bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary Severe Acute Respiratory Syndrome Coronavirus Infection Limits Replication but Not Lung Inflammation upon Homologous Rechallenge
Authors: Clay Candice , Donart Nathan , Fomukong Ndingsa , Knight Jennifer B. , Lei Wanli , Price Lance , Hahn Fletcher , Van Westrienen Jesse , Harrod Kevin S.
Published: February 2012

Our knowledge regarding immune-protective and immunopathogenic events in severe acute respiratory syndrome coronavirus (SARS-CoV) infection is limited, and little is known about the dynamics of the immune response at the primary site of disease. Here, an African green monkey (AGM) model was used to elucidate immune mechanisms that facilitate viral clearance but may also contribute to persistent lung inflammation following SARS-CoV infection. During primary infection, SARS-CoV replicated in the AGM lung for up to 10 days. Interestingly, lung inflammation was more prevalent following viral clearance, as leukocyte numbers peaked at 14 days postinfection (dpi) and remained elevated at 28 dpi compared to those of mock-infected controls. Lung macrophages but not dendritic cells were rapidly activated, and both cell types had high activation marker expression at late infection time points. Lung proinflammatory cytokines were induced at 1 to 14 dpi, but most returned to baseline by 28 dpi except interleukin 12 (IL-12) and gamma interferon. In SARS-CoV homologous rechallenge studies, 11 of the 12 animals were free of replicating virus at day 5 after rechallenge. However, incidence and severity of lung inflammation was not reduced despite the limited viral replication upon rechallenge. Evaluating the role of antibodies in immune protection or potentiation revealed a progressive increase in anti-SARS-CoV antibodies in lung and serum that did not correlate temporally or spatially with enhanced viral replication. This study represents one of the first comprehensive analyses of lung immunity, including changes in leukocyte populations, lung-specific cytokines, and antibody responses following SARS-CoV rechallenge in AGMs.
Induction of the Cellular MicroRNA, Hs_154, by West Nile Virus Contributes to Virus-Mediated Apoptosis through Repression of Antiapoptotic Factors
Authors: Smith Jessica L. , Grey Finn E. , Uhrlaub Jennifer L. , Nikolich-Zugich Janko , Hirsch Alec J.
Published: February 2012

MicroRNAs (miRNAs) are a class of noncoding small RNAs that regulate multiple cellular processes, as well as the replication and pathogenesis of many DNA viruses and some RNA viruses. Examination of cellular miRNA profiles in West Nile virus (WNV)-infected HEK293 and SK-N-MC cells revealed increased expression of multiple miRNA species. One of these miRNAs, Hs_154, was significantly induced not only in WNV-infected neuronal cells in culture but also in the central nervous system tissues of infected mice and, upon transfection, caused a significant reduction in viral replication. Analysis of mRNA transcripts enriched through immunoprecipitation of the RNA-induced silencing complex identified several transcripts that contain seed sequence matches to Hs_154 in their 3′ untranslated regions (UTRs). Two of these targets, the CCCTC-binding factor (CTCF) and the epidermal growth factor receptor (EGFR)-coamplified and overexpressed protein (ECOP/VOPP1) proteins display reduced expression in WNV-infected cells, and the 3′ UTRs of these transcripts were sufficient to cause downregulation of expression in infected cells or in cells transfected with Hs_154, findings consistent with miRNA targeting of these transcripts. CTCF and ECOP have been shown to be associated with cell survival, implicating miRNA-directed repression of these targets in WNV-induced cell death. Consistent with this hypothesis, expression of these genes in WNV-infected cells results in a reduction in the number of cells undergoing apoptosis. These observations suggest that induction of Hs_154 expression after WNV infection modulates the apoptotic response to WNV and that cellular miRNA expression can be quickly altered during WNV infection to control aspects of the host response.
A Local, Interactive Network of 3′ RNA Elements Supports Translation and Replication of Turnip Crinkle Virus
Authors: Yuan Xuefeng , Shi Kerong , Simon Anne E.
Published: February 2012

The majority of the 3′ untranslated region (UTR) of
Turnip crinkle virus
(TCV) was previously identified as forming a highly interactive structure with a ribosome-binding tRNA-shaped structure (TSS) acting as a scaffold and undergoing a widespread conformational shift upon binding to RNA-dependent RNA polymerase (RdRp). Tertiary interactions in the region were explored by identifying two highly detrimental mutations within and adjacent to a hairpin H4 upstream of the TSS that reduce translation
in vivo
and cause identical structural changes in the loop of the 3′ terminal hairpin Pr. Second-site changes that compensate for defects in translation/accumulation and reverse the structural differences in the Pr loop were found in the Pr stem, as well as in a specific stem within the TSS and within the capsid protein (CP) coding region, suggesting that the second-site changes were correcting a conformational defect and not restoring specific base pairing. The RdRp-mediated conformational shift extended upstream through this CP open reading frame (ORF) region after bypassing much of an intervening, largely unstructured region, supporting a connection between 3′ elements and coding region elements. These data suggest that the Pr loop, TSS, and H4 are central elements in the regulation of translation and replication in TCV and allow for development of an RNA interactome that maps the higher-order structure of a postulated RNA domain within the 3′ region of a plus-strand RNA virus.
Single-Dose Immunization with Virus Replicon Particles Confers Rapid Robust Protection against Rift Valley Fever Virus Challenge
Authors: Dodd Kimberly A. , Bird Brian H. , Metcalfe Maureen G. , Nichol Stuart T. , Albariño César G.
Published: February 2012

Rift Valley fever virus (RVFV) causes outbreaks of severe disease in people and livestock throughout Africa and the Arabian Peninsula. The potential for RVFV introduction outside the area of endemicity highlights the need for fast-acting, safe, and efficacious vaccines. Here, we demonstrate a robust system for the reverse genetics generation of a RVF virus replicon particle (VRP
RVF
) vaccine candidate. Using a mouse model, we show that VRP
RVF
immunization provides the optimal balance of safety and single-dose robust efficacy. VRP
RVF
can actively synthesize viral RNA and proteins but lacks structural glycoprotein genes, preventing spread within immunized individuals and reducing the risk of vaccine-induced pathogenicity. VRP
RVF
proved to be completely safe following intracranial inoculation of suckling mice, a stringent test of vaccine safety. Single-dose subcutaneous immunization with VRP
RVF
, although it is highly attenuated, completely protected mice against a virulent RVFV challenge dose which was 100,000-fold greater than the 50% lethal dose (LD
50
). Robust protection from lethal challenge was observed by 24 h postvaccination, with 100% protection induced in as little as 96 h. We show that a single subcutaneous VRP
RVF
immunization initiated a systemic antiviral state followed by an enhanced adaptive response. These data contrast sharply with the much-reduced survivability and immune responses observed among animals immunized with nonreplicating viral particles, indicating that replication, even if confined to the initially infected cells, contributes substantially to protective efficacy at early and late time points postimmunization. These data demonstrate that replicon vaccines successfully bridge the gap between safety and efficacy and provide insights into the kinetics of antiviral protection from RVFV infection.
Cohort profile: Ho Chi Minh City Youth Cohort—changes in diet, physical activity, sedentary behaviour and relationship with overweight/obesity in adolescents
Authors: Trang Nguyen Hoang Hanh Doan , Hong Tang Kim , Dibley Michael John
Published: February 2012

Objectives

The Ho Chi Minh Youth cohort study aimed to assess the change in nutritional status; indicators of adiposity; diet; physical activity and sedentary behaviours; home, neighbourhood and school microenvironments and their complex relationships in adolescents in urban areas of Ho Chi Minh City.

Design

Prospective 5-year cohort.

Setting

Systematic random sampling was used to select 18 schools in urban districts.

Participants

Children were followed up over 5 years with an assessment in each year. Consent, from both adolescents and their parents, was required. At baseline, 759 students were recruited into the cohort, and of these students, 740 remained in the cohort for the first round, 712 for the second round, 630 for the third round and 585 for the last round of follow-up.

Primary and secondary outcome measures

Anthropometric measurements were taken using established guidelines. Six main groups of exposure factors including dietary intake and behaviours, physical activity and sedentary behaviours, family social and physical environment, school environment, socioeconomic status and parental characteristics were measured.

Results

Retention rate was high (77%). Within 5-year period, the prevalence of combined overweight and obesity using International Obesity Task Force cut-off values increased from 14.2% to 21.8%. Time spent on physical activity decreased significantly in the 5-year period from 87 to 50 min/day. Time spent on sedentary behaviours increased in the 5-year period from 512 to 600 min/day.

Conclusions

The complete data analysis of this cohort study will allow a full exploration of the role of environmental and lifestyle behaviours on adolescent overweight and obesity and also identify the factors most strongly associated with excess weight gain and the appearance of overweight and obesity in different age groups of adolescents from this large city in Vietnam.
Unequal access to ART: exploratory results from rural and urban case studies of ART use
Authors: Cleary Susan May , Birch Stephen , Moshabela Mosa , Schneider Helen
Published: February 2012

Introduction

South Africa has the world's largest antiretroviral treatment (ART) programme. While services in the public sector are free at the point of use, little is known about overall access barriers. This paper explores these barriers from the perspective of ART users enrolled in services in two rural and two urban settings.

Methods

Using a comprehensive framework of access, interviews were conducted with over 1200 ART users to assess barriers along three dimensions: availability, affordability and acceptability. Summary statistics were computed and comparisons of access barriers between sites were explored using multivariate linear and logistic regressions.

Results

While availability access barriers in rural settings were found to be mitigated through a more decentralised model of service provision in one site, affordability barriers were considerably higher in rural versus urban settings. 50% of respondents incurred catastrophic healthcare expenditure and 36% borrowed money to cover these expenses in one rural site. On acceptability, rural users were less likely to report feeling respected by health workers. Stigma was reported to be lowest in the two sites with the most decentralised services and the highest coverage of those in need.

Conclusions

While results suggest inequitable access to ART for rural relative to urban users, nurse-led services offered through primary healthcare facilities mitigated these barriers in one rural site. This is an important finding given current policy emphasis on decentralised and nurse-led ART in South Africa. This study is one of the first to present comprehensive evidence on access barriers to assist in the design of policy solutions.
Prevention of mother-to-child transmission of HIV: assessing the accuracy of routinely collected data on maternal antiretroviral prophylaxis coverage in Kenya
Authors: Ferguson Laura , Grant Alison D , Ong'ech John O , Vusha Sophie , Watson-Jones Deborah , Ross David A
Published: February 2012

Objective

To explore the accuracy of routinely collected prevention of mother-to-child transmission of HIV (PMTCT) coverage data in Kenya.

Methods

In case studies at two government hospitals, the authors reviewed national reporting guidelines, interviewed nurses and undertook a retrospective analysis of routine hospital data from antenatal care, maternity and HIV services from January 2009 to June 2010. Each woman attending these services was given a unique study number to enable analysis of her recorded use of PMTCT services across different hospital visits. These data were compared with the hospitals' monthly PMTCT reports to the district.

Results

Where a woman made more than one visit, PMTCT drug provision could be reported multiple times for the same woman, and women known to be HIV positive prior to pregnancy were omitted from the denominator of PMTCT coverage calculations. Practices for reporting data on maternal PMTCT prophylaxis provision varied in the two hospitals. According to the study data, using the hospital registers and accounting for multiple visits by the same woman, 642 women were known to have HIV and 412 (64%) were given maternal PMTCT prophylaxis. According to the monthly reports, 430 women were diagnosed as having HIV in pregnancy-related services and 538 (125%) were given maternal PMTCT prophylaxis.

Conclusions

If replicated elsewhere, these reporting practices could lead to overestimation of national PMTCT coverage. Simple yet accurate routine data collection systems are needed to monitor PMTCT coverage accurately and to highlight where changes need to be made so as to ensure that infants are born HIV free.
What are the elements of the tobacco endgame?
Authors: Thomson George , Edwards Richard , Wilson Nick , Blakely Tony
Published: February 2012

The available literature on tobacco endgames tends to be limited to discussing means, targets and difficulties. This article offers additional ideas on the key elements of endgame strategies and the circumstances in which these are likely to be adopted and implemented. We suggest such strategies will include explicit plans, will define the nature of `the end of tobacco use/sale' and have target dates within 20 years. The likely circumstances for endgame strategy development include low (probably under 15% adult smoking) prevalence and/or rapid prevalence reductions, wide support and strong political leadership. Even with some or all these circumstances, opposition from business, internal government forces and international factors may influence results.
MINIMAL TRAFFIC MODEL WITH SAFE DRIVING CONDITIONS
Authors: TERBORG HEINRICH , PÉREZ LUIS A.
Published: February 2012

We have developed a new computational traffic model in which security aspects are fundamental. In this paper we show that this model reproduces many known empirical aspects of vehicular traffic such as the three states of traffic flow and the backward speed of the downstream front of a traffic jam (C), without the aid of adjustable parameters. The model is studied for both open and closed single lane traffic systems. Also, we were able to analytically compute the value of C as 15.37 km/h from a relation that only includes the human reaction time, the mean vehicle length and the effective friction coefficient during the braking process of a vehicle as its main components.
UPPER SEMICONTINUITY OF GLOBAL ATTRACTORS FOR 2D NAVIER–STOKES EQUATIONS
Authors: ZHAO CAIDI , DUAN JINQIAO
Published: February 2012

In this paper, the authors consider the two-dimensional Navier–Stokes equations defined on Ω = ℝ × (-L, L) and [Formula: see text], where [Formula: see text] is an expanding sequence of simply connected, bounded and smooth subdomains of Ω such that Ωm → Ω as m → ∞. Let [Formula: see text] and [Formula: see text] be the global attractors of the equations corresponding to Ω and Ωm, respectively, we establish that for any neighborhood [Formula: see text] of [Formula: see text], the global attractor [Formula: see text] enters [Formula: see text] if m is large enough.
A VERY SIMPLE CRITERION FOR CHARACTERIZING THE CROSSING DIRECTION OF TIME-DELAY SYSTEMS WITH DELAY-DEPENDENT PARAMETERS
Authors: WANG ZAI HUA
Published: February 2012

In this paper, a very simple criterion has been established for checking the crossing direction of a characteristic root crossing the imaginary axis for a class of time-delay systems with delay-dependent parameters, an important topic both in stability analysis and Hopf bifurcation. The criterion uses two easy-to-obtain functions with clear physical meaning from the critical stability condition and it generalizes a popular result in the literature.
NOISE LEVEL ESTIMATION FOR A CHAOTIC TIME SERIES
Authors: XU PENGCHENG , LI W. K. , JAYAWARDENA A. W.
Published: February 2012

In this study, the correlation sum and the correlation integral for chaotic time series using the Supremum norm and the Euclidean norm are discussed. The correlation integrals are then used to develop governing equations for the correlation sum, noise level and correlation dimension in which the correlation dimension and the noise level are linearly dependent on each other. Some linear estimation methods for the noise level are then introduced by using these equations. The estimation methods are applied to four chaotic time series (two artificial and two real-world). By comparing the performances of the estimations of the noise level, the best estimating method is then suggested.
FEEDBACK-INDUCED COMPLEX DYNAMICS IN A TWO-COMPONENT REGULATORY CIRCUIT
Authors: QIU HUAHAI , ZHOU TIANSHOU
Published: February 2012

Coupled positive and negative feedback loops form an essential building block of cellular signaling pathways, but the dynamics of such a system remain to be fully explored. Here, we systematically analyze a two-component circuit with interlinked positive and negative feedback loops, focusing on feedback-induced dynamics and their mechanisms. We show that feedbacks can induce monostability, oscillation, and excitability as well as the coexistence of two attractors (including that of two different stable steady states (called Type-I bistability) and that of both a stable steady state and a stable limit cycle (called Type-II bistability)). In particular for Type-II bistability, we find that feedback-controlled molecular noise can induce stochastic switching between two different attractors, and that the first passage time between them exhibits a multi-peak distribution. These investigations provide insights for understanding the biological functions of coupled positive and negative feedback circuits from the viewpoint of dynamics.
BIFURCATION ANALYSIS ON AN HIV-1 MODEL WITH CONSTANT INJECTION OF RECOMBINANT
Authors: YU PEI , ZOU XINGFU
Published: February 2012

This paper is a continuation of our previous work on an HIV-1 therapy model of fighting a virus with another virus [Jiang et al., 2009]. The work in [Jiang et al., 2009] investigated cascading bifurcations between equilibrium solutions, as well as Hopf bifurcation from a double-infected equilibrium solution. In this paper, we propose a modification of the model in [Revilla & Garcia-Ramos, 2003; Jiang et al., 2009] by adding a constant η to the recombinant virus equation, which accounts for the treatment of constant injection of recombinants. We study the dynamics of the new model and find that η plays an important role in the therapy. Unlike the previous model without injection of recombinant, which has three equilibrium solutions, this new model can only allow two biologically meaningful equilibrium solutions.

It is shown that there is [Formula: see text] depending on η, such that the HIV free equilibrium solution [Formula: see text] is globally asymptotically stable when the basic reproduction ratio, [Formula: see text]; [Formula: see text] becomes unstable when [Formula: see text]. In the latter case, there occurs the double-infection equilibrium solution, [Formula: see text], which is stable when [Formula: see text] for some [Formula: see text] larger than [Formula: see text], and loses its stability when [Formula: see text] passes the critical value [Formula: see text] and bifurcates into a family of limit cycles through Hopf bifurcation. Our results show that appropriate injection rate can help eliminate the HIV virus in the sense that the HIV free equilibrium can be made globally asymptotically stable by choosing η > 0 sufficiently large. This is in contrast to the conclusion for the case with η = 0 in which, the recombinants do not help eliminate the HIV virus but only help reduce the HIV load in the long term sense.
ON THE MAXIMUM NUMBER OF LIMIT CYCLES OF A CLASS OF GENERALIZED LIÉNARD DIFFERENTIAL SYSTEMS
Authors: ALAVEZ-RAMÍREZ JUSTINO , BLÉ GAMALIEL , LÓPEZ-LÓPEZ JORGE , LLIBRE JAUME
Published: February 2012

Applying the averaging theory of first, second and third order to one class generalized polynomial Liénard differential equations, we improve the known lower bounds for the maximum number of limit cycles that this class can exhibit.
MEMRISTIVE CHAOTIC CIRCUITS BASED ON CELLULAR NONLINEAR NETWORKS
Authors: BUSCARINO ARTURO , FORTUNA LUIGI , FRASCA MATTIA , GAMBUZZA LUCIA VALENTINA , SCIUTO GREGORIO
Published: February 2012

Memristors are gaining increasing interest in the scientific community for their possible applications, e.g. high-speed low-power processors or new biological models for associative memories. Due to the intrinsic nonlinear characteristic of memristive devices, it is possible to use them in the design of new dynamical circuits that are able to show complex behavior, like chaos. In this paper, two new memristive chaotic circuits are presented discussing, in particular, an approach based on Cellular Nonlinear Networks for the implementation of the memristive device. The approach investigated in this paper allows to obtain memristors with common off-the-shelf components and to observe the onset of new chaotic attractors in nonlinear circuits with memristors. Furthermore, the circuits presented in this paper, being the first examples of memristive chaotic circuits based on CNNs, can be considered as the link between the three inventions by Leon O. Chua, i.e. the memristor, the first chaotic electronic circuit and Cellular Nonlinear Networks.
TIME AND IRREVERSIBILITY IN AN ACCELERATING UNIVERSE
Authors: ROMERO GUSTAVO E. , PÉREZ DANIELA
Published: February 2012

It is a remarkable fact that all processes occurring in the observable universe are irreversible, whereas the equations through which the fundamental laws of physics are formulated are invariant under time reversal. The emergence of irreversibility from the fundamental laws has been a topic of consideration by physicists, astronomers and philosophers since Boltzmann's formulation of his famous "H" theorem. In this paper, we shall discuss some aspects of this problem and its connection with the dynamics of spacetime, within the framework of modern cosmology. We conclude that the existence of cosmological horizons allows a coupling of the global state of the universe with the local events determined through electromagnetic processes.
THE HYDRODYNAMICS OF ATOMS OF SPACETIME: GRAVITATIONAL FIELD EQUATION IS NAVIER–STOKES EQUATION
Authors: PADMANABHAN T.
Published: February 2012

There is considerable evidence to suggest that field equations of gravity have the same conceptual status as the equations of hydrodynamics or elasticity. We add further support to this paradigm by showing that Einstein"s field equations are identical in form to Navier–Stokes equations of hydrodynamics, when projected on to any null surface. In fact, these equations can be obtained directly by extremizing of entropy associated with the deformations of null surfaces thereby providing a completely thermodynamic route to gravitational field equations. Several curious features of this remarkable connection (including a phenomenon of "dissipation without dissipation") are described and the implications for the emergent paradigm of gravity is highlighted.
A GRAVITATIONAL MECHANISM FOR COSMOLOGICAL SCREENING
Authors: TSAMIS N. C. , WOODARD R. P.
Published: February 2012

Infrared gravitons are continually produced during inflation. Like all particles, their contribution to the vacuum energy comes not only from their bare kinetic energy but also from the interactions they have with other gravitons. These interactions can be substantial — despite the particles being highly infrared — because they occur over the enormous spatial volume of the universe. Furthermore, the interactions grow with time evolution because more and more such gravitons come into causal contact with one another. Since gravity is universally attractive, these interactions can act to slow and eventually stop accelerated expansion.
GRAVITATION, HOLOGRAPHIC PRINCIPLE, AND THE NUMBER OF SPATIAL DIMENSIONS
Authors: HOD SHAHAR
Published: February 2012

The holographic bound asserts that the entropy S of a system is bounded from above by a quarter of the area [Formula: see text] of a circumscribing surface measured in Planck areas: [Formula: see text]. This bound is widely regarded a desideratum of any fundamental theory of nature. In fact, the bound is known to be valid for generic systems in three spatial dimensions. However, in this essay we explicitly show that hyperentropic systems (those violating the holographic entropy bound) do exist in higher-dimensional spacetimes. This is a new and surprising result which should be taken into account in the construction of any fundamental quantum theory of gravity.
ON THE MEANING OF GENERAL COVARIANCE AND THE RELEVANCE OF OBSERVERS IN GENERAL RELATIVITY
Authors: HERRERA L.
Published: February 2012

Since the appearance of General Relativity, its intrinsec general covariance has been very often misinterpreted as implying that physically meaningful quantities (and conclusions extracted from the theory) have to be absolutely independent on observers. This incorrect point of view is sometimes expressed by discarding the very concept of observer in the structure and applications of the theory. As we shall stress in this essay, through some examples, the concept of observer is as essential to General Relativity as it is to any physical theory.
THE VALUE OF THE COSMOLOGICAL CONSTANT
Authors: BARROW JOHN D. , SHAW DOUGLAS J.
Published: February 2012

We make the cosmological constant, Λ, into a field and restrict the variations of the action with respect to it by causality. This creates an additional Einstein constraint equation. It restricts the solutions of the standard Einstein equations and is the requirement that the cosmological wave function possess a classical limit. When applied to the Friedmann metric it requires that the cosmological constant measured today, tU, be [Formula: see text], as observed. This is the classical value of Λ that dominates the wave function of the universe. Our new field equation determines Λ in terms of other astronomically measurable quantities. Specifically, it predicts that the spatial curvature parameter of the universe is [Formula: see text], which will be tested by Planck Satellite data. Our theory also creates a new picture of self-consistent quantum cosmological history.
RECENT DEVELOPMENTS IN GRAVITATIONAL COLLAPSE AND SPACETIME SINGULARITIES
Authors: JOSHI PANKAJ S. , MALAFARINA DANIELE
Published: February 2012

It is now known that when a massive star collapses under the force of its own gravity, the final fate of such a continual gravitational collapse will be either a black hole or a naked singularity under a wide variety of physically reasonable circumstances within the framework of general theory of relativity. The research of recent years has provided considerable clarity and insight on stellar collapse, black holes and the nature and structure of spacetime singularities. We discuss several of these developments here. There are also important fundamental questions that remain unanswered on the final fate of collapse of a massive matter cloud in gravitation theory, especially on naked singularities which are hypothetical astrophysical objects and on the nature of cosmic censorship hypothesis. These issues have key implications for our understanding on black hole physics today, its astrophysical applications, and for certain basic questions in cosmology and possible quantum theories of gravity. We consider these issues here and summarize recent results and current progress in these directions. The emerging astrophysical and observational perspectives and implications are discussed, with particular reference to the properties of accretion disks around black holes and naked singularities, which may provide characteristic signatures and could help distinguish these objects.
Vulnerability of the retinal microvasculature to oxidative stress: ion channel-dependent mechanisms
Authors: Fukumoto Masanori , Nakaizumi Atsuko , Zhang Ting , Lentz Stephen I. , Shibata Maho , Puro Donald G.
Published: February 2012

Although oxidative stress is a hallmark of important vascular disorders such as diabetic retinopathy, it remains unclear why the retinal microvasculature is particularly vulnerable to this pathophysiological condition. We postulated that redox-sensitive ion channels may play a role. Using H2O2 to cause oxidative stress in microvascular complexes freshly isolated from the adult rat retina, we assessed ionic currents, cell viability, intracellular oxidants, and cell calcium by using perforated-patch recordings, trypan blue dye exclusion, and fura-2 fluorescence, respectively. Supporting a role for the oxidant-sensitive ATP-sensitive K (KATP) channels, we found that these channels are activated during exposure of retinal microvessels to H2O2. Furthermore, their inhibition by glibenclamide significantly lessened H2O2-induced microvascular cell death. Additional experiments established that by increasing the influx of calcium into microvascular cells, the KATP channel-mediated hyperpolarization boosted the vulnerability of these cells to oxidative stress. In addition to the KATP channel-dependent mechanism for increasing the lethality of oxidative stress, we also found that the vulnerability of cells in the capillaries, but not in the arterioles, was further boosted by a KATP channel-independent mechanism, which our experiments indicated involves the oxidant-induced activation of calcium-permeable nonspecific cation channels. Taken together, our findings support a working model in which both KATP channel-independent and KATP channel-dependent mechanisms render the capillaries of the retina particularly vulnerable to oxidative stress. Identification of these previously unappreciated mechanisms for boosting the lethality of oxidants may provide new targets for pharmacologically limiting damage to the retinal microvasculature during periods of oxidative stress.
High-glycemic index carbohydrates abrogate the antiobesity effect of fish oil in mice
Authors: Hao Qin , Lillefosse Haldis H. , Fjære Even , Myrmel Lene Secher , Midtbø Lisa K. , Jarlsby Ragnhild H. , Ma Tao , Jia Bingbing , Petersen Rasmus K. , Sonne Si B. , Chwalibog André , Frøyland Livar , Liaset Bjørn , Kristiansen Karsten , Madsen Lise
Published: February 2012

Fish oil rich in n-3 polyunsaturated fatty acids is known to attenuate diet-induced obesity and adipose tissue inflammation in rodents. Here we aimed to investigate whether different carbohydrate sources modulated the antiobesity effects of fish oil. By feeding C57BL/6J mice isocaloric high-fat diets enriched with fish oil for 6 wk, we show that increasing amounts of sucrose in the diets dose-dependently increased energy efficiency and white adipose tissue (WAT) mass. Mice receiving fructose had about 50% less WAT mass than mice fed a high fish oil diet supplemented with either glucose or sucrose, indicating that the glucose moiety of sucrose was responsible for the obesity-promoting effect of sucrose. To investigate whether the obesogenic effect of sucrose and glucose was related to stimulation of insulin secretion, we combined fish oil with high and low glycemic index (GI) starches. Mice receiving the fish oil diet containing the low-GI starch had significantly less WAT than mice fed high-GI starch. Moreover, inhibition of insulin secretion by administration of nifedipine significantly reduced WAT mass in mice fed a high-fish oil diet in combination with sucrose. Our data show that the macronutrient composition of the diet modulates the effects of fish oil. Fish oil combined with sucrose, glucose, or high-GI starch promotes obesity, and the reported anti-inflammatory actions of fish oil are abrogated. In conclusion, our data indicate that glycemic control of insulin secretion modulates metabolic effects of fish oil by demonstrating that high-GI carbohydrates attenuate the antiobesity effects of fish oil.
Body height and blood pressure regulation in humans during anti-orthostatic tilting
Authors: Arvedsen Sine K. , Damgaard Morten , Norsk Peter
Published: February 2012

The hypothesis was tested that the cardiovascular changes during an upper body anti-orthostatic maneuver in humans are more pronounced in tall than in short individuals, because of the larger intravascular hydrostatic pressure gradients. In 34 males and 41 females [20–30 yr, body height (BH) = 147–206 cm], inter-individual multiple linear regression analyses adjusted for gender and body weight were conducted between changes in cardiovascular variables versus BH during tilting of the upper body from vertical to horizontal while keeping the legs horizontal. In all the subjects, tilting induced increases in stroke volume and arterial pulse pressure and a decrease in heart rate, which each correlated significantly with BH. In males ( n = 51, BH = 163–206 cm), 24-h ambulatory mean arterial pressure increased significantly with BH ( P = 0.004, r = 0.40, α = 0.15 mmHg/cm) so that systolic/diastolic blood pressure increased by 2/2 mmHg per 15 cm increase in BH. There was no significant correlation between mean arterial pressure and BH in females ( n = 53, BH = 147–193 cm). In conclusion, a larger BH induces larger cardiovascular changes during anti-orthostatic tilting, and in males 24-h ambulatory mean arterial pressure increases with BH. The lack of a mean arterial pressure to BH correlation in females is probably because of their lower BH and greater variability in blood pressure.
Role of receptor-mediated endocytosis in the antiangiogenic effects of human T lymphoblastic cell-derived microparticles
Authors: Yang Chun , Xiong Wei , Qiu Qian , Shao Zuo , Hamel David , Tahiri Houda , Leclair Grégoire , Lachapelle Pierre , Chemtob Sylvain , Hardy Pierre
Published: February 2012

Microparticles possess therapeutic potential regarding angiogenesis. We have demonstrated the contribution of apoptotic human CEM T lymphocyte-derived microparticles (LMPs) as inhibitors of angiogenic responses in animal models of inflammation and tumor growth. In the present study, we characterized the antivascular endothelial growth factor (VEGF) effects of LMPs on pathological angiogenesis in an animal model of oxygen-induced retinopathy and explored the role of receptor-mediated endocytosis in the effects of LMPs on human retinal endothelial cells (HRECs). LMPs dramatically inhibited cell growth of HRECs, suppressed VEGF-induced cell migration in vitro experiments, and attenuated VEGF-induced retinal vascular leakage in vivo. Intravitreal injections of fluorescently labeled LMPs revealed accumulation of LMPs in retinal tissue, with more than 60% reductions of the vascular density in retinas of rats with oxygen-induced neovascularization. LMP uptake experiments demonstrated that the interaction between LMPs and HRECs is dependent on temperature. In addition, endocytosis is partially dependent on extracellular calcium. RNAi-mediated knockdown of low-density lipoprotein receptor (LDLR) reduced the uptake of LMPs and attenuated the inhibitory effects of LMPs on VEGF-A protein expression and HRECs cell growth. Intravitreal injection of lentivirus-mediated RNA interference reduced LDLR protein expression in retina by 53% and significantly blocked the antiangiogenic effects of LMPs on pathological vascularization. In summary, the potent antiangiogenic LMPs lead to a significant reduction of pathological retinal angiogenesis through modulation of VEGF signaling, whereas LDLR-mediated endocytosis plays a partial, but pivotal, role in the uptake of LMPs in HRECs.
A role for the organic anion transporter OAT3 in renal creatinine secretion in mice
Authors: Vallon Volker , Eraly Satish A. , Rao Satish Ramachandra , Gerasimova Maria , Rose Michael , Nagle Megha , Anzai Naohiko , Smith Travis , Sharma Kumar , Nigam Sanjay K. , Rieg Timo
Published: February 2012

Tubular secretion of the organic cation, creatinine, limits its value as a marker of glomerular filtration rate (GFR) but the molecular determinants of this pathway are unclear. The organic anion transporters, OAT1 and OAT3, are expressed on the basolateral membrane of the proximal tubule and transport organic anions but also neutral compounds and cations. Here, we demonstrate specific uptake of creatinine into mouse mOat1- and mOat3-microinjected Xenopus laevis oocytes at a concentration of 10 μM (i.e., similar to physiological plasma levels), which was inhibited by both probenecid and cimetidine, prototypical competitive inhibitors of organic anion and cation transporters, respectively. Renal creatinine clearance was consistently greater than inulin clearance (as a measure of GFR) in wild-type (WT) mice but not in mice lacking OAT1 ( Oat1−/−) and OAT3 ( Oat3−/−). WT mice presented renal creatinine net secretion (0.23 ± 0.03 μg/min) which represented 45 ± 6% of total renal creatinine excretion. Mean values for renal creatinine net secretion and renal creatinine secretion fraction were not different from zero in Oat1−/− (−0.03 ± 0.10 μg/min; −3 ± 18%) and Oat3−/− (0.01 ± 0.06 μg/min; −6 ± 19%), with greater variability in Oat1−/−. Expression of OAT3 protein in the renal membranes of Oat1−/− mice was reduced to ∼6% of WT levels, and that of OAT1 in Oat3−/− mice to ∼60%, possibly as a consequence of the genes for Oat1 and Oat3 having adjacent chromosomal locations. Plasma creatinine concentrations of Oat3−/− were elevated in clearance studies under anesthesia but not following brief isoflurane anesthesia, indicating that the former condition enhanced the quantitative contribution of OAT3 for renal creatinine secretion. The results are consistent with a contribution of OAT3 and possibly OAT1 to renal creatinine secretion in mice.
Tactile exploration of virtual objects for blind and sighted people: the role of beta 1 EEG band in sensory substitution and supramodal mental mapping
Authors: Campus C. , Brayda L. , De Carli F. , Chellali R. , Famà F. , Bruzzo C. , Lucagrossi L. , Rodriguez G.
Published: February 2012

The neural correlates of exploration and cognitive mapping in blindness remain elusive. The role of visuo-spatial pathways in blind vs. sighted subjects is still under debate. In this preliminary study, we investigate, as a possible estimation of the activity in the visuo-spatial pathways, the EEG patterns of blind and blindfolded-sighted subjects during the active tactile construction of cognitive maps from virtual objects compared with rest and passive tactile stimulation. Ten blind and ten matched, blindfolded-sighted subjects participated in the study. Events were defined as moments when the finger was only stimulated (passive stimulation) or the contour of a virtual object was touched (during active exploration). Event-related spectral power and coherence perturbations were evaluated within the beta 1 band (14–18 Hz). They were then related to a subjective cognitive-load estimation required by the explorations [namely, perceived levels of difficulty (PLD)]. We found complementary cues for sensory substitution and spatial processing in both groups: both blind and sighted subjects showed, while exploring, late power decreases and early power increases, potentially associated with motor programming and touch, respectively. The latter involved occipital areas only for blind subjects (long-term plasticity) and only during active exploration, thus supporting tactile-to-visual sensory substitution. In both groups, coherences emerged among the fronto-central, centro-parietal, and occipito-temporal derivations associated with visuo-spatial processing. This seems in accordance with mental map construction involving spatial processing, sensory-motor processing, and working memory. The observed involvement of the occipital regions suggests that a substitution process also occurs in sighted subjects. Only during explorations did coherence correlate positively with PLD for both groups and in derivations, which can be related to visuo-spatial processing, supporting the existence of supramodal spatial processing independently of vision capabilities.
Stem Cells and Gene Therapy for Cartilage Repair
Authors: Longo Umile Giuseppe , Petrillo Stefano , Franceschetti Edoardo , Berton Alessandra , Maffulli Nicola , Denaro Vincenzo
Published: February 2012

Cartilage defects represent a common problem in orthopaedic practice. Predisposing factors include traumas, inflammatory conditions, and biomechanics alterations. Conservative management of cartilage defects often fails, and patients with this lesions may need surgical intervention. Several treatment strategies have been proposed, although only surgery has been proved to be predictably effective. Usually, in focal cartilage defects without a stable fibrocartilaginous repair tissue formed, surgeons try to promote a natural fibrocartilaginous response by using marrow stimulating techniques, such as microfracture, abrasion arthroplasty, and Pridie drilling, with the aim of reducing swelling and pain and improving joint function of the patients. These procedures have demonstrated to be clinically useful and are usually considered as first-line treatment for focal cartilage defects. However, fibrocartilage presents inferior mechanical and biochemical properties compared to normal hyaline articular cartilage, characterized by poor organization, significant amounts of collagen type I, and an increased susceptibility to injury, which ultimately leads to premature osteoarthritis (OA). Therefore, the aim of future therapeutic strategies for articular cartilage regeneration is to obtain a hyaline-like cartilage repair tissue by transplantation of tissues or cells. Further studies are required to clarify the role of gene therapy and mesenchimal stem cells for management of cartilage lesions.
Tumor Lymphangiogenesis as a Potential Therapeutic Target
Authors: Duong Tam , Koopman Peter , Francois Mathias
Published: February 2012

Metastasis the spread of cancer cells to distant organs, is the main cause of death for cancer patients. Metastasis is often mediated by lymphatic vessels that invade the primary tumor, and an early sign of metastasis is the presence of cancer cells in the regional lymph node (the first lymph node colonized by metastasizing cancer cells from a primary tumor). Understanding the interplay between tumorigenesis and lymphangiogenesis (the formation of lymphatic vessels associated with tumor growth) will provide us with new insights into mechanisms that modulate metastatic spread. In the long term, these insights will help to define new molecular targets that could be used to block lymphatic vessel-mediated metastasis and increase patient survival. Here, we review the molecular mechanisms of embryonic lymphangiogenesis and those that are recapitulated in tumor lymphangiogenesis, with a view to identifying potential targets for therapies designed to suppress tumor lymphangiogenesis and hence metastasis.
Pharmacokinetic Study of Di-Phenyl-Di-(2,4-Difluobenzohydroxamato)Tin(IV): Novel Metal-Based Complex with Promising Antitumor Potential
Authors: Li Yunlan , Gao Zhuyan , Guo Pu , Li Qingshan
Published: February 2012

Di-phenyl-di-(2,4-difluobenzohydroxamato)tin(IV)(DPDFT), a new metal-based arylhydroxamate antitumor complex, showed highin vivoandin vitroantitumor activity with relative low toxicity, but no data was reported regarding its pharmacokinetics and dependent toxicity. In this paper, a rapid, sensitive, and reproducible HPLC methodin vivousing Diamonsil ODS column with a mixture of methanol and phosphoric acid in water (30 : 70, V/V, pH 3.0) as mobile phase was developed and validated for the determination of DPDFT. The plasma was deproteinized with methanol that contained acetanilide as the internal standard (I.S.). The photodiode array detector was set at a wavelength of 228 nm at room temperature and a linear curve over the concentration range 0.1~25 μg·mL-1(r= 0.9993) was obtained. The method was used to determine the concentration-time profiles for DPDFT in the plasma after single intravenous administration with doses of 5, 10, 15 mg·kg-1to rats. The pharmacokinetics parameter calculations and modeling were carried out using the 3p97 software. The results showed that the concentration-time curves of DPDFT in rat plasma could be fitted to two-compartment model.
Myocardial Restoration: Is It the Cell or the Architecture or Both?
Authors: Vu Duc Thang , Kofidis Theo
Published: February 2012

Myocardial infarction is the leading cause of death in developed countries. Cardiac cell therapy has been introduced to clinical trials for more than ten years but its results are still controversial. Tissue engineering has addressed some limitations of cell therapy and appears to be a promising solution for cardiac regeneration. In this review, we would like to summarize the current understanding about the therapeutic effect of cell therapy and tissue engineering under purview of functional and structural aspects, highlighting actual roles of each therapy towards clinical application.
Effects of Self-Empowered Teams on Rates of Adverse Drug Events in Primary Care
Authors: Singh Ranjit , Anderson Diana , McLean-Plunkett Elizabeth , Wisniewski Angela , Kee Renee , Gold Kelvin , Fox Chet , Singh Gurdev
Published: February 2012

Background.
Most safety issues in primary care arise from adverse drug events. Team Resource Management intervention was developed to identify systemic safety issues to design and implement interventions to address prioritized issues. Objectives. Evaluate impact of intervention on rates of events and preventable events in a vulnerable population. Design. Cluster randomized trial. 12 practices randomly assigned to either: (1) Intervention; (2) Intervention with Practice Enhancement Assistants; (3) No intervention. The intervention took 12 months. Main Outcome Measure. Rate and severity of events and preventable events measured using a Trigger Tool chart review method for the 12-month periods before and after the start of the intervention. Results. In the ‘‘intervention with Assistants’’
group there was a statistically significant decrease in the overall rate of events and in the rate of moderate/severe events. Analysis of Variance with study arm and time as the factors and moderate/severe events as the outcome showed a significant interaction between arm and time supporting the notion that the ‘‘Intervention with Assistants’’ practices had a greater reduction in moderate/severe preventable events. Conclusions. The intervention had a significant effect on medication safety as estimated using a trigger tool. Further exploration of role of Assistants and trigger tool is warranted.