bluuebunny/crossref_metadata_2025 huggingface dataset:
Permissivity of Dipeptidyl Peptidase 4 Orthologs to Middle East Respiratory Syndrome Coronavirus Is Governed by Glycosylation and Other Complex Determinants
Authors: Peck Kayla M. , Scobey Trevor , Swanstrom Jesica , Jensen Kara L. , Burch Christina L. , Baric Ralph S. , Heise Mark T.
Published: July 2017

Middle East respiratory syndrome coronavirus (MERS-CoV) utilizes dipeptidyl peptidase 4 (DPP4) as an entry receptor. While bat, camel, and human DPP4 support MERS-CoV infection, several DPP4 orthologs, including mouse, ferret, hamster, and guinea pig DPP4, do not. Previous work revealed that glycosylation of mouse DPP4 plays a role in blocking MERS-CoV infection. Here, we tested whether glycosylation also acts as a determinant of permissivity for ferret, hamster, and guinea pig DPP4. We found that, while glycosylation plays an important role in these orthologs, additional sequence and structural determinants impact their ability to act as functional receptors for MERS-CoV. These results provide insight into DPP4 species-specific differences impacting MERS-CoV host range and better inform our understanding of virus-receptor interactions associated with disease emergence and host susceptibility.

IMPORTANCE
MERS-CoV is a recently emerged zoonotic virus that is still circulating in the human population with an ∼35% mortality rate. With no available vaccines or therapeutics, the study of MERS-CoV pathogenesis is crucial for its control and prevention. However,
in vivo
studies are limited because MERS-CoV cannot infect wild-type mice due to incompatibilities between the virus spike and the mouse host cell receptor, mouse DPP4 (mDPP4). Specifically, mDPP4 has a nonconserved glycosylation site that acts as a barrier to MERS-CoV infection. Thus, one mouse model strategy has been to modify the mouse genome to remove this glycosylation site. Here, we investigated whether glycosylation acts as a barrier to infection for other nonpermissive small-animal species, namely, ferret, guinea pig, and hamster. Understanding the virus-receptor interactions for these DPP4 orthologs will help in the development of additional animal models while also revealing species-specific differences impacting MERS-CoV host range.
Pseudorabies Virus US3-Induced Tunneling Nanotubes Contain Stabilized Microtubules, Interact with Neighboring Cells via Cadherins, and Allow Intercellular Molecular Communication
Authors: Jansens Robert J. J. , Van den Broeck Wim , De Pelsmaeker Steffi , Lamote Jochen A. S. , Van Waesberghe Cliff , Couck Liesbeth , Favoreel Herman W.
Published: July 2017

Tunneling nanotubes (TNTs) are long bridge-like structures that connect eukaryotic cells and mediate intercellular communication. We found earlier that the conserved alphaherpesvirus US3 protein kinase induces long cell projections that contact distant cells and promote intercellular virus spread. In this report, we show that the US3-induced cell projections constitute TNTs. In addition, we report that US3-induced TNTs mediate intercellular transport of information (e.g., green fluorescent protein [GFP]) in the absence of other viral proteins. US3-induced TNTs are remarkably stable compared to most TNTs described in the literature. In line with this, US3-induced TNTs were found to contain stabilized (acetylated and detyrosinated) microtubules. Transmission electron microscopy showed that virus particles are individually transported in membrane-bound vesicles in US3-induced TNTs and are released along the TNT and at the contact area between a TNT and the adjacent cell. Contact between US3-induced TNTs and acceptor cells is very stable, which correlated with a marked enrichment in adherens junction components beta-catenin and E-cadherin at the contact area. These data provide new structural insights into US3-induced TNTs and how they may contribute to intercellular communication and alphaherpesvirus spread.

IMPORTANCE
Tunneling nanotubes (TNT) represent an important and yet still poorly understood mode of long-distance intercellular communication. We and others reported earlier that the conserved alphaherpesvirus US3 protein kinase induces long cellular protrusions in infected and transfected cells. Here, we show that US3-induced cell projections constitute TNTs, based on structural properties and transport of biomolecules. In addition, we report on different particular characteristics of US3-induced TNTs that help to explain their remarkable stability compared to physiological TNTs. In addition, transmission electron microscopy assays indicate that, in infected cells, virions travel in the US3-induced TNTs in membranous transport vesicles and leave the TNT via exocytosis. These data generate new fundamental insights into the biology of (US3-induced) TNTs and into how they may contribute to intercellular virus spread and communication.
Mutations in the E2 Glycoprotein and the 3′ Untranslated Region Enhance Chikungunya Virus Virulence in Mice
Authors: Hawman David W. , Carpentier Kathryn S. , Fox Julie M. , May Nicholas A. , Sanders Wes , Montgomery Stephanie A. , Moorman Nathaniel J. , Diamond Michael S. , Morrison Thomas E.
Published: July 2017

