bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclosporin A-sensitive cytotoxicity of flurbiprofen non-stereoselectively mediated by cytochrome P450 metabolism in three-dimensional cultured rat hepatocytes
Authors: Tanino Tadatoshi , Funakami Yoshinori , Nagai Noriaki , Kato Yoshihisa
Published: June 2015

Objectives

2-Arylpropionic acid (profen) drugs are associated with severe hepatotoxicity; however, risk factors are still poorly understood. Acyl-coenzyme A (acyl-CoA) thioesters of profen drugs play a more important role in the covalent binding to rat hepatocyte proteins than the respective acyl-glucuronides. Therefore, we examined whether acyl-glucuronides, acyl-CoA thioesters and oxidative metabolites of profen drugs stereoselectively participated in liver damage.

Methods

Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) leakage from three-dimensional cultured rat hepatocytes.

Key findings

LDH leakage was not induced by R-2-phenylpropionic acid and R-ibuprofen greatly forming acyl-CoA thioesters. S-Naproxen metabolized mainly by Uridine 5′-diphosphate (UDP)-glucuronosyl-transferase did not enhance LDH leakage. However, flurbiprofen (FLP) induced LDH leakage. A selective cytochrome P450 (CYP) 2C11 inhibitor suppressed 40–50% of the R-FLP and S-FLP-induced cytotoxicity. Borneol non-stereoselectively accelerated the FLP-induced cytotoxicity. The R-FLP-induced cytotoxicity decreased intracellular adenosine triphosphate (ATP) levels to 50% of untreated hepatocytes. An inhibitor of mitochondrial permeability transition pore, cyclosporin A (Cys A), rescued ATP levels and LDH leakage back to control levels.

Conclusion

The reactive acyl-CoA thioesters and acyl-glucuronides were not associated with liver damage, denying one of the leading hypotheses. CYP metabolism of FLP non-stereoselectively participated in Cys A-sensitive cytotoxicity, suggesting mitochondrial injury.
The Enhanced liver fibrosis score is associated with clinical outcomes and disease progression in patients with chronic liver disease
Authors: Irvine Katharine M. , Wockner Leesa F. , Shanker Mihir , Fagan Kevin J. , Horsfall Leigh U. , Fletcher Linda M. , Ungerer Jacobus P. J. , Pretorius Carel J. , Miller Gregory C. , Clouston Andrew D. , Lampe Guy , Powell Elizabeth E.
Published: June 2015

Background and Aims

Current tools for risk stratification of chronic liver disease subjects are limited. We aimed to determine whether the serum‐based ELF (Enhanced Liver Fibrosis) test predicted liver‐related clinical outcomes, or progression to advanced liver disease, and to compare the performance of ELF to liver biopsy and non‐invasive algorithms.

Methods

Three hundred patients with ELF scores assayed at the time of liver biopsy were followed up (median 6.1 years) for liver‐related clinical outcomes (n = 16) and clear evidence of progression to advanced fibrosis (n = 18), by review of medical records and clinical data.

Results

Fourteen of 73 (19.2%) patients with ELF score indicative of advanced fibrosis (≥9.8, the manufacturer's cut‐off) had a liver‐related clinical outcome, compared to only two of 227 (<1%) patients with ELF score <9.8. In contrast, the simple scores APRI and FIB‐4 would only have predicted subsequent decompensation in six and four patients respectively. A unit increase in ELF score was associated with a 2.53‐fold increased risk of a liver‐related event (adjusted for age and stage of fibrosis). In patients without advanced fibrosis on biopsy at recruitment, 55% (10/18) with an ELF score ≥9.8 showed clear evidence of progression to advanced fibrosis (after an average 6 years), whereas only 3.5% of those with an ELF score <9.8 (8/207) progressed (average 14 years). In these subjects, a unit increase in ELF score was associated with a 4.34‐fold increased risk of progression.

Conclusions

The ELF score is a valuable tool for risk stratification of patients with chronic liver disease.
To Be Free and Normal: Addiction, Governance, and the Therapeutics of Buprenorphine
Authors: Harris Shana
Published: June 2015

Methadone maintenance has dominated opiate addiction treatment in the United States for decades. Since 2002, opiate addiction has also been treated in general medical settings with a substance called buprenorphine. Based on interviews and participant observation conducted in northern California, this article analyzes how discourses of freedom and normalcy in patient and provider narratives reflect and affect experiences with this treatment modality. I discuss how buprenorphine treatment, in contrast to methadone maintenance, offers patients and providers a greater sense of autonomy and flexibility in how they receive and deliver treatment. It presents them with new obligations, responsibilities, and choices around care and conduct. It simultaneously perpetuates and shapes a desire to be “free” and “normal.” I argue that the therapeutics of buprenorphine govern patients and providers through this desire for freedom and normalcy. Buprenorphine is thus a technology of governmentality that extends neoliberal discourses and values and produces self‐governing subjects.
Identification of novel Xanthomonas euvesicatoria type III effector proteins by a machine‐learning approach
Authors: Teper Doron , Burstein David , Salomon Dor , Gershovitz Michael , Pupko Tal , Sessa Guido
Published: June 2015

