bluuebunny/crossref_metadata_2025 huggingface dataset:
Inverse Computational Fluid Dynamics: Influence of Discretization and Model Errors on Flows in Water Network Including Junctions
Authors: Waeytens Julien , Chatellier Patrice , Bourquin Frédéric
Published: April 2015

We address the reconstruction of relevant two-dimensional (2D) flows in drinking water networks, especially in key elements such as pipe junctions, in view of representative water quality simulations. From the optimal control theory, a specific inverse technique using few sensors and computational fluid dynamics (CFD) models has been developed. First, we determine the boundary velocities, i.e., the control parameters, by minimizing a data misfit functional. Then, knowing the boundary velocities, a direct solve of the flow model is performed to get the space–time cartography of the water flow. To reduce the number of control parameters to be determined and thus restrict the number of sensors, the spatial shape of the boundary velocities is considered as an a priori information given by the water pipes engineering literature. Thus, only the time evolution of the boundary velocities has to be determined. The whole numerical procedure proposed in this paper easily fits in a general purpose finite element software, featuring user's friendliness for a wide engineering audience. Two ways are investigated to reduce the computation time associated to the flow reconstruction. The adjoint framework is used in the minimization process. The reconstruction of the flow using coarse discretizations and simple flow models, instead of 2D Navier–Stokes equations, is studied. The influence of the flow modeling and of the dicretization on the quality of the reconstructed velocity is studied on two examples: a water pipe junction and a 200 m subsection from a French water network. In the water pipe junction, we show that at a Reynolds number of 200 a hybrid approach combining an unsteady Stokes reconstruction and a single direct Navier–Stokes simulation outperforms the algorithms based on a single model. In the network subsection, we obtain an L2 error less than 1% between the reference velocity based on Navier–Stokes equations (Reynolds number of 200) and the velocity reconstructed from Stokes equation. In this case, the reconstruction lasts less than 1 min. Stokes based reconstruction of a Navier–Stokes flow in junctions at Reynolds number up to 100 yields the same accuracy and proves fast.
Noninvasive hemodynamic assessment, treatment outcome prediction and follow‐up of aortic coarctation from MR imaging
Authors: Ralovich Kristóf , Itu Lucian , Vitanovski Dime , Sharma Puneet , Ionasec Razvan , Mihalef Viorel , Krawtschuk Waldemar , Zheng Yefeng , Everett Allen , Pongiglione Giacomo , Leonardi Benedetta , Ringel Richard , Navab Nassir , Heimann Tobias , Comaniciu Dorin
Published: April 2015

Purpose:

Coarctation of the aorta (CoA) is a congenital heart disease characterized by an abnormal narrowing of the proximal descending aorta. Severity of this pathology is quantified by the blood pressure drop (△P) across the stenotic coarctation lesion. In order to evaluate the physiological significance of the preoperative coarctation and to assess the postoperative results, the hemodynamic analysis is routinely performed by measuring the △P across the coarctation site via invasive cardiac catheterization. The focus of this work is to present an alternative, noninvasive measurement of blood pressure drop △P through the introduction of a fast, image‐based workflow for personalized computational modeling of the CoA hemodynamics.

Methods:

The authors propose an end‐to‐end system comprised of shape and computational models, their personalization setup using MR imaging, and a fast, noninvasive method based on computational fluid dynamics (CFD) to estimate the pre‐ and postoperative hemodynamics for coarctation patients. A virtual treatment method is investigated to assess the predictive power of our approach.

Results:

Automatic thoracic aorta segmentation was applied on a population of 212 3D MR volumes, with mean symmetric point‐to‐mesh error of 3.00 ± 1.58 mm and average computation time of 8 s. Through quantitative evaluation of 6 CoA patients, good agreement between computed blood pressure drop and catheter measurements is shown: average differences are 2.38 ± 0.82 mm Hg (pre‐), 1.10 ± 0.63 mm Hg (postoperative), and 4.99 ± 3.00 mm Hg (virtual stenting), respectively.

Conclusions:

The complete workflow is realized in a fast, mostly‐automated system that is integrable in the clinical setting. To the best of our knowledge, this is the first time that three different settings (preoperative—severity assessment, poststenting—follow‐up, and virtual stenting—treatment outcome prediction) of CoA are investigated on multiple subjects. We believe that in future—given wider clinical validation—our noninvasive in‐silico method could replace invasive pressure catheterization for CoA.
Noncoplanar VMAT for nasopharyngeal tumors: Plan quality versus treatment time
Authors: Wild Esther , Bangert Mark , Nill Simeon , Oelfke Uwe
Published: April 2015

Purpose:

The authors investigated the potential of optimized noncoplanar irradiation trajectories for volumetric modulated arc therapy (VMAT) treatments of nasopharyngeal patients and studied the trade‐off between treatment plan quality and delivery time in radiation therapy.

Methods:

For three nasopharyngeal patients, the authors generated treatment plans for nine different delivery scenarios using dedicated optimization methods. They compared these scenarios according to dose characteristics, number of beam directions, and estimated delivery times. In particular, the authors generated the following treatment plans: (1) a 4π plan, which is a not sequenced, fluence optimized plan that uses beam directions from approximately 1400 noncoplanar directions and marks a theoretical upper limit of the treatment plan quality, (2) a coplanar 2π plan with 72 coplanar beam directions as pendant to the noncoplanar 4π plan, (3) a coplanar VMAT plan, (4) a coplanar step and shoot (SnS) plan, (5) a beam angle optimized (BAO) coplanar SnS IMRT plan, (6) a noncoplanar BAO SnS plan, (7) a VMAT plan with rotated treatment couch, (8) a noncoplanar VMAT plan with an optimized great circle around the patient, and (9) a noncoplanar BAO VMAT plan with an arbitrary trajectory around the patient.

