and the flexible conjugation chemistry for alternative diagnostic and therapeutic agents, this nanoparticle platform can be potentially used for the diagnosis and treatment of a variety of tumor types. [Cancer Res 2009;69(15):6200–7]
Characterization of an Extensive Transverse Tubular Network in Sheep Atrial Myocytes and its Depletion in Heart Failure
Authors: Dibb Katharine M. , Clarke Jessica D. , Horn Margaux A. , Richards Mark A. , Graham Helen K. , Eisner David A. , Trafford Andrew W.
Published: July 2009

Background—

In ventricular myocytes, the majority of structures that couple excitation to the systolic rise of Ca
2+
are located at the transverse tubular (t-tubule) membrane. In the failing ventricle, disorganization of t-tubules disrupts excitation contraction coupling. The t-tubule membrane is virtually absent in the atria of small mammals resulting in spatiotemporally distinct profiles of intracellular Ca
2+
release on stimulation in atrial and ventricular cells. The aims of this study were to determine (i) whether atrial myocytes from a large mammal (sheep) possess t-tubules, (ii) whether these are functionally important, and (iii) whether they are disrupted in heart failure.

Methods and Results—

Sheep left atrial myocytes were stained with di-4-ANEPPS. Nearly all control cells had an extensive t-tubule network resulting in each voxel in the cell being nearer to a membrane (sarcolemma or t-tubule) than would otherwise be the case. T-tubules decrease the distance of 50% of voxels from a membrane from 3.35�0.15 to 0.88�0.04 μm. During depolarization, intracellular Ca
2+
rises simultaneously at the cell periphery and center. In heart failure induced by rapid ventricular pacing, there was an almost complete loss of atrial t-tubules. The distance of 50% of voxels from a membrane increased to 2.04�0.08 μm, and there was a loss of early Ca
2+
release from the cell center.

Conclusion—

Sheep atrial myocytes possess a substantial t-tubule network that synchronizes the systolic Ca
2+
transient. In heart failure, this network is markedly disrupted. This may play an important role in changes of atrial function in heart failure.
Drug-Eluting Stent Thrombosis in Routine Clinical Practice
Authors: Lasala John M. , Cox David A. , Dobies David , Baran Kenneth , Bachinsky William B. , Rogers Edwin W. , Breall Jeffrey A. , Lewis David H. , Song Aijun , Starzyk Ruth M. , Mascioli Stephen R. , Dawkins Keith D. , Baim Donald S.
Published: July 2009

Background—

Stent thrombosis (ST) is an uncommon but serious complication of drug-eluting and bare metal stents. To assess drug-eluting stent ST in contemporary practice, we analyzed 2-year data from the 7492-patient ARRIVE registry.

Methods and Results—

Patients were enrolled at the initiation of percutaneous coronary intervention with no inclusion/exclusion criteria beyond use of the paclitaxel-eluting TAXUS stent. Two-year follow-up was 94% with independent adjudication of major cardiac events. A second, autonomous committee adjudicated Academic Research Consortium (ARC) definite/probable ST. Cumulative 2-year ARC-defined ST was 2.6% (1.0% early ST [<30 days], 0.7% late ST [31 to 365 days], and 0.8% very late ST [>1 year]). Simple-use (single-vessel and single-stent) cases had lower rates than expanded use (broader patient/lesion characteristics, 2-year cumulative: 1.4% versus 3.3%,
P
<0.001; early ST: 0.4% versus 1.4%,
P
<0.001; late ST: 0.5% versus 0.8%,
P
=0.14; very late ST: 0.4% versus 1.0%,
P
=0.008). Within 7 days of ST, 23% of patients died; 28% suffered Q-wave myocardial infarction. Mortality was higher with early ST (39%) than late ST (12%,
P
<0.001) or very late ST (13%,
P
<0.001). Multivariate analysis showed anatomic factors increased early ST (lesion >28 mm, lesion calcification) and late ST (vessel <3.0 mm); biological factors increased very late ST (renal disease, prior brachytherapy). Although early ST (71.4%) and very late ST (23.1%) patients had dual antiplatelet therapy at the time of ST, premature thienopyridine discontinuation was a strong independent predictor of both.

Conclusions—

The relative risks of early and late ST differ. Knowledge of ST risk for specific subgroups may guide revascularization options until the completion of randomized trials in these broad populations.
Effect of High-Dose Intracoronary Adenosine Administration During Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction
Authors: Fokkema Marieke L. , Vlaar Pieter J. , Vogelzang Mathijs , Gu Youlan L. , Kampinga Marthe A. , de Smet Bart J. , Jessurun Gillian A. , Anthonio Rutger L. , van den Heuvel Ad F. , Tan Eng-Shiong , Zijlstra Felix
Published: July 2009

Background—

Coronary microvascular dysfunction is frequently seen in patients with ST-elevation myocardial infarction after primary percutaneous coronary intervention. Previous studies have suggested that the administration of intravenous adenosine resulted in an improvement of myocardial perfusion and a reduction in infarct size. Intracoronary adenosine (bolus of 30 to 60 μg) is a guideline-recommended therapy to improve myocardial reperfusion. The effect of intracoronary adenosine during primary percutaneous coronary intervention has not been investigated in a large randomized trial.

