The adaptor protein ARA55 and the nuclear kinase HIPK1 assist c-Myb in recruiting p300 to chromatin

Publication date: Available online 8 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Mads Bengtsen, Linda Sørensen, Linn Aabel, Marit Ledsaak, Vilborg Matre, Odd Stokke Gabrielsen
LIM-domain proteins, containing multiple cysteine-rich zinc finger-like motifs, have been shown to play diverse roles in several cellular processes. A common theme is that they mediate important protein-protein interactions that are key to their function. Androgen receptor-associated protein 55 (ARA55) belongs to this family of bridging proteins containing four C-terminal LIM domains. It has a dual role with functions both at focal adhesions and in the nucleus, apparently shuttling between the two compartments. In the present work, we have expanded our understanding of its nuclear functions by showing that it interacts with three nuclear regulators not previously linked to ARA55. We first identified ARA55 as a novel interaction partner of the nuclear kinase HIPK1 and found that ARA55, like HIPK1, also interacts with the transcription factor c-Myb. In search of a function for these associations, we observed that the coactivator p300 not only binds to c-Myb, but to ARA55 as well. When combined, c-Myb, p300, HIPK1 and ARA55 caused strong synergistic activation of a chromatinized reporter gene. In parallel, all partners, including p300, were efficiently recruited to chromatin at the c-Myb-bound promoter. Consistent with this cooperation, we found that c-Myb and ARA55 share a common set of target genes in an osteosarcoma cellular context. We propose that ARA55 and HIPK1 assist c-Myb in recruiting the coactivator and acetyltransferase p300 to chromatin.



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I strongly recommend that all practicing physicians consider such a list, and review it occasionally. I wish for the judgement to know what is best for my patients and to weigh the merits of interventions; surgically, medically, and radiotherapeutically. I wish that I can master the complexities of the practice of medicine and be worthwhile as a physician. I wish for the honesty and integrity to objectively assess my competencies and fallibilities. I wish for the intellectual drive to maintain currency of knowledge. I wish for the wisdom to assess and maintain appropriate costs for medical care. I wish for the integrity to avoid marketing my skills and accomplishments unrealistically and erroneously. I wish for the compassion that allows me to separate my personal problems from the needs of the patients that I serve. I wish for the courage to challenge the wisdom of those that create policies and regulations that fail to consider the full dimension and scope of medical care. Please p

Brazilian Journal of Otorhinolaryngology

Print version ISSN 1808-8694

On-line version ISSN 1808-8686

Braz. j. otorhinolaryngol. vol.83 no.2 São Paulo 

http://dx.doi.org/10.1016/j.bjorl.2017.01.001 

EDITORIAL

Ethics in the twenty first century otolaryngology☆

Charles W. Cummings1 

1Johns Hopkins University, Baltimore, USA. E-mail: ccumming@jhmi.edu

In the United States, the climate of the practice of Medicine is in transition and under siege by policy revisionists and governmental/political opportunists. Regulatory and legislative hubris has enshrouded the medical arena through formulaic dictums and onerous regulations oft times constructed by individuals who have no clinical experience or knowledge. The art of Medicine is being dismantled by emphasis on outcomes based solely on statistical evidence, with no concern for the human variables. Objective analysis is not inherently bad provided the personal and social factors are properly emphasized in the analysis. Freedom to make clinical decisions MUST be preserved for optimal care.

This phenomenon exerts undue pressure on the clinician leading to professional frustration and anemia of job satisfaction. Also, the environment which enables the best of care is further challenged and compromised.

Never the less, we, as physicians, must continue to acknowledge our calling and respond to the gifts of our profession. It seems appropriate to review the commitments that we have made to ourselves and our patients. Over the years, I have created a wish list concerning the way I want to conduct myself to satisfy my professional goals. What follows are those wishes. I strongly recommend that all practicing physicians consider such a list, and review it occasionally.

I wish for the judgement to know what is best for my patients and to weigh the merits of interventions; surgically, medically, and radiotherapeutically.

I wish that I can master the complexities of the practice of medicine and be worthwhile as a physician.

I wish for the honesty and integrity to objectively assess my competencies and fallibilities.

I wish for the intellectual drive to maintain currency of knowledge.

I wish for the wisdom to assess and maintain appropriate costs for medical care.

I wish for the integrity to avoid marketing my skills and accomplishments unrealistically and erroneously.

I wish for the compassion that allows me to separate my personal problems from the needs of the patients that I serve.

I wish for the courage to challenge the wisdom of those that create policies and regulations that fail to consider the full dimension and scope of medical care.

Please preserve the art of Medicine. We must steward our wonderful calling.

☆Please cite this article as: Cummings CW. Ethics in the twenty first century otolaryngology. Braz J Otorhinolaryngol. 2017;83:119.2

Conflicts of interest

The author declares no conflicts of interest.

© 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda.

 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

 

Sede da Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico Facial

Av. Indianópolia, 1287

04063-002 São Paulo/SP Brasil

Tel.: (0xx11) 5053-7500

Fax: (0xx11) 5053-7512

revista@aborlccf.org.br

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Preparation and characterization of tunable oil-encapsulated alginate microfibers

Publication date: 15 August 2017
Source:Materials & Design, Volume 128
Author(s): A.S. Chaurasia, F. Jahanzad, S. Sajjadi
A single-step microfluidic approach was developed which allowed a wide range of oil-loaded calcium-alginate microfibers to be fabricated at the same compositions but with different morphologies. A framework for characterization of wavy fibers was developed which linked the fiber morphology and tensile strength to the encapsulation type and geometry. The geometry of oil encapsulates as well as the fibers surface morphology were conveniently tuned via the gelation reaction dynamics and phase flow rates. A 2D mathematical reconstruction of the fiber's surface revealed that fibers having spherical and ellipsoid encapsulates enjoyed the highest surface roughness. Tubular fibers endured the highest tensile force before failure, compared to fibers with other encapsulate geometries at a fixed alginate phase ratio (ϕalg). Fibers with increased ϕalg withstood a higher tensile force. However, the strength of fibers reduced if the increase in ϕalg altered the encapsulate geometry from tubular to discrete oil segments. Tubular fibers also underwent maximum elastic and plastic deformation prior to failure, among all fibers.

Graphical abstract

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Direct measurement of residual strains in CFRP-tungsten hybrids using embedded strain gauges

Publication date: 5 August 2017
Source:Materials & Design, Volume 127
Author(s): M. Kanerva, P. Antunes, E. Sarlin, O. Orell, J. Jokinen, M. Wallin, T. Brander, J. Vuorinen
In this work, the implementation of fully embedded electrical resistance strain gauges was studied for a hybrid material system. The samples were laminated using carbon-fiber-reinforced plastic (CFRP) and tungsten. The raw materials and the adhesive used for bonding strain sensors were characterized to understand the overlapping sources of non-linearity and error. Test-specific correction functions for a thermal output were determined for the strain gauge measurement and comparative fiber Bragg grating (FBG) measurement. The strain accumulation in the fiber direction during the cool-down phase for different cure cycles was analyzed using a finite element simulation. According to the results, embedded electrical resistance strain gauges can be used to determine the thermal expansion of a hybrid laminate with acceptable accuracy when thermal output is compensated for using case-specific correction functions accounting for measurement setup, the stiffness of the gauge bonding adhesive, and embedding.

Graphical abstract

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Mechanical performance of piezoelectric fiber composites and electroelastic field concentration near the electrode edges

Publication date: 15 August 2017
Source:Materials & Design, Volume 128
Author(s): Xi Yuan, Song Zhu, Xianfang Li, Chao Chen, Kechao Zhou, Dou Zhang
As important smart materials, piezoelectric fiber composites (PFCs) have shown excellent performance in many areas. However, the electric field strength concentration at the edge of the interdigital electrode may lead to crack propagation and eventual actuating failure of PFCs. In this paper, a novel analytical solution on the electroelastic response of PFCs is proposed to characterize the mechanical performance and obtain optimal structure parameters. The problem is converted to a singular integral equation with logarithmic kernel. By solving the resulting equation, the distributions of electric potential, electric displacement, electric field strength, and strain of PFCs fiber are obtained. The finite element method (FEM) is employed to confirm the results. The results demonstrate that the electric displacement and strain of PFCs are dramatically affected by the permittivity properties and piezoelectric constant of materials. The PFCs made by PZT-5H have higher surface electric displacement than PZT-5A and PZT-4. For a ratio of W/L=1/4, both the electric field and strain obtained the minimal value at the electrode edges, which is better for the mechanical performance of PFCs. Moreover, when the thickness of fibers decreases, the actuating performance of PFCs improves and the probability of fracture failure lessens.

Graphical abstract

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Effects of arsenic on adipocyte metabolism: Is arsenic an obesogen?

Publication date: Available online 8 May 2017
Source:Molecular and Cellular Endocrinology
Author(s): Zeltzin A. Ceja-Galicia, Alberto Daniel, Ana María Salazar, Pablo Pánico, Patricia Ostrosky-Wegman, Andrea Díaz-Villaseñor
The environmental obesogen model proposes that in addition to a high-calorie diet and diminished physical activity, other factors such as environmental pollutants and chemicals are involved in the development of obesity. Although arsenic has been recognized as a risk factor for Type 2 Diabetes with a specific mechanism, it is still uncertain whether arsenic is also an obesogen. The impairment of white adipose tissue (WAT) metabolism is crucial in the onset of obesity, and distinct studies have evaluated the effects of arsenic on it, however only in some of them for obesity-related purposes. Thus, the known effects of arsenic on WAT/adipocytes were integrated based on the diverse metabolic and physiological processes that occur in WAT and are altered in obesity, specifically: adipocyte growth, adipokine secretion, lipid metabolism, and glucose metabolism. The currently available information suggests that arsenic can negatively affect WAT metabolism, resulting in arsenic being a potential obesogen.

Graphical abstract

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Crosstalk between STAT5 activation and PI3K/AKT functions in normal and transformed mammary epithelial cells

Publication date: Available online 8 May 2017
Source:Molecular and Cellular Endocrinology
Author(s): Patrick D. Rädler, Barbara L. Wehde, Kay-Uwe Wagner
Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) have been shown to function downstream of several peptide hormones and cytokines that are required for postnatal development and secretory function of the mammary gland. As part of an extended network, these signal transducers can engage in crosstalk with other pathways to facilitate synergistic, and sometimes antagonistic, actions of different growth factors. Specifically, signaling through the JAK2/STAT5 cascade has been demonstrated to be indispensable for the specification, proliferation, differentiation, and survival of secretory mammary epithelial cells. Following a concise description of major cellular programs in mammary gland development and the role of growth factors that rely on JAK/STAT signaling to orchestrate these programs, this review highlights the significance of active STAT5 and its crosstalk with the PI3 kinase and AKT1 for mediating the proliferation of alveolar progenitors and survival of their functionally differentiated descendants in the mammary gland. Based on its ability to provide self-sufficiency in growth signals that are also capable of overriding intrinsic cell death programs, persistently active STAT5 can serve as a potent oncoprotein that contributes to the genesis of breast cancer. Recent experimental evidence demonstrated that, similar to normal developmental programs, oncogenic functions of STAT5 rely on molecular crosstalk with PI3K/AKT signaling for the initiation, and in some instances the progression, of breast cancer. The multitude by which STATs can interact with individual mediators of the PI3K/AKT signaling cascade may provide novel avenues for targeting signaling nodes within molecular networks that are crucial for the survival of cancer cells.



