bluuebunny/crossref_metadata_2025 huggingface dataset:
Acupuncture for adults with overactive bladder: a systematic review protocol
Authors: Mo Qian , Wang Yang , Ye Yongming , Yu Jinna , Liu Zhishun
Published: January 2015

Introduction

Overactive bladder (OAB) is a symptom syndrome defined by the International Continence Society (ICS) as ‘the presence of urinary urgency (both daytime and nighttime), usually accompanied by increased frequency and nocturia with or without urge urinary incontinence in the absence of a urinary tract infection or other obvious pathology’. Clinical studies indicate that acupuncture could reduce micturition over 24 h, urgency episodes over 24 h, and improve quality of life among people with OAB. This systematic review protocol details the proposed methods for evaluating the effectiveness and safety of acupuncture for OAB.

Methods and analysis

The following databases will be searched for relevant studies: the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Incontinence Group Trials Register, MEDLINE, EMBASE, Chinese Biomedical Literature Database (CBM), Chinese Medical Current Content (CMCC), Chinese Scientific Journal Database (VIP database), Wan-Fang Data, and China National Knowledge Infrastructure (CNKI) and will hand search a list of medical journals as a supplement. Any randomised controlled trials in English or Chinese without restriction of publication status will be included with treatment of OAB. Outcomes will mainly include number of micturition episodes over 24 h, number of urgency episodes over 24 h and number of incontinence episodes over 24 h. Two reviewers will independently screen the titles, abstracts or even full texts, and extract data. Two other reviewers will assess study quality. Revman 5.1 software will be used to conduct meta-analysis and calculate the risk ratio for dichotomous data. Weighted mean difference or standard mean difference will be calculated for continuous data. The Cochrane collaboration's tool will be used to assess the risk of bias.

Dissemination

This systematic review protocol will provide information on acupuncture therapy for OAB. The results will be disseminated through peer-reviewed publication or conference presentations.

Protocol registration

PROSPERO CRD42014010181.
Healthy Start vitamins—a missed opportunity: findings of a multimethod study
Authors: McFadden Alison , Green Josephine M , McLeish Jenny , McCormick Felicia , Williams Victoria , Renfrew Mary J
Published: January 2015

Objective

To evaluate and provide a real-life view of the operation of the Healthy Start vitamins scheme.

Setting

The study took place in primary care and community settings that served rural, urban and ethnically diverse populations, in two sentinel sites: London, and Yorkshire and the Humber. An online consultation and stakeholder workshops elicited views from across England.

Participants

669 health and social care practitioners including health visitors, midwives, public health practitioners, general practitioners, paediatricians and support staff participated in focus group discussions (n=49) and an online consultation (n=620). 56 participants representing health and social care practitioners, policymakers, service commissioners, and voluntary and independent sectors took part in stakeholder workshops.

Methods

Three-phase multimethod study comprising focus group discussions, an online consultation and stakeholder workshops. Qualitative data were analysed thematically and quantitative data from the online survey were analysed using descriptive statistics.

Results

Study participants were concerned about the low uptake of Healthy Start vitamin supplements and the consequences of this for health outcomes for women and young children. They experienced Healthy Start vitamin distribution as logistically complex, requiring the time, resources and creative thinking of a range of local and regional practitioners from senior strategists to administrative support workers. In the light of this, many participants argued that moving to universal provision of vitamin supplements would be more cost-effective than the current system.

Conclusions

There is consistency of views of health practitioners that the current targeted system of providing free vitamin supplements for low-income childbearing women and young children via the Healthy Start programme is not fulfilling its potential to address vitamin deficiencies. There is wide professional and voluntary sector support for moving from the current targeted system to provision of free vitamin supplements for all pregnant and new mothers, and children up to their fifth birthday.
Correct recognition and management of anaphylaxis: not much change over a decade
Authors: Plumb Benjamin , Bright Philip , Gompels Mark M , Unsworth David Joe
Published: January 2015

Background

Anaphylaxis is increasing in incidence. This potentially fatal condition requires immediate intramuscular adrenaline as a vital part of early treatment. A 2002 survey of UK Senior House Officers showed a lack of knowledge regarding the recognition and management of anaphylaxis. Since then major changes in medical education and updated national guidelines have aimed to ensure that doctors can recognise and treat anaphylaxis appropriately.

Objectives

To determine current knowledge concerning the recognition and management of anaphylaxis among junior doctors compared to their predecessors.

Methods

Using the same methodology as in 2002, we asked 68 Foundation doctors to read five clinical scenarios potentially suggesting anaphylaxis and indicate how they would respond to each case. Their results were compared to those of Senior House Officers in 2002.

Results

68 of 107 (64%) junior doctors completed the questionnaire. All recognised the need for adrenaline in anaphylaxis, but only 74% selected the correct intramuscular route, and 34% the correct route and dose. 82% of junior doctors would inappropriately give adrenaline to the patient who had inhaled a foreign body (case 2). A higher percentage of the 2013 cohort indicated the correct route and dose of adrenaline in anaphylaxis than their 2002 colleagues. However, a greater percentage also selected adrenaline treatment inappropriately in non-anaphylactic case scenarios.