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes debilitating musculoskeletal pain and inflammation and can persist for months to years after acute infection. Although studies of humans and experimentally infected animals suggest that CHIKV infection persists in musculoskeletal tissues, the mechanisms for this remain poorly understood. To evaluate this further, we isolated CHIKV from the serum of persistently infectedRag1−/−mice at day 28. When inoculated into naive wild-type (WT) mice, this persistently circulating CHIKV strain displayed a capacity for earlier dissemination and greater pathogenicity than the parental virus. Sequence analysis revealed a nonsynonymous mutation in the E2 glycoprotein (E2 K200R) and a deletion within the 3′ untranslated region (3′-UTR). The introduction of these changes into the parental virus conferred enhanced virulence in mice, although primary tropism for musculoskeletal tissues was maintained. The E2 K200R mutation was largely responsible for enhanced viral dissemination and pathogenicity, although these effects were augmented by the 3′-UTR deletion. Finally, studies withIrf3/Irf7−/−andIfnar1−/−mice suggest that the E2 K200R mutation enhances viral dissemination from the site of inoculation independently of interferon regulatory factor 3 (IRF3)-, IRF7-, and IFNAR1-mediated responses. As our findings reveal viral determinants of CHIKV dissemination and pathogenicity, their further study should help to elucidate host-virus interactions that determine acute and chronic CHIKV infection.

IMPORTANCECHIKV is a globally spreading, mosquito-transmitted virus that causes debilitating acute and chronic musculoskeletal disease in humans. The viral genetic determinants that dictate the severity of acute and chronic diseases are not understood. To improve our understanding of CHIKV pathogenesis, we evaluated a CHIKV strain isolated from the serum of chronically infected immunocompromised mice. Sequence analysis of this persistent CHIKV strain identified two mutations, an amino acid change in the E2 viral attachment protein and a deletion within the 3′-UTR of the viral genome. We identified roles for these mutations in the enhancement of viral dissemination from the inoculation site and in disease severity. These data improve our understanding of the viral determinants of CHIKV pathogenesis and adaptive changes that occur during viral persistence.
Variable Virulence of Biotype 3 Vibrio vulnificus due to MARTX Toxin Effector Domain Composition
Authors: Kim Byoung Sik , Gavin Hannah E. , Satchell Karla J. F.
Published: July 2017

Vibrio vulnificus
is a serious infection linked to climate change. The virulence capacity of these bacteria can vary by gene exchange, resulting in new variants of the primary virulence toxin. In this study, we tested whether the emergence of an epidemic strain of
V. vulnificus
with a novel toxin variant correlated with a change in virulence. We found that restoring the biotype 3 toxin variant to the putative progenitor-type toxin resulted in dramatically increased virulence, revealing that the emergence of the biotype 3 strain could be linked to virulence reduction. This reduced virulence, previously found also in the biotype 1 strain, suggests that reduced virulence may stimulate outbreaks, as strains have greater capacity to enter the human food chain through reduced impact to environmental hosts.
Alterations of adrenal steroidomic profiles in preterm infants at birth
Authors: Travers Simon , Martinerie Laetitia , Boileau Pascal , Lombès Marc , Pussard Eric
Published: July 2017

Objective

Preterm infants have relative adrenal and kidney immaturity. Recently, we linked their urine sodium loss to a hypoaldosteronism at variance with an appropriate stimulation of the renin-angiotensin system. To investigate this defective aldosterone secretion, we analyse the biosynthesis pathways of adrenal steroids in neonates according to gestational age (GA).

Design

Multicentre study (Premaldo) including 152 neonates classified into three groups: group 1 (very preterm (VPT)): <33  gestational weeks (GW); group 2 (preterm (PT)): 33–36 GW and group 3 (term (T)): ≥GW.

Method

Steroidomic profiles of mineralocorticoids, glucocorticoids and adrenal androgens were established from umbilical cord at birth (n=152) and peripheral blood at day 3 (n=70) using a recently developed liquid chromatography mass spectrometry method (LC-MS/MS). The enzymatic activity of each biosynthesis step was estimated by the product-to-substrate ratio.

Results

At birth, VPT infants exhibit a global defect in adrenal steroid synthesis pathways leading to lower levels of aldosterone, cortisol and androstenedione than in term infants. This defect was strongly related to GA. On day 3, steroid precursors (progesterone, 11-deoxycorticosterone (DOC), 17-hydroxyprogesterone(17-OH-P) and 11-deoxycortisol (S)) were higher in VPT and negatively correlated with GA. Despite of precursors’ accumulation, aldosterone and cortisol were similar in the three groups. At birth and day 3, a low cortisol/11-deoxycortisol ratio was found in preterm infants, suggesting an 11-beta-hydroxylase activity (CYP11B1) deficiency.