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Luminescent properties of heterotrinuclear 3d–4f complexes constructed from a naphthalenediol-based acyclic bis(salamo)-type ligand

Publication date: 5 September 2017
Source:Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, Volume 184
Author(s): Wen-Kui Dong, Shan-Shan Zheng, Jin-Tong Zhang, Yang Zhang, Yin-Xia Sun
Heterotrinuclear 3d–4f complexes with a naphthalenediol-based acyclic bis(salamo)-type ligand have been synthesized and structurally characterized. Spectral titrations clearly show that the heterotrinuclear complexes [Zn2(L)La(OAc)3] (1), [Zn2(L)Ce(OAc)3] (2) and [Zn2(L)Dy(OAc)3(CH3OH)]·CH2Cl2 (3) are acquired by the substitution reaction of the obtained homotrinuclear Zn(II) complex with 1 equiv. of Ln(NO3)3 (Ln³⁺=La³⁺, Ce³⁺ and Dy³⁺). Two Zn(II) ions are penta- and hexa-coordinated with geometries of distorted tetragonal pyramid and octahedron. La(III) ion is deca-coordinated, adopting a distorted bicapped square antiprism geometry. Ce(III) ion is nona-coordinated with geometry of distorted capped square antiprism as well as Dy(III) ion. The different coordination modes of acetate ions in complexes 1, 2 and 3 lead to different coordination numbers of the lanthanide(III) ions. Furthermore, the structures and fluorescence properties have been discussed.

Graphical abstract

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Trace element levels in an area impacted by old mining operations and their relationship with beehive products

Publication date: 1 December 2017
Source:Science of The Total Environment, Volumes 599–600
Author(s): E. Álvarez-Ayuso, P. Abad-Valle
The environmental status of an area impacted by Roman mining activities was assessed in order to establish the current risks posed by such old mine emplacements. For this purpose, soil samples were collected throughout the mining area and analysed for their total, mobile and mobilizable trace element (As, Cd, Mo, Sb and Zn) contents. Additionally, beehive products (honey and pollen) were also sampled and evaluated for their use as environmental indicators of the area. The results obtained were compared with those from a control non-polluted area. The mine soils presented slightly increased levels of Cd and Sb (about 2- to -3-fold their normal soil concentrations), whereas the enrichment of As reached considerable levels, with concentrations almost ten-fold of those considered the threshold for causing toxicity. Leachable As contents exhibited very high values (1.2–21.9mgkg⁻¹), indicating the need for risk attenuation measures. All trace elements were mainly partitioned in the soil residual fraction, especially Mo (76–99%) and Sb (61–91%). Significant partitioning levels were also found in the reducible fraction of As (up to 35%) and Cd (up to 38%), and in the oxidizable fraction of Mo (up to 23%). The reducible pool of As was particularly relevant due to the eventual mobilization of this element under reducing conditions. Among the beehive products tested, honey proved not to be useful as an environmental indicator, whereas pollen showed great potential as an indicator when the contamination levels were moderate to high.

Graphical abstract

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A screen-printed voltammetric electronic tongue for the analysis of complex mixtures of metal ions

Publication date: October 2017
Source:Sensors and Actuators B: Chemical, Volume 250
Author(s): Clara Pérez-Ràfols, Núria Serrano, José Manuel Díaz-Cruz, Cristina Ariño, Miquel Esteban
A voltammetric electronic tongue was constituted by four screen-printed modified electrodes: a carbon nanofiber modified electrode, an ex-situ antimony film electrode prepared from carbon nanofiber modified electrode, and two carbon nanofiber electrodes chemically modified with Cys and GSH. The tongue was successfully applied to the analysis of a complex mixture of metal ions (4 analytes and 2 interferences) by differential pulse anodic stripping voltammetry. Each sensor was firstly studied for the determination of each metal separately confirming that all electrodes showed differentiated response for the metals. The obtained voltammetric signals provided by the sensor array were processed by Partial Least Squares regression (PLS) to resolve the overlapped nature of the obtained multimetal stripping measurements. This PLS model was built considering a hierarchical model in order to reduce the large amount of data. The method was applied to synthetic mixtures of Cd(II), Pb(II), Tl(I), and Bi(III) in the presence of Zn(II) and In(III) at the levels of μg L⁻¹ and successfully validated with correlation coefficients of both calibration and prediction higher than 0.9 obtained from predicted vs. expected concentration graphs. Moreover, the simultaneous determination of Cd(II), Pb(II), Tl(I), and Bi(III) in the presence of Zn(II) and In(III) in a spiked tap water was also satisfactory achieved, providing comparable results to those obtained by ICP-MS.

Graphical abstract

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Heavy metals translocation and accumulation from the rhizosphere soils to the edible parts of the medicinal plant Fengdan (Paeonia ostii) grown on a metal mining area, China

Publication date: September 2017
Source:Ecotoxicology and Environmental Safety, Volume 143
Author(s): Zhang Jun Shen, De Cong Xu, Yan Song Chen, Zhen Zhang
Fengdan (Paeonia ostii) is one of Chinese 34 famous medicinal materials. This study investigated the concentrations of Arsenic (As), Chromium (Cr), Cadmium (Cd), Copper (Cu), Lead (Pb), Iron (Fe), Manganese (Mn), and Zinc (Zn) in rhizosphere soils, cortex mouton and seeds of Fengdan planted in a metal mining area, China. The mean concentrations of As, Cd, Cu, and Zn in the rhizosphere soils were above the limits set by the Chinese Soil Environmental Quality Standard (GB 15618-1995). The contamination factor (CF) of Cd was >5, while it was >2for As, Cu, Pb, and Zn in all the soils. The integrated pollution index for all the soils was >3 and ˂ 5. Metal concentrations in the edible parts of Fengdan were in the following decreasing order: Mn>Fe>Zn>Cu>Pb>As>Cr≥Cd. The transfer factor mean values for As, Cu, Cd and Fe in the cortex moutan of old Fengdan (over 6 years) were significantly higher than in young Fengdan. Available metal concentrations, pH and soil organic matter content influenced the metal concentrations of the cortex moutan. The results indicated that mining and smelting operations have led to heavy metals contamination of soils and medicinal parts of Fengdan. The major metal pollutants were elemental Cd, Cu, Pb, and Zn. Heavy metals mainly accumulated in the cortex moutan of Fengdan. The mean concentrations of Cd, Cu, and Pb in the old cortex moutan (over 6 years) were above those of the Chinese Green Trade Standards for Medicinal Plants and Preparations in Foreign Trade (WM/T2-2004).

Graphical abstract

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Fate of inorganic elements during fast pyrolysis of biomass in a cyclone reactor

Publication date: 1 September 2017
Source:Fuel, Volume 203
Author(s): Henrik Wiinikka, Ann-Christine Johansson, Linda Sandström, Olov G.W. Öhrman
In order to reduce ash related operational problem and particle emissions during pyrolysis oil combustion it is important to produce pyrolysis oil with very low concentration of inorganics. In this paper, the distribution of all major inorganic elements (S, Si, Al, Ca, Fe, K, Mg, Mn, Na, P, Ti and Zn) in the pyrolysis products (solid residue and two fractions of pyrolysis oil) was investigated during pyrolysis of stem wood, bark, forest residue, salix and reed canary grass. The raw materials were pyrolysed in a cyclone reactor and the produced pyrolysis oils were recovered as two oil fractions, a condensed fraction and an aerosol fraction. The inorganic composition of the ingoing raw material, the solid residue and the two pyrolysis oil fractions were analysed with inductively coupled plasma spectrometry techniques.All major inorganic elements, except sulphur, were concentrated in the solid residue. A significant amount of sulphur was released to the gas phase during pyrolysis. For zinc, potassium and iron about 1–10wt% of the ingoing amount, depending on the raw material, was found in the pyrolysis oil. For the rest of the inorganics, generally less than 1wt% of the ingoing amount was found in the pyrolysis oil. There were also differences in distribution of inorganics between the condensed and the aerosol oil fractions. The easily volatilized inorganic elements such as sulphur and potassium were found to a larger extent in the aerosol fraction, whereas the refractory elements were found to a larger extent in the condensed fraction. This implies that oil fractionation can be a method to produce oil fractions with different inorganic concentrations which thereafter can be used in different technical applications depending on their demand on the inorganic composition of the pyrolysis oil.



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Cardiovascular Outcome Trials in Patients With Advanced Kidney Disease: Time for Action.

Author: Zannad, Faiez MD, PhD; Rossignol, Patrick MD, PhD

Page: 1769-1771

http://ift.tt/2pYBUKA

Public Reporting II: State of the Art-Current Public Reporting in Cardiovascular Medicine.

Author: Weintraub, William S. MD; Garratt, Kirk N. MD

Page: 1772-1774

http://ift.tt/2q0pksn

Sources of Sodium in US Adults From 3 Geographic Regions.

Author: Harnack, Lisa J. DrPH; Cogswell, Mary E. DrPH; Shikany, James M. PhD; Gardner, Christopher D. PhD; Gillespie, Cathleen MS; Loria, Catherine M. PhD; Zhou, Xia MS; Yuan, Keming MS; Steffen, Lyn M. PhD

Page: 1775-1783

http://ift.tt/2pYufvW

Sources of Dietary Sodium: Implications for Patients, Physicians, and Policy.

Author: Appel, Lawrence J. MD, MPH; Foti, Kathryn MPH

Page: 1784-1787

http://ift.tt/2q0K96O

Effect of Aggressive Blood Pressure Control on the Recurrence of Atrial Fibrillation After Catheter Ablation: A Randomized, Open-Label Clinical Trial (SMAC-AF [Substrate Modification With Aggressive Blood Pressure Control]).

Author: Parkash, Ratika MD, MS; Wells, George A. PhD; Sapp, John L. MD; Healey, Jeffrey S. MD; Tardif, Jean-Claude MD; Greiss, Isabelle MD; Rivard, Lena MD, MSc; Roux, Jean-Francois MD; Gula, Lorne MD; Nault, Isabelle MD; Novak, Paul MD; Birnie, David MD; Ha, Andrew MD; Wilton, Stephen B. MD, MSc; Mangat, Iqwal MD; Gray, Christopher MD; Gardner, Martin MD; Tang, Anthony S.L. MD

Page: 1788-1798

http://ift.tt/2pYqOoX

Screening for Atrial Fibrillation: A Report of the AF-SCREEN International Collaboration.

Author: Freedman, Ben MBBS, PhD *; Camm, John MD *; Calkins, Hugh MD *; Healey, Jeffrey S. MD, MSc *; Rosenqvist, Marten MD, PhD *; Wang, Jiguang MD, PhD *; Albert, Christine M. MD, MPH; Anderson, Craig S. PhD; Antoniou, Sotiris BPharm(Hons), MSc; Benjamin, Emelia J. MD, ScM; Boriani, Giuseppe MD, PhD; Brachmann, Johannes MD, PhD; Brandes, Axel MD, DMSc; Chao, Tze-Fan MD, PhD; Conen, David MD, MPH; Engdahl, Johan MD, PhD; Fauchier, Laurent MD, PhD; Fitzmaurice, David A. MD; Friberg, Leif MD, PhD; Gersh, Bernard J. MB, ChB, DPhil; Gladstone, David J. MD, PhD; Glotzer, Taya V. MD; Gwynne, Kylie MA; Hankey, Graeme J. MD; Harbison, Joseph MD; Hillis, Graham S. MBChB, PhD; Hills, Mellanie T. BSc; Kamel, Hooman MD; Kirchhof, Paulus MD; Kowey, Peter R. MD; Krieger, Derk MD, PhD; Lee, Vivian W. Y. BSc, PharmD; Levin, Lars-Ake PhD; Lip, Gregory Y. H. MD; Lobban, Trudie; Lowres, Nicole PhD; Mairesse, Georges H. MD; Martinez, Carlos MD, MSc; Neubeck, Lis BA(Hons), PhD; Orchard, Jessica BEc/LLB, MPH; Piccini, Jonathan P. MD, MHS; Poppe, Katrina PhD; Potpara, Tatjana S. MD, PhD; Puererfellner, Helmut MD; Rienstra, Michiel MD, PhD; Sandhu, Roopinder K. MD, MPH; Schnabel, Renate B. MD, MSc *; Siu, Chung-Wah MD; Steinhubl, Steven MD; Svendsen, Jesper H. MD, DMSc; Svennberg, Emma MD, PhD; Themistoclakis, Sakis MD; Tieleman, Robert G. MD, PhD; Turakhia, Mintu P. MD, MAS; Tveit, Arnljot MD, PhD; Uittenbogaart, Steven B. MD, MSc; Van Gelder, Isabelle C. MD, PhD; Verma, Atul MD; Wachter, Rolf MD; Yan, Bryan P. MBBS.

Page: 1851-1867

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Transcatheter Treatment of Severe Tricuspid Regurgitation With the Edge-to-Edge MitraClip Technique.

Author: Nickenig, Georg MD; Kowalski, Marek MD; Hausleiter, Jorg MD; Braun, Daniel MD; Schofer, Joachim MD; Yzeiraj, Ermela MD; Rudolph, Volker MD; Friedrichs, Kai MD; Maisano, Francesco MD; Taramasso, Maurizio MD; Fam, Neil MD; Bianchi, Giovanni MD; Bedogni, Francesco MD; Denti, Paolo MD; Alfieri, Ottavio MD; Latib, Azeem MD; Colombo, Antonio MD; Hammerstingl, Christoph MD; Schueler, Robert MD

Page: 1802-1814

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Blood Pressure Control in Atrial Fibrillation: One of Many Critical Components in Risk Factor Modification.

Author: Lau, Dennis H. MBBS, PhD; Hendriks, Jeroen PhD; Kalman, Jonathan M. MBBS, PhD; Sanders, Prashanthan MBBS, PhD

Page: 1799-1801

http://ift.tt/2q0Jtyj

Percutaneous Therapy for Tricuspid Regurgitation: A New Frontier for Interventional Cardiology.

Author: Kapadia, Samir MD; Krishnaswamy, Amar MD; Tuzcu, E. Murat MD

Page: 1815-1818

http://ift.tt/2q0K8Qi

Pooled Safety Analysis of Evolocumab in Over 6000 Patients From Double-Blind and Open-Label Extension Studies.

Author: Toth, Peter P. MD, PhD; Descamps, Olivier MD, PhD; Genest, Jacques MD; Sattar, Naveed MD, PhD; Preiss, David MD, PhD; Dent, Ricardo MD; Djedjos, Constantine MD; Wu, Yuna PhD; Geller, Michelle MD; Uhart, Magdalena MD; Somaratne, Ransi MD; Wasserman, Scott M. MD; for the PROFICIO Investigators

Page: 1819-1831

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Defined Engineered Human Myocardium With Advanced Maturation for Applications in Heart Failure Modeling and Repair.

Author: Tiburcy, Malte MD; Hudson, James E. PhD; Balfanz, Paul; Schlick, Susanne MS; Meyer, Tim PhD; Chang Liao, Mei-Ling PhD; Levent, Elif PhD; Raad, Farah PhD; Zeidler, Sebastian PhD; Wingender, Edgar PhD; Riegler, Johannes PhD; Wang, Mouer MD; Gold, Joseph D. PhD; Kehat, Izhak MD, PhD; Wettwer, Erich PhD; Ravens, Ursula MD, PhD; Dierickx, Pieterjan PhD; van Laake, Linda W. MD, PhD; Goumans, Marie Jose PhD; Khadjeh, Sara PhD; Toischer, Karl MD; Hasenfuss, Gerd MD; Couture, Larry A. PhD; Unger, Andreas PhD; Linke, Wolfgang A. PhD; Araki, Toshiyuki PhD; Neel, Benjamin MD, PhD; Keller, Gordon PhD; Gepstein, Lior MD, PhD; Wu, Joseph C. MD, PhD; Zimmermann, Wolfram-Hubertus MD

Page: 1832-1847

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One Stride Forward: Maturation and Scalable Production of Engineered Human Myocardium.

Author: Yang, Xiulan PhD; Murry, Charles E. MD, PhD

Page: 1848-1850

http://ift.tt/2pYxMKR

Added Sugars and Cardiovascular Disease Risk in Children: A Scientific Statement From the American Heart Association.

Author: Vos, Miriam B. MD, MSPH, FAHA; Chair; Kaar, Jill L. PhD; Welsh, Jean A. PhD, MPH, RN; Van Horn, Linda V. PhD, RD, FAHA; Feig, Daniel I. MD, PhD; Anderson, Cheryl A.M. PhD, MPH, MS, FAHA; Patel, Mahesh J. MD; Cruz Munos, Jessica MD; Krebs, Nancy F. MD, MS; Xanthakos, Stavra A. MD, MS; Johnson, Rachel K. PhD, MPH, RD, FAHA; On behalf of the American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; Council on Functional Genomics and Translational Biology; and Council on Hypertension

Page: e1017-e1034

http://ift.tt/2pYDs7w

Highlights of the American College of Cardiology Annual Scientific Sessions 2017.

Author: Kuvin, Jeffrey T. MD; Kates, Andrew M. MD

Page: 1868-1869

http://ift.tt/2q0N6EG

Wide QRS Complex Tachycardia: What Is the Diagnosis?.

Author: Wang, Gaopin; Liu, Renguang; Chang, Qinghua MD

Page: 1870-1872

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Impact of Structural Cerebral Damage in Adults With Tetralogy of Fallot.

Author: Sluman, Maayke A. MD; Richard, Edo MD, PhD; Bouma, Berto J. MD, PhD; van Dalen, Jan Willem MSc; van Wanrooij, Lennard L. MSc; Groenink, Maarten MD, PhD; Caan, Matthan W. A. PhD; Nederveen, Aart J. PhD; Mutsaerts, Henk-Jan M. M. MD, PhD; Majoie, Charles B. L. M. MD, PhD; Schmand, Ben A. PhD; Mulder, Barbara J. M. MD, PhD

Page: 1873-1875

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Letter by Damen et al Regarding Article, "A Critical Appraisal of Aspirin in Secondary Prevention: Is Less More?".

Author: Damen, Sander A. J. MD; Brouwer, Marc A. MD, PhD; Verheugt, Freek W. A. MD, PhD

Page: e1035-e1036

http://ift.tt/2q0YCzJ

Response by Valgimigli and Gargiulo to Letter Regarding Article, "A Critical Appraisal of Aspirin in Secondary Prevention: Is Less More?".

Author: Valgimigli, Marco MD, PhD; Gargiulo, Giuseppe MD

Page: e1037-e1038

http://ift.tt/2pYqIxB

Letter by Puri et al Regarding Article, "Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control".

Author: Puri, Raman DM; Puri, Sonam MD; Rajani, Anil MD

Page: e1039-e1040

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Correction to: Percutaneous Therapy for Tricuspid Regurgitation: A New Frontier for Interventional Cardiology.

Author:

Page: e1041

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β Cell Renewal versus Differentiation: Slow and Steady Wins the Race

Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Ondine Cleaver
Pancreatic endocrine progenitor cells proliferate and transiently express the bHLH transcription factor Ngn3. In recent issues of Developmental Cell, Azzarelli et al. (2017) and Krentz et al. (2017) demonstrate how CDK phosphorylation of Ngn3 governs the switch between their renewal and differentiation. Lengthening the cell cycle allows Ngn3 accumulation, outpacing phosphorylation-induced degradation.

Teaser

Pancreatic endocrine progenitor cells proliferate and transiently express the bHLH transcription factor Ngn3. In recent issues of Developmental Cell, Azzarelli et al. (2017) and Krentz et al. (2017) demonstrate how CDK phosphorylation of Ngn3 governs the switch between their renewal and differentiation. Lengthening the cell cycle allows Ngn3 accumulation, outpacing phosphorylation-induced degradation.


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A Geometric Model of Stripe Refinement

Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Eric D. Siggia
Organizing data about patterning and morphogenesis into a coherent framework remains a challenge in developmental biology. Reporting in Science, Corson et al. (2017) apply innovative analysis to an old problem of bristle patterns in Drosophila, reducing the nonlinear interactions among tens of cells to a succinct model with quantitative predictions.

Teaser

Organizing data about patterning and morphogenesis into a coherent framework remains a challenge in developmental biology. Reporting in Science, Corson et al. (2017) apply innovative analysis to an old problem of bristle patterns in Drosophila, reducing the nonlinear interactions among tens of cells to a succinct model with quantitative predictions.


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The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force

Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Rhett A. Kovall, Brian Gebelein, David Sprinzak, Raphael Kopan
The Notch signaling pathway relies on a proteolytic cascade to release its transcriptionally active intracellular domain, on force to unfold a protective domain and permit proteolysis, on extracellular domain glycosylation to tune the forces exerted by endocytosed ligands, and on a motley crew of nuclear proteins, chromatin modifiers, ubiquitin ligases, and a few kinases to regulate activity and half-life. Herein we provide a review of recent molecular insights into how Notch signals are triggered and how cell shape affects these events, and we use the new insights to illuminate a few perplexing observations.

Teaser

In this review, Kovall et al. describe structure-based insights into Notch receptor/ligand interactions, the proteins involved in receptor modifications and cleavage, details on what forces are required to activate Notch, how cell shape might affect this process, and how the active NICD molecule mediates changes in gene expression.


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Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca2+ Efflux Channel in the Tubulovesicle

Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Nirakar Sahoo, Mingxue Gu, Xiaoli Zhang, Neel Raval, Junsheng Yang, Michael Bekier, Raul Calvo, Samarjit Patnaik, Wuyang Wang, Greyson King, Mohammad Samie, Qiong Gao, Sasmita Sahoo, Sinju Sundaresan, Theresa M. Keeley, Yanzhuang Wang, Juan Marugan, Marc Ferrer, Linda C. Samuelson, Juanita L. Merchant, Haoxing Xu
Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich tubulovesicles (TVs) toward apical membranes in response to histamine stimulation via cyclic AMP elevation. Here, we found that TRPML1 (ML1), a protein that is mutated in type IV mucolipidosis (ML-IV), is a tubulovesicular channel essential for TV exocytosis and acid secretion. Whereas ML-IV patients are reportedly achlorhydric, transgenic overexpression of ML1 in mouse parietal cells induced constitutive acid secretion. Gastric acid secretion was blocked and stimulated by ML1 inhibitors and agonists, respectively. Organelle-targeted Ca²⁺ imaging and direct patch-clamping of apical vacuolar membranes revealed that ML1 mediates a PKA-activated conductance on TV membranes that is required for histamine-induced Ca²⁺ release from TV stores. Hence, we demonstrated that ML1, acting as a Ca²⁺ channel in TVs, links transmitter-initiated cyclic nucleotide signaling with Ca²⁺-dependent TV exocytosis in parietal cells, providing a regulatory mechanism that could be targeted to manage acid-related gastric diseases.

Graphical abstract

Teaser

Acid secretion from the parietal cells of the stomach is essential for food digestion. Sahoo et al. identified TRPML1 as a histamine-activated Ca²⁺ channel in the tubulovesicles required for gastric acid secretion. Synthetic agonists and inhibitors of TRPML1 may be developed to control acid secretion and treat acid-related gastric diseases.


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More Cytoplasm, More Problems

Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Predrag Jevtić, Daniel L. Levy
In this issue of Developmental Cell, Kyogoku and Kitajima (2017) investigate the effect of cytoplasmic volume on the fidelity of chromosome segregation during meiosis in mouse oocytes. The authors find that large cytoplasmic volume affects spindle pole morphology, chromosome alignment, and stringency of checkpoint signaling, resulting in error-prone chromosome segregation.

Teaser

In this issue of Developmental Cell, Kyogoku and Kitajima (2017) investigate the effect of cytoplasmic volume on the fidelity of chromosome segregation during meiosis in mouse oocytes. The authors find that large cytoplasmic volume affects spindle pole morphology, chromosome alignment, and stringency of checkpoint signaling, resulting in error-prone chromosome segregation.


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Large Cytoplasm Is Linked to the Error-Prone Nature of Oocytes

Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Hirohisa Kyogoku, Tomoya S. Kitajima
Chromosome segregation during meiosis in oocytes is error prone. The uniquely large cytoplasmic size of oocytes, which provides support for embryogenesis after fertilization, might be a predisposing factor for meiotic errors. However, this hypothesis remains unproven. Here, we show that cytoplasmic size affects the functionality of the acentrosomal spindle. Artificially decreasing the cytoplasmic size in mouse oocytes allows the acentrosomal spindle poles to have a better-focused distribution of microtubule-organizing centers and to biorient chromosomes more efficiently, whereas enlargement of the cytoplasmic size has the opposite effects. Moreover, we found that the cytoplasmic size-dependent dilution of nuclear factors, including anaphase inhibitors that are preformed at the nuclear membrane, limits the spindle's capacity to prevent anaphase entry with misaligned chromosomes. The present study defines a large cytoplasmic volume as a cell-intrinsic feature linked to the error-prone nature of oocytes. This may represent a trade-off between meiotic fidelity and post-fertilization developmental competence.

Graphical abstract

Teaser

Kyogoku and Kitajima show that cytoplasmic size affects the functionality of the acentrosomal spindle and the stringency of the spindle checkpoint in mouse oocytes, thus providing evidence that the large cytoplasmic size of oocytes is linked to error-prone chromosome segregation during female meiosis, which is a leading cause of aneuploidy.


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The PomXYZ Proteins Self-Organize on the Bacterial Nucleoid to Stimulate Cell Division

Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Dominik Schumacher, Silke Bergeler, Andrea Harms, Janet Vonck, Sabrina Huneke-Vogt, Erwin Frey, Lotte Søgaard-Andersen
Cell division site positioning is precisely regulated to generate correctly sized and shaped daughters. We uncover the strategy used by the social bacterium Myxococcus xanthus to position the FtsZ cytokinetic ring at midcell. PomX, PomY, and the nucleoid-binding ParA/MinD ATPase PomZ self-assemble forming a large nucleoid-associated complex that localizes at the division site before FtsZ to directly guide and stimulate division. PomXYZ localization is generated through self-organized biased random motion on the nucleoid toward midcell and constrained motion at midcell. Experiments and theory show that PomXYZ motion is produced by diffusive PomZ fluxes on the nucleoid into the complex. Flux differences scale with the intracellular asymmetry of the complex and are converted into a local PomZ concentration gradient across the complex with translocation toward the higher PomZ concentration. At midcell, fluxes equalize resulting in constrained motion. Flux-based mechanisms may represent a general paradigm for positioning of macromolecular structures in bacteria.

Teaser

Schumacher et al. find that the PomXYZ complex self-organizes on the bacterial nucleoid and promotes positioning of the cytokinetic ring. Diffusive fluxes of PomZ into the complex scale with intracellular asymmetry and are converted into a local PomZ concentration gradient that promotes biased motion toward and constrained motion at midcell.


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RhoD Inhibits RhoC-ROCK-Dependent Cell Contraction via PAK6

Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Charlotte H. Durkin, Flavia Leite, João V. Cordeiro, Yutaka Handa, Yoshiki Arakawa, Ferran Valderrama, Michael Way
RhoA-mediated regulation of myosin-II activity in the actin cortex controls the ability of cells to contract and bleb during a variety of cellular processes, including cell migration and division. Cell contraction and blebbing also frequently occur as part of the cytopathic effect seen during many different viral infections. We now demonstrate that the vaccinia virus protein F11, which localizes to the plasma membrane, is required for ROCK-mediated cell contraction from 2 hr post infection. Curiously, F11-induced cell contraction is dependent on RhoC and not RhoA signaling to ROCK. Moreover, RhoC-driven cell contraction depends on the upstream inhibition of RhoD signaling by F11. This inhibition prevents RhoD from regulating its downstream effector Pak6, alleviating the suppression of RhoC by the kinase. Our observations with vaccinia have now demonstrated that RhoD recruits Pak6 to the plasma membrane to antagonize RhoC signaling during cell contraction and blebbing.

Graphical abstract

Teaser

Many different viral infections induce cell contraction and blebbing. Durkin, Leite, et al. show that during vaccinia infection, RhoC and not RhoA regulates this ROCK-mediated cytopathic effect of cell contraction. They delineate a pathway for RhoC regulation, in which the viral protein F11 blocks RhoC antagonism by RhoD-recruited Pak6.


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Abl Regulates Planar Polarized Junctional Dynamics through β-Catenin Tyrosine Phosphorylation

Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Masako Tamada, Dene L. Farrell, Jennifer A. Zallen




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The involvement of brain-derived neurotrophic factor in 3,4-methylenedioxymethamphetamine-induced place preference and behavioral sensitization

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Akihiro Mouri, Yukihiro Noda, Minae Niwa, Yurie Matsumoto, Takayoshi Mamiya, Atsumi Nitta, Kiyofumi Yamada, Shoei Furukawa, Tatsunori Iwamura, Toshitaka Nabeshima
3,4-Methylenedioxymethamphetamine (MDMA) is known to induce dependence and psychosis in humans. Brain-derived neurotrophic factor (BDNF) is involved in the synaptic plasticity and neurotrophy in midbrain dopaminergic neurons. This study aimed to investigate the role of BDNF in MDMA-induced dependence and psychosis. A single dose of MDMA (10mg/kg) induced BDNF mRNA expression in the prefrontal cortex, nucleus accumbens, and amygdala, but not in the striatum or the hippocampus. However, repeated MDMA administration for 7 days induced BDNF mRNA expression in the striatum and hippocampus. Both precursor and mature BDNF protein expression increased in the nucleus accumbens, mainly in the neurons. Additionally, rapidly increased extracellular serotonin levels and gradually and modestly increased extracellular dopamine levels were noted within the nucleus accumbens of mice after repeated MDMA administration. Dopamine receptor antagonists attenuated the effect of repeated MDMA administration on BDNF mRNA expression in the nucleus accumbens. To examine the role of endogenous BDNF in the behavioral and neurochemical effects of MDMA, we used mice with heterozygous deletions of the BDNF gene. MDMA-induced place preference, behavioral sensitization, and an increase in the levels of extracellular serotonin and dopamine within the nucleus accumbens, were attenuated in BDNF heterozygous knockout mice. These results suggest that BDNF is implicated in MDMA-induced dependence and psychosis by activating the midbrain serotonergic and dopaminergic neurons.



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Antidepressant-like effect of valproic acid—Possible involvement of PI3K/Akt/mTOR pathway

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Isabel Vieira de Assis Lima, Ana Flávia Almeida-Santos, Talita Hélen Ferreira-Vieira, Daniele Cristina Aguiar, Fabíola Mara Ribeiro, Alline Cristina Campos, Antônio Carlos Pinheiro de Oliveira
RationaleFew studies suggest that antidepressants exert their effects by activating some signaling pathways, including the phosphatidylinositol 3-kinase (PI3K). Moreover, valproic acid (VPA) activates the PI3K pathway. Thus, here we investigated the antidepressant-like effect of VPA and if its effect is related to PI3K/Akt/mTOR activation.MethodsC57Bl/6 (WT) and PI3Kγ^−/− mice received VPA injections (30, 100 or 300mg/kg, i.p.) and 30min after they were submitted to the forced swimming (FS), tail suspension (TS) and open field (OF) tests. Another group was pretreated with rapamycin (5mg/kg, i.p.) 150min before VPA administration. Akt phosphorylation levels were measured by Western blotting.ResultsIn WT mice, VPA (30mg/kg) reduced the immobility time in both FS and TS tests. However, VPA (300mg/kg) increased the immobility time in FS test. All doses of VPA did not alter locomotor activity. In PI3Kγ^−/− mice, none of the doses revealed antidepressant-like effect. However, in the OF test, the lower dose of VPA increased the travelled distance in comparison with vehicle group. An increase in Akt phosphorylation levels was observed in WT, but not in PI3Kγ^−/− mice. Finally, the pretreatment of WT mice with rapamycin abolished the antidepressant-like effect of VPA (30mg/kg) in FS test.ConclusionThese data suggest that the antidepressant-like effects of VPA might depend on PI3K and mTOR activation. Thus, more studies are necessary to investigate the mechanisms involved in the antidepressant-like effect induced by VPA in order to investigate novel therapeutic targets for the treatment of depression.



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Semantic memory deficits are associated with pica in individuals with acquired brain injury

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Michitaka Funayama, Taro Muramatsu, Akihiro Koreki, Motoichiro Kato, Masaru Mimura, Yoshitaka Nakagawa
Although pica is one of the most prominent signs in individuals with severe cognitive impairment, the mechanisms and neural basis for pica have not been well elucidated. To address this issue, patients with acquired brain injury who showed pica and hyperorality were investigated. Eleven patients with pica, i.e., individuals who eat non-food items, and eight patients with hyperorality but who never eat non-food items were recruited. The cognitive and behavioral assessments and neural substrates of the two groups were compared. For basic cognitive and behavioral functions, two kinds of mental state examination—the mini-mental state examination and the new clinical scale for rating of mental states of the elderly—were administered. For pica-related behavioral features, frontal release signs, semantic memory deficits, and changes in eating behaviors were compared. Compared with the hyperorality group, the pica group had more severe semantic memory deficits and fewer frontal release signs, whereas there was no significant difference in changes in eating behaviors. Individuals in the pica group always had a lesion in the posterior part of the middle temporal gyrus. These findings suggest that semantic memory deficits following temporal lobe damage are associated with pica.



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A new construct of antibody-drug conjugates for treatment of B-cell non-Hodgkin's lymphomas

Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Libin Zhang, Yixin Fang, Jindřich Kopeček, Jiyuan Yang
The aim of this study was to develop a new class of antibody-drug conjugates (ADCs) with the potential to not only enhance treatment efficacy but also improve tolerability for patients with B-cell lymphomas. Classic ADCs consist of monoclonal antibodies (mAbs) linked to drugs or toxins. They selectively deliver toxic moieties to tumor cells. As such, they greatly improve the therapeutic index compared to traditional chemotherapeutic agents. However, the therapeutic efficacy and safety of ADCs are dependent on linker stability and payload toxicity. Limited payload number on a single antibody (drug-to-antibody ratio, or DAR) has been driving investigators to use extremely toxic agents; however, even very low off-target binding of these ADCs may kill patients. Herein we report a new design of ADCs that consists of rituximab (RTX) and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer–epirubicin conjugates. The latter was selectively attached to RTX via reduced disulfide bonds. Such design allows the introduction of a large payload of drug on the antibody without adding attachment sites and without compromising the antigen-targeting ability. The binding of the new conjugate, namely RTX-P-EPI, to Ramos cells (with high CD20 expression) was confirmed. The cytotoxicity of RTX-P-EPI against Raji and Ramos cells was also determined. Interestingly, two-fold inhibition of cell proliferation was observed when using RTX-P-EPI compared with their equivalent physical mixture of RTX and P-EPI. Treatment of male SCID mice bearing subcutaneous Ramos B-cell lymphoma tumors demonstrated that RTX-P-EPI possessed superior efficacy when compared to combination of RTX with chemotherapy EPI (RTX+EPI) and P-EPI (RTX+P-EPI), whereas single RTX and a non-specific conjugate IgG-P-EPI only showed marginal effect. The conjugate RTX-EPI in which EPI was directly attached to RTX demonstrated much less antitumor activity compared with RTX-P-EPI. The results suggest that this new design possesses synergistic potential of immunotherapy combined with established macromolecular therapy; moreover, a conventional chemo-agent could be utilized to generate highly effective ADCs and to achieve lower risk of off-target toxicity.

Graphical abstract

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Professor Arto Urtti —A northern light from the land of the midnight sun

Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103





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Six month delivery of GDNF from PLGA/vitamin E biodegradable microspheres after intravitreal injection in rabbits

Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Cristina García-Caballero, Esther Prieto-Calvo, Patricia Checa-Casalengua, Elena García-Martín, Vicente Polo-Llorens, Julián García-Feijoo, Irene Teresa Molina-Martínez, Irene Bravo-Osuna, Rocío Herrero-Vanrell
Local long-term delivery of glial cell line derived neurotrophic factor (GDNF) from vitamin E/poly-lactic-co-glycolic acid microspheres (MSs) protects retinal ganglion cells in an animal model of glaucoma for up to 11weeks. However, the pharmacokinetics of GDNF after intravitreal injection of MSs is not known. We evaluated the GDNF levels after a single intravitreal injection of GDNF/VitE MSs. Biodegradable MSs were prepared by the solid-oil-in-water emulsion-solvent evaporation technique and characterized. Rabbits received a single intravitreal injection (50μL) of GDNF/VitE MSs (4%w/v; 24 right eyes; 74.85ng GDNF), blank MSs (4%w/v; 24 left eyes), and balanced salt solution (4 eyes). Two controls eyes received no injections. At 24h, 1, 4, 6, 8, 12, 18, and 24weeks after injection, the eyes were enucleated, and the intravitreal GDNF levels were quantified. Pharmacokinetic data were analysed according to non-compartmental model. Intraocular GDNF levels of 717.1±145.1pg/mL were observed at 24h for GDNF-loaded MSs, followed by a plateau (745.3±25.5pg/mL) until day 28. After that, a second plateau (17.4±3.7pg/mL) occurred from 8 to 24weeks post-injection, significantly higher than the basal levels. Eyes injected with GDNF/vitE and Blank-MSs did not show any abnormalities during the six-months follow up after administration. The single injection of GDNF/VitE MSs provided a sustained controlled release of the neurotrophic factor in a controlled fashion for up to six months.

Graphical abstract

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Identification of novel MRP3 inhibitors based on computational models and validation using an in vitro membrane vesicle assay

Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Izna Ali, Matthew A. Welch, Yang Lu, Peter W. Swaan, Kim L.R. Brouwer
IntroductionMultidrug resistance-associated protein 3 (MRP3), an efflux transporter on the hepatic basolateral membrane, may function as a compensatory mechanism to prevent the accumulation of anionic substrates (e.g., bile acids) in hepatocytes. Inhibition of MRP3 may disrupt bile acid homeostasis and is one hypothesized risk factor for the development of drug-induced liver injury (DILI). Therefore, identifying potential MRP3 inhibitors could help mitigate the occurrence of DILI.MethodsBayesian models were developed using MRP3 transporter inhibition data for 86 structurally diverse drugs. The compounds were split into training and test sets of 57 and 29 compounds, respectively, and six models were generated based on distinct inhibition thresholds and molecular fingerprint methods. The six Bayesian models were validated against the test set and the model with the highest accuracy was utilized for a virtual screen of 1470 FDA-approved drugs from DrugBank. Compounds that were predicted to be inhibitors were selected for in vitro validation. The ability of these compounds to inhibit MRP3 transport at a concentration of 100μM was measured in membrane vesicles derived from stably transfected MRP3-over-expressing HEK-293 cells with [³H]-estradiol-17β-d-glucuronide (E217G; 10μM; 5min uptake) as the probe substrate.ResultsA predictive Bayesian model was developed with a sensitivity of 73% and specificity of 71% against the test set used to evaluate the six models. The area under the Receiver Operating Characteristic (ROC) curve was 0.710 against the test set. The final selected model was based on compounds that inhibited substrate transport by at least 50% compared to the negative control, and functional-class fingerprints (FCFP) with a circular diameter of six atoms, in addition to one-dimensional physicochemical properties. The in vitro screening of predicted inhibitors and non-inhibitors resulted in similar model performance with a sensitivity of 64% and specificity of 70%. The strongest inhibitors of MRP3-mediated E217G transport were fidaxomicin, suramin, and dronedarone. Kinetic assessment revealed that fidaxomicin was the most potent of these inhibitors (IC50=1.83±0.46μM). Suramin and dronedarone exhibited IC50 values of 3.33±0.41 and 47.44±4.41μM, respectively.ConclusionBayesian models are a useful screening approach to identify potential inhibitors of transport proteins. Novel MRP3 inhibitors were identified by virtual screening using the selected Bayesian model, and MRP3 inhibition was confirmed by an in vitro transporter inhibition assay. Information generated using this modeling approach may be valuable in predicting the potential for DILI and/or MRP3-mediated drug-drug interactions.

Graphical abstract

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Editorial board members

Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103





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Synthetic nanocarriers for the delivery of polynucleotides to the eye

Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Sofia M. Saraiva, Vanessa Castro-López, Covadonga Pañeda, María José Alonso
This review is a comprehensive analysis of the progress made so far on the delivery of polynucleotide-based therapeutics to the eye, using synthetic nanocarriers. Attention has been addressed to the capacity of different nanocarriers for the specific delivery of polynucleotides to both, the anterior and posterior segments of the eye, with emphasis on their ability to (i) improve the transport of polynucleotides across the different eye barriers; (ii) promote their intracellular penetration into the target cells; (iii) protect them against degradation and, (iv) deliver them in a long-term fashion way. Overall, the conclusion is that despite the advantages that nanotechnology may offer to the area of ocular polynucleotide-based therapies (especially AS-ODN and siRNA delivery), the knowledge disclosed so far is still limited. This fact underlines the necessity of more fundamental and product-oriented research for making the way of the said nanotherapies towards clinical translation.

Graphical abstract

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Effect of hyaluronic acid-binding to lipoplexes on intravitreal drug delivery for retinal gene therapy

Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Thomas F Martens, Karen Peynshaert, Thaís Leite Nascimento, Elias Fattal, Marcus Karlstetter, Thomas Langmann, Serge Picaud, Jo Demeester, Stefaan C De Smedt, Katrien Remaut, Kevin Braeckmans
Intravitreal administration of nanomedicines could be valuable for retinal gene therapy, if their mobility in the vitreous and therapeutic efficacy in the target cells can be guaranteed. Hyaluronic acid (HA) as an electrostatic coating of polymeric gene nanomedicines has proven to be beneficial on both accounts. While electrostatic coating provides an easy way of coating cationic nanoparticles, the stability of electrostatic complexes in vivo is uncertain. In this study, therefore, we compare electrostatic with covalent coating of gene nanocarriers with HA for retinal gene therapy via intravitreal administration. Specifically, DOTAP:DOPE/plasmid DNA lipoplexes coated with HA are evaluated in terms of intravitreal mobility using a previously optimized ex vivo model. We find that both electrostatic and covalent HA coating considerably improve the mobility of the lipoplexes in the vitreous humor of excised bovine eyes. In addition we evaluate in vitro uptake and transfection efficiency in ARPE-19 cells. Contrary to PEGylated lipoplexes it is found that HA coated lipoplexes are efficiently internalized into ARPE-19 cells. Covalent HA-coated lipoplexes had an 8-fold increase of transgene expression compared to the uncoated lipoplexes. We conclude that covalent HA-coating of gene nanomedicines is a promising approach for retinal gene therapy by intravitreal administration.

Graphical abstract

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Expression and splicing of ABC and SLC transporters in the human blood-brain barrier measured with RNAseq

Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Adam M. Suhy, Amy Webb, Audrey C. Papp, Ethan G. Geier, Wolfgang Sadee
The blood-brain barrier (BBB) expresses numerous membrane transporters that supply needed nutrients to the central nervous system (CNS), consisting mostly of solute carriers (SLC transporters), or remove unwanted substrates via extrusion pumps through the action of ATP binding cassette (ABC) transporters. Previous work has identified many BBB transporters using hybridization arrays or qRT-PCR, using targeted probes. Here we have performed next-generation sequencing of the transcriptome (RNAseq) extracted from cerebral cortex tissues and brain microvessel endothelial cells (BMEC) obtained from two donors. The same RNA samples had previously been measured for transporter expression using qRT-PCR (Geier et al., 2013), yielding similar expression levels for overlapping mRNAs (R=0.66, p<0.001). RNAseq confirms a number of transporters highly enriched in BMECs (e.g., ABCB1, ABCG2, SLCO2B1, and SLC47A1), but also detects novel BMEC transporters. Multiple splice isoforms detected by RNAseq are either robustly enriched or depleted in BMECs, indicating differential RNA processing in the BBB. The Complete RNAseq data are publically available (GSE94064).

Graphical abstract

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A structure-activity relationship study of ABCC2 inhibitors

Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Gloria Wissel, Feng Deng, Pavel Kudryavtsev, Leo Ghemtio, Peter Wipf, Henri Xhaard, Heidi Kidron
Multidrug resistance associated protein 2 (MRP2/ABCC2) is a membrane transport protein that can potentially affect the disposition of many substrate drugs and their metabolites. Recently, we studied the interaction of a library of 432 compounds with ABCC2, and the structure-activity relationship (SAR) of a subset of 64 compounds divided into four scaffolds (Wissel, G. et al., 2015. Bioorg Med Chem., 23(13), pp.3513–25). We have now expanded this test set by investigating 114 new compounds, of which 71 are representative of the previous four scaffolds and 43 compounds belong to a new scaffold. Interaction with ABCC2 was assessed by measuring the compounds effect on 5(6)-carboxy-2′,7′-dichlorofluorescein transport in the vesicular transport assay. In line with our previous study, we observed that anionic charge is not essential for inhibition of ABCC2 transport, even though it often increases the inhibitory activity within the analogue series. Additionally, we found that halogen substitutions often increase the inhibitory activity. The results confirm the importance of structural features such as aromaticity and lipophilicity for ABCC2 inhibitory activity.

Graphical abstract

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Multiple analyses indicate that NR1I3 regulating C6 and TNN may be involved in hip BMD regulation

Publication date: Available online 8 May 2017
Source:Journal of Genetics and Genomics
Author(s): Ying-Ying Han, Lan-Juan Zhao, Yong Lin, Hao He, Qing Tian, Wei Zhu, Hui Shen, Xiang-Ding Chen, Hong-Wen Deng




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Attentional blink to alcohol cues in binge drinkers versus non-binge drinkers

Publication date: October 2017
Source:Addictive Behaviors, Volume 73
Author(s): Francesco M. DePalma, Natalie Ceballos, Reiko Graham
Previous studies have shown alcohol-related attentional biases in social drinkers; however, the temporal dynamics of these biases are not well understood. The current study examined this issue in 94 participants (27 male) categorized as binge drinkers (BD) or non-binge drinkers (NBD). Two versions of an alcohol-related attentional blink (AB) paradigm were used: one with words and one with images. It was predicted that BDs (versus NBDs) would exhibit reduced AB for alcohol cues, which would be enhanced for the pictorial version of the task (versus words). The relationships between AB and alcohol craving, quantity and frequency of alcohol consumption, symptoms of alcohol use disorder, and family history of alcohol use disorder (AUD) were also examined. While an AB was observed for both alcohol and non-alcohol targets in the NBD group, no AB was found for alcohol targets in the BD group. Furthermore, the magnitude of the AB was related to drinking, such that higher self-reported hazardous drinking was associated with smaller ABs to alcohol-related targets. However, AB was not related to craving or family history of AUD. These results suggest that alcohol-related stimuli are processed more efficiently by BDs, especially those with hazardous alcohol consumption patterns. These results may inform treatment and prevention efforts targeting binge drinkers.



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Associations of blood glucose dynamics with antihyperglycemic treatment and glycemic variability in type 1 and type 2 diabetes

Abstract

Aims

The dynamical structure of glucose fluctuation has largely been disregarded in the contemporary management of diabetes.

Methods

In a retrospective study of patients with diabetes, we evaluated the relationship between glucose dynamics, antihyperglycemic therapy, glucose variability, and glucose exposure, while taking into account potential determinants of the complexity index. We used multiscale entropy (MSE) analysis of continuous glucose monitoring data from 131 subjects with type 1 (n = 18), type 2 diabetes (n = 102), and 11 nondiabetic control subjects. We compared the MSE complexity index derived from the glucose time series among the treatment groups, after adjusting for sex, age, diabetes duration, body mass index, and carbohydrate intake.

Results

In type 2 diabetic patients who were on a diet or insulin regimen with/without oral agents, the MSE index was significantly lower than in nondiabetic subjects but was lowest in the type 1 diabetes group (p < 0.001). The decline in the MSE complexity across the treatment groups correlated with increasing glucose variability and glucose exposure. Statistically, significant correlations existed between higher MSE complexity indices and better glycemic control. In multivariate regression analysis, the antidiabetic therapy was the most powerful predictor of the MSE (β = −0.940 ± 0.242, R ² = 0.306, p < 0.001), whereas the potential confounders failed to contribute.

Conclusions

The loss of dynamical complexity in glucose homeostasis correlates more closely with therapy modalities and glucose variability than with clinical measures of glycemia. Thus, targeting the glucoregulatory system by adequate therapeutic interventions may protect against progressive worsening of diabetes control.

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Patient-reported outcome measures and patient-reported experience measures

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Antibiotic stewardship in critical care

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Management of acute upper GI bleeding

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Perioperative management of the patient with diabetes requiring emergency surgery

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Perioperative management of opioid-tolerant patients

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Parkinson's disease

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IL-33 protects murine viral fulminant hepatitis by targeting coagulation hallmark protein FGL2/fibroleukin expression

Publication date: July 2017
Source:Molecular Immunology, Volume 87
Author(s): Haijing Yu, Yang Liu, Jiaquan Huang, Hongwu Wang, Weiming Yan, Dong Xi, Guanxin Shen, Xiaoping Luo, Qin Ning
Fulminant hepatitis (FH) is characterized by rapid liver failure and high mortality. The pathogenesis of viral FH includes virus-induced immune activation, inflammation, and subsequent hepatic apoptosis and necrosis. However, the mechanisms that underlie FH progression are unclear. IL-33 is a member of the IL-1-related cytokines, considered to be an "alarmin" that participates in various diseases, but its precise role in the coagulation of FH is not very clear. In our study, we found that IL-33 is significantly elevated in mice infected with murine hepatitis virus strain 3 (MHV-3). This is accompanied by an increase in pro-coagulant fibrinogen-like protein 2 (FGL2) in the liver. Previous studies have suggested that an increase in FGL2 is diagnostic of FH and liver necrosis, and animals with no FGL2 had better survivorship during FH. Our studies showed that IL-33 administration in a MHV-3 infection promoted survival during FH, with a significant reduction in FGL2 expression and liver inflammation. In vitro IL-33 treatment abrogated MHV-3 and IFN-γ induced FGL2 expression in RAW264.7 and THP-1 cells, respectively. In conclusion, our research suggests that IL-33 protects against viral fulminant hepatitis in mice by antagonizing expression of the pro-coagulant protein FGL2.



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Indocyanine Green Fluorescence-Guided Surgery after IV Injection in Metastatic Colorectal Cancer: A Systematic Review

Publication date: Available online 8 May 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Gabriel Liberale, Pierre Bourgeois, Denis Larsimont, Michel Moreau, Vincent Donckier, Takeaki Ishizawa
ObjectiveIndocyanine green fluorescence-guided surgery (ICG-FGS) has emerged as a potential new imaging modality for improving the detection of hepatic, lymph node (LN), and peritoneal metastases in colorectal cancer (CRC) patients. The aim of this paper is to review the available literature in the clinical setting of ICG-FGS for tumoral detection in various fields of metastatic colorectal disease.MethodsPubMed and Medline literature databases were searched for original articles on the use of ICG in the setting of clinical studies on colorectal cancer. The search terms used were "near-infrared fluorescence", "intraoperative imaging", "indocyanine green", "human" and "colorectal cancer".ResultsICG fluorescence imaging (ICG-FI) is clearly supported as an intraoperative technique that allows the detection of additional superficial hepatic metastases of CRC. Data on the role of ICG-FI in the intraoperative detection of peritoneal metastases and LN metastases are scarce but encouraging and ICG-FI could potentially improve the staging and treatment of these patients.ConclusionICG-FI is a promising imaging technique in the detection of small infraclinic LN, hepatic, and peritoneal metastatic deposits that may allow better staging and more complete surgical resection with a potential prognostic benefit for patients.



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Unusual cases of necrotizing fasciitis: a clinical experience from Turkey

Abstract

Background

Necrotizing fasciitis is a rare, destructive soft tissue infection which starts on the skin and subcutaneous tissue, and spreads quickly towards the deeper tissues. Its etiology includes trauma, surgical intervention, perineal abscess, soft tissue infection, minor invasive procedures, abrasion, contusion, burn, laceration, bite, and penetrating injuries. The mortality of the disease can increase in the presence of predisposing factors such as diabetes, hypertension, immunodeficiency, self-care insufficiency, alcoholism, and advanced age. The clinical presentation of necrotizing fasciitis may vary. It is often observed in the abdominal region, the lower extremity, the perineal, perianal, scrotal and genital regions.

Methods

Between December 2011 and September 2016, a retrospective study of all patients admitted due to necrotic wounds and/or tissue defects was undertaken. Their clinical records were reviewed with respect to age, sex, associated morbidities, defect localization, treatment, and outcomes.

Results

Thirteen cases were admitted to the emergency department. There were 10 female and 3 male patients. The defects were located in the gluteal (one), trochanteric (one), thoracic (two), upper extremity (three), lower extremity (two) and perineal region (four). Pressure sores, insect bites, trauma, diabetes mellitus and perineal infections were detected in the etiology of the cases. As observed in our study, NF can present with very different etiological, demographical and clinical findings.

Conclusions

The cases presented some rarely observed characteristics in terms of age, sex, etiology, and infection localization. Therefore, it should be kept in mind that necrotizing fasciitis can exhibit extraordinary characteristics causing confusion with other soft tissue infections, and a detailed and meticulous evaluation must be performed for diagnosis.

Level of Evidence: Level IV, therapeutic study.

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Determinants of Sugar-Sweetened Beverage Consumption among Low-Income Children: Are There Differences by Race/Ethnicity, Age, and Sex?

Publication date: Available online 8 May 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Natasha Tasevska, Derek DeLia, Cori Lorts, Michael Yedidia, Punam Ohri-Vachaspati
BackgroundUnderstanding determinants of high consumption of sugar-sweetened beverages (SSBs), a highly prevalent obesogenic behavior, will help build effective customized public health interventions.ObjectiveOur aim was to identify child and parent lifestyle and household demographic factors predictive of high SSB consumption frequency in children from low-income, ethnically diverse communities that may help inform public health interventions.DesignWe used a cross-sectional telephone household survey.Participants/settingParticipants were 717 boys and 686 girls aged 3 to 18 years old from the New Jersey Childhood Obesity Study living in five low-income cities (Camden, New Brunswick, Newark, Trenton, and Vineland). The adult most knowledgeable about household food shopping completed a questionnaire over the telephone inquiring about their and their child's dietary and physical activity habits, and household-, parent-, and child-level demographics.Main outcome measuresChild's SSB consumption frequency was measured.Statistical analysis performedMultivariate ordered logit models were designed to investigate a variety of variables hypothesized to affect the frequency of SSB consumption. Exploratory stratified analyses by race, sex, and age were also conducted.ResultsEight percent of our study participants never consumed SSBs, 45% consumed SSBs at least once per day, and 23% consumed twice or more per day. SSB consumption was higher among children 12 to 18 years vs 3 to 5 years (P<0.0001), of non-Hispanic black vs non-Hispanic white race/ethnicity (P=0.010), who were moderate fast food consumers vs never consumers (P=0.003), and those whose parents were high vs low SSB consumers (P<0.0001). Living in a non–English-speaking household (P=0.030), having a parent with a college or higher education vs less than high school (P=0.003), and having breakfast 6 to 7 days/wk vs never to 2 days/wk or less were associated with lower SSB consumption (P=0.001).ConclusionsWe identified a number of household-, parent-, and child-level predictors of SSB consumption, which varied by race, sex, and age, useful for building customized interventions targeting certain behaviors in ethnically diverse, low-income children.



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Breast implant associated Anaplastic Large Cell Lymphoma in Australia and New Zealand - high surface area textured implants are associated with increased risk.

Background: The association between breast implants and breast implant associated anaplastic large cell lymphoma (BIA-ALCL), has been confirmed. Implant related risk has been difficult to estimate due to incomplete or unknown implant histories and lack of clarity on the number of implants utilized. Methods: All cases in Australia and New Zealand were identified and analyzed. Textured implants reported in this group were subjected to surface area analysis. Sales data from three leading breast implant manufacturers (Mentor/Allergan/Silimed) dating back to 1999 were secured to estimate implant specific risk. Results: 55 cases of BIA-ALCL were diagnosed in Australia and New Zealand between 2007 and 2016. The mean age of patients was 47.1 and the mean time of implant exposure was 7.46 years. There were 4 deaths in the series related to mass and/or metastatic presentation. All patients were exposed to textured implants. Surface area analysis confirmed that higher surface area was associated with 64 of the 75 implants utilized (85.3%). Biocell salt loss textured (Allergan/Inamed/McGhan) accounted for 58.7% of implants utilized in this series. Comparative analysis showed the risk of developing BIA-ALCL was found to be 14.11 times higher with Biocell textured implants and 10.84 higher with polyurethane (Silimed) textured implants as compared with Siltex textured implants. Conclusion: This study has calculated implant specific risk of BIA-ALCL. Higher surface area textured implants have been shown to significantly increase risk of BIA-ALCL in Australia and New Zealand. We present a unifying hypothesis to explain these observations. (C)2017American Society of Plastic Surgeons

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In vitro study on antagonism mechanism of glutathione, sodium selenite and mercuric chloride

Publication date: 15 August 2017
Source:Talanta, Volume 171
Author(s): Yu Qiao, Xi Huang, Beibei Chen, Man He, Bin Hu
It has been broadly recognized that the antagonism between selenium (Se) and mercury (Hg) can reduce the toxicity of mercury in organism. Glutathione (GSH) can participate in the metabolism of Se and Hg in vivo and promote the formation of low-toxic Hg-Se complexes, which is a vital way of detoxification for Hg. In this paper, the reaction mechanism of GSH-Se(IV) binary system, GSH-Hg(II) binary system and GSH-Se(IV)-Hg(II) ternary system were systematically studied from the aspects of stoichiometry, thermodynamics and kinetics, via hyphenated techniques including high performance liquid chromatography (HPLC)-ultraviolet (UV) detection, HPLC-inductively coupled plasma mass spectrometry (ICP-MS) and HPLC-electrospray ionization mass spectrometry (ESI-MS). For GSH-Se(IV) binary system, selenodiglutathione (GSSeSG) was the crucial intermediate; the reaction was exothermic and irreversible at constant pressure; it followed second-order kinetics with a fast kinetics (rate constant (k)=4534.2mol⁻¹Ls⁻¹). For GSH-Se(IV)-Hg(II) ternary system, GSSeSeSG would form by the extremely weak dissociation of two molecules of GSSeSG; Hg(II) would rapidly coordinate with GSSeSeSG to generate (HgxSey)n(GS)m precipitates. The mechanism of GSH-Se(IV)-Hg(II) antagonism system involves two processes, the competitive combination of Hg and Se with GSH and the formation of (HgxSey)n(GS)m complexes.

Graphical abstract

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Chest Pain Unit Network in Germany: Its Effect on Patients With Acute Coronary Syndromes

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Mortality and Acute Kidney Injury in Asians With Atrial Fibrillation Treated With Dabigatran or Warfarin

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Ambulatory Hemodynamic Monitoring Reduces Heart Failure Hospitalizations in "Real-World" Clinical Practice

AbstractBackground

In the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association [NYHA] Functional Class III Heart Failure Patients) trial, heart failure hospitalization (HFH) rates were lower in patients managed with guidance from an implantable pulmonary artery pressure sensor compared with usual care.

Objectives

This study examined the effectiveness of ambulatory hemodynamic monitoring in reducing HFH outside of the clinical trial setting.

Methods

We conducted a retrospective cohort study using U.S. Medicare claims data from patients undergoing pulmonary artery pressure sensor implantation between June 1, 2014, and December 31, 2015. Rates of HFH during pre-defined periods before and after implantation were compared using the Andersen-Gill extension to the Cox proportional hazards model while accounting for the competing risk of death, ventricular assist device implantation, or cardiac transplantation. Comprehensive heart failure (HF)–related costs were compared over the same periods.

Results

Among 1,114 patients receiving implants, there were 1,020 HFHs in the 6 months before, compared with 381 HFHs, 139 deaths, and 17 ventricular assist device implantations and/or transplants in the 6 months after implantation (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.49 to 0.61; p < 0.001). This lower rate of HFH was associated with a 6-month comprehensive HF cost reduction of $7,433 per patient (IQR: $7,000 to $7,884), and was robust in analyses restricted to 6-month survivors. Similar reductions in HFH and costs were noted in the subset of 480 patients with complete data available for 12 months before and after implantation (HR: 0.66; 95% CI: 0.57 to 0.76; p < 0.001).

Conclusions

As in clinical trials, use of ambulatory hemodynamic monitoring in clinical practice is associated with lower HFH and comprehensive HF costs. These benefits are sustained to 1 year and support the "real-world" effectiveness of this approach to HF management.

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Neurocognitive Risk With PCSK9 Inhibitors: Need for More Robust Evidence

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Real-World Data on Heart Failure Readmission Reduction: Real or Real Uncertain?

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Using Predicted Cardiovascular Disease Risk in Conjunction With Blood Pressure to Guide Antihypertensive Medication Treatment

Abstract

Using cardiovascular disease (CVD) risk instead of or in addition to blood pressure (BP) to guide antihypertensive treatment is an active area of research. The purpose of this review is to provide an overview of studies that could inform this treatment paradigm. We review data from randomized trials on relative and absolute CVD risk reduction that can occur when antihypertensive treatment is guided by CVD risk. We also review population-level data on using CVD risk in conjunction with BP to guide antihypertensive treatment, the broad distribution in CVD risk for people with similar BP levels, and the use of CVD risk for guiding antihypertensive treatment among subgroups including older adults, young adults, and those with diabetes mellitus or chronic kidney disease. In addition, we review potential challenges in implementing antihypertensive treatment recommendations that incorporate CVD risk. In closing, we provide recommendations for using CVD risk in combination with BP to guide antihypertensive treatment.

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Multiple Comorbidities and Response to Cardiac Resynchronization Therapy: MADIT-CRT Long-Term Follow-Up

AbstractBackground

Data regarding cardiac resynchronization therapy (CRT) in patients with multiple comorbidities are limited.

Objectives

This study evaluated the association of multiple comorbidities with the benefits of CRT over implantable cardioverter-defibrillator (ICD) alone.

Methods

We examined 1,214 MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) study patients with left bundle branch block (LBBB) and 0, 1, 2, or ≥3 comorbidities, including renal dysfunction, hypertension (HTN), diabetes, coronary artery disease, history of atrial arrhythmias, history of ventricular arrhythmias, current smoking, and cerebrovascular accident. In an adjusted analysis, we analyzed risk of heart failure (HF) events or death by comorbidity group in all patients and in patients with CRT with defibrillator (CRT-D) versus ICD. Then we examined percent change in left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV ejection fraction, left atrial volume, and LV dyssynchrony at 1-year in CRT-D patients by comorbidity group.

Results

There was an inverse relationship between comorbidity burden and improvements in LV end-systolic volume, LV end-diastolic volume, left ventricular ejection fraction, left atrial volume, and LV dyssynchrony. In an adjusted model, there was an increasing risk of death or nonfatal HF events with increasing comorbidity burden regardless of treatment group (p < 0.001). During a mean follow-up of 4.65 years, there was no interaction with respect to comorbidity burden and the benefit of CRT-D versus ICD only for death or nonfatal HF events (interaction p = 0.943). In the groups with greatest comorbidity burden (2 and ≥3), the absolute risk reduction associated with CRT-D over ICD alone appeared greater than that seen for groups with less comorbidity burden (0 and 1).

Conclusions

During long-term follow-up of MADIT-CRT study patients with LBBB randomized to CRT-D, there were differences in HF or death risk and in the degree of reverse remodeling among comorbidity groups. However, the burden of comorbidity does not appear to compromise the clinical benefits of CRT-D compared with ICD alone.

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Role of Acquired Cardiovascular Disease in Tetralogy of Fallot Patients >50 Years of Age

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Navigating Choices Among a Sea of Comorbidities

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Reply: The Enigma of Left Ventricular Non-Compaction

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Prognostic Implications of Moderate Aortic Stenosis in Patients With Left Ventricular Systolic Dysfunction

AbstractBackground

Left ventricular (LV) systolic dysfunction and moderate aortic stenosis (AS) are more frequent with advancing age and often coexist. Afterload reduction is the mainstay of pharmacological treatment of heart failure (HF). Aortic valve replacement (AVR) is only formally indicated for symptomatic severe AS.

Objectives

This study sought to determine the clinical outcome of patients with concomitant moderate AS and LV systolic dysfunction.

Methods

Echocardiographic and clinical data of patients with moderate AS and LV systolic dysfunction between 2010 and 2015 from 4 large academic institutions were retrospectively analyzed. Moderate AS was defined as aortic valve area between 1.0 and 1.5 cm² and LV systolic dysfunction defined as LV ejection fraction <50%. The primary endpoint was a composite of all-cause death, AVR, and HF hospitalization.

Results

A total of 305 patients (mean age 73 ± 11 years; 75% male) were included. The majority were symptomatic at the time of index echocardiogram (New York Heart Association [NYHA] functional class II: 42%; NYHA functional class III: 28%; and NYHA functional class IV: 4%). Ischemic heart disease was present in 72% of patients. At 4-year follow-up, the primary composite endpoint occurred in 61%. The main predictors for the primary endpoint were male sex (p = 0.022), NYHA functional class III or IV (p < 0.001), and peak aortic jet velocity (p < 0.001). The rate of the composite of all-cause death or HF hospitalization was 48%, rate of all-cause death was 36%, and rate of HF hospitalization was 27%. AVR occurred in 24% of patients.

Conclusions

Patients with concomitant moderate AS and LV systolic dysfunction are at high risk for clinical events. Further studies are needed to determine if earlier AVR in these patients might improve clinical outcome.

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JACC Instructions for Authors

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Aortic Stenosis Is Still Very Tricky, Especially When it Is Moderate

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Advocacy for Health Care: All Hands on Deck!

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Relation of Mitral Valve Surgery Volume to Repair Rate, Durability, and Survival

AbstractBackground

Degenerative mitral valve repair rates remain highly variable, despite established benefits of repair over replacement. The contribution of surgeon-specific factors is poorly defined.

Objectives

This study evaluated the influence of surgeon case volume on degenerative mitral valve repair rates and outcomes.

Methods

A mandatory New York State database was queried and 5,475 patients were identified with degenerative mitral disease who underwent mitral valve operations between 2002 and 2013. Mitral repair rates, mitral reoperations within 12 months of repair, and survival were analyzed using multivariable Cox modeling and restricted cubic spline function.

Results

Median annual surgeon volume of any mitral operations was 10 (range 1 to 230), with a mean repair rate of 55% (n = 20,797 of 38,128). In the subgroup of patients with degenerative disease, the mean repair rate was 67% (n = 3,660 of 5,475), with a range of 0% to 100%. Mean repair rates ranged from 48% (n = 179 of 370) for surgeons with total annual volumes of ≤10 mitral operations to 77% (n = 1,710 of 2,216) for surgeons with total annual volumes of >50 mitral operations (p < 0.001). Higher total annual surgeon volume was associated with increased repair rates of degenerative mitral valve disease (adjusted odds ratio [OR]: 1.13 for every additional 10 mitral operations; 95% confidence interval [CI]: 1.10 to 1.17; p < 0.001); a steady decrease in reoperation risk until 25 total mitral operations annually; and improved 1-year survival (adjusted hazard ratio: 0.95 for every additional 10 operations; 95% CI: 0.92 to 0.98; p = 0.001). For surgeons with a total annual volume of ≤25 mitral operations, repair rates were higher (63.8%; n = 180 of 282) if they operated in the same institution as a surgeon with total annual mitral volumes of >50 and degenerative mitral valve repair rates of >70%, compared with surgeons operating in the other institutions (51.3%; n = 580 of 1,130) (adjusted OR: 1.79; 95% CI: 1.24 to 2.60; p < 0.001).

Conclusions

This study suggests that individual surgeon volume is a determinant of not only mitral repair rates, but also freedom from reoperation, and survival. The data from this study support the guideline's concept of reference referral to experienced mitral surgeons to improve outcomes in patients with degenerative mitral valve disease.

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Global Cardiovascular Health: A Role for the Interventionalist

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The Specialty of Mitral Valve Repair

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Truncating Variants in Titin Independently Predict Early Arrhythmias in Patients With Dilated Cardiomyopathy

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Post-Operative Chylothorax in Patients With Congenital Heart Disease

AbstractBackground

Post-operative chylothorax in patients with congenital heart disease is a challenging problem with substantial morbidity and mortality. Currently, the etiology of chylothorax is poorly understood and treatment options are limited.

Objectives

This study aimed to report lymphatic imaging findings, determine the mechanism of chylothorax after cardiac surgery, and analyze the outcomes of lymphatic embolization.

Methods

We conducted a retrospective review of 25 patients with congenital heart disease and post-operative chylothorax who presented for lymphatic imaging and intervention between July 2012 and August 2016.

Results

Based on dynamic contrast-enhanced magnetic resonance lymphangiography and intranodal lymphangiography, we identified 3 distinct etiologies of chylothorax: 2 patients (8%) with traumatic leak from a thoracic duct (TD) branch, 14 patients (56%) with pulmonary lymphatic perfusion syndrome (PLPS), and 9 patients (36%) with central lymphatic flow disorder (CLFD), the latter defined as abnormal central lymphatic flow, effusions in more than 1 compartment, and dermal backflow. Patients with traumatic leak and PLPS were combined into 1 group of 16 patients without CLFD, of whom 14 (88%) had an intact TD. Sixteen patients underwent lymphatic intervention, including complete TD embolization. All 16 patients had resolution of chylothorax, with a median of 7.5 days from intervention to chest tube removal and 15 days from intervention to discharge. The 9 patients with CLFD were considered a separate group, of whom 3 (33%) had an intact TD. Seven patients underwent lymphatic intervention but none survived.

Conclusions

Most patients in this study had nontraumatic chylothorax and dynamic contrast-enhanced magnetic resonance lymphangiography was essential to determine etiology. Lymphatic embolization was successful in patients with traumatic leak and PLPS and, thus, should be considered first-line treatment. Interventions in patients with CLFD were not successful to resolve chylothorax and alternate approaches need to be developed.

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The Enigma of Left Ventricular Hypertrabeculation: Knowledge About Pregnancies, Sports, and Neuromuscular Disorders Is Needed

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Utility of intraoral stents in external beam radiotherapy for head and neck cancer

Publication date: July–August 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 4
Author(s): Hiroshi Doi, Masao Tanooka, Toshihisa Ishida, Kuniyasu Moridera, Kenji Ichimiya, Kazuo Tarutani, Kazuhiro Kitajima, Masayuki Fujiwara, Hiromitsu Kishimoto, Norihiko Kamikonya
AimThis study aimed to assess the utility and stability of intraoral stent during intensity-modulated radiation therapy (IMRT).BackgroundThe benefits of intraoral stents in radiotherapy are unclear.Materials and methodsWe analyzed 386 setup errors in 12 patients who received IMRT for head and neck cancers without intraoral stents (intraoral stent [−]) and 183 setup errors in 6 patients who received IMRT with intraoral stents (intraoral stent [+]). All patients were matched according to the immobilization method (masks and boards). Setup errors were measured as the distance from the initial setup based on the marking on the skin and mask to the corrected position based on bone matching on cone beam computed tomography.ResultsThe mean interfractional setup errors in the right–left, craniocaudal, anterior–posterior (AP), and three-dimensional (3D) directions were −0.33, 0.08, −0.25, and 2.75mm in the intraoral stent (−) group and −0.37, 0.24, −0.63, and 2.42mm in the intraoral stent (+) group, respectively (P=0.50, 0.65, 0.01, and 0.02, respectively). The systematic errors for the same directions were 0.89, 1.46, 1.15, and 0.88mm in the intraoral stent (−) group and 0.62, 1.69, 0.68, and 0.56mm in the intraoral stents (+) group, respectively. The random errors were 1.43, 1.43, 1.44, and 1.22mm in the intraoral stent (−) group and 1.06, 1.11, 1.05, and 0.92mm in the intraoral stents (+) group, respectively.ConclusionSetup errors can be significantly reduced in the AP and 3D-directions by using intraoral stents.



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Using Epigenetic Reprogramming to Treat Pediatric Brain Cancer

Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Milan G. Chheda, David H. Gutmann
In this issue of Cancer Cell, Nagaraja et al. dissect the molecular mechanisms underlying therapeutic responses to transcriptional disruptors in the fatal pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). Moreover, they identify super-enhancers mediating these effects, highlighting how normal brain developmental programs can be hijacked in cancer.

Teaser

In this issue of Cancer Cell, Nagaraja et al. dissect the molecular mechanisms underlying therapeutic responses to transcriptional disruptors in the fatal pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). Moreover, they identify super-enhancers mediating these effects, highlighting how normal brain developmental programs can be hijacked in cancer.


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The Tribble with APL: A New Road to Therapy

Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Ruaidhrí Carmody, Karen Keeshan
The t(15;17) translocation generates a PML-RARα fusion protein causative for acute promyelocytic leukemia (APL). Li et al. now identify the pseudokinase stress protein TRIB3 as an important factor in APL disease progression and therapy resistance. Targeting the interaction of TRIB3 and PML-RARα using peptide technology provides a novel therapeutic approach.

Teaser

The t(15;17) translocation generates a PML-RARα fusion protein causative for acute promyelocytic leukemia (APL). Li et al. now identify the pseudokinase stress protein TRIB3 as an important factor in APL disease progression and therapy resistance. Targeting the interaction of TRIB3 and PML-RARα using peptide technology provides a novel therapeutic approach.


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