Methods and Results—

Patients presenting with acute ST-elevation myocardial infarction were randomized to 2 bolus injections of intracoronary adenosine (2�120 μg in 20 mL NaCl) or placebo (2�20 mL NaCl). The first bolus injection was given after thrombus aspiration and the second after stenting of the infarct-related artery. The primary end point was the incidence of residual ST-segment deviation <0.2 mV, 30 to 60 minutes after percutaneous coronary intervention. Secondary end points were ST-segment elevation resolution, myocardial blush grade, Thrombolysis in Myocardial Infarction flow on the angiogram after percutaneous coronary intervention, enzymatic infarct size, and clinical outcome at 30 days. A total of 448 patients were randomized to intracoronary adenosine (N=226) or placebo (N=222). The incidence of residual ST-segment deviation <0.2 mV did not differ between patients randomized to adenosine or placebo (46.2% versus 52.2%,
P
=NS). In addition, there were no significant differences in secondary outcome measures.

Conclusions—

In this randomized placebo controlled trial enrolling 448 patients with ST-elevation myocardial infarction, administration of intracoronary adenosine after thrombus aspiration and after stenting of the infarct-related artery did not result in improved myocardial perfusion.
Dopamine, Paranormal Belief, and the Detection of Meaningful Stimuli
Authors: Krummenacher Peter , Mohr Christine , Haker Helene , Brugger Peter
Published: July 2009

Dopamine (DA) is suggested to improve perceptual and cognitive decisions by increasing the signal-to-noise ratio. Somewhat paradoxically, a hyperdopaminergia (arguably more accentuated in the right hemisphere) has also been implied in the genesis of unusual experiences such as hallucinations and paranormal thought. To test these opposing assumptions, we used two lateralized decision tasks, one with lexical (tapping left-hemisphere functions), the other with facial stimuli (tapping right-hemisphere functions). Participants were 40 healthy right-handed men, of whom 20 reported unusual, “paranormal” experiences and beliefs (“believers”), whereas the remaining participants were unexperienced and critical (“skeptics”). In a between-subject design, levodopa (200 mg) or placebo administration was balanced between belief groups (double-blind procedure). For each task and visual field, we calculated sensitivity (d′) and response tendency (criterion) derived from signal detection theory. Results showed the typical right visual field advantage for the lexical decision task and a higher d′ for verbal than facial stimuli. For the skeptics, d′ was lower in the levodopa than in the placebo group. Criterion analyses revealed that believers favored false alarms over misses, whereas skeptics displayed the opposite preference. Unexpectedly, under levodopa, these decision preferences were lower in both groups. We thus infer that levodopa (1) decreases sensitivity in perceptual–cognitive decisions, but only in skeptics, and (2) makes skeptics less and believers slightly more conservative. These results stand at odd to the common view that DA generally improves signal-to-noise ratios. Paranormal ideation seems an important personality dimension and should be assessed in investigations on the detection of signals in noise.
Word Retrieval Failures in Old Age: The Relationship between Structure and Function
Authors: Shafto Meredith A. , Stamatakis Emmanuel A. , Tam Phyllis P. , Tyler L. K.
Published: July 2009

A common complaint of normal aging is the increase in word-finding failures such as tip-of-the-tongue states (TOTs). Behavioral research identifies TOTs as phonological retrieval failures, and recent findings [Shafto, M. A., Burke, D. M., Stamatakis, E. A., Tam, P., & Tyler, L. K. On the tip-of-the-tongue: Neural correlates of increased word-finding failures in normal aging. Journal of Cognitive Neuroscience, 19, 2060–2070, 2007] link age-related increases in TOTs to atrophy in left insula, a region implicated in phonological production. Here, younger and older adults performed a picture naming task in the fMRI scanner. During successful naming, left insula activity was not affected by age or gray matter integrity. Age differences only emerged during TOTs, with younger but not older adults generating a “boost” of activity during TOTs compared to successful naming. Older adults also had less activity than younger adults during TOTs compared to “don't know” responses, and across all participants, less TOT activity was affiliated with lower gray matter density. For older adults, lower levels of activity during TOTs accompanied higher TOT rates, supporting the role of an age-related neural mechanism impacting older more than younger adults. Results support a neural account of word retrieval in old age wherein, despite widespread age-related atrophy, word production processes are not universally impacted by age. However, atrophy undermines older adults' ability to modulate neural responses needed to overcome retrieval failures.