Results:

VMAT using optimized noncoplanar irradiation trajectories reduced the mean and maximum doses in organs at risk compared to coplanar VMAT plans by 19% on average while the target coverage remains constant. A coplanar BAO SnS plan was superior to coplanar SnS or VMAT; however, noncoplanar plans like a noncoplanar BAO SnS plan or noncoplanar VMAT yielded a better plan quality than the best coplanar 2π plan. The treatment plan quality of VMAT plans depended on the length of the trajectory. The delivery times of noncoplanar VMAT plans were estimated to be 6.5 min in average; 1.6 min longer than a coplanar plan but on average 2.8 min faster than a noncoplanar SnS plan with comparable treatment plan quality.

Conclusions:

The authors’ study reconfirms the dosimetric benefits of noncoplanar irradiation of nasopharyngeal tumors. Both SnS using optimized noncoplanar beam ensembles and VMAT using an optimized, arbitrary, noncoplanar trajectory enabled dose reductions in organs at risk compared to coplanar SnS and VMAT. Using great circles or simple couch rotations to implement noncoplanar VMAT, however, was not sufficient to yield meaningful improvements in treatment plan quality. The authors estimate that noncoplanar VMAT using arbitrary optimized irradiation trajectories comes at an increased delivery time compared to coplanar VMAT yet at a decreased delivery time compared to noncoplanar SnS IMRT.
Novel magnetic heating probe for multimodal cancer treatment
Authors: Kan‐Dapaah Kwabena , Rahbar Nima , Soboyejo Wole
Published: April 2015

Purpose:

Multifunctional materials consisting of polymers and magnetic nanoparticles (MNPs) are highly sought after in the field of biomedical engineering. These materials offer new opportunities for the development of novel cancer treatment modalities that can increase the efficacy of cancer therapy. In this paper, a novel probe for multimodal cancer treatment is proposed and analyzed. The probe is essentially a cannula with two main parts: a distal heat generating tip made of a magnetic nanocomposite and a proximal insulated shaft.

Methods:

A description of the concept and functional operations of the probe is presented. In an effort to assess its feasibility, the authors evaluated the ability of probe tip (made of PMMA‐Fe3O4 nanocomposite) to generate heat in biological tissue using alternating magnetic field (AMF) parameters (field strength and frequency) that are acceptable for human use. Heat generation by MNPs was determined using the linear response theory. The effects of Fe3O4 volume fraction on heat generation as well as treatment time on the thermal dose were studied. The finite element method model was tested for its validity using an analytical model.

Results:

Lesions were revealed to have an ellipsoidal shape and their sizes were affected by treatment time. However, their shapes remained unchanged. The comparison with the analytical model showed reasonably a good agreement to within 2%. Furthermore, the authors’ numerical predictions also showed reasonable agreement with the experimental results previously reported in the literature.

Conclusions:

The authors’ predictions demonstrate the feasibility of their novel probe to achieve reasonable lesion sizes, during hyperthermic or ablative heating using AMF parameters (field strength and frequency) that are acceptable for human use.
Specific activation of the TLR1-TLR2 heterodimer by small-molecule agonists
Authors: Cheng Kui , Gao Meng , Godfroy James I. , Brown Peter N. , Kastelowitz Noah , Yin Hang
Published: April 2015

A small-molecule agonist of the Toll-like receptor 1/2 signaling pathway does it by stabilizing heterodimeric associations.
PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors
Authors: Iwamoto Hideki , Zhang Yin , Seki Takahiro , Yang Yunlong , Nakamura Masaki , Wang Jian , Yang Xiaojuan , Torimura Takuji , Cao Yihai
Published: April 2015

Notch inhibitors cause cancer growth in tumors expressing PIGFβ protein.
Electrically controlling single-spin qubits in a continuous microwave field
Authors: Laucht Arne , Muhonen Juha T. , Mohiyaddin Fahd A. , Kalra Rachpon , Dehollain Juan P. , Freer Solomon , Hudson Fay E. , Veldhorst Menno , Rahman Rajib , Klimeck Gerhard , Itoh Kohei M. , Jamieson David N. , McCallum Jeffrey C. , Dzurak Andrew S. , Morello Andrea
Published: April 2015

Control of individual spin qubits through local electric fields, suitable for large-scale silicon quantum computers.
Crowdsourced earthquake early warning
Authors: Minson Sarah E. , Brooks Benjamin A. , Glennie Craig L. , Murray Jessica R. , Langbein John O. , Owen Susan E. , Heaton Thomas H. , Iannucci Robert A. , Hauser Darren L.
Published: April 2015

Consumer devices and real and simulated earthquake data demonstrate that earthquake early warning can be achieved via crowdsourcing.
Dynamic Succession of Groundwater Functional Microbial Communities in Response to Emulsified Vegetable Oil Amendment during Sustained
In Situ
U(VI) Reduction
Authors: Zhang Ping , Wu Wei-Min , Van Nostrand Joy D. , Deng Ye , He Zhili , Gihring Thomas , Zhang Gengxin , Schadt Chris W. , Watson David , Jardine Phil , Criddle Craig S. , Brooks Scott , Marsh Terence L. , Tiedje James M. , Arkin Adam P. , Zhou Jizhong
Published: April 2015

A pilot-scale field experiment demonstrated that a one-time amendment of emulsified vegetable oil (EVO) reduced groundwater U(VI) concentrations for 1 year in a fast-flowing aquifer. However, little is known about how EVO amendment stimulates the functional gene composition, structure, and dynamics of groundwater microbial communities toward prolonged U(VI) reduction. In this study, we hypothesized that EVO amendment would shift the functional gene composition and structure of groundwater microbial communities and stimulate key functional genes/groups involved in EVO biodegradation and reduction of electron acceptors in the aquifer. To test these hypotheses, groundwater microbial communities after EVO amendment were analyzed using a comprehensive functional gene microarray. Our results showed that EVO amendment stimulated sequential shifts in the functional composition and structure of groundwater microbial communities. Particularly, the relative abundance of key functional genes/groups involved in EVO biodegradation and the reduction of NO
3
−
, Mn(IV), Fe(III), U(VI), and SO
4
2−
significantly increased, especially during the active U(VI) reduction period. The relative abundance for some of these key functional genes/groups remained elevated over 9 months. Montel tests suggested that the dynamics in the abundance, composition, and structure of these key functional genes/groups were significantly correlated with groundwater concentrations of acetate, NO
3
−
, Mn(II), Fe(II), U(VI), and SO
4
2−
. Our results suggest that EVO amendment stimulated dynamic succession of key functional microbial communities. This study improves our understanding of the composition, structure, and function changes needed for groundwater microbial communities to sustain a long-term U(VI) reduction.
Validation of Reference Genes for Transcriptional Analyses in Pleurotus ostreatus by Using Reverse Transcription-Quantitative PCR
Authors: Castanera Raúl , López-Varas Leticia , Pisabarro Antonio G. , Ramírez Lucía
Published: April 2015

Recently, the lignin-degrading basidiomycete
Pleurotus ostreatus
has become a widely used model organism for fungal genomic and transcriptomic analyses. The increasing interest in this species has led to an increasing number of studies analyzing the transcriptional regulation of multigene families that encode extracellular enzymes. Reverse transcription (RT) followed by real-time PCR is the most suitable technique for analyzing the expression of gene sets under multiple culture conditions. In this work, we tested the suitability of 13 candidate genes for their use as reference genes in
P. ostreatus
time course cultures for enzyme production. We applied three different statistical algorithms and obtained a combination of stable reference genes for optimal normalization of RT-quantitative PCR assays. This reference index can be used for future transcriptomic analyses and validation of transcriptome sequencing or microarray data. Moreover, we analyzed the expression patterns of a laccase and a manganese peroxidase (
lacc10
and
mnp3
, respectively) in lignocellulose and glucose-based media using submerged, semisolid, and solid-state fermentation. By testing different normalization strategies, we demonstrate that the use of nonvalidated reference genes as internal controls leads to biased results and misinterpretations of the biological responses underlying expression changes.
Resistance Genes and Genetic Elements Associated with Antibiotic Resistance in Clinical and Commensal Isolates of Streptococcus salivarius
Authors: Chaffanel Fanny , Charron-Bourgoin Florence , Libante Virginie , Leblond-Bourget Nathalie , Payot Sophie
Published: April 2015

The diversity of clinical (
n
= 92) and oral and digestive commensal (
n
= 120) isolates of
Streptococcus salivarius
was analyzed by multilocus sequence typing (MLST). No clustering of clinical or commensal strains can be observed in the phylogenetic tree. Selected strains (92 clinical and 46 commensal strains) were then examined for their susceptibilities to tetracyclines, macrolides, lincosamides, aminoglycosides, and phenicol antibiotics. The presence of resistance genes
tet
(M),
tet
(O),
erm
(A),
erm
(B),
mef
(A/E), and
catQ
and associated genetic elements was investigated by PCR, as was the genetic linkage of resistance genes. High rates of erythromycin and tetracycline resistance were observed among the strains. Clinical strains displayed either the
erm
(B) (macrolide-lincosamide-streptogramin B [MLS
B
] phenotype) or
mef
(A/E) (M phenotype) resistance determinant, whereas almost all the commensal strains harbored the
mef
(A/E) resistance gene, carried by a macrolide efflux genetic assembly (MEGA) element. A genetic linkage between a macrolide resistance gene and genes of Tn
916
was detected in 23 clinical strains and 5 commensal strains, with a predominance of Tn
3872
elements (
n
= 13), followed by Tn
6002
(
n
= 11) and Tn
2009
(
n
= 4) elements. Four strains harboring a
mef
(A/E) gene were also resistant to chloramphenicol and carried a
catQ
gene. Sequencing of the genome of one of these strains revealed that these genes colocalized on an IQ-like element, as already described for other viridans group streptococci. ICE
St3
-related elements were also detected in half of the isolates. This work highlights the potential role of
S. salivarius
in the spread of antibiotic resistance genes both in the oral sphere and in the gut.
Impact of Protein Palmitoylation on the Virulence Potential of Cryptococcus neoformans
Authors: Nichols Connie B. , Ost Kyla S. , Grogan Dayton P. , Pianalto Kaila , Hasan Shirin , Alspaugh J. Andrew
Published: April 2015

The localization and specialized function of Ras-like proteins are largely determined by posttranslational processing events. In a highly regulated process, palmitoyl groups may be added to C-terminal cysteine residues, targeting these proteins to specific membranes. In the human fungal pathogen
Cryptococcus neoformans
, Ras1 protein palmitoylation is essential for growth at high temperature but is dispensable for sexual differentiation. Ras1 palmitoylation is also required for localization of this protein on the plasma membrane. Together, these results support a model in which specific Ras functions are mediated from different subcellular locations. We therefore hypothesize that proteins that activate Ras1 or mediate Ras1 localization to the plasma membrane will be important for
C. neoformans
pathogenesis. To further characterize the Ras1 signaling cascade mediating high-temperature growth, we have identified a family of protein
S
-acyltransferases (PATs), enzymes that mediate palmitoylation, in the
C. neoformans
genome database. Deletion strains for each candidate gene were generated by homogenous recombination, and each mutant strain was assessed for Ras1-mediated phenotypes, including high-temperature growth, morphogenesis, and sexual development. We found that full Ras1 palmitoylation and function required one particular PAT, Pfa4, and deletion of the
PFA4
gene in
C. neoformans
resulted in altered Ras1 localization to membranes, impaired growth at 37°C, and reduced virulence.
Innovation in immediate neonatal care: development of the Bedside Assessment, Stabilisation and Initial Cardiorespiratory Support (BASICS) trolley
Authors: Weeks A D , Watt P , Yoxall C W , Gallagher A , Burleigh A , Bewley S , Heuchan A M , Duley L
Published: April 2015

Objective

Babies receive oxygen through their umbilical cord while in the uterus and for a few minutes after birth. Currently, if the baby is not breathing well at birth, the cord is cut so as to transfer the newborn to a resuscitation unit. We sought to develop a mobile resuscitation trolley on which newly born babies can be resuscitated while still receiving oxygenated blood and the ‘placental transfusion’ through the umbilical cord. This would also prevent separation of the mother and baby in the first minutes after birth.

Design

Multidisciplinary iterative product development.

Setting

Clinical Engineering Department of a University Teaching Hospital.

Methods

Following an initial design meeting, a series of prototypes were developed. At each stage, the prototype was reviewed by a team of experts in the laboratory and in the hospital delivery suite to determine ease of use and fitness for purpose. A commercial company was identified to collaborate on the trolley's development and secure marking with the Conformité Européenne mark, allowing the trolley to be introduced into clinical practice.

Results

The trolley is a small mobile resuscitation unit based on the concept of an overbed hospital table. It can be manoeuvred to within 50 cm of the mother's pelvis so that the umbilical cord can remain intact during resuscitation, irrespective of whether the baby is born naturally, by instrumental delivery or by caesarean section. Warmth for the newborn comes from a heated mattress and the trolley has the facility to provide suction, oxygen and air.

Conclusions

This is the first mobile resuscitation device designed specifically to facilitate newborn resuscitation at the bedside and with an intact cord. The next step is to assess its safety, its acceptability to clinicians and parents, and to determine whether it allows resuscitation with an intact cord.
Clinical and radiographic features of contagious ovine digital dermatitis and a novel lesion grading system
Authors: Angell J. W. , Blundell R. , Grove‐White D. H. , Duncan J. S.
Published: April 2015

Contagious ovine digital dermatitis (CODD) is an infectious foot disease of sheep causing severe lameness. Diagnosis is currently made using broad anecdotal descriptions. The aim of this study was to systematically and formally describe the clinical presentation of the disease in terms of (1) a lesion grading system; (2) associated radiographic changes and (3) severity of associated lameness. A five‐point lesion grading system was developed and applied to 908 sheep affected by CODD from six farms. Sheep with lesions typical of each grade were euthanased and their feet radiographed. Radiographic abnormalities including soft tissue and bony changes were evident in feet with lesions graded 2–5. In order to quantify the welfare impact of CODD, all the 908 sheep were locomotion scored. Five hundred and eighty‐five (64.5% (95% CI 61.4% to 67.6%)) were lame. The locomotion score for affected sheep increased with worsening pathological changes. Once healing had begun the locomotion score decreased. In conclusion the five‐point grading system may be used to clinically describe stages of CODD lesions. The radiographic changes revealed examples of deeper pathological changes and there was a strong association between the lesion grading system and locomotion score in affected sheep.
What do European veterinary codes of conduct actually say and mean? A case study approach
Authors: Magalhães‐Sant'Ana M. , More S. J. , Morton D. B. , Osborne M. , Hanlon A.
Published: April 2015

Codes of Professional Conduct (CPCs) are pivotal instruments of self‐regulation, providing the standards to which veterinarians should, and sometimes must, comply. Despite their importance to the training and guidance of veterinary professionals, research is lacking on the scope and emphasis of the requirements set out in veterinary CPCs. This paper provides the first systematic investigation of veterinary CPCs. It relies on a case study approach, combining content and thematic analyses of five purposively selected European CPCs: Federation of Veterinarians of Europe (FVE), Denmark, Ireland, Portugal and the UK. Eight overarching themes were identified, including ‘definitions and framing concepts’, ‘duties to animals’, ‘duties to clients’, ‘duties to other professionals’, ‘duties to competent authorities’, ‘duties to society’, ‘professionalism’ and ‘practice‐related issues’. Some differences were observed, which may be indicative of different approaches to the regulation of the veterinary profession in Europe (which is reflected in having a ‘code of ethics’ or a ‘code of conduct’), cultural differences on the status of animals in society, and regulatory bodies’ proactivity in adapting to professional needs and to societal changes regarding the status of animals. These findings will contribute to an improved understanding of the roles of CPCs in regulating the veterinary profession in Europe.
Mycobacterium smegmatissynthesizes in vitro androgens and estrogens from different steroid precursors
Authors: Dlugovitzky Diana G. , Fontela María Sol , Martinel Lamas Diego J. , Valdez Ricardo A. , Romano Marta C.
Published: April 2015

Fast-growing mycobacteria such as Mycobacterium sp. and Mycobacterium smegmatis degrade natural sterols. They are a model to study tuberculosis. Interestingly, M. smegmatis has been found in river effluents derived from paper production, and therefore, it would be important to gain further insight into its capacity to synthesize steroids that are potential endocrine disruptors affecting the development and reproduction of fishes. To our knowledge, the capacity of M. smegmatis to synthesize estrogens and even testosterone has not been previously reported. Therefore, the objective of this study was to investigate the capacity of M. smegmatis to synthesize in vitro testosterone and estrogens from tritiated precursors and to investigate the metabolic pathways involved. Results obtained by thin-layer chromatography showed that3H-progesterone was transformed to 17OH-progesterone, androstenedione, testosterone, estrone, and estradiol after 6, 12, or 24 h of incubation.3H-androstenedione was transformed into testosterone and estrogens, mainly estrone, and3H-testosterone was transformed to estrone and androstenedione. Incubation with3H-dehydroepiandrosterone rendered androstenediol, testosterone, and estrogens. This ability to transform less potent sex steroids like androstenedione and estrone into other more active steroids like testosterone and estradiol or vice versa suggests that M. smegmatis can influence the amount of self-synthesized strong androgens and estrogens and can transform those found in the environment.
HLA-B27
Authors: Bowness Paul
Published: April 2015

Possession of the human leukocyte antigen (HLA) class I molecule B27 is strongly associated with ankylosing spondylitis (AS), but the pathogenic role of HLA-B27 is unknown. Two broad theories most likely explain the role of HLA-B27 in AS pathogenesis. The first is based on the natural immunological function of HLA-B27 of presenting antigenic peptides to cytotoxic T cells. Thus, HLA-B27-restricted immune responses to self-antigens, or arthritogenic peptides, might drive immunopathology. B27 can also “behave badly,” misfolding during assembly and leading to endoplasmic reticulum stress and autophagy responses. β2m-free B27 heavy chain structures including homodimers (B272) can also be expressed at the cell surface following endosomal recycling of cell surface heterotrimers. Cell surface free heavy chains and B272bind to innate immune receptors on T, NK, and myeloid cells with proinflammatory effects. This review describes the natural function of HLA-B27, its disease associations, and the current theories as to its pathogenic role.
Protein assemblies of sodium and inward rectifier potassium channels control cardiac excitability and arrhythmogenesis
Authors: Willis B. Cicero , Ponce-Balbuena Daniela , Jalife José
Published: April 2015

The understanding of how cardiac ion channels function in the normal and the diseased heart has greatly increased over the last four decades thanks to the advent of patch-clamp technology and, more recently, the emergence of genetics, as well as cellular and molecular cardiology. However, our knowledge of how these membrane-embedded proteins physically interact with each other within macromolecular complexes remains incomplete. This review focuses on how the main cardiac inward sodium channel (NaV1.5) and the strong inward rectifier potassium channel (Kir2.1) function within macromolecular complexes to control cardiac excitability. It has become increasingly clear that these two important ion channel proteins physically interact with multiple other protein partners and with each other from early stages of protein trafficking and targeting through membrane anchoring, recycling, and degradation. Recent findings include compartmentalized regulation of NaV1.5 channel expression and function through a PDZ (postsynaptic density protein, Drosophila disc large tumor suppressor, and zonula occludens-1 protein) domain-binding motif, and interaction of caveolin-3 with Kir2.1 and ankyrin-G as a molecular platform for NaV1.5 signaling. At the cardiomyocyte membrane, NaV1.5 and Kir2.1 interact through at least two distinct PDZ domain-scaffolding proteins (synapse-associated protein-97 and α1-syntrophin), thus modulating reciprocally their cell-surface expression at two different microdomains. Emerging evidence also shows that inheritable mutations in plakophilin-2, ankyrin-G, dystrophin, syntrophin, synapse-associated protein-97, and caveolin-3, among others, modify functional expression and/or localization in the cardiac cell of NaV1.5, Kir2.1 or both to give rise to arrhythmogenic diseases. Unveiling the mechanistic underpinnings of macromolecular interactions should increase our understanding of inherited and acquired arrhythmogenic cardiac diseases and may lead to advances in therapy.
Bacillus anthracis edema but not lethal toxin challenge in rats is associated with depressed myocardial function in hearts isolated and tested in a Langendorff system
Authors: Li Yan , Abu-Asab Mones , Su Junwu , Qiu Ping , Feng Jing , Ohanjanian Lernik , Kumar Hanish Sampath , Fitz Yvonne , Eichacker Peter Q. , Cui Xizhong
Published: April 2015