The Gram‐negative bacterium Xanthomonas euvesicatoria (Xcv) is the causal agent of bacterial spot disease in pepper and tomato. Xcv pathogenicity depends on a type III secretion (T3S) system that delivers effector proteins into host cells to suppress plant immunity and promote disease. The pool of known Xcv effectors includes approximately 30 proteins, most identified in the 85‐10 strain by various experimental and computational techniques. To identify additional Xcv 85‐10 effectors, we applied a genome‐wide machine‐learning approach, in which all open reading frames (ORFs) were scored according to their propensity to encode effectors. Scoring was based on a large set of features, including genomic organization, taxonomic dispersion, hypersensitive response and pathogenicity (hrp)‐dependent expression, 5′ regulatory sequences, amino acid composition bias and GC content. Thirty‐six predicted effectors were tested for translocation into plant cells using the hypersensitive response (HR)‐inducing domain of AvrBs2 as a reporter. Seven proteins (XopAU, XopAV, XopAW, XopAP, XopAX, XopAK and XopAD) harboured a functional translocation signal and their translocation relied on the HrpF translocon, indicating that they are bona fide T3S effectors. Remarkably, four belong to novel effector families. Inactivation of the xopAP gene reduced the severity of disease symptoms in infected plants. A decrease in cell death and chlorophyll content was observed in pepper leaves inoculated with the xopAP mutant when compared with the wild‐type strain. However, populations of the xopAP mutant in infected leaves were similar in size to those of wild‐type bacteria, suggesting that the reduction in virulence was not caused by impaired bacterial growth.
A Moldovan ‘sheep'? – framing Moldovan passivity
Authors: Humă Roxana Adina
Published: June 2015

This article offers a different perspective for understanding Moldovan discourses of passivity by turning its attention to representations of national identity. Its main focus is a Moldovan ballad, Mioriţa, and the way in which it discursively both frames and legitimises inaction. It builds on the idea that Mioriţa is a central part of the way in which Moldovans represent their identity with respect to the writings of Ion Druţă, its main promoter in Moldovan society. More importantly, the ballad is conceptually linked to national characteristics such as lamentation and kindness, characteristics that can be summed up under the headline of ‘passivity’. Thus, drawing from constructivist and post‐structuralist approaches, the article stresses how these elements inform the Moldovan view of the self, its identity and even its representations of foreign affairs, framing the Moldovan lack of agency on a discursive level.
North Africa's Spain: peripheral national identities and the nation‐state as neo‐empire
Authors: Karell Daniel
Published: June 2015

When ethno‐cultural heterogeneity exists and thrives within a nation‐state, social tension and ethno‐nationalist sentiments are not considered surprising. Yet in many nation‐states, various native‐born communities have diverse and potentially contradictory national identities without the desire for self‐determination. In this paper, I explore the circumstances in which ethno‐culturally distinct, peripheral communities may develop variants of the dominant national identity – ensuring that they remain excluded from the national narrative – yet remain part of the nation‐state. To do so, I conduct a comparative analysis of the native‐born Muslim communities in Spain's two North African exclaves. I find that most Muslims are Spanish citizens yet understandings of ‘Spanish‐ness’ appear to vary between the exclaves. I use these findings to propose further steps for refining current conceptualisations of the nation‐state, in an effort to better understand cases in which variations in the dominant national identity exist, but without ethno‐nationalist sentiments.
The role of evolutionarily conserved germ‐line DH sequence in B‐1 cell development and natural antibody production
Authors: Vale Andre M. , Nobrega Alberto , Schroeder Harry W.
Published: June 2015

Because of N addition and variation in the site of VDJ joining, the third complementarity‐determining region of the heavy chain (CDR‐H3) is the most diverse component of the initial immunoglobulin antigen‐binding site repertoire. A large component of the peritoneal cavity B‐1 cell component is the product of fetal and perinatal B cell production. The CDR‐H3 repertoire is thus depleted of N addition, which increases dependency on germ‐line sequence. Cross‐species comparisons have shown that DH gene sequence demonstrates conservation of amino acid preferences by reading frame. Preference for reading frame 1, which is enriched for tyrosine and glycine, is created both by rearrangement patterns and by pre‐BCR and BCR selection. In previous studies, we have assessed the role of conserved DH sequence by examining peritoneal cavity B‐1 cell numbers and antibody production in BALB/c mice with altered DH loci. Here, we review our finding that changes in the constraints normally imposed by germ‐line–encoded amino acids within the CDR‐H3 repertoire profoundly affect B‐1 cell development, especially B‐1a cells, and thus natural antibody immunity. Our studies suggest that both natural and somatic selection operate to create a restricted B‐1 cell CDR‐H3 repertoire.
Stochastic volatility models for theBrent oil futures market: forecasting and extracting conditional moments
Authors: Solibakke Per Bjarte
Published: June 2015

This paper builds and implements a multifactor stochastic volatility model for the latent (and observable) volatility from the front month future contracts at theIntercontinentalCommodityExchange (ICE),London, applyingBayesianMarkov chainMonteCarlo simulation methodologies for estimation, inference and model adequacy assessment. Stochastic volatility is the main way time‐varying volatility is modelled in financial markets. An appropriate scientific model description, specifying volatility as having its own stochastic process, broadens the applications into derivative pricing purposes, risk assessment and asset allocation and portfolio management. From an estimated optimal and appropriate stochastic volatility model, the paper reports risk and portfolio measures, extracts conditional one‐step‐ahead moments (smoothing), forecasts one‐step‐ahead conditional volatility (filtering), evaluates shocks from conditional variance functions, analyses multistep‐ahead dynamics and calculates conditional persistence measures. (Exotic) option prices can be calculated using the re‐projected conditional volatility. Observed market prices and implied volatilities establish market risk premiums. The analysis adds insight and enables forecasts to be made, building up the methodology for developing valid scientific commodity market models.
Caval agenesis in the pediatric liver donor
Authors: Khorsandi Shirin Elizabeth , Ruiz Edo Neus , Vilca‐Melendez Hector , Heaton Nigel
Published: June 2015