Conclusions

Despite updated guidelines, junior doctors continue to have poor knowledge about the recognition and management of anaphylaxis, with some still considering inappropriate intravenous adrenaline. More effort should be given to the recognition of anaphylaxis in early medical training.
Estimates for compression norms and additivity violation in quantum information
Authors: Collins Benoît , Fukuda Motohisa , Zhong Ping
Published: January 2015

The free contraction norm (or the (t)-norm) was introduced by Belinschi, Collins and Nechita as a tool to compute the typical location of the collection of singular values associated to a random subspace of the tensor product of two Hilbert spaces. In turn, it was used again by them in order to obtain sharp bounds for the violation of the additivity of the minimum output entropy (MOE) for random quantum channels with Bell states. This free contraction norm, however, is difficult to compute explicitly. The purpose of this note is to give a good estimate for this norm. Our technique is based on results of super convergence in the context of free probability theory. As an application, we give a new, simple and conceptual proof of the violation of the additivity of the MOE.
On totally geodesic submanifolds in the Jacobian locus
Authors: Colombo Elisabetta , Frediani Paola , Ghigi Alessandro
Published: January 2015

We study submanifolds of Agthat are totally geodesic for the locally symmetric metric and which are contained in the closure of the Jacobian locus but not in its boundary. In the first section we recall a formula for the second fundamental form of the period map Mg↪ Agdue to Pirola, Tortora and the first author. We show that this result can be stated quite neatly using a line bundle over the product of the curve with itself. We give an upper bound for the dimension of a germ of a totally geodesic submanifold passing through [C] ∈ Mgin terms of the gonality of C. This yields an upper bound for the dimension of a germ of a totally geodesic submanifold contained in the Jacobian locus, which only depends on the genus. We also study the submanifolds of Agobtained from cyclic covers of ℙ1. These have been studied by various authors. Moonen determined which of them are Shimura varieties using deep results in positive characteristic. Using our methods we show that many of the submanifolds which are not Shimura varieties are not even totally geodesic.
Tetrahydroxystilbene Glucoside Improves TNF-α-Induced Endothelial Dysfunction: Involvement of TGFβ/Smad Pathway and Inhibition of Vimentin Expression
Authors: Yao Wenjuan , Gu Chengjing , Shao Haoran , Meng Guoliang , Wang Huiming , Jing Xiang , Zhang Wei
Published: January 2015

Endothelial dysfunction plays an important role in the pathogenesis of atherogenesis. 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), an active component of the rhizome extract from Polygonum multiflorum (PM), exhibits significant anti-atherosclerotic activity. Here, we used human umbilical vein endothelial cells (HUVECs) induced by tumor necrosis factor-α (TNF-α) in vitro to investigate the cytoprotective effects of TSG on TNF-α-induced endothelial injury and the related mechanisms. Pretreatment with 50 and 100 μM TSG markedly attenuated TNF-α-induced loss of cell viability and release of lactate dehydrogenase (LDH) and inhibited TNF-α-induced cell apoptosis. The inhibition of vimentin expression was involved in the cytoprotection afforded by TSG. Using inhibitors for PI3K and TGFβ or siRNA for Akt and Smad2, we found that vimentin production in HUVECs is regulated by TGFβ/Smad signaling, but not by PI3K–Akt–mTOR signaling. Meanwhile, TSG inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by TNF-α. These results suggest that TSG protects HUVECs against TNF-α-induced cell damage by inhibiting vimentin expression via the interruption of the TGFβ/Smad signaling pathway.
Concrete quarks
Authors: Zweig George
Published: January 2015

A short history of the physics of strongly interacting particles is presented. Events leading to the discovery, and eventual acceptance, of concrete quarks are described. (Other aspects of quark history are given in Refs. 1 and 2.)
What is a quark?
Authors: Kane Gordon L. , Perry Malcolm J.
Published: January 2015

We are used to thinking of quarks as fundamental particles in the same way we think of the electron, or gauge bosons, neutrinos, leptons. In strong theory, these objects are unified with gravitation and the physics of spacetime into what is hoped to be an ultimate theory, string/M theory. The string/M theory paradigm completely changes the way we think of the so-called elementary particles in quantum field theory.
From Ω- to Ωb, doubly heavy baryons and exotics
Authors: Karliner Marek
Published: January 2015

I discuss accurate theoretical predictions for masses of baryons containing the b quark. I point out an approximate effective supersymmetry between heavy quark baryons and mesons and provide predictions for the magnetic moments of Λc and Λb. Proper treatment of the color-magnetic hyperfine interaction in QCD is crucial for obtaining these results. Closely related methods are then applied to doubly-heavy hadrons: the recently observed exotic [Formula: see text] mesons and QQq baryons. Predictions are given for the masses and decay modes of additional [Formula: see text] mesons and of QQq baryons: Ξcc(ccq), Ξbb(bbq) and Ξbc(bcq), which might soon be seen experimentally, as indicated by the large number of Bc mesons observed by LHCb.
Neutrino masses from CMB B-mode polarization and cosmic growth rate
Authors: Hirano Koichi
Published: January 2015

Constraints on neutrino masses are estimated based on future observations of the cosmic microwave background (CMB), which includes the B-mode polarization produced by CMB lensing from the Planck satellite, and the growth rate of cosmic structure from the Euclid redshift survey by using the Markov–Chain Monte-Carlo (MCMC) method. The error in the bound on the total neutrino mass is estimated to be Δ ∑ mν = 0.075 eV with a 68% confidence level. By using the growth rate rather than the galaxy power spectrum, accurate constraints are obtained, since the growth rate is less influenced by the uncertainty regarding galaxy bias than by the galaxy power spectrum.
Dirac equations with confining potentials
Authors: Noble J. H. , Jentschura U. D.
Published: January 2015