Although direct myocardial depression has been implicated in the lethal effects of Bacillus anthracis lethal toxin (LT), in hearts isolated from healthy rats and perfused under constant pressure, neither LT or edema toxin (ET) in typically lethal concentrations depressed myocardial function. In the present study, we challenged rats with LT and ET and performed in vivo and ex vivo heart measures. Sprague-Dawley rats infused over 24 h with LT ( n = 94), ET ( n = 99), or diluent (controls; n = 50) were studied at 8, 24, or 48 h. Compared with control rats (all survived), survival rates with LT (56.1%) and ET (37.3%) were reduced ( P < 0.0001) similarly ( P = 0.66 for LT vs. ET). LT decreased mean arterial blood pressure from 12 to 20 h ( P ≤ 0.05), whereas ET decreased it progressively throughout ( P < 0.05). On echocardiography, LT decreased left ventricular (LV) ejection fraction at 8 and 48 h but increased it at 24 h and decreased cardiac output ( P ≤ 0.05 for the time interaction or averaged over time). ET decreased systolic and diastolic volumes and increased LV ejection fraction at 24 h ( P ≤ 0.05). In isolated hearts perfused for 120 min under constant pressure, LT did not significantly alter LV systolic or developed pressures at any time point, whereas ET decreased both of these at 24 h ( P < 0.0001 initially). ET but not LT progressively increased plasma creatine phosphokinase and cardiac troponin levels ( P < 0.05). In conclusion, despite echocardiographic changes, in vivo lethal LT challenge did not produce evidence of myocardial depression in isolated rat hearts. While lethal ET challenge did depress isolated heart function, this may have resulted from prior hypotension and ischemia.
Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism
Authors: Fletcher Marianne E. , Boshier Piers R. , Wakabayashi Kenji , Keun Hector C. , Smolenski Ryszard T. , Kirkham Paul A. , Adcock Ian M. , Barton Paul J. , Takata Masao , Marczin Nandor
Published: April 2015

Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione- S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-π but not GST-μ expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD+/NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-π, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications.
Characterization of spontaneous air space enlargement in mice lacking microfibrillar-associated protein 4
Authors: Holm Anne Trommelholt , Wulf-Johansson Helle , Hvidsten Svend , Jorgensen Patricia Troest , Schlosser Anders , Pilecki Bartosz , Ormhøj Maria , Moeller Jesper Bonnet , Johannsen Claus , Baun Christina , Andersen Thomas , Schneider Jan Philipp , Hegermann Jan , Ochs Matthias , Götz Alexander A. , Schulz Holger , de Angelis Martin Hrabě , Vestbo Jørgen , Holmskov Uffe , Sorensen Grith Lykke
Published: April 2015

Microfibrillar-associated protein 4 (MFAP4) is localized to elastic fibers in blood vessels and the interalveolar septa of the lungs and is further present in bronchoalveolar lavage. Mfap4 has been previously suggested to be involved in elastogenesis in the lung. We tested this prediction and aimed to characterize the pulmonary function changes and emphysematous changes that occur in Mfap4-deficient ( Mfap4−/−) mice. Significant changes included increases in total lung capacity and compliance, which were evident in Mfap4−/−mice at 6 and 8 mo but not at 3 mo of age. Using in vivo breath-hold gated microcomputed tomography (micro-CT) in 8-mo-old Mfap4−/−mice, we found that the mean density of the lung parenchyma was decreased, and the low-attenuation area (LAA) was significantly increased by 14% compared with Mfap4+/+mice. Transmission electron microscopy (TEM) did not reveal differences in the organization of elastic fibers, and there was no difference in elastin content, but a borderline significant increase in elastin mRNA expression in 3-mo-old mice. Stereological analysis showed that alveolar surface density in relation to the lung parenchyma and total alveolar surface area inside of the lung were both significantly decreased in Mfap4−/−mice by 25 and 15%, respectively. The data did not support an essential role of MFAP4 in pulmonary elastic fiber organization or content but indicated increased turnover in young Mfap4−/−mice. However, Mfap4−/−mice developed a spontaneous loss of lung function, which was evident at 6 mo of age, and moderate air space enlargement, with emphysema-like changes.
Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model
Authors: Bai Ren-Yuan , Staedtke Verena , Wanjiku Teresia , Rudek Michelle A. , Joshi Avadhut , Gallia Gary L. , Riggins Gregory J.
Published: April 2015

Purpose: Mebendazole (MBZ), first used as an antiparasitic drug, shows preclinical efficacy in models of glioblastoma and medulloblastoma. Three different mebendazole polymorphs (A, B, and C) exist, and a detailed assessment of the brain penetration, pharmacokinetics, and antitumor properties of each individual mebendazole polymorph is necessary to improve mebendazole-based brain cancer therapy.

Experimental Design and Results: In this study, various marketed and custom-formulated mebendazole tablets were analyzed for their polymorph content by IR spectroscopy and subsequently tested in an orthotopic GL261 mouse glioma model for efficacy and tolerability. The pharmacokinetics and brain concentration of mebendazole polymorphs and two main metabolites were analyzed by LC/MS. We found that polymorph B and C both increased survival in a GL261 glioma model, as B exhibited greater toxicity. Polymorph A showed no benefit. Polymorph B and C both reached concentrations in the brain that exceeded the IC50 in GL261 cells 29-fold. In addition, polymorph C demonstrated an AUC0–24h brain-to-plasma (B/P) ratio of 0.82, whereas B showed higher plasma AUC and lower B/P ratio. In contrast, polymorph A presented markedly lower levels in the plasma and brain. Furthermore, the combination with elacridar was able to significantly improve the efficacy of polymorph C in GL261 glioma and D425 medulloblastoma models in mice.

Conclusions: Among mebendazole polymorphs, C reaches therapeutically effective concentrations in the brain tissue and tumor with fewer side effects, and is the better choice for brain cancer therapy. Its efficacy can be further enhanced by combination with elacridar. Clin Cancer Res; 21(15); 3462–70. ©2015 AACR.
Short- but Not Long-Term Melatonin Administration Reduces Central Levels of Brain-Derived Neurotrophic Factor in Rats with Inflammatory Pain
Authors: Laste Gabriela , Ripoll Rozisky Joanna , Caumo Wolnei , Lucena da Silva Torres Iraci
Published: April 2015

Objective: To evaluate the effect of short- and long-term administration of melatonin on central brain-derived neurotrophic factor (BDNF) levels in rats with acute and chronic inflammatory pain. Methods: The animals were allocated to one of two experiments: experiment 1 or experiment 2. In experiment 1, all animals were injected with complete Freund's adjuvant (CFA) to induce inflammation and were randomly allocated to receiving melatonin (60 mg/kg) or vehicle. Injections were administered 1 h after CFA and once daily for 2 more days (for a total of 3 days of melatonin administration). In experiment 2, fifteen days after CFA injection, the animals were treated with melatonin (50 mg/kg) or vehicle for 8 days. The animals were killed by decapitation 24 h after the last melatonin or vehicle administration, and an ELISA assay was performed to detect BDNF expression in the spinal cord, brainstem, and prefrontal cortex of the rats in both groups. Data were analyzed using Student's t test and the results are expressed as means ± SEM. Results: In the first experiment, the BDNF levels of the melatonin group were reduced in the prefrontal cortex (Student's t test, p = 0.01) and increased in the spinal cord (Student's t test, p = 0.04). In experiment 2, BDNF levels were similar in both groups for all structures (Student's t test, p > 0.00 for all). A two-way ANOVA reveled a significant effect of structures (p = 0.0001) but not of treatment (p > 0.05). The prefrontal cortex presented higher BDNF levels than other structures (ANOVA/Student-Newman-Keuls test, p = 0.0001). Considering the relationship between BDNF levels in all three structures, we found an effect of central nervous system structures (p = 0.01) and an interaction between treatment and structures (p = 0.04). Conclusion: The high spinal cord BDNF levels and the low prefrontal cortical BDNF levels observed in rats with acute CFA-induced inflammation following short-term melatonin administration may be related to the pain-modulating and neuroprotective effects of this protein. Long-term melatonin administration did not alter BDNF levels in chronic inflammation.
Safety and Efficacy of Fondaparinux for Prophylaxis of Venous Thromboembolism after Colorectal Cancer Resection: A Propensity Score Matched Analysis
Authors: Yamaoka Yusuke , Ikeda Masataka , Ikenaga Masakazu , Haraguchi Naotsugu , Miyake Masakazu , Sekimoto Mitsugu
Published: April 2015

Background/Aims: The aim of this study was to examine the safety and efficacy of fondaparinux (FPX) for venous thromboembolism (VTE) prophylaxis after colorectal cancer surgery. Methods: Records of 953 patients with colorectal cancer who underwent resection between 2006 and 2013 were reviewed. Patients were divided into two groups: the FPX group (n = 362), treated with subcutaneous FPX plus intermittent pneumatic compression (IPC) and the IPC group (n = 591), treated with IPC alone. The incidence of symptomatic VTE, major bleeding, minor bleeding, and other postoperative complications were compared using propensity score matching. Results: Symptomatic VTE occurred only in one patient (0.2%) in the IPC group. In the FPX group, the incidence of major and minor bleeding was 0.55% (2 of 362) and 9.4% (34 of 362), respectively. After propensity score matching, there were no differences between the two groups in the incidence of symptomatic VTE, major bleeding, and other common postoperative complications. Only the incidence of minor bleeding was significantly higher in the FPX group compared to the IPC group. Conclusion: FPX is potentially an effective form of VTE prophylaxis; it is safe in terms of both postoperative bleeding and other common complications after colorectal cancer surgery.
The Value of Rectal Cultures in Treatment of Sepsis Following Post-Transrectal Ultrasound-Guided Prostate Biopsy
Authors: Gottesman Tamar , Yossepowich Orit , Harari-Schwartz Orna , Tsivian Alexander , Idler Jay , Dan Michael
Published: April 2015

Background: Cases with sepsis after transrectal ultrasound-guided prostate biopsy (TRUSPB) were documented, with special focus on cultures and susceptibility of isolates. We also evaluated the contribution of concomitant rectal cultures to the treatment of selective cases. Materials and Methods: Patients with sepsis after TRUSPB were followed prospectively. Manifestations and risk factors for antimicrobial resistance were documented. Results of urine and blood cultures and antimicrobial susceptibility were recorded for all participating patients. In 40 patients, rectal swab cultures were obtained concomitantly. Results: Ninety-five patients were consecutively studied. Sepsis symptoms started showing up within 48 h after biopsy in 93% of patients. At least one of the cultures was positive in 72 patients. E. coli grew in 70 cases; isolates were highly resistant: 67% displayed multidrug-resistance. Rectal cultures grew E. coli in 38 cases. In patients with positive E. coli in rectum and in at least one additional culture (blood and/or urine), the antibiogram was identical in all cases but one. Eight cases had negative cultures. Conclusion: The prevalence of antimicrobial resistance among E. coli isolates from patients with TRUSPB sepsis was alarming. Susceptibilities of rectal E. coli isolates used for deescalation of initial empiric treatment in culture-negative TRUSPB sepsis can contribute to the reduction of broad-spectrum antibiotics exposure.
Monopolar versus Plasmakinetic™ Energy Effect on Prostatic Tissue Damage in Terms of PSA Levels: A Prospective Randomized Trial
Authors: Demir Aslan , Karadag Mert Ali , Cecen Kursat , Uslu Mehmet , Arslan Omer Erkam
Published: April 2015

Introduction: We investigated the monopolar and bipolar energy effects on prostate and correlated the results with the type of pathology, thus determining the relationship between tissue damage and the PSA level. Material and Methods: One hundred and twenty four patients underwent TURP and according to the energy source, 2 groups were designed as monopolar (Group 1) and bipolar energy (Group 2). Hemoglobin and free and total PSA were measured preoperatively and 6 hours postoperatively, and differences were calculated. The weight of resected tissue and operation time were also recorded. Two groups were also formed later according to the pathology as chronic prostatitis (CP) and BPH. The findings were analyzed. Results: There were no statistical differences between the groups in terms of age; prostate volumes; resected tissue; operation times; pre- and postoperative Hb, total-free PSA, IPSS, PVR, and quality of life scores; or postoperative maximum flow rates. Changes in total-free PSA (25.7 and 10.8 ng/dl for PSA; 13.2 and 5.76 ng/dl for free PSA for Groups 1 and 2, respectively) were significantly different between Groups 1 and 2. There was a statistical difference in total PSA between the groups among CP patients (28.18 and 11.73 ng/dl for Groups 1 and 2, respectively). But no statistical difference existed among BPH patients. The change in Hb differed based on pathological results. Conclusion: Bipolar TURP is less invasive than monopolar TURP on the basis of postoperative PSA levels. In addition, bleeding during TURP is affected not by the kind of energy, but by the pathology.
Avaliação cirúrgica e laboratorial da utilização de pericárdio homólogo em lesões por abrasão em serosa de cólon maior (flexura pélvica) de equinos
Authors: Leiria Paulo Ari Tietböhl , Ogassawara Aline , Salles Mariana , Maiorka Paulo , Zoppa André Luis Do Valle de
Published: April 2015

Aderências intra-abdominais são complicações de cirurgias de equinos que podem resultar em processos obstrutivos e comprometer a sobrevida dos animais. O presente estudo utilizou dez equinos hígidos, machos, sem raça definida (SRD), com quatro a 15 anos de idade e peso vivo situado entre 300 e 400 quilogramas (kg). Os animais foram submetidos à laparotomia esquerda em estação com o objetivo de serem induzidas aderências, testar a utilização intestinal de membrana biológica de pericárdio como prevenção e avaliar as diferentes alterações sistêmicas e do líquido abdominal. Após sedação e analgesia local, foi utilizado o acesso cirúrgico em grade, na flexura pélvica foi criada uma área de abrasão que, no Grupo 1, foi coberta por pericárdio homólogo e no Grupo 2, lavada com solução fisiológica. Após reposicionamento foi realizada a sutura muscular, de subcutâneo e pele. O pós-operatório constou de avaliações clínicas, citologia do líquido abdominal, hematologia e bioquímica sérica nos momentos M0- pré-operatório e M7, M14, M21 e M28 dias de pós-operatório. Nova laparotomia foi realizada aos 30 dias para verificar aderências, aspecto e biópsia intestinal. A técnica cirúrgica possibilitou menor trauma e campo operatório restrito. A evolução clínica foi satisfatória e cicatriz fibrosa foi identificada entre os planos musculares. Aderências não foram observadas. As avaliações laboratoriais demonstraram aumento de bilirrubinas, hematócrito, monócito, ureia sanguíneos e de proteína, densidade e leucócitos segmentados no líquido peritoneal. Conclui-se que a abrasão foi insuficiente para promover aderências fibrosas. O implante, sem comprovada eficácia, é viável e possível, por não resultar em diferenças laboratoriais significativas ou alterações deletérias.
Avaliação fitoquímica e potencial cicatrizante do extrato etanólico dos frutos de Jucá (Libidibia ferrea) em ratos Wistar
Authors: Kobayashi Yuri Teiichi da Silva , Almeida Vívian Tavares de , Bandeira Talita , Alcântara Bianca Nascimento de , Silva Andressa Santa Brígida da , Barbosa Wagner Luiz Ramos , Silva Paula Barbosa da , Monteiro Maria Vivina Barros , Almeida Milton Begeres de
Published: April 2015

Libidibia ferrea é uma planta muito utilizada popularmente para fins terapêuticos, inclusive para acelerar processos de cicatrização de feridas cutâneas. O presente trabalho pesquisou a composição química e avaliou o potencial cicatrizante do extrato etanólico dos frutos de L. ferrea (Mart. ex Tul.) em ratos. Foram utilizados 24 ratos Wistar divididos em quatro grupos. De todos os animais, foi retirado um fragmento de pele do dorso e cada grupo recebeu um tratamento diferente: solução de NaCl 0,9%, digliconato de clorexidina 1%, extrato etanólico dos frutos de Libidibia ferrea 12,5% e 50%. O processo de cicatrização foi avaliado macro e microscopicamente. Para a cicatrização de pele em ratos o extrato etanólico dos frutos de L. ferrea a 12,5% é significativamente mais eficiente do que a 50%. Saponinas, ácidos orgânicos, açúcares redutores, fenóis e taninos, sesquiterpenolactonas e outras lactonas, e antraquinonas foram encontrados no extrato.