The following is the first report of a pediatric organ donor with caval agenesis and the subsequent use of this liver for transplantation. Caval embryology and potential implications of utilizing a donor liver with caval agenesis are reviewed.
Hepatitis E Virus of Subtype 3a in a Pig Farm, South‐Eastern France
Authors: Colson P. , Saint‐Jacques P. , Ferretti A. , Davoust B.
Published: June 2015

Hepatitis E virus (HEV) has emerged during the past decade as a causative agent of autochthonous hepatitis and is a clinical concern in Western developed countries. It has been increasingly recognized that pigs are a major reservoir of HEV of genotypes 3 and 4 worldwide and pig‐derived food items represent a potential source of infections by these viruses in humans. Hepatitis E virus RNA testing was performed here on faeces from rectal swabs sampled in 2012 from 50 3‐month‐old farm pigs from the same farm located in south‐eastern France than in a previous work conducted in 2007. Pig HEV sequences corresponding to genomic fragments of ORF2 and ORF1 genes were obtained after RT‐PCR amplification with in‐house protocols. Hepatitis E virus genotype was determined by phylogenetic analysis. Prevalence was similar to that determined 5 years earlier (68% versus 62%). Two robust phylogenetic clusters of HEV subtypes 3a and 3f were identified, and these sequences obtained in 2012 largely differ compared with those obtained in 2007. Notably, HEV sequences obtained in 2012 from a majority (62%) of the infected pigs belonged to subtype 3a, which was not previously described in France, including not being found in any of humans, pigs or wild boars. Further studies are needed to assess the circulation of HEV‐3a in pigs and humans in this country. In addition, along with previous findings, this study supports the need for increased information to the public on the risk of HEV infection through contacts with pigs or consumption of pig‐derived products in France.
The calcium‐sensing receptor: one of a kind
Authors: Lopez‐Fernandez Irene , Schepelmann Martin , Brennan Sarah C. , Yarova Polina L. , Riccardi Daniela
Published: June 2015

New Findings

What is the topic of this review?

The extracellular calcium‐sensing receptor, CaSR, ensures whole‐body Ca2+ homeostasis. Recent developments highlight the importance of the CaSR beyond mineral ion metabolism. This review focuses on novel roles and the use of CaSR‐based therapeutics within the vasculature, the gut and the lung.

What advances does it highlight?

The ability of the CaSR to act as a multimodal chemosensor has led to the identification of signalling pathways that are ligand and cellular context dependent. Development of cell‐specific CaSR modulators is now being harnessed to rescue aberrant CaSR function outside the extracellular Ca2+ homeostatic system.

The extracellular calcium‐sensing receptor, CaSR, is the first G protein‐coupled receptor found to have an inorganic ion, calcium (Ca2+), as its physiological agonist. It is highly expressed in all organs involved in the regulation of mineral ion metabolism, namely the parathyroid gland, the kidney and bone. The CaSR is the master controller of extracellular Ca2+ concentration, as highlighted by the evidence that both inherited and acquired mutations in the CASR gene cause disturbances in mineral ion metabolism. CaSR positive allosteric modulators have been successfully employed in the clinic for over a decade to restore CaSR function, which is reduced in hyperparathyroidism secondary to kidney failure, while negative allosteric modulators are currently being tested in patients with hypocalcaemia with hypercalciuria due to gain‐of‐function CASR mutations. In addition to its expression within the bone–kidney–parathyroid axis, the CaSR can be found in other tissues, including but not limited to the gut, the vasculature and the lung. Here, the CaSR acts as a chemosensor, integrating signals deriving from nutrient availability, salinity, acidification and the presence of ubiquitous polyamines. Knowledge of what these stimuli are and of the cell‐specific signalling responses they evoke is crucial to our understanding of the non‐calciotropic roles of the CaSR in physiology and how these are affected in disease states.
Influence of blood flow occlusion on the development of peripheral and central fatigue during small muscle mass handgrip exercise
Authors: Broxterman R. M. , Craig J. C. , Smith J. R. , Wilcox S. L. , Jia C. , Warren S. , Barstow T. J.
Published: June 2015

Key points

Critical power represents an important threshold for neuromuscular fatigue development and may, therefore, dictate intensities for which exercise tolerance is determined by the magnitude of fatigue accrued.

Peripheral fatigue appears to be constant across O2delivery conditions for large muscle mass exercise, but this consistency is equivocal for smaller muscle mass exercise.

We sought to determine the influence of blood flow occlusion during handgrip exercise on neuromuscular fatigue development and to examine the relationship between neuromuscular fatigue development andW ′.

Blood flow occlusion influenced the development of both peripheral and central fatigue, thus providing further evidence that the magnitude of peripheral fatigue is not constant across O2delivery conditions for small muscle mass exercise.

W ′ appears to be related to the magnitude of fatigue accrued during exercise, which may explain the reported consistency of intramuscular metabolic perturbations and work performed for severe‐intensity exercise.

The influence of the muscle metabolic milieu on peripheral and central fatigue is currently unclear. Moreover, the relationships between peripheral and central fatigue and the curvature constant (W ′) have not been investigated. Six men (age: 25 ± 4 years, body mass: 82 ± 10 kg, height: 179 ± 4 cm) completed four constant power handgrip tests to exhaustion under conditions of control exercise (Con), blood flow occlusion exercise (Occ), Con with 5 min post‐exercise blood flow occlusion (Con + Occ), and Occ with 5 min post‐exercise blood flow occlusion (Occ + Occ). Neuromuscular fatigue measurements andW ′ were obtained for each subject. Each trial resulted in significant peripheral and central fatigue. Significantly greater peripheral (79.7 ± 5.1% vs. 22.7 ± 6.0%) and central (42.6 ± 3.9% vs. 4.9 ± 2.0%) fatigue occurred for Occ than for Con. In addition, significantly greater peripheral (83.0 ± 4.2% vs. 69.0 ± 6.2%) and central (65.5 ± 14.6% vs. 18.6 ± 4.1%) fatigue occurred for Occ + Occ than for Con + Occ.W ′ was significantly related to the magnitude of global (r = 0.91) and peripheral (r = 0.83) fatigue. The current findings demonstrate that blood flow occlusion exacerbated the development of both peripheral and central fatigue and that post‐exercise blood flow occlusion prevented the recovery of both peripheral and central fatigue. Moreover, the current findings suggest thatW ′ may be determined by the magnitude of fatigue accrued during exercise.
Increased excitability of medium‐sized dorsal root ganglion neurons by prolonged interleukin‐1β exposure is K+ channel dependent and reversible
Authors: Stemkowski Patrick L. , Noh Myung‐chul , Chen Yishen , Smith Peter A.
Published: June 2015

Key points

Neuropathic pain resulting from peripheral nerve injury is initiated and maintained by persistent ectopic activity in primary afferent neurons.

Sciatic nerve injury increases the excitability of medium‐sized dorsal root ganglion (DRG) neurons. Levels of the inflammatory cytokine interleukin 1β (IL‐1β) increase and peak after 7 days.

Five to six days of exposure of medium sized DRG neurons to 100 pm IL‐1β promotes persistent increases in excitability which abate within 3–4 days of cytokine removal. This is associated with a profound attenuation of K+ channel currents but only modest increases in function of cyclic nucleotide‐sensitive hyperpolarization‐activated channels (HCNs) and of voltage‐gated Na+ and Ca2+ channel currents.

It is unlikely, therefore, that direct interaction of IL‐1β with DRG neurons is capable of initiating an enduring phenotypic shift in their electrophysiological properties that follows sciatic nerve injury.

The findings also underline the importance of K+ channel modulation in the actions of inflammatory mediators on peripheral neurons.

Chronic constriction injury of rat sciatic nerve promotes signs of neuropathic pain. This is associated with an increase in the level of interleukin 1β (IL‐1β) in primary afferents that peaks at 7 days. This initial cytokine exposure has been proposed to trigger an enduring alteration in neuronal phenotype that underlies chronic hyper‐excitability in sensory nerves, which initiates and maintains chronic neuropathic pain. We have shown previously that 5–6 days of exposure of rat dorsal root ganglia (DRGs) to 100 pm IL‐1β increases the excitability of medium‐sized neurons. We have now found using whole‐cell recording that this increased excitability reverts to control levels within 3–4 days of cytokine removal. The effects of IL‐1β were dominated by changes in K+ currents. Thus, the amplitudes of A‐current, delayed rectifier and Ca2+‐sensitive K+ currents were reduced by ∼68%, ∼64% and ∼36%, respectively. Effects of IL‐1β on other cation currents were modest by comparison. There was thus a slight decrease in availability of high voltage‐activated Ca2+ channel current, a small increase in rates of activation of hyperpolarization‐activated cyclic nucleotide‐gated channel current (IH), and a shift in the voltage dependence of activation of tetrodotoxin‐sensitive sodium current (TTX‐S INa) to more negative potentials. It is unlikely, therefore, that direct interaction of IL‐1β with DRG neurons initiates an enduring phenotypic shift in their electrophysiological properties following sciatic nerve injury. Persistent increases in primary afferent excitability following nerve injury may instead depend on altered K+ channel function and on the continued presence of slightly elevated levels IL‐1β and other cytokines.
Peeling Silicene From Model Silver Substrates in Molecular Dynamics Simulations
Authors: Qin Zhao , Xu Zhiping , Buehler Markus J.
Published: June 2015

Silicene is a two-dimensional (2D) allotrope of silicon with a rippled or corrugated honeycomb structure in analogy to graphene. Its semiconducting properties make it attractive for developing future nano-electronic devices. However, it has been challenging to obtain its naked form by using a mechanical exfoliation method as what has been applied to graphene. Here, we use fully atomistic simulations with an effective potential for the silver substrate derived from first-principles calculations to investigate possible ways of peeling silicene solely by mechanical force. We find that the peeling direction is critical for exfoliating silicene and the peeling at a 45 deg angle with the substrate is the most efficient one to detach silicene. Our study could help to understand the mechanics of silicene on substrates and guide the technology of isolation of silicene from the substrate on which it is synthesized.
A data‐mining framework for large scale analysis of dose‐outcome relationships in a database of irradiated head and neck cancer patients
Authors: Robertson Scott P. , Quon Harry , Kiess Ana P. , Moore Joseph A. , Yang Wuyang , Cheng Zhi , Afonso Sarah , Allen Mysha , Richardson Marian , Choflet Amanda , Sharabi Andrew , McNutt Todd R.
Published: June 2015

Purpose:

To develop a hypothesis‐generating framework for automatic extraction of dose‐outcome relationships from an in‐house, analytic oncology database.

Methods:

Dose–volume histograms (DVH) and clinical outcomes have been routinely stored to the authors’ database for 684 head and neck cancer patients treated from 2007 to 2014. Database queries were developed to extract outcomes that had been assessed for at least 100 patients, as well as DVH curves for organs‐at‐risk (OAR) that were contoured for at least 100 patients. DVH curves for paired OAR (e.g., left and right parotids) were automatically combined and included as additional structures for analysis. For each OAR‐outcome combination, only patients with both OAR and outcome records were analyzed. DVH dose points, , at a given normalized volume threshold Vt were stratified into two groups based on severity of toxicity outcomes after treatment completion. The probability of an outcome was modeled at each Vt = [0%, 1%, …, 100%] by logistic regression. Notable OAR‐outcome combinations were defined as having statistically significant regression parameters (p < 0.05) and an odds ratio of at least 1.05 (5% increase in odds per Gy).

Results:

A total of 57 individual and combined structures and 97 outcomes were queried from the database. Of all possible OAR‐outcome combinations, 17% resulted in significant logistic regression fits (p < 0.05) having an odds ratio of at least 1.05. Further manual inspection revealed a number of reasonable models based on either reported literature or proximity between neighboring OARs. The data‐mining algorithm confirmed the following well‐known OAR‐dose/outcome relationships: dysphagia/larynx, voice changes/larynx, esophagitis/esophagus, xerostomia/parotid glands, and mucositis/oral mucosa. Several surrogate relationships, defined as OAR not directly attributed to an outcome, were also observed, including esophagitis/larynx, mucositis/mandible, and xerostomia/mandible.

Conclusions:

Prospective collection of clinical data has enabled large‐scale analysis of dose‐outcome relationships. The current data‐mining framework revealed both known and novel dosimetric and clinical relationships, underscoring the potential utility of this analytic approach in hypothesis generation. Multivariate models and advanced, 3D dosimetric features may be necessary to further evaluate the complex relationship between neighboring OAR and observed outcomes.
Laser-assisted guiding of electric discharges around objects
Authors: Clerici Matteo , Hu Yi , Lassonde Philippe , Milián Carles , Couairon Arnaud , Christodoulides Demetrios N. , Chen Zhigang , Razzari Luca , Vidal François , Légaré François , Faccio Daniele , Morandotti Roberto
Published: June 2015

We demonstrate that laser beam shaping can be used to precisely control an electric discharge trail, avoiding or bypassing obstacles in the line of sight.
Correlation between GyrA Substitutions and Ofloxacin, Levofloxacin, and Moxifloxacin Cross-Resistance in Mycobacterium tuberculosis
Authors: Willby Melisa , Sikes R. David , Malik Seidu , Metchock Beverly , Posey James E.
Published: June 2015

The newer fluoroquinolones moxifloxacin (MXF) and levofloxacin (LVX) are becoming more common components of tuberculosis (TB) treatment regimens. However, the critical concentrations for testing susceptibility of
Mycobacterium tuberculosis
to MXF and LVX are not yet well established. Additionally, the degree of cross-resistance between ofloxacin (OFX) and these newer fluoroquinolones has not been thoroughly investigated. In this study, the MICs for MXF and LVX and susceptibility to the critical concentration of OFX were determined using the agar proportion method for 133 isolates of
M. tuberculosis
. Most isolates resistant to OFX had LVX MICs of >1 μg/ml and MXF MICs of >0.5 μg/ml. The presence of mutations within the
gyrA
quinolone resistance-determining regions (QRDR) correlated well with increased MICs, and the level of LVX and MXF resistance was dependent on the specific
gyrA
mutation present. Substitutions Ala90Val, Asp94Ala, and Asp94Tyr resulted in low-level MXF resistance (MICs were >0.5 but ≤2 μg/ml), while other mutations led to MXF MICs of >2 μg/ml. Based on these results, a critical concentration of 1 μg/ml is suggested for LVX and 0.5 μg/ml for MXF drug susceptibility testing by agar proportion with reflex testing for MXF at 2 μg/ml.
Exploration of the Pharmacokinetic-Pharmacodynamic Relationships for Fosfomycin Efficacy Using an
In Vitro
Infection Model
Authors: VanScoy Brian D. , McCauley Jennifer , Ellis-Grosse Evelyn J. , Okusanya Olanrewaju O. , Bhavnani Sujata M. , Forrest Alan , Ambrose Paul G.
Published: June 2015

Fosfomycin, a phosphonic class antibiotic with a broad spectrum of antibacterial activity, has been used outside the United States since the early 1970s for the treatment of a variety of infections. In the United States, an oral (tromethamine salt) formulation is used for uncomplicated urinary tract infections. Recently, there has been interest in the use of an intravenous solution (ZTI-01) for the treatment of a broad range of infections associated with multidrug-resistant bacteria. In this era of multidrug-resistant bacteria with few treatment options, it is critical to understand the pharmacokinetic-pharmacodynamic (PK-PD) determinants for fosfomycin efficacy. Since such data are limited, a one-compartment
in vitro
infection model was used to determine the PK-PD index associated with efficacy and the magnitude of this measure necessary for various levels of effect. One challenge isolate (
Escherichia coli
ATCC 25922, for which the fosfomycin agar MIC is 0.5 mg/liter and the broth microdilution MIC is 1 mg/liter) was evaluated in the dose fractionation studies, and two additional clinical
E. coli
isolates were evaluated in the dose-ranging studies. Mutation frequency studies indicated the presence of an inherently fosfomycin resistant
E. coli
subpopulation (agar MIC = 32 to 64 mg/liter) within the standard starting inoculum of a susceptibility test. Due to the presence of this resistant subpopulation, we identified the percentage of the dosing interval that drug concentrations were above the inherent resistance inhibitory concentration found at baseline to be the PK-PD index associated with efficacy (
r
2
= 0.777). The magnitudes of this PK-PD index associated with net bacterial stasis and 1- and 2-log
10
CFU/ml reductions from baseline at 24 h were 11.9, 20.9, and 32.8, respectively. These data provide useful information for modernizing and optimizing ZTI-01 dosing regimens for further study.
Catechol Siderophore Transport by Vibrio cholerae
Authors: Wyckoff Elizabeth E. , Allred Benjamin E. , Raymond Kenneth N. , Payne Shelley M.
Published: June 2015

Siderophores, small iron-binding molecules secreted by many microbial species, capture environmental iron for transport back into the cell.
Vibrio cholerae
synthesizes and uses the catechol siderophore vibriobactin and also uses siderophores secreted by other species, including enterobactin produced by
Escherichia coli
.
E. coli
secretes both canonical cyclic enterobactin and linear enterobactin derivatives likely derived from its cleavage by the enterobactin esterase Fes. We show here that
V. cholerae
does not use cyclic enterobactin but instead uses its linear derivatives.
V. cholerae
lacked both a receptor for efficient transport of cyclic enterobactin and enterobactin esterase to promote removal of iron from the ferrisiderophore complex. To further characterize the transport of catechol siderophores, we show that the linear enterobactin derivatives were transported into
V. cholerae
by either of the catechol siderophore receptors IrgA and VctA, which also transported the synthetic siderophore MECAM [1,3,5-
N
,
N
′,
N
″-tris-(2,3-dihydroxybenzoyl)-triaminomethylbenzene]. Vibriobactin is transported via the additional catechol siderophore receptor ViuA, while the
Vibrio fluvialis
siderophore fluvibactin was transported by all three catechol receptors. ViuB, a putative
V. cholerae
siderophore-interacting protein (SIP), functionally substituted for the
E. coli
ferric reductase YqjH, which promotes the release of iron from the siderophore in the bacterial cytoplasm. In
V. cholerae
, ViuB was required for the use of vibriobactin but was not required for the use of MECAM, fluvibactin, ferrichrome, or the linear derivatives of enterobactin. This suggests the presence of another protein in
V. cholerae
capable of promoting the release of iron from these siderophores.

IMPORTANCE
Vibrio cholerae
is a major human pathogen and also serves as a model for the
Vibrionaceae
, which include other serious human and fish pathogens. The ability of these species to persist and acquire essential nutrients, including iron, in the environment is epidemiologically important but not well understood. In this work, we characterize the ability of
V. cholerae
to acquire iron by using siderophores produced by other organisms. We resolve confusion in the literature regarding its ability to use the
Escherichia coli
siderophore enterobactin and identify the receptor and TonB system used for the transport of several siderophores. The use of some siderophores did not require the ferric reductase ViuB, suggesting that an uncharacterized ferric reductase is present in
V. cholerae
.
Optimal management of polycystic ovary syndrome in adolescence
Authors: Hecht Baldauff Natalie , Arslanian Silva
Published: June 2015

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of reproduction and metabolism, which emerges at puberty, and is characterised by a wide spectrum of signs and symptoms of hyperandrogenism, anovulation, hyperinsulinaemia and associated comorbidities. Unlike adult PCOS, there are no agreed-upon diagnostic criteria for adolescent PCOS, but hyperandrogenaemia remains the sine qua non for its diagnosis. Many adolescent girls with PCOS are overweight/obese, and have a heightened risk for comorbidities such as dysglycaemia, dyslipidaemia, fatty liver disease, sleep apnoea and cardiovascular disease. Therefore, early and accurate diagnosis is essential for implementation of appropriate treatment and management. Available treatments include lifestyle modifications, hormonal contraceptives and insulin sensitisers. However, there are limited data on the best treatment modalities in adolescents. The objective of this review is to describe the clinical manifestations of PCOS in adolescents and the appropriate diagnostic work-up. The optimal treatment modalities based on a review of the available adult and adolescent literature will be discussed.
β-lactam-associated eosinophilic colitis
Authors: Mogilevski Tamara , Nickless David , Hume Sam
Published: June 2015

A 42-year-old man with a history of childhood asthma presented with a 2-week history of watery diarrhoea and marked peripheral eosinophilia in the setting of recent use of cephalexin. His colonoscopy revealed patchy colitis. Biopsies were consistent with eosinophilic colitis. Two months later he received a course of amoxicillin resulting in recurrence of peripheral eosinophilia. Given the time-frame of β-lactam administration to symptom onset and elimination of all other precipitating causes, he was diagnosed with β-lactam-associated eosinophilic colitis. The patient’s symptoms resolved and peripheral eosinophil count decreased with no specific treatment. Eosinophilic colitis is a rare heterogeneous condition, the pathogenesis of which is likely to be an interplay between environmental and genetic factors. It can be secondary to a helminthic infection or a drug reaction and has been associated with ulcerative colitis. If secondary causes of eosinophilic colitis have been excluded, the mainstay of treatment is with corticosteroids.
Intra-DIC (distal intracranial catheter) deployment of the Pipeline embolization device: a novel rescue strategy for failed device expansion
Authors: Lin Li-Mei , Colby Geoffrey P , Jiang Bowen , Nundkumar Neelesh , Huang Judy , Tamargo Rafael J , Coon Alexander L
Published: June 2015

Background

The Pipeline embolization device (PED) is a braided flow diverter that requires a combination of meticulous maneuvers to assure proper device opening and expansion. Mechanical, anatomical, or technical challenges can result in a partially deployed PED with failed expansion.

Objective

To present a new alternative method of PED deployment using the Navien distal intracranial catheter (DIC) as a salvage maneuver for cases where PED opening fails with standard techniques.

Methods

We retrospectively reviewed a prospective, single-center aneurysm database to identify all patients who underwent endovascular treatment of intracranial aneurysms using the PED with the Navien distal intracranial catheter access platform. Cases requiring PED deployment within the Navien catheter were reviewed. Data was collected for patient demographics, aneurysm characteristics, and technical details of the interventional procedure.

Results

Eleven PED neurointerventions requiring intra-Navien PED deployment to fully open the PED were identified. Mean patient age was 55.5±9.9 years (range 37–76 years). Mean aneurysm size was 12.5 mm±4.9 mm (range 2–42 mm). All aneurysms were located in the anterior circulation (anterior cerebral artery, n=1; supraclinoid, n=1; ophthalmic/paraophthalmic, n=6; cavernous, n=3; petrocervical, n=1). Mean fluoroscopy time was 67.1±20.5 min. The intra-Navien technique was used to open the proximal PED (n=7) and the mid-portion (n=4). Post-processing of the PED with a balloon was used in six cases.

Conclusions

When a partially deployed PED remains constrained despite exhaustion of standard maneuvers to facilitate opening, the technique of intra-Navien PED deployment is a valuable rescue strategy. This new alternative method of PED deployment can be used to open a stretched device with successful completion of the PED implantation.
INNOVATION MANAGEMENT PRACTICES IN PRODUCTION-INTENSIVE SERVICE FIRMS
Authors: AAS TOR HELGE , BREUNIG KARL JOACHIM , HYDLE KATJA MARIA , PEDERSEN PER EGIL
Published: June 2015

This paper posits that innovation management practices are contingent upon the type of industry, and examines the innovation management practices in a distinctive set of service firms: production-intensive service firms. Production-intensive services are standardised services produced at a large scale. These services have received little attention from prior comprehensive qualitative innovation management practices research. The examination in this paper is based on in-depth interviews with 21 key-employees in five large Scandinavian production-intensive service firms. The results revealed a number of innovation management practices specific to production-intensive service firms in the four dimensions of strategy and culture, front end of innovation and portfolio management, development process, as well as intellectual and organisational resources. The findings expose that production-intensive service firms are less likely to have an explicit innovation strategy and they are unlikely to measure the strategic impact of innovation activities. Furthermore, the innovation processes in production-intensive service firms tend to be flexible, although formal descriptions exist. The findings extend knowledge on innovation management practices research and provide useful lessons and implications for managers who seek to develop new production-intensive services. The findings also demonstrate that there is a need to acknowledge a contingent view of innovation management practices that are receptive to the type of context the innovation occur in.
MOTIVATION FATIGUE AS A THREAT TO INNOVATION: BYPASSING THE PRODUCTIVITY DILEMMA IN R&D BY CYCLIC PRODUCTION
Authors: MATTSSON JAN , HELMERSSON HELGE , STETLER KATARINA
Published: June 2015

What do employees need in order to be innovative? In this paper, we explored how employees with different lengths of tenure within the research and development (R&D) department of a company in the automotive industry answer this question. We found that the needs vary depending on the length of the employee’s tenure. New employees view innovation as an organisational work issue and employees with longer tenure seek the support of management in changing the work situation themselves in a way that will enhance innovation. In contrast, employees who have been with the company over 10 years show signs of resignation and blame management for the problems around innovation that they experience. However, one opinion that all groups of different tenures share is that there is not enough time to engage in innovation activities. To address some of these different needs, we suggest viewing productivity as a cycle of two outcomes: product information and knowledge creation. When one is low, the other peaks, and vice versa. This view of dual value creation in R&D is one way to bypass the productivity dilemma.
Cuplength estimates in Morse cohomology
Authors: Albers Peter , Hein Doris
Published: June 2015

The main goal of this paper is to give a unified treatment to many known cuplength estimates with a view towards Floer theory. As the base case, we prove that for [Formula: see text]-perturbations of a function which is Morse–Bott along a closed submanifold, the number of critical points is bounded below in terms of the cuplength of that critical submanifold. As we work with rather general assumptions the proof also applies in a variety of Floer settings. For example, this proves lower bounds (some of which were known) for the number of fixed points of Hamiltonian diffeomorphisms, Hamiltonian chords for Lagrangian submanifolds, translated points of contactomorphisms, and solutions to a Dirac-type equation.
Active Learning Algorithms for the Classification of Hyperspectral Sea Ice Images
Authors: Han Yanling , Ren Jing , Hong Zhonghua , Zhang Yun , Zhang Long , Meng Wanting , Gu Qiming
Published: June 2015

Sea ice is one of the most critical marine disasters, especially in the polar and high latitude regions. Hyperspectral image is suitable for monitoring the sea ice, which contains continuous spectrum information and has better ability of target recognition. The principal bottleneck for the classification of hyperspectral image is a large number of labeled training samples required. However, the collection of labeled samples is time consuming and costly. In order to solve this problem, we apply the active learning (AL) algorithm to hyperspectral sea ice detection which can select the most informative samples. Moreover, we propose a novel investigated AL algorithm based on the evaluation of two criteria: uncertainty and diversity. The uncertainty criterion is based on the difference between the probabilities of the two classes having the highest estimated probabilities, while the diversity criterion is based on a kernelk-means clustering technology. In the experiments of Baffin Bay in northwest Greenland on April 12, 2014, our proposed AL algorithm achieves the highest classification accuracy of 89.327% compared with other AL algorithms and random sampling, while achieving the same classification accuracy, the proposed AL algorithm needs less labeling cost.
Comparative Study of Crosstalk Reduction Techniques in RF Printed Circuit Board Using FDTD Method
Authors: Packianathan Rajeswari , Srinivasan Raju
Published: June 2015

Miniaturization of the feature size in modern electronic circuits results from placing interconnections in close proximity with a high packing density. As a result, coupling between the adjacent lines has increased significantly, causing crosstalk to become an important concern in high-performance circuit design. In certain applications, microstriplines may be used in printed circuit boards for propagating high-speed signals, rather than striplines. Here, the electromagnetic coupling effects are analyzed for various microstrip transmission line structures, namely, microstriplines with a guard trace, double stub microstriplines, and parallel serpentine microstriplines using the finite-difference time-domain method. The numerical results are compared with simulation results, where the variants are simulated using an Ansoft high-frequency structure simulator. The analysis and simulation results are experimentally validated by fabricating a prototype and establishing a good correspondence between them. Numerical results are compared with simulation and experimental results, showing that double stub microstriplines reduce the far end crosstalk by 7 dB and increase the near end crosstalk by about 2 dB compared with the parallel microstriplines. Parallel serpentine microstriplines reduce the far end crosstalk by more than 10 dB and also reduce more than 15 mV of peak far end crosstalk voltage, compared with parallel microstriplines.
Structured Pd/γ-Al2O3 Prepared by Washcoated Deposition on a Ceramic Honeycomb for Compressed Natural Gas Applications
Authors: Adamowska Małgorzata , Da Costa Patrick
Published: June 2015

The preparation of a coating procedure was studied, from the washcoating with γ-alumina to the deposition of palladium by excess solvent or incipient wetness impregnation.
The powder and the washcoat layers were studied by different characterisation techniques such as SEM, BET surface area, and XRD. Vibration-resistance and heat-resistance were also evaluated. It was shown that the alumina layer is quite well deposited on the channel walls (SEM images). However, a detachment of the washcoat layer was observed after ultrasound treatment. It was proved that the monolith Pd impregnation method by incipient wetness impregnation is more efficient. The presence of palladium was confirmed using HRTEM, the palladium was present under the Pd (II) oxidation state, and the size of PdO particles varies between 2.5 and 3.1 nm. The catalytic properties of the monolith catalyst were carried out using temperature programmed surface reaction (TPSR). The efficiency of the procedure of the monolith catalyst preparation was confirmed by comparing the activity of the prepared catalyst with the one of a model catalyst.
Deep Sclerectomy with Goniosynechiolysis Ab Interno for Chronic Glaucoma Associated with Peripheral Anterior Synechiae
Authors: Mirshahi Alireza , Raak Peter , Ponto Katharina , Stoffelns Bernhard , Lorenz Katrin , Scharioth Gábor B.
Published: June 2015

Purpose. To report one-year results of phacoemulsification combined with deep sclerectomy and goniosynechiolysis ab interno for chronic glaucoma associated with peripheral anterior synechiae (PAS).Methods. We retrospectively analyzed medical charts of 16 patients (20 eyes) treated by one-site combined phacoemulsification and deep sclerectomy with goniosynechiolysis ab interno. PAS were transected by a spatula introduced into the anterior chamber through a paracentesis. To account for the correlation of right and left eyes a linear mixed model with unstructured covariance structure was calculated.Results. The mean preoperative intraocular pressure (IOP) was20.3±5.2 mmHg with2.4±1.0medications. One year postoperatively, the mean IOP was15.3±3.3 mmHg (P=0.004, pairedt-test) with0.6±1.0medications. A postoperative IOP of ≤21 mmHg without medication was achieved in 17 of 19 eyes (89.5%) and in 12/19 eyes (63.2%) at 3 and 12 months after surgery, respectively. In the remaining eyes (10.5% at 3 months and 36.8% at 12 months), additional medication led to an IOP ≤21 mmHg or the target pressure. No case required further glaucoma surgery. In one eye, conversion of the surgery to trabeculectomy was necessary due to Descemet’s window rupture.Conclusions. With goniosynechiolysis ab interno, effective and safe nonpenetrating glaucoma surgery is possible in presence of PAS.