This paper is devoted to a study of relativistic eigenstates of Dirac particles which are simultaneously bound by a static Coulomb potential and added linear confining potentials. Under certain conditions, despite the addition of radially symmetric, linear confining potentials, specific bound-state energies surprisingly preserve their exact Dirac–Coulomb values. The generality of the "preservation mechanism" is investigated. To this end, a Foldy–Wouthuysen transformation is used to calculate the corrections to the spin-orbit coupling induced by the linear confining potentials. We find that the matrix elements of the effective operators obtained from the scalar, and time-like confining potentials mutually cancel for specific ratios of the prefactors of the effective operators, which must be tailored to the preservation mechanism. The result of the Foldy–Wouthuysen transformation is used to verify that the preservation is restricted (for a given Hamiltonian) to only one reference state, rather than traceable to a more general relationship among the obtained effective low-energy operators. The results derived from the nonrelativistic effective operators are compared to the fully relativistic radial Dirac equations. Furthermore, we show that the preservation mechanism does not affect antiparticle (negative-energy) states.
Light field integration in SUGRA theories
Authors: Gallego Diego
Published: January 2015

We revisit the integration of fields in 𝒩 = 1 Supergravity with the requirement that the effective theory has a reliable two-derivative supersymmetric description. In particular, we study, in a supersymmetric manifest way, the situation where the fields that are mapped out have masses comparable to the Supersymmetry breaking scale and masses of the remaining fields. We find that as long as one stands in regions of the field configuration space where the analytic continuation to superspace of the F-flatness conditions be reliable equations of motion for the fields that are being mapped out, and provided their solutions are stable regardless the dynamics of the remaining fields, such a two-derivative description is a reliable truncation of the full effective theory. The study is mainly focused to models with two chiral sectors, H and L, described by a Kähler invariant function with schematic dependencies of the form [Formula: see text], which leads to a nearly decoupled theory that allows the previous requirements to be easily satisfied in a consistent way. Interestingly, enough for the matters of our study, this kind of models present a scenario that is as safe as the one presented in sequestered models. It is also possible to allow gauge symmetries as long as these appear also factorized in hidden and visible sectors. Then, the integration of the hidden vector superfields is compulsory and proceeds reliably through the D-flatness condition analytically continued to superspace.
Anisimov's Theorem for inverse semigroups
Authors: Kambites Mark
Published: January 2015

The idempotent problem of a finitely generated inverse semigroup is the formal language of all words over the generators representing idempotent elements. This paper proves that a finitely generated inverse semigroup with regular idempotent problem is necessarily finite. This answers a question of Gilbert and Noonan Heale, and establishes a generalization to inverse semigroups of Anisimov's Theorem for groups.
A new notion of vertex independence and rank for finite graphs
Authors: Rhodes John , Silva Pedro V.
Published: January 2015

A new notion of vertex independence and rank for a finite graph G is introduced. The independence of vertices is based on the boolean independence of columns of a natural boolean matrix associated to G. Rank is the cardinality of the largest set of independent columns. Some basic properties and some more advanced theorems are proved. Geometric properties of the graph are related to its rank and independent sets.
A new proof of the locality of R
Authors: Straubing Howard
Published: January 2015

We give a simple proof of a wreath product decomposition for locally ℛ-trivial finite categories. As immediate consequences we obtain two classic results of Stiffler on the decomposition of ℛ-trivial monoids and locally ℛ-trivial semigroups. A small modification of the argument provides a new proof of a recent theorem of Bojańczyk, Straubing and Walukiewicz on the decomposition of forest algebras.
Derivations and bounded nilpotence index
Authors: Nielsen Pace P. , Ziembowski Michał
Published: January 2015

We construct a nil ring R which has bounded index of nilpotence 2, is Wedderburn radical, and is commutative, and which also has a derivation δ for which the differential polynomial ring R[x;δ] is not even prime radical. This example gives a strong barrier to lifting certain radical properties from rings to differential polynomial rings. It also demarcates the strength of recent results about locally nilpotent PI rings.
Seismic Performance of High Strength Reinforced Concrete Buildings Evaluated by Nonlinear Pushover and Dynamic Analyses
Authors: Lin K. C. , Hung H. H. , Sung Y. C.
Published: January 2015

This paper investigates the combined effect of flexural and shear actions on the failure modes of the high strength reinforced concrete (HRC) members using the proposed algorithm for plastic hinge formation. The accuracy of the present procedure for the HRC columns was verified by comparing the results obtained with those of the cyclic loading tests performed in Japan. To evaluate the seismic performance of the HRC high-rise buildings, a seismic performance checklist for the HRC buildings was recommended. Based on the proposed algorithm for formation of plastic hinges, the seismic performance of HRC buildings based on the static pushover analysis is evaluated. From the results of the pushover analysis, a simplified lumped-mass stick model was developed, which is adopted to evaluate the seismic performance using the nonlinear time history analysis. For the purpose of illustration, the seismic performance of a high-rise building constructed with HRC was investigated by both the nonlinear pushover and nonlinear dynamic analyses using the proposed procedure and concepts. The results of this paper serve as a useful reference for the seismic design and evaluation of HRC high-rise structures.
BRICOLAGE AND GROWTH STRATEGIES: EFFECTS ON THE PERFORMANCE OF PALESTINIAN WOMEN-LED FIRMS
Authors: BOJICA ANA M. , ISTANBOULI ABEER , FUENTES-FUENTES MARIA DEL MAR
Published: January 2015