Conclusions

At birth, VPT infants exhibit a global deficit in mineralocorticoids, glucocorticoids and adrenal androgens that attenuates on day 3 of life. Steroid profiling using LC-MS/MS provides evidence for a partial defect in 11-hydroxylase along with prematurity.
Improving validation methods for molecular diagnostics: application of Bland-Altman, Deming and simple linear regression analyses in assay comparison and evaluation for next-generation sequencing
Authors: Misyura Maksym , Sukhai Mahadeo A , Kulasignam Vathany , Zhang Tong , Kamel-Reid Suzanne , Stockley Tracy L
Published: July 2017

Aims

A standard approach in test evaluation is to compare results of the assay in validation to results from previously validated methods. For quantitative molecular diagnostic assays, comparison of test values is often performed using simple linear regression and the coefficient of determination (R2), using R2as the primary metric of assay agreement. However, the use of R2alone does not adequately quantify constant or proportional errors required for optimal test evaluation. More extensive statistical approaches, such as Bland-Altman and expanded interpretation of linear regression methods, can be used to more thoroughly compare data from quantitative molecular assays.

Methods

We present the application of Bland-Altman and linear regression statistical methods to evaluate quantitative outputs from next-generation sequencing assays (NGS). NGS-derived data sets from assay validation experiments were used to demonstrate the utility of the statistical methods.

Results

Both Bland-Altman and linear regression were able to detect the presence and magnitude of constant and proportional error in quantitative values of NGS data. Deming linear regression was used in the context of assay comparison studies, while simple linear regression was used to analyse serial dilution data. Bland-Altman statistical approach was also adapted to quantify assay accuracy, including constant and proportional errors, and precision where theoretical and empirical values were known.

Conclusions

The complementary application of the statistical methods described in this manuscript enables more extensive evaluation of performance characteristics of quantitative molecular assays, prior to implementation in the clinical molecular laboratory.
From HCOOH to CO on Pd catalyst: theoretical study
Authors: Wang Yingying , Chen Zijiao
Published: July 2017

The present theoretical and experimental results in the literature for formic acid (HCOOH) oxidation into CO on Pd(111) cannot rationalize the well-known, easy CO poisoning. The present study reexamines HCOOH oxidation on Pd(111) by performing density functional theory calculations. Upon a thorough search, we present a new adsorption configuration of HCOOH on Pd(111). From the calculated energy pathway, we proposed that CO arises from the reduction of the hydrogenation product CO2 and direct dehydration of formic acid during HCOOH oxidation on Pd(111), with latter step being energetically easier. The present theoretical study rationalizes the early experimental findings and provides insights into the deactivation problem of Pd catalyst in the process of HCOOH oxidation.
Simulating the phase II metabolism of raloxifene on a screen-printed electrode
Authors: Vasiliadou Rafaela , Welham Kevin J.
Published: July 2017

Raloxifene (RLX) is a selective estrogen receptor modulator widely used for the treatment of osteoporosis in post-menopause women. Toxicological in vitro studies suggested the reactivity of RLX through phase I metabolism. Herein, we describe a simple and inexpensive method for monitoring the reactive metabolism and detoxification of RLX by electrochemistry (EC) and mass spectrometry (MS). The phase I metabolite was synthesized electrochemically on a screen-printed electrode (SPE) and subsequently reacted with glutathione (GSH). The resulted GSH-adducts and GSH disulfides were characterized off-line by electrospray ionization (ESI)–MS.
The Archaeological Study of Sacrifice
Authors: Schwartz Glenn M.
Published: July 2017

Sacrifice is one of the most common manifestations of human religious thought and behavior, yet archaeology has only recently begun to devote significant attention to the practice. This article reviews the diverse ways in which archaeologists have studied sacrifice and how work might proceed in the future. Both animal and human sacrifice are considered, along with the question of whether these two manifestations of ritual killing are significantly distinct. After examining how sacrifice can be identified in the archaeological record, the review outlines important new developments in bioarchaeology and zooarchaeology that facilitate study of the geographical origin of victims, lifestyle, and health prior to sacrifice, preparations for sacrifice, methods of ritual killing, and postmortem treatment. Proceeding beyond the mechanics of the practice, the article discusses how archaeologists can study sacrifice in its social context as well as its spatial and temporal dimensions.
Urinary renin-angiotensin markers in polycystic kidney disease
Authors: Salih Mahdi , Bovée Dominique M. , Roksnoer Lodi C. W. , Casteleijn Niek F. , Bakker Stephan J. L. , Gansevoort Ronald T. , Zietse Robert , Danser A. H. Jan , Hoorn Ewout J.
Published: July 2017

In autosomal dominant polycystic kidney disease (ADPKD), activation of the renin-angiotensin aldosterone system (RAAS) may contribute to hypertension and disease progression. Although previous studies have focused on circulating RAAS components, preliminary evidence suggests that APDKD may increase urinary RAAS components. Therefore, our aim was to analyze circulating and urinary RAAS components in ADPKD. We cