bluuebunny/crossref_metadata_2025 huggingface dataset:
Socioeconomic variation in height: analysis of National Child Measurement Programme data for England
Authors: Hancock Caroline , Bettiol Silvana , Smith Lesley
Published: September 2015

Objective

Short stature is associated with increased risk of ill health and mortality and can negatively impact on an individual's economic opportunity and psychological well-being. The aim of this study was to investigate the association between height and area-level deprivation by ethnic group in children in England.

Design

Cross-sectional analysis of data gathered from the National Child Measurement Programme 2008/2009 to 2012/2013.

Participants/methods

Children (n=1 213 230) aged 4–5 and 10–11 years attending state-maintained primary schools in England. Mean height SD score (SDS) (based on the British 1990 growth reference) was calculated for children by Income Deprivation Affecting Children Index as a measure of area-level deprivation. Analyses were performed by sex and age group for white British, Asian and black ethnicities.

Results

For white British children mean height decreased 0.2 SDS between the least and the most deprived quintile. For Asian children the relationship was weaker and varied between 0.08 and 0.18 SDS. For white British boys the magnitude of association was similar across age groups; for Asian boys the magnitude was higher in the age group of 10–11 years and in white British girls aged 10–11 years the association decreased. Height SDS was similar across all levels of deprivation for black children.

Conclusions

Social inequalities were shown in the height of children from white British and Asian ethnic groups. Further evaluation of height in black children is warranted. Action is needed to reduce inequalities in height by addressing the modifiable negative environmental factors that prevent healthy growth and development of children.
Admission to hospital for bronchiolitis in England: trends over five decades, geographical variation and association with perinatal characteristics and subsequent asthma
Authors: Green Christopher A , Yeates David , Goldacre Allie , Sande Charles , Parslow Roger C , McShane Philip , Pollard Andrew J , Goldacre Michael J
Published: September 2015

Background

Admission of infants to hospital with bronchiolitis consumes considerable healthcare resources each winter. We report an analysis of hospital admissions in England over five decades.

Methods

Data were analysed from the Hospital In-Patient Enquiry (HIPE, 1968–1985), Hospital Episode Statistics (HES, 1989–2011), Oxford Record Linkage Study (ORLS, 1963–2011) and Paediatric Intensive Care Audit Network (PICANet, 2003–2012). Cases were identified using International Classification of Diseases (ICD) codes in discharge records. Bronchiolitis was given a separate code in ICD9 (used in England from 1979). Geographical variation was analysed using Local Authority area boundaries. Maternal and perinatal risk factors associated with bronchiolitis and subsequent admissions for asthma were analysed using record-linkage.

Results

All-England HIPE and HES data recorded 468 138 episodes of admission for bronchiolitis in infants aged <1 year between 1979 and 2011. In 2011 the estimated annual hospital admission rate was 46.1 (95% CI 45.6 to 46.6) per 1000 infants aged <1 year. Between 2004 and 2011 the rates rose by an average of 1.8% per year in the all-England HES data, whereas admission rates to paediatric intensive care changed little (1.3 to 1.6 per 1000 infants aged <1 year). A fivefold geographical variation in hospital admission rates was observed. Young maternal age, low social class, low birth weight and maternal smoking were among factors associated with an increased risk of hospital admission with bronchiolitis.

Conclusions

Hospital admissions for infants with bronchiolitis have increased substantially in recent years. However, cases requiring intensive care have changed little since 2004.
Comparison of drug coverage in Canada before and after the establishment of the pan-Canadian Pharmaceutical Alliance
Authors: Milliken Debbie , Venkatesh Jaya , Yu Rebecca , Su Zhuo , Thompson Melissa , Eurich Dean
Published: September 2015

Objectives

This study was conducted to determine whether establishment of the pan-Canadian Pharmaceutical Alliance (pCPA) was associated with significant changes in drug listing decisions across Canada.

Analysis and results

This study included drug indications that received a Common Drug Review or pan-Canadian Oncology Drug Review listing recommendation within 3 years before (‘pre-PCPA era’ group; n=79) and 3 years after (‘PCPA era’ group; n=91) the pCPA was established in August 2010. At the time of this study (30 April 2014), nine pCPA-participating jurisdictions had listed 35–59% of drug indications in the pre-pCPA era group and a nearly identical range, 36–59%, in the pCPA era group. Within the pCPA-era group, 31 drug indications (34%) had completed pCPA negotiations (‘pCPA negotiation’ subgroup); the jurisdictions had listed 39–77% of these drug indications. Comparison of the pCPA era group to the pre-pCPA era group indicated that the proportion listed did not change significantly in any jurisdiction, and time-to-listing increased significantly in New Brunswick and decreased significantly in Alberta, Manitoba, and Ontario. When the pCPA negotiation subgroup was compared to the pre-pCPA era group, the proportion listed increased significantly in British Columbia, Saskatchewan, Manitoba and Newfoundland and Labrador, and time-to-listing increased significantly in New Brunswick and Nova Scotia and decreased significantly in Manitoba and Ontario. A sensitivity analysis suggested more favourable results regarding the pCPA's impact.

Conclusions

While the pCPA might have had a varied effect on time-to-listing, this study's primary analysis did not observe a significant impact on the overall proportion of new drug indications listed across jurisdictions. This may be due to the fact that, at the time of this study, only a limited number of drug indications had completed pCPA negotiations. This study provides a framework for future evaluations of the pCPA's impact as it continues to evolve.
Designing and recruiting to UK autism spectrum disorder research databases: do they include representative children with valid ASD diagnoses?
Authors: Warnell F , George B , McConachie H , Johnson M , Hardy R , Parr J R
Published: September 2015

Objectives

(1) Describe how the Autism Spectrum Database-UK (ASD-UK) was established; (2) investigate the representativeness of the first 1000 children and families who participated, compared to those who chose not to; (3) investigate the reliability of the parent-reported Autism Spectrum Disorder (ASD) diagnoses, and present evidence about the validity of diagnoses, that is, whether children recruited actually have an ASD; (4) present evidence about the representativeness of the ASD-UK children and families, by comparing their characteristics with the first 1000 children and families from the regional Database of children with ASD living in the North East (Daslne), and children and families identified from epidemiological studies.

Setting

Recruitment through a network of 50 UK child health teams and self-referral.

Patients

Parents/carers with a child with ASD, aged 2–16 years, completed questionnaires about ASD and some gave professionals’ reports about their children.

Results

1000 families registered with ASD-UK in 30 months. Children of families who participated, and of the 208 who chose not to, were found to be very similar on: gender ratio, year of birth, ASD diagnosis and social deprivation score. The reliability of parent-reported ASD diagnoses of children was very high when compared with clinical reports (over 96%); no database child without ASD was identified. A comparison of gender, ASD diagnosis, age at diagnosis, school placement, learning disability, and deprivation score of children and families from ASD-UK with 1084 children and families from Daslne, and families from population studies, showed that ASD-UK families are representative of families of children with ASD overall.

Conclusions

ASD-UK includes families providing parent-reported data about their child and family, who appear to be broadly representative of UK children with ASD. Families continue to join the databases and more than 3000 families can now be contacted by researchers about UK autism research.
Improving the recording of surgical drain output
Authors: Lyons Nicholas , Heron Paul , Bethune Rob
Published: September 2015

Monitoring the output from surgical drains is an important part of post-operative care and is often undertaken poorly. Failure to have accurate documentation of daily outputs may delay the removal of drains and increase the risk of complications. Following discussions with medical and nursing staff we listed eight key criteria that should be routinely monitored for surgical drains. A baseline measurement demonstrated only 20% compliance with these criteria. As such we decided to design a chart, after discussing with the multidisciplinary team, with adequate space to document drain output clearly. Post-intervention data collection showed a reasonable uptake of the chart (70%) with overall criteria compliance increasing to 55%.

We made further interventions designed to raise awareness of the chart, which increased chart uptake to 79% and compliance to 63%, leading to the adoption of the chart by the department. Twelve months after introducing the chart we conducted a final data collection which demonstrated the chart was now being used in 100% of patients and that overall criteria compliance had increased to 78%. While some of the key criteria are still not documented for all patients, we have demonstrated that the introduction of a simple and well-designed drain chart can significantly improve the documentation of drain output, thereby improving patient safety and discharge efficiency.
Patient characteristics associated with longer emergency department stay: a rapid review
Authors: Kreindler Sara A , Cui Yang , Metge Colleen J , Raynard Melissa
Published: September 2015

Background

Prolonged emergency department (ED) stays make a disproportionate contribution to ED overcrowding, but the factors associated with longer stays have not been systematically reviewed.

Objective

To identify the patient characteristics associated with ED length of stay (LOS) and ascertain whether a predictive model existed.

Methods

This rapid systematic review included published, English-language studies that assessed at least one patient-level predictor of ED LOS (defined as a continuous or dichotomous variable) in an adult or mixed adult/paediatric population within an Organization for Economic Cooperation and Development country. Findings were synthesised narratively.

Results

We identified 35 relevant studies; most included multiple predictors, but none developed a predictive model. The factors most commonly associated with long ED LOS were need for admission (10 of 10 studies) and older age (which may be a proxy for age-related differences in health condition and severity; 9 of 10), receipt of diagnostic tests or consults (8 of 8) and ambulance arrival (4 of 5). Acuity often showed a bell-shaped relationship with LOS (ie, patients with moderate acuity stayed longest).

Limitations

Methodological choices made in the interests of rapidity limited the review's comprehensiveness and depth.

Conclusions

Despite a sizeable body of literature, the available information is insufficiently precise to inform clinical or service-planning decisions; there is a need for a predictive model, including specific patient complaints. Deeper understanding of the determinants of ED LOS could help to identify patients and/or populations who require special intervention or resources to prevent a protracted stay.
Medical student mandala making for holistic well-being
Authors: Potash Jordan S , Chen Julie Yun , Tsang Joyce Pui Yan
Published: September 2015

The objective of this qualitative research study was to discover how creating mandalas (art made in reference to a circle) might provide medical students with an opportunity for reflection on their current psychological state. As part of their year 3 family medicine rotation, medical students participated in an art-making workshop, during which, they created mandalas based on their current emotional state. Afterwards, they engaged in reflective writing and discussion. The responses of 180 students were analysed and coded according to the mandala classification framework ‘Archetypal Stages of The Great Round of Mandala’. The results indicated that students were actively struggling in integrating conflicting perspectives as they were attempting to reconcile their professional identity as doctors. Additional results pertaining to psychosocial characteristics included navigating difficult emotions, requiring nurturance, handling endings, contemplating existential concerns and managing stress. The study has implications for making use of mandala making within a Jungian framework as means for medical students to reflect on their emotional state and achieve psychological balance.
Outcomes following repair of anomalous coronary artery from the pulmonary artery in infants: results from a procedure-based national database
Authors: Fudulu Daniel Paul , Dorobantu Dan Mihai , Sharabiani Mansour Taghavi Azar , Angelini Gianni Davide , Caputo Massimo , Parry Andrew John , Stoica Serban Constantin
Published: September 2015

Background

Anomalous coronary artery from the pulmonary artery (ACAPA) is a very rare congenital anomaly that often occurs during infancy. Patients can present in a critical condition.

Methods

We analysed procedure-related data from a national audit database for the period 2000–2013.

Results

A total of 120 patients <1 year had repair of isolated ACAPA using a coronary transfer or the tunnel (Takeuchi) operation. Seven patients (6.8%) required a mitral valve procedure at index and eight patients (7.8%) had a mitral valve repair/replacement during follow-up, including mitral reoperations. Follow-up data (>30 days) were available in 102 patients and the mean follow-up time was 4.7 years. The 30-day overall mortality was 1.9%, higher for neonates (16.7% vs 1%, p=0.1) and after postoperative extracorporeal membrane oxygenation (ECMO) (20% vs 1%, p=0.09). At 10 years the survival estimate is 95.1%, freedom from coronary and mitral reintervention being 95.9% and 91.2%, respectively. Use of postoperative ECMO was a risk factor for long-term mortality (p<0.001). Risk factors for coronary reintervention were age under 30 days (p=0.06) and the need for postoperative ECMO (p=0.02). Age under 30 days (p=0.002) was a risk factor for mitral reintervention.

Conclusions

To our knowledge this is the largest series to date. These preliminary national results show that early outcomes are good and medium-term attrition acceptable. Poor outcomes are correlated with early presentation, also with the need for postoperative circulatory support.
Locally covariant charged fields and background independence
Authors: Zahn Jochen
Published: September 2015

We discuss gauge background independence at the example of the charged Dirac field. We show that a perturbative version of background independence, termed perturbative agreement by Hollands and Wald, can be fulfilled, and discuss some of its consequences.
DOES INVESTOR ATTENTION MATTER TO RENMINBI TRADING?
Authors: CHEN TAO
Published: September 2015

Given that renminbi always breaks the historical high against USD, psychological literature on limited investor attention motivates me to consider whether this eye-grabbing event would have an impact on renminbi trading. Empirical evidence suggests that both nearness to the historical high and hitting the historical high negatively affect renminbi future returns. This result survives from a variety of robustness checks. My findings are consistent with the conservatism theory and suggest that investors tend to under-react in response to the news of breaking the historical high.
Synthesis and structure stability of Ba2CuO3+δ under high pressure
Authors: Li W. M. , Liu Q. Q. , Liu Y. , Feng S. M. , Wang X. C. , Jin C. Q. , Li X. D. , Liu J.
Published: September 2015

The [Formula: see text] sample with the nominal composition was synthesized. Powder X-ray diffraction (XRD) experiments confirm that it crystallizes in an orthorhombic structure with space group Immm. The synchrotron powder XRD results suggest that the crystal structure of [Formula: see text] keeps stable under pressure up to 34 GPa at room temperature with nearly isotropic compressibility. The equation of state for [Formula: see text] was obtained. The results offer opportunities to further synthesize and research [Formula: see text] superconductor with tetragonal [Formula: see text] structure.
Feasibility of low-cost magnetic rail designs by integrating ferrite magnets and NdFeB magnets for HTS Maglev systems
Authors: Sun R. X. , Deng Z. G. , Gou Y. F. , Li Y. J. , Zheng J. , Wang S. Y. , Wang J. S.
Published: September 2015

Permanent magnet guideway (PMG) is an indispensable part of high temperature superconducting (HTS) Maglev systems. Present PMGs are made of NdFeB magnets with excellent performance and cost much. As another permanent magnet material, the ferrite magnet is weak at magnetic energy product and coercive force, but inexpensive. So, it is a possible way to integrate the ferrite and NdFeB magnets for cutting down the cost of present PMGs. In the paper, the equivalent on magnetic field intensity between ferrite magnets and NdFeB magnets was evaluated by finite element simulation. According to the calculation results, the magnetic field of the PMG integrating ferrite magnets and NdFeB magnets can be increased remarkably comparing with the pure ferrite PMG. It indicates that low-cost PMG designs by integrating the two permanent magnet materials are feasible for the practical HTS Maglev system.
Periodic Motion of the van der Pol Equation with Impulsive Effect
Authors: Zheng Shasha , Fu Xilin
Published: September 2015

In this paper, we investigate the dynamics of the periodic motion for switched van der Pol equation with impulsive effect, utilizing the theory of mapping dynamics in switching systems. For the optimized problem, we consider such impulsive dynamical model as switched system and analyze its features from a discontinuous point of view. Then, conceptions of switching sets as well as discrete mappings are briefly reviewed. By constructing generic mappings, we analyze the flow's periodic behaviors from the perspective of mapping structures. Finally, we apply our analysis and criterion to a specific impulsive model at fixed points and the periodic motions with impulse to the boundary are illustrated.
On the Dynamics of the Unified Chaotic System Between Lorenz and Chen Systems
Authors: Llibre Jaume , Rodrigues Ana
Published: September 2015

A one-parameter family of differential systems that bridges the gap between the Lorenz and the Chen systems was proposed by Lu, Chen, Cheng and Celikovsy. The goal of this paper is to analyze what we can say using analytic tools about the dynamics of this one-parameter family of differential systems. We shall describe its global dynamics at infinity, and for two special values of the parameter a we can also describe the global dynamics in the whole ℝ3using the invariant algebraic surfaces of the family. Additionally we characterize the Hopf bifurcations of this family.
Geometric conemanifold structures on 𝕋p/q, the result of p/q surgery in the left-handed trefoil knot 𝕋
Authors: Lozano María Teresa , Montesinos-Amilibia José María
Published: September 2015

As an example of the transitions between some of the eight geometries of Thurston, investigated in [M. T. Lozano and J. M. Montesinos-Amilibia, On the degeneration of some 3-manifold geometries via unit groups of quaternion algebras RACSAM 109 (2015) 669–715], we study the geometries supported by the conemanifolds obtained by surgery on the trefoil knot with singular set the core of the surgery. The geometric structures are explicitly constructed. The most interesting phenomenon is the transition from SL(2, ℝ)-geometry to S3-geometry through Nil-geometry. A plot of the different geometries is given, in the spirit of the analogous plot of Thurston for the geometries supported by surgeries on the figure-eight knot.
A Novel Explicit Positivity-Preserving Finite-Difference Scheme for Simulating Bounded Growth of Biological Films
Authors: Sun G. F. , Liu G. R. , Li M.
Published: September 2015

In this paper, a novel explicit finite-difference (FD) method is presented to approximate the positive and bounded growth of biological films that is governed by partial differential equations (PDEs) with a nonlinear density-dependent diffusion reaction rate. In such a unique nonlinear equation, the diffusion operator degenerates for small biomass densities, and becomes singular when approaching the upper bound of the biomass density. Our novel FD scheme is designed to transfer the nonlinear terms in the PDE into linear ones that can be solved very efficiently, while ensuring the bounds of the solution between zero and one. This is achieved through (1) a proper design of intertwined FD approximations for the diffusion function, time and spatial variations and (2) the control of the time-step based on stability criteria. A theoretical stability analysis is conducted and it reveals that our method is indeed stable (bounded and not oscillations) in suitable grid spacing and time-steps. The present scheme is applicable for solving convection-diffusion PDEs with variable coefficients, including but not limited to biofilm growth.
Blood flow restriction training and the exercise pressor reflex: a call for concern
Authors: Spranger Marty D. , Krishnan Abhinav C. , Levy Phillip D. , O'Leary Donal S. , Smith Scott A.
Published: September 2015

Blood flow restriction (BFR) training (also known as Kaatsu training) is an increasingly common practice employed during resistance exercise by athletes attempting to enhance skeletal muscle mass and strength. During BFR training, blood flow to the exercising muscle is mechanically restricted by placing flexible pressurizing cuffs around the active limb proximal to the working muscle. This maneuver results in the accumulation of metabolites (e.g., protons and lactic acid) in the muscle interstitium that increase muscle force and promote muscle growth. Therefore, the premise of BFR training is to simulate and receive the benefits of high-intensity resistance exercise while merely performing low-intensity resistance exercise. This technique has also been purported to provide health benefits to the elderly, individuals recovering from joint injuries, and patients undergoing cardiac rehabilitation. Since the seminal work of Alam and Smirk in the 1930s, it has been well established that reductions in blood flow to exercising muscle engage the exercise pressor reflex (EPR), a reflex that significantly contributes to the autonomic cardiovascular response to exercise. However, the EPR and its likely contribution to the BFR-mediated cardiovascular response to exercise is glaringly missing from the scientific literature. Inasmuch as the EPR has been shown to generate exaggerated increases in sympathetic nerve activity in disease states such as hypertension (HTN), heart failure (HF), and peripheral artery disease (PAD), concerns are raised that BFR training can be used safely for the rehabilitation of patients with cardiovascular disease, as has been suggested. Abnormal BFR-induced and EPR-mediated cardiovascular complications generated during exercise could precipitate adverse cardiovascular or cerebrovascular events (e.g., cardiac arrhythmia, myocardial infarction, stroke and sudden cardiac death). Moreover, although altered EPR function in HTN, HF, and PAD underlies our concern for the widespread implementation of BFR, use of this training mechanism may also have negative consequences in the absence of disease. That is, even normal, healthy individuals performing resistance training exercise with BFR are potentially at increased risk for deleterious cardiovascular events. This review provides a brief yet detailed overview of the mechanisms underlying the autonomic cardiovascular response to exercise with BFR. A more complete understanding of the consequences of BFR training is needed before this technique is passively explored by the layman athlete or prescribed by a health care professional.
Progressive development of cardiomyopathy following altered autonomic activity in status epilepticus
Authors: Read Morgayn I. , McCann Dominic M. , Millen Rebecca N. , Harrison Joanne C. , Kerr D. Steven , Sammut Ivan A.
Published: September 2015

Seizures are associated with altered autonomic activity, which has been implicated in the development of cardiac dysfunction and structural damage. This study aimed to investigate the involvement of the autonomic nervous system in seizure-induced cardiomyopathy. Male Sprague-Dawley rats (320–350 g) were implanted with EEG/ECG electrodes to allow simultaneous telemetric recordings during seizures induced by intrahippocampal (2 nmol, 1 μl/min) kainic acid and monitored for 7 days. Seizure activity occurred in conjunction with increased heart rate (20%), blood pressure (25%), and QTc prolongation (15%). This increased sympathetic activity was confirmed by the presence of raised plasma noradrenaline levels at 3 h post-seizure induction. By 48 h post-seizure induction, sympathovagal balance was shifted in favor of sympathetic dominance, as indicated by both heart rate variability (LF/HF ratio of 3.5 ± 1.0) and pharmacological autonomic blockade. Functional cardiac deficits were evident at 7 and 28 days, as demonstrated by echocardiography showing a decreased ejection fraction (14% compared with control, P < 0.05) and dilated cardiomyopathy present at 28 days following seizure induction. Histological changes, including cardiomyocyte vacuolization, cardiac fibrosis, and inflammatory cell infiltration, were evident within 48 h of seizure induction and remained present for up to 28 days. These structural changes most probably contributed to an increased susceptibility to aconitine-induced arrhythmias. This study confirms that prolonged seizure activity results in acute and chronic alterations in cardiovascular control, leading to a deterioration in cardiac structure and function. This study further supports the need for modulation of sympathetic activity as a promising therapeutic approach in seizure-induced cardiomyopathy.
Rat cardiac troponin T mutation (F72L)-mediated impact on thin filament cooperativity is divergently modulated by α- and β-myosin heavy chain isoforms
Authors: Chandra Vikram , Gollapudi Sampath K. , Chandra Murali
Published: September 2015

The primary causal link between disparate effects of human hypertrophic cardiomyopathy (HCM)-related mutations in troponin T (TnT) and α- and β-myosin heavy chain (MHC) isoforms on cardiac contractile phenotype remains poorly understood. Given the divergent impact of α- and β-MHC on the NH2-terminal extension (44–73 residues) of TnT, we tested if the effects of the HCM-linked mutation (TnTF70L) were differentially altered by α- and β-MHC. We hypothesized that the emergence of divergent thin filament cooperativity would lead to contrasting effects of TnTF70Lon contractile function in the presence of α- and β-MHC. The rat TnT analog of the human F70L mutation (TnTF72L) or the wild-type rat TnT (TnTWT) was reconstituted into demembranated muscle fibers from normal (α-MHC) and propylthiouracil-treated (β-MHC) rat hearts to measure steady-state and dynamic contractile function. TnTF72L-mediated effects on tension, myofilament Ca2+sensitivity, myofilament cooperativity, rate constants of cross-bridge (XB) recruitment dynamics, and force redevelopment were divergently modulated by α- and β-MHC. TnTF72Lincreased the rate of XB distortion dynamics by 49% in α-MHC fibers but had no effect in β-MHC fibers; these observations suggest that TnTF72Laugmented XB detachment kinetics in α-MHC, but not β-MHC, fibers. TnTF72Lincreased the negative impact of strained XBs on the force-bearing XBs by 39% in α-MHC fibers but had no effect in β-MHC fibers. Therefore, TnTF72Lleads to contractile changes that are linked to dilated cardiomyopathy in the presence of α-MHC. On the other hand, TnTF72Lleads to contractile changes that are linked to HCM in the presence of β-MHC.
Rate-dependent activation failure in isolated cardiac cells and tissue due to Na+ channel block
Authors: Varghese Anthony , Spindler Anthony J. , Paterson David , Noble Denis
Published: September 2015

While it is well established that class-I antiarrhythmics block cardiac sodium channels, the mechanism of action of therapeutic levels of these drugs is not well understood. Using a combination of mathematical modeling and in vitro experiments, we studied the failure of activation of action potentials in single ventricular cells and in tissue caused by Na+ channel block. Our computations of block and unblock of sodium channels by a theoretical class-Ib antiarrhythmic agent predict differences in the concentrations required to cause activation failure in single cells as opposed to multicellular preparations. We tested and confirmed these in silico predictions with in vitro experiments on isolated guinea-pig ventricular cells and papillary muscles stimulated at various rates (2–6.67 Hz) and exposed to various concentrations (5 × 10−6 to 500 × 10−6 mol/l) of lidocaine. The most salient result was that whereas large doses (5 × 10−4 mol/l or higher) of lidocaine were required to inhibit action potentials temporarily in single cells, much lower doses (5 × 10−6 mol/l), i.e., therapeutic levels, were sufficient to have the same effect in papillary muscles: a hundredfold difference. Our experimental results and mathematical analysis indicate that the syncytial nature of cardiac tissue explains the effects of clinically relevant doses of Na+ channel blockers.
Role of connexin 43 in vascular hyperpermeability and relationship to Rock1-MLC20pathway in septic rats
Authors: Zhang Jie , Yang Guang-ming , Zhu Yu , Peng Xiao-yong , Li Tao , Liu Liang-ming
Published: September 2015

Connexin (Cx)43 has been shown to participate in several cardiovascular diseases. Increased vascular permeability is a common and severe complication in sepsis or septic shock. Whether or not Cx43 takes part in the regulation of vascular permeability in severe sepsis is not known, and the underlying mechanism has not been described. With cecal ligation and puncture-induced sepsis in rats and lipopolysaccharide (LPS)-treated vascular endothelial cells (VECs) from pulmonary veins, the role of Cx43 in increased vascular permeability and its relationship to the RhoA/Rock1 pathway were studied. It was shown that vascular permeability in the lungs, kidneys, and mesentery in sepsis rats and LPS-stimulated monolayer pulmonary vein VECs was significantly increased and positively correlated with the increased expression of Cx43 and Rock1 in these organs and cultured pulmonary vein VECs. The connexin inhibitor carbenoxolone (10 mg/kg iv) and the Rock1 inhibitor Y-27632 (2 mg/kg iv) alleviated the vascular leakage of lung, mesentery, and kidney in sepsis rats. Overexpressed Cx43 increased the phosphorylation of 20-kDa myosin light chain (MLC20) and the expression of Rock1 and increased the vascular permeability and decreased the transendothelial electrical resistance of pulmonary vein VECs. Cx43 RNA interference decreased the phosphorylation of MLC20and the expression of Rock1 and decreased LPS-stimulated hyperpermeability of cultured pulmonary vein VECs. The Rock1 inhibitor Y-27632 alleviated LPS- and overexpressed Cx43-induced hyperpermeability of monolayer pulmonary vein VECs. This report shows that Cx43 participates in the regulation of vascular permeability in sepsis and that the mechanism is related to the Rock1-MLC20phosphorylation pathway.
Differential deposition of fibronectin by asthmatic bronchial epithelial cells
Authors: Ge Qi , Zeng Qingxiang , Tjin Gavin , Lau Edmund , Black Judith L. , Oliver Brian G. G. , Burgess Janette K.
Published: September 2015

Altered ECM protein deposition is a feature in asthmatic airways. Fibronectin (Fn), an ECM protein produced by human bronchial epithelial cells (HBECs), is increased in asthmatic airways. This study investigated the regulation of Fn production in asthmatic or nonasthmatic HBECs and whether Fn modulated HBEC proliferation and inflammatory mediator secretion. The signaling pathways underlying transforming growth factor (TGF)-β1-regulated Fn production were examined using specific inhibitors for ERK, JNK, p38 MAPK, phosphatidylinositol 3 kinase, and activin-like kinase 5 (ALK5). Asthmatic HBECs deposited higher levels of Fn in the ECM than nonasthmatic cells under basal conditions, whereas cells from the two groups had similar levels of Fn mRNA and soluble Fn. TGF-β1 increased mRNA levels and ECM and soluble forms of Fn but decreased cell proliferation in both cells. The rate of increase in Fn mRNA was higher in nonasthmatic cells. However, the excessive amounts of ECM Fn deposited by asthmatic cells after TGF-β1 stimulation persisted compared with nonasthmatic cells. Inhibition of ALK5 completely prevented TGF-β1-induced Fn deposition. Importantly, ECM Fn increased HBEC proliferation and IL-6 release, decreased PGE2 secretion, but had no effect on VEGF release. Soluble Fn had no effect on cell proliferation and inflammatory mediator release. Asthmatic HBECs are intrinsically primed to produce more ECM Fn, which when deposited into the ECM, is capable of driving remodeling and inflammation. The increased airway Fn may be one of the key driving factors in the persistence of asthma and represents a novel, therapeutic target.
Maternal-pup interaction disturbances induce long-lasting changes in the newborn rat pulmonary vasculature
Authors: Shifrin Yulia , Sadeghi Sina , Pan Jingyi , Jain Amish , Fajardo Andres F. , McNamara Patrick J. , Belik Jaques
Published: September 2015

The factors accounting for the pathological maintenance of a high pulmonary vascular (PV) resistance postnatally remain elusive, but neonatal stressors may play a role in this process. Cross-fostering in the immediate neonatal period is associated with adult-onset vascular and behavioral changes, likely triggered by early-in-life stressors. In hypothesizing that fostering newborn rats induces long-lasting PV changes, we evaluated them at 14 days of age during adulthood and compared the findings with animals raised by their biological mothers. Fostering resulted in reduced maternal-pup contact time when compared with control newborns. At 2 wk of age, fostered rats exhibited reduced pulmonary arterial endothelium-dependent relaxation secondary to downregulation of tissue endothelial nitric oxide synthase expression and tetrahydrobiopterin deficiency-induced uncoupling. These changes were associated with neonatal onset-increased ANG II receptor type 1 expression, PV remodeling, and right ventricular hypertrophy that persisted into adulthood. The pulmonary arteries of adult-fostered rats exhibited a higher contraction dose response to ANG II and thromboxane A2, the latter of which was abrogated by the oxidant scavenger Tempol. In conclusion, fostering-induced neonatal stress induces long-standing PV changes modulated via the renin-angiotensin system.
Divergent fibroblast growth factor signaling pathways in lung fibroblast subsets: where do we go from here?
Authors: Ruiz-Camp Jordi , Morty Rory E.
Published: September 2015

Lung fibroblasts play a key role in postnatal lung development, namely, the formation of the alveolar gas exchange units, through the process of secondary septation. Although evidence initially highlighted roles for fibroblasts in the production and remodeling of the lung extracellular matrix, more recent studies have described the presence of different fibroblast subsets in the developing lung. These subsets include myofibroblasts and lipofibroblasts and their precursors. These cells are believed to play different roles in alveologenesis and are localized to different regions of the developing septa. The precise roles played by these different fibroblast subsets remain unclear. Understanding the signaling pathways that control the discrete functions of these fibroblast subsets would help to clarify the roles and the regulation of lung fibroblasts during lung development. Here, we critically evaluate a recent report that described divergent fibroblast growth factor (FGF) signaling pathways in two different subsets of lung fibroblasts that express different levels of green fluorescent protein (GFP) driven by the platelet-derived growth factor receptor-α promoter. The GFP expression was used as a surrogate for lipofibroblasts (GFPlow) and myofibroblasts (GFPhigh). It was suggested that Fgf10/Fgf1 and Fgf18/Fgfr3 autocrine pathways may be operative in GFPlowand GFPhighcells, respectively, and that these pathways might regulate the proliferation and migration of different fibroblast subsets during alveologenesis. These observations lay important groundwork for the further exploration of FGF function during normal lung development, as well as in aberrant lung development associated with bronchopulmonary dysplasia.
Effect of swimming exercise on three-dimensional trabecular bone microarchitecture in ovariectomized rats
Authors: Ju Yong-In , Sone Teruki , Ohnaru Kazuhiro , Tanaka Kensuke , Fukunaga Masao
Published: September 2015

Swimming is generally considered ineffective for increasing bone mass in humans, at least compared with weight-bearing sports. However, swimming exercise has sometimes been shown to have a strong positive effect on bone mass in small animals. This study investigated the effects of swimming on bone mass, strength, and microarchitecture in ovariectomized (OVX) rats. OVX or sham operations were performed on 18-wk-old female Fisher 344 rats. Rats were randomly divided into four groups: sham sedentary (Sham-CON), sham swimming exercised (Sham-SWI), OVX sedentary (OVX-CON), and OVX swimming exercised (OVX-SWI). Rats in exercise groups performed swimming in a water bath for 60 min/day, 5 days/wk, for 12 wk. Bone mineral density (BMD) in right femurs was analyzed using dual-energy X-ray absorptiometry. Three-dimensional trabecular architecture at the distal femoral metaphysis was analyzed using microcomputed tomography (μCT). Geometrical properties of diaphyseal cortical bone were evaluated in the midfemoral region using μCT. The biomechanical properties of femurs were analyzed using three-point bending. Femoral BMD was significantly decreased following ovariectomy. This change was suppressed by swimming. Trabecular bone thickness, number, and connectivity were decreased by ovariectomy, whereas structure model index (i.e., ratio of rod-like to plate-like trabeculae) increased. These changes were also suppressed by swimming exercise. Femurs displayed greater cortical width and maximum load in SWI groups than in CON groups. Together, these results demonstrate that swimming exercise drastically alleviated both OVX-induced decreases in bone mass and mechanical strength and the deterioration of trabecular microarchitecture in rat models of osteoporosis.
Analysis of KRAS/NRAS Mutations in a Phase III Study of Panitumumab with FOLFIRI Compared with FOLFIRI Alone as Second-line Treatment for Metastatic Colorectal Cancer
Authors: Peeters Marc , Oliner Kelly S. , Price Timothy J. , Cervantes Andrés , Sobrero Alberto F. , Ducreux Michel , Hotko Yevhen , André Thierry , Chan Emily , Lordick Florian , Punt Cornelis J.A. , Strickland Andrew H. , Wilson Gregory , Ciuleanu Tudor E. , Roman Laslo , Van Cutsem Eric , He Pei , Yu Hua , Koukakis Reija , Terwey Jan-Henrik , Jung Andre S. , Sidhu Roger , Patterson Scott D.
Published: September 2015

Purpose: We evaluated the influence of RAS mutation status on the treatment effect of panitumumab in a prospective–retrospective analysis of a randomized, multicenter phase III study of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183).

Experimental Design: Outcomes were from the study's primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints.

Results: The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio (HR) for panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population [PFS HR, 0.70 (95% confidence interval [CI], 0.54–0.91); P = 0.007 vs. 0.73 (95% CI, 0.59–0.90); P = 0.004; OS HR, 0.81 (95% CI, 0.63–1.03); P = 0.08 vs. 0.85 (95% CI, 0.70–1.04); P = 0.12]. Patients with RAS mutations were unlikely to benefit from panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the panitumumab–FOLFIRI group versus 10% in the FOLFIRI group.

Conclusions: Patients with RAS mutations were unlikely to benefit from panitumumab–FOLFIRI and the benefit–risk of panitumumab–FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC. Clin Cancer Res; 21(24); 5469–79. ©2015 AACR.

See related commentary by Salazar and Ciardiello, p. 5415
Afatinib plus Cetuximab Delays Resistance Compared to Single-Agent Erlotinib or Afatinib in Mouse Models of TKI-Naïve EGFR L858R-Induced Lung Adenocarcinoma
Authors: Pirazzoli Valentina , Ayeni Deborah , Meador Catherine B. , Sanganahalli Basavaraju G. , Hyder Fahmeed , de Stanchina Elisa , Goldberg Sarah B. , Pao William , Politi Katerina
Published: September 2015

Purpose: The EGFR tyrosine kinase inhibitors (TKIs), erlotinib and afatinib, have transformed the treatment of advanced EGFR-mutant lung adenocarcinoma. However, almost all patients who respond develop acquired resistance on average approximately 1 year after starting therapy. Resistance is commonly due to a secondary mutation in EGFR (EGFRT790M). We previously found that the combination of the EGFR TKI afatinib and the EGFR antibody cetuximab could overcome EGFRT790M-mediated resistance in preclinical models. This combination has shown a 29% response rate in a clinical trial in patients with acquired resistance to first-generation TKIs. An outstanding question is whether this regimen is beneficial when used as first-line therapy.

Experimental Design: Using mouse models of EGFR-mutant lung cancer, we tested whether the combination of afatinib plus cetuximab delivered upfront to mice with TKI-naïve EGFRL858R-induced lung adenocarcinomas delayed tumor relapse and drug-resistance compared with single-agent TKIs.

Results: Afatinib plus cetuximab markedly delayed the time to relapse and incidence of drug-resistant tumors, which occurred in only 63.6% of the mice, in contrast to erlotinib or afatinib treatment where 100% of mice developed resistance. Mechanisms of tumor escape observed in afatinib plus cetuximab resistant tumors include the EGFRT790M mutation and Kras mutations. Experiments in cell lines and xenografts confirmed that the afatinib plus cetuximab combination does not suppress the emergence of EGFRT790M.

Conclusions: These results highlight the potential of afatinib plus cetuximab as an effective treatment strategy for patients with TKI-naïve EGFR-mutant lung cancer and indicate that clinical trial development in this area is warranted. Clin Cancer Res; 22(2); 426–35. ©2015 AACR.
Loss of SMAD4 Promotes Colorectal Cancer Progression by Accumulation of Myeloid-Derived Suppressor Cells through the CCL15–CCR1 Chemokine Axis
Authors: Inamoto Susumu , Itatani Yoshiro , Yamamoto Takamasa , Minamiguchi Sachiko , Hirai Hideyo , Iwamoto Masayoshi , Hasegawa Suguru , Taketo Makoto Mark , Sakai Yoshiharu , Kawada Kenji
Published: September 2015

Purpose: We previously reported that loss of SMAD4 promotes chemokine CCL15 expression to recruit CCR1+ myeloid cells via the CCL15–CCR1 axis, which facilitates metastasis of colorectal cancer to the liver. The purposes of this study were to investigate whether essentially the same mechanism works in tumor invasion of the primary colorectal cancer and to evaluate the clinical importance of CCL15 expression and CCR1+ cell accumulation.

Experimental Design: Using human colorectal cancer cell lines with reduced expression of SMAD4 or CCL15, we investigated tumor growth activities in vivo. We used immunohistochemistry (IHC) to investigate expression of SMAD4, CCL15, and CCR1 with 333 clinical specimens of primary colorectal cancer. We next characterized the CCR1+ cells using double immunofluorescence staining with several specific cell-type markers. Finally, we determined the serum CCL15 levels in 132 colorectal cancer patients.

Results: In an orthotopic xenograft model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1+ cells, resulting in aggressive tumor growth. IHC indicated that loss of SMAD4 was significantly associated with CCL15 expression, and that CCL15-positive primary colorectal cancers recruited approximately 2.2 times more numbers of CCR1+ cells at their invasion front than CCL15-negative colorectal cancers. Importantly, these CCR1+ cells were of the myeloid-derived suppressor cell (MDSC) phenotype (CD11b+, CD33+, and HLA-DR−). Most CCR1+ cells showed the granulocytic-MDSC phenotype (CD15+), whereas some showed the monocytic-MDSC phenotype (CD14+). Serum CCL15 levels in colorectal cancer patients were significantly higher than in controls.

Conclusions: Blocking the recruitment of CCR1+ MDSCs may represent a novel molecular-targeted therapy, and serum CCL15 concentration can be a novel biomarker for colorectal cancer. Clin Cancer Res; 22(2); 492–501. ©2015 AACR.
MAPRE1 as a Plasma Biomarker for Early-Stage Colorectal Cancer and Adenomas
Authors: Taguchi Ayumu , Rho Jung-hyun , Yan Qingxiang , Zhang Yuzheng , Zhao Yang , Xu Hanwen , Tripathi Satyendra Chandra , Wang Hong , Brenner Dean E. , Kucherlapati Melanie , Kucherlapati Raju , Boutin Adam T. , Wang Y. Alan , DePinho Ronald A. , Feng Ziding , Lampe Paul D. , Hanash Samir M.
Published: September 2015

Blood-based biomarkers for early detection of colorectal cancer could complement current approaches to colorectal cancer screening. We previously identified the APC-binding protein MAPRE1 as a potential colorectal cancer biomarker. Here, we undertook a case–control validation study to determine the performance of MAPRE1 in detecting early colorectal cancer and colon adenoma and to assess the potential relevance of additional biomarker candidates. We analyzed plasma samples from 60 patients with adenomas, 30 with early colorectal cancer, 30 with advanced colorectal cancer, and 60 healthy controls. MAPRE1 and a set of 21 proteins with potential biomarker utility were assayed using high-density antibody arrays, and carcinoembryonic antigen (CEA) was assayed using ELISA. The biologic significance of the candidate biomarkers was also assessed in colorectal cancer mouse models. Plasma MAPRE1 levels were significantly elevated in both patients with adenomas and patients with colorectal cancer compared with controls (P < 0.0001). MAPRE1 and CEA together yielded an area under the curve of 0.793 and a sensitivity of 0.400 at 95% specificity for differentiating early colorectal cancer from controls. Three other biomarkers (AK1, CLIC1, and SOD1) were significantly increased in both adenoma and early colorectal cancer patient plasma samples and in plasma from colorectal cancer mouse models at preclinical stages compared with controls. The combination of MAPRE1, CEA, and AK1 yielded sensitivities of 0.483 and 0.533 at 90% specificity and sensitivities of 0.350 and 0.467 at 95% specificity for differentiating adenoma and early colorectal cancer, respectively, from healthy controls. These findings suggest that MAPRE1 can contribute to the detection of early-stage colorectal cancer and adenomas together with other biomarkers. Cancer Prev Res; 8(11); 1112–9. ©2015 AACR.