This study explores the relationships between bricolage, firm performance and growth opportunities in contexts characterized by extreme resource scarcity. Using a sample of 160 Palestinian female entrepreneurs as representative of entrepreneurs acting in extremely resource-deprived environments, we find that bricolage has a positive influence on firm performance. Further, as predicted in the hypotheses, the role of bricolage differs depending on the type of strategy the firm develops. When firms seek to introduce new products/services or modifications in their current products/services, a high level of bricolage hinders performance. Conversely, when firms seek to expand by introducing their current products/services in new markets and opening new locations, bricolage enhances performance. This study offers a more nuanced understanding than previous research of the role of bricolage in contexts of extreme resource constraints.
The Cauchy problem for a system of nonlinear heat equations in two space dimensions
Authors: Chouichi Amel , Otsmane Sarah
Published: January 2015

This paper is devoted to system of semilinear heat equations with exponential-growth nonlinearity in two-dimensional space which is the analogue of the scalar model problem studied in [S. Ibrahim, R. Jrad, M. Majdoub and T. Saanouni, Local well posedness of a 2D semilinear heat equation, Bull. Belg. Math. Soc.21 (2014) 1–17]. First, we prove the local existence and unconditional uniqueness of solutions in the Sobolev space (H1× H1)(ℝ2). The uniqueness part is nontrivial although it follows Brezis–Cazenave's proof [H. Brezis and T. Cazenave, A nonlinear heat equation with singular initial data, J. Anal. Math.68 (1996) 73–90] in the case of monomial nonlinearity in dimension d ≥ 3. Next, we show that in the defocusing case our solution is bounded, and therefore exists globally in time. Finally, for this system, we treat the question of blow-up in finite time under the negativity condition on the energy functional. The technique to be used is adapted from [Bull. Belg. Math. Soc. 21 (2014) 1–17].
de Morgan algebras with double pseudocomplementation
Authors: Fang Jie , Wang Lei-Bo
Published: January 2015

We investigate de Morgan algebras with double pseudocomplementation. In particular, we characterize the congruence relations of such algebras, and provide a complete description of subdirectly irreducible members of this class.
The Wedderburn b-decomposition for a class of almost alternative baric algebras
Authors: Ferreira B. L. M. , Guzzo H. , Ferreira J. C. M.
Published: January 2015

In this paper we deal with the Wedderburn b-decomposition for baric algebras of (γ, δ) type.
Pseudo-differential operators associated with the Jacobi differential operator and Fourier-cosine wavelet transform
Authors: Prasad Akhilesh , Singh Manoj K.
Published: January 2015

Using the inverse of Fourier–Jacobi transform a symbol is defined, and the pseudo-differential operator (p.d.o.) 𝒫α, β (x,D) associated with Jacobi-differential operator in terms of this symbol is defined. It is shown that the p.d.o. is bounded in a certain Sobolev type space associated with the Fourier–Jacobi transform. Continuous Jacobi wavelet transform (JWT) and Fourier-cosine wavelet transform are defined and a reconstruction formula is obtained for Fourier-cosine wavelet transform. Properties of Fourier-cosine wavelet transform are investigated.
On the unitary units of the group algebra 𝔽2kQ16
Authors: Raza Zahid , Ali Riasat
Published: January 2015

In this note, the structure of unitary unit groups V*(𝔽2kQ16) is investigated, where Q16, is quaternion group of order 16, and 𝔽2kis any finite field of characteristic 2, with 2kelements. In particular, we give the center Z(V*(𝔽2kQ16)) of unitary units subgroup V*(𝔽2kQ16) of group algebra 𝔽2kQ16. The structure of the unitary unit subgroup V*(𝔽2kQ16) is described with the help of the Z(V*(𝔽2kQ16)).
Hot clasts and cold blasts: thermal heterogeneity in boiling-over pyroclastic density currents
Authors: Rader Erika , Geist Dennis , Geissman John , Dufek Joe , Harpp Karen
Published: January 2015

Partial thermal remanent magnetization data from clasts in pyroclastic density current (PDC) deposits provide information on the emplacement temperatures of both lithic and juvenile magmatic clasts contained in the deposits. We collected palaeomagnetic data from clasts in PDC deposits emplaced during historical eruptions of two volcanoes in Ecuador, the 2006 eruption at Tungurahua and the 1877 eruption at Cotopaxi. These eruptions were characterized by emplacement of PDCs mainly related to boiling-over activity. The deposits of these eruptions are similar and are characterized by cauliflower-textured juvenile scoria clasts up to 1 m in diameter and a diverse assemblage of lithic clasts surrounded by an unwelded ashy matrix. On the basis of progressive thermal demagnetization experiments, we infer that emplacement temperatures for most of the lithic clasts in PDC deposits are below 90 °C. In contrast, palaeomagnetic data from juvenile clasts from the same deposits provide emplacement temperatures higher than 540 °C. These data indicate the PDC were thermally heterogeneous over short length scales (decimetres) also after deposition. We hypothesize that PDCs emplaced by the boiling-over mechanism cool quickly owing to atmosphere entrainment, causing the juvenile clasts to form a rind that retains heat and that also prevents lithic clasts from appreciable heating. Several deposits on Cotopaxi, despite being morphologically similar to the PDC deposits, contain both cold lithic and juvenile clasts, which we interpret to be lahar deposits formed by PDCs travelling across glacial ice and snow. Rare deposits containing both hot lithic and hot juvenile clasts are classified as well-mixed, hot PDCs, and were erupted during a more energetic phase at Tungurahua.
From planet Earth to society: a new dynamic in Portugal concerning geoscience education and outreach activities
Authors: Silva Elizabeth , Sá Artur A. , Roxo Maria J.
Published: January 2015

Since the United Nations declared 2008 as the International Year of Planet Earth (IYPE) (during the triennium of 2007–2009), under the motto ‘Earth Sciences for Society’, many impacts and changes were generated in Portuguese society. Particular attention was given to educational activities concerning geosciences and these were promoted by several entities in Portugal.

The Portuguese National Commission for United Nations Educational, Scientific and Cultural Organization (UNESCO) has assumed an increasing role in the science sector with the promotion of initiatives and the creation of several scientific committees acting as national branches of UNESCO scientific programmes. This is the case of the National Committee for the International Geosciences Programme (NC–IGCP), which has been responsible for multiple initiatives that have been promoted and implemented in the area of geosciences and that contribute to the improvement of scientific literacy.

The work developed by NC–IGCP has contributed to developing new ways of promoting geosciences and to creating awareness about the role of geoscientists for a better world based in a sustainable development guided by ethical principles.

The use of tools such as itinerant exhibitions, educational training courses, school contests and information available on the website have allowed closer support and visibility to the development of fundamental science projects and outreach activities in Earth sciences.
Chronic NOS inhibition accelerates NAFLD progression in an obese rat model
Authors: Sheldon Ryan D. , Padilla Jaume , Jenkins Nathan T. , Laughlin M. Harold , Rector R. Scott
Published: January 2015

The progression in nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis is a serious health concern, but the underlying mechanisms remain unclear. We hypothesized that chronic inhibition of nitric oxide (NO) synthase (NOS) via Nω-nitro-l-arginine methyl ester (l-NAME) would intensify liver injury in a rat model of obesity, insulin resistance, and NAFLD. Obese Otsuka Long-Evans Tokushima fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats received control or l-NAME (65–70 mg·kg−1·day−1)-containing drinking water for 4 wk. l-NAME treatment significantly ( P < 0.05) reduced serum NO metabolites and food intake in both groups. Remarkably, despite no increase in body weight, l-NAME treatment increased hepatic triacylglycerol content (+40%, P < 0.05) vs. control OLETF rats. This increase was associated with impaired ( P < 0.05) hepatic mitochondrial state 3 respiration. Interestingly, the opposite effect was found in LETO rats, where l-NAME increased ( P < 0.05) hepatic mitochondrial state 3 respiration. In addition, l-NAME induced a shift toward proinflammatory M1 macrophage polarity, as indicated by elevated hepatic CD11c ( P < 0.05) and IL-1β ( P = 0.07) mRNA in OLETF rats and reduced expression of the anti-inflammatory M2 markers CD163 and CD206 ( P < 0.05) in LETO rats. Markers of total macrophage content (CD68 and F4/80) mRNA were unaffected by l-NAME in either group. In conclusion, systemic NOS inhibition in the obese OLETF rats reduced hepatic mitochondrial respiration, increased hepatic triacylglycerol accumulation, and increased hepatic inflammation. These findings suggest an important role for proper NO metabolism in the hepatic adaptation to obesity.
Brain-derived neurotrophic factor modulates angiotensin signaling in the hypothalamus to increase blood pressure in rats
Authors: Erdos Benedek , Backes Iara , McCowan Michael L. , Hayward Linda F. , Scheuer Deborah A.
Published: January 2015

Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) in response to hypertensive stimuli including stress and hyperosmolarity. However, it is unclear whether BDNF in the PVN contributes to increases in blood pressure (BP). We tested the hypothesis that increased BDNF levels within the PVN would elevate baseline BP and heart rate (HR) and cardiovascular stress responses by altering central angiotensin signaling. BP was recorded using radiotelemetry in male Sprague-Dawley rats after bilateral PVN injections of adeno-associated viral vectors expressing green fluorescent protein (GFP) or myc epitope-tagged BDNF fusion protein. Cardiovascular responses to acute stress were evaluated 3 to 4 wk after injections. Additional GFP and BDNF-treated animals were equipped with osmotic pumps for intracerebroventricular infusion of saline or the angiotensin type-1 receptor (AT1R) inhibitor losartan (15 μg·0.5 μl−1·h−1). BDNF treatment significantly increased baseline BP (121 ± 3 mmHg vs. 99 ± 2 mmHg in GFP), HR (394 ± 9 beats/min vs. 314 ± 4 beats/min in GFP), and sympathetic tone indicated by HR- and BP-variability analysis and adrenomedullary tyrosine hydroxylase protein expression. In contrast, body weight and BP elevations to acute stressors decreased. BDNF upregulated AT1R mRNA by ∼80% and downregulated Mas receptor mRNA by ∼50% in the PVN, and losartan infusion partially inhibited weight loss and increases in BP and HR in BDNF-treated animals without any effect in GFP rats. Our results demonstrate that BDNF overexpression in the PVN results in sympathoexcitation, BP and HR elevations, and weight loss that are mediated, at least in part, by modulating angiotensin signaling in the PVN.
Extracellular Ca2+-induced force restoration in K+-depressed skeletal muscle of the mouse involves an elevation of [K+]i: implications for fatigue
Authors: Cairns Simeon P. , Leader John P. , Loiselle Denis S. , Higgins Amanda , Lin Wei , Renaud Jean-Marc
Published: January 2015

We examined whether a Ca2+-K+ interaction was a potential mechanism operating during fatigue with repeated tetani in isolated mouse muscles. Raising the extracellular Ca2+ concentration ([Ca2+]o) from 1.3 to 10 mM in K+-depressed slow-twitch soleus and/or fast-twitch extensor digitorum longus muscles caused the following: 1) increase of intracellular K+ activity by 20–60 mM (raised intracellular K+ content, unchanged intracellular fluid volume), so that the K+-equilibrium potential increased by ∼10 mV and resting membrane potential repolarized by 5–10 mV; 2) large restoration of action potential amplitude (16–54 mV); 3) considerable recovery of excitable fibers (∼50% total); and 4) restoration of peak force with the peak tetanic force-extracellular K+ concentration ([K+]o) relationship shifting rightward toward higher [K+]o. Double-sigmoid curve-fitting to fatigue profiles (125 Hz for 500 ms, every second for 100 s) showed that prior exposure to raised [K+]o (7 mM) increased, whereas lowered [K+]o (2 mM) decreased, the rate and extent of force loss during the late phase of fatigue (second sigmoid) in soleus, hence implying a K+ dependence for late fatigue. Prior exposure to 10 mM [Ca2+]o slowed late fatigue in both muscle types, but was without effect on the extent of fatigue. These combined findings support our notion that a Ca2+-K+ interaction is plausible during severe fatigue in both muscle types. We speculate that a diminished transsarcolemmal K+ gradient and lowered [Ca2+]o contribute to late fatigue through reduced action potential amplitude and excitability. The raised [Ca2+]o-induced slowing of fatigue is likely to be mediated by a higher intracellular K+ activity, which prolongs the time before stimulation-induced K+ efflux depolarizes the sarcolemma sufficiently to interfere with action potentials.
A Novel CDC25B Promoter–Based Oncolytic Adenovirus Inhibited Growth of Orthotopic Human Pancreatic Tumors in Different Preclinical Models
Authors: Weber Helga L. , Gidekel Manuel , Werbajh Santiago , Salvatierra Edgardo , Rotondaro Cecilia , Sganga Leonardo , Haab Gabriela Acosta , Curiel David T. , Cafferata Eduardo G. , Podhajcer Osvaldo L.
Published: January 2015

Purpose: We decided to construct a novel oncolytic adenovirus whose replication was driven by the CDC25B promoter for its use in preclinical models of pancreatic cancer.

Experimental Design: We placed the essential E1A gene under control of the CDC25B promoter. Based on preliminary data, we pseudotyped the adenovirus with a chimeric fiber of serotypes 5/3. We investigated the in vitro lytic effect and the in vivo therapeutic efficacy in combination with gemcitabine on human pancreatic tumor xenografts orthotopically growing in nude mice and in tumors growing in Syrian hamsters. We also assessed biochemical markers of hepatic toxicity and CA19.9 levels.

Results: AV25CDC exhibited a strong in vitro lytic effect on pancreatic cancer cells. In vivo administration of AV25CDC combined with gemcitabine in mice harboring subcutaneously growing SW1990 pancreatic tumors almost abrogated tumor growth. Nude mice harboring 15-day-old orthotopic tumors, treated intratumorally or systemically with AV25CDC combined with gemcitabine, exhibited 70% to 80% reduction in tumor size compared with control mice that lasted for at least 60 days. Chemovirotherapy treatment induced a return to normal levels of biochemical parameters of hepatic toxicity; these mice exhibited more than 90% reduction in CA19.9 serum levels compared with control. Chemovirotherapy efficacy was confirmed in mice harboring Mia PaCa-2 tumors and in Syrian hamster harboring HaP-T1 tumors. We observed that viral treatment disrupted tumor architecture and induced an increase in MMP-9 activity that might facilitate gemcitabine penetrability.

Conclusion: These data demonstrate that AV25CDC is an effective oncolytic agent candidate for pancreatic cancer chemovirotherapy combination. Clin Cancer Res; 21(7); 1665–74. ©2015 AACR.
Differential Effects of Tyrosine Kinase Inhibitors on Normal and Oncogenic EGFR Signaling and Downstream Effectors
Authors: Kim Youngjoo , Apetri Mihaela , Luo BeiBei , Settleman Jeffrey E. , Anderson Karen S.
Published: January 2015

Constitutive activation of EGFR due to overexpression or mutation in tumor cells leads to dysregulated downstream cellular signaling pathways. Therefore, EGFR as well as its downstream effectors have been identified as important therapeutic targets. The FDA-approved small-molecule inhibitors of EGFR, gefitinib (Iressa) and erlotinib (Tarceva), are clinically effective in a subset of patients with non–small cell lung cancer (NSCLC) whose tumors harbor activating mutations within the kinase domain of EGFR. The current study examined effects of these drugs in 32D cells expressing native (WT) or oncogenic (L858R) EGFR as well as in cancer cell lines A431 and H3255. Distinct patterns for gefitinib and erlotinib inhibition of EGFR autophosphorylation at individual tyrosines were revealed for wild-type (WT) and L858R EGFR. Phosphorylation of Y845 has been shown to be important in cancer cells and Y1045 phosphorylation is linked to Cbl-mediated ubiquitination and degradation. Dramatic differences were observed by greater potency of these drugs for inhibiting downstream effectors for L858R EGFR including Cbl and STAT5. Selective targeting of Cbl may play a role in oncogene addiction and effects on STAT5 identify features of signaling circuitry for L858R EGFR that contribute to drug sensitivity and clinical efficacy. These data provide new understanding of the EGFR signaling environment and suggest useful paradigms for predicting patient response to EGFR-targeted therapy as well as combination treatments.

Implications: This study offers fundamental insights for understanding molecular mechanisms of drug sensitivity on oncogenic forms of EGFR and downstream signaling components as well as considerations for further drug optimization and design of combination therapy. Mol Cancer Res; 13(4); 765–74. ©2015 AACR.
Combined Inhibition of MAP Kinase and KIT Signaling Synergistically Destabilizes ETV1 and Suppresses GIST Tumor Growth
Authors: Ran Leili , Sirota Inna , Cao Zhen , Murphy Devan , Chen Yuedan , Shukla Shipra , Xie Yuanyuan , Kaufmann Michael C. , Gao Dong , Zhu Sinan , Rossi Ferdinando , Wongvipat John , Taguchi Takahiro , Tap William D. , Mellinghoff Ingo K. , Besmer Peter , Antonescu Cristina R. , Chen Yu , Chi Ping
Published: January 2015

Gastrointestinal stromal tumor (GIST), originating from the interstitial cells of Cajal (ICC), is characterized by frequent activating mutations of the KIT receptor tyrosine kinase. Despite the clinical success of imatinib, which targets KIT, most patients with advanced GIST develop resistance and eventually die of the disease. The ETS family transcription factor ETV1 is a master regulator of the ICC lineage. Using mouse models of Kit activation and Etv1 ablation, we demonstrate that ETV1 is required for GIST initiation and proliferation in vivo, validating it as a therapeutic target. We further uncover a positive feedback circuit where MAP kinase activation downstream of KIT stabilizes the ETV1 protein, and ETV1 positively regulates KIT expression. Combined targeting of ETV1 stability by imatinib and MEK162 resulted in increased growth suppression in vitro and complete tumor regression in vivo. The combination strategy to target ETV1 may provide an effective therapeutic strategy in GIST clinical management.

Significance: ETV1 is a lineage-specific oncogenic transcription factor required for the growth and survival of GIST. We describe a novel strategy of targeting ETV1 protein stability by the combination of MEK and KIT inhibitors that synergistically suppress tumor growth. This strategy has the potential to change first-line therapy in GIST clinical management. Cancer Discov; 5(3); 304–15. ©2015 AACR.

See related commentary by Duensing, p. 231

This article is highlighted in the In This Issue feature, p. 213
Is the Measurement of Serum Ischemia-Modified Albumin the Best Test to Diagnose Ovarian Torsion?
Authors: Guven Suleyman , Kart Cavit , Guvendag Guven Emine Seda , Cetin Esra Can , Menteşe Ahmet
Published: January 2015

Aim: The aim of this study is to evaluate the diagnostic value of serum oxidative stress marker levels (ischemia-modified albumin, IMA; malondialdehyde, MDA) and total oxidant status (TOS), total antioxidant status (TAS) and oxidative stress index (OSI) levels that occur in ovarian torsion and to determine the threshold value of these markers in the diagnosis of ovarian torsion. Methods: In this prospective case-control study, 34 women (the study group) with acute pelvic pain (20 with and 14 without ovarian torsion) and 40 control subjects were included. The diagnosis of ovarian torsion was confirmed with laparoscopy in all cases. Preoperative serum samples were collected in the study group. Serum oxidative stress marker levels (IMA and MDA) and TOS, TAS and OSI levels were measured. Results: Serum MDA, TOS and IMA concentrations were significantly higher in women with ovarian torsion than in the healthy control group. However, serum TAS, TOS and OSI concentrations were significantly higher in women without ovarian torsion than within the healthy control group. Only IMA significantly distinguished patients with or without ovarian torsion. The best IMA value, according to the receiver operating characteristic curve, was 0.7045 absorbance units, with 90.00% sensitivity and 92.31% specificity. The patients in the ovarian torsion group had significantly lower serum TAS and OSI levels compared with patients without ovarian torsion. Conclusion: The elevated serum IMA levels with high sensitivity-specificity values observed in women with ovarian torsion seem to have a potential role as a serum marker in the preoperative diagnosis of ovarian torsion in emergency settings.
Different Effects of Cholestyramine on Postprandial Secretions of Cholecystokinin and Peptide YY in Women with Bulimia Nervosa
Authors: Rigamonti Antonello E. , Sartorio Alessandro , Scognamiglio Pasquale , Bini Silvia , Monteleone Alessio M. , Mastromo Daniele , Marazzi Nicoletta , Cella Silvano G. , Monteleone Palmiero
Published: January 2015

Objective: Patients with bulimia nervosa (BN) are reported to have decreased postprandial levels of cholecystokinin (CCK) and peptide YY (PYY). Fatty nutrients are the most powerful stimulus for releasing these peptides. Cholestyramine is an anion exchanger which adsorbs bile salts and reduces the digestion of lipids, affecting the secretion of both CCK and PYY. To further characterise the physiology of these peptides in BN, we aimed to investigate the effects of cholestyramine (12 g, per os) or placebo administered with a high-fat meal on CCK and PYY secretions in bulimic versus healthy women. Results: Postprandial CCK levels significantly increased in both healthy and bulimic women after placebo + the high-fat meal, without any significant difference between the two groups. Cholestyramine administration significantly increased postprandial CCK responses in both healthy and bulimic women; however, significantly lower CCK levels were observed in BN. Postprandial PYY levels significantly increased after placebo administration in healthy women after the high-fat meal, whereas no significant changes were found in bulimic women. Cholestyramine, administered with the high-fat meal, significantly reduced postprandial PYY response in healthy women, but not in bulimic women. Finally, there was a negative correlation of the area under the curve with respect to the increase of PYY (after placebo administration) with binge frequency in the bulimic women. Conclusion: In BN an altered postprandial secretion of CCK may be evidenced when cholestyramine is combined with a high-fat meal. Instead, the postprandial secretion of PYY is significantly blunted and not affected by cholestyramine administration.
Reproduction and Breast Cancer Risk
Authors: Hanf Volker , Hanf Dorothea
Published: January 2015

Reproduction is doubtlessly one of the main biological meanings of life. It is therefore not surprising that various aspects of reproduction impact on breast cancer risk. Various developmental levels may become targets of breast tumorigenesis. This review follows the chronologic sequence of events in the life of a female at risk, starting with the intrauterine development. Furthermore, the influence of both contraceptive measures and fertility treatment on breast cancer development is dealt with, as well as various pregnancy-associated factors, events, and perinatal outcomes. Finally, the contribution of breast feeding to a reduced breast cancer risk is discussed.
Orofacial Granulomatosis: Clinical Signs of Different Pathologies
Authors: Troiano Giuseppe , Dioguardi Mario , Giannatempo Giovanni , Laino Luigi , Testa Nunzio Francesco , Cocchi Roberto , De Lillo Alfredo , Lo Muzio Lorenzo
Published: January 2015

Orofacial granulomatosis (OFG) is an uncommon disease characterized by persistent or recurrent soft tissue enlargement, oral ulceration and a variety of other orofacial features. It could be an oral manifestation of a systemic disease. For a correct differential diagnosis, local and systemic conditions characterized by granulomatous inflammation should be excluded using appropriate clinical and laboratory investigations. In fact, the diagnosis of OFG may be confirmed only by histopathological identification of noncaseating granulomas. The literature from 1943 to 2014 was reviewed with emphasis on the etiology of OFG and on clinical manifestations of systemic pathologies associated with OFG. The precise cause of OFG is still unknown, although several theories have been suggested, such as infection, hereditary factors and allergy. OFG is a disease that has a wide spectrum of presentation, which may include the oral manifestation of a systemic condition such as Crohn's disease, sarcoidosis, granulomatosis with polyangiitis and Melkersson-Rosenthal syndrome.
The Development of Orange Pigment Overlying Choroidal Metastasis
Authors: Riechardt Aline Isabel , Gundlach Enken , Joussen Antonia M. , Willerding Gregor D.
Published: January 2015

Aims: The aim of this study was to correlate the ophthalmoscopic and histopathological findings of orange pigment overlying a choroidal metastasis. Methods: This is a single case report with clinical follow-up and histopathological examination. Results: Histopathology revealed a choroidal metastasis with subretinal CD68-positive macrophages showing autofluorescent deposits in fluorescence microscopy. Conclusion: The development of orange pigment is not pathognomonic for choroidal melanoma but may be seen in other lesions such as carcinoma metastasis.
Selective Cyclooxygenase-1 Inhibition by P6 and Gastrotoxicity: Preliminary Investigation
Authors: Perrone Maria Grazia , Lofrumento Dario Domenico , Vitale Paola , De Nuccio Francesco , La Pesa Velia , Panella Andrea , Calvello Rosa , Cianciulli Antonia , Panaro Maria Antonietta , Scilimati Antonio
Published: January 2015

Background/Aims: Gastrointestinal damage (GD) is commonly associated with the inhibition of cyclooxygenase (COX)-1, one of the two known COXs, by traditional non-steroidal anti-inflammatory drugs. More recent evidences have proven that GD is caused by the simultaneous inhibition of the two COXs. This study was designed to evaluate the effect of the selective COX-1 inhibition on gastric integrity. Methods: GD was evaluated in male CD1 mice. Drugs were administered by gastric gavage at a dose of 50 mg/kg (injection volume of 100 µl). Control mice received an equal volume of the vehicle (10% ethanol). Each mouse, in groups of at least 6 mice, received one dose/day for 5 days. Results: In Western blot analysis, COX-1 expression levels were found to be significantly reduced in mice treated with 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) in comparison to mice pretreated with aspirin (ASA), which exhibited higher levels of COX-1, thus confirming the high selectivity of P6 towards COX-1 enzyme inhibition. Mucosal sections obtained from ASA-treated mice showed breaks in the epithelial barrier and a marked alteration of foveolae and gastric glands, whereas stomachs isolated from mice sacrificed after 5 days of chronic administration of P6 (at a dose of up to 50 mg/kg/day) showed sporadic transient mucosal hyperemia and did not seem to display any significant gastric damage. Conclusions: The selective COX-1 inhibition by P6 does not cause gastric damage in mice but preserves mucosal integrity.
Down Syndrome and Nonautoimmune Hypothyroidisms in Neonates and Infants
Authors: Kariyawasam Dulanjalee , Carré Aurore , Luton Dominique , Polak Michel
Published: January 2015

Down syndrome is characterized by a high prevalence of thyroid dysfunction during childhood. In this paper, we review the different kinds of thyroid dysfunction that occur excluding those of autoimmune origin: congenital hypothyroidism (elevated plasma TSH with low plasma T4 occurring at birth usually detected by neonatal screening), subclinical hypothyroidism (elevated plasma TSH with plasma T4 in the normal range, which can be congenital or acquired) and acquired primary hypothyroidism (elevated plasma TSH and low plasma T4 occurring after birth). These dysfunctions, while not due to autoimmunity, are of thyroidal origin. However, the mechanisms leading to these different thyroidal abnormalities have not been clearly defined; in particular, it is difficult to determine whether the different types of dysfunction have a common cause, or if the causes are distinct. Treatment is prescribed according to the type of thyroidal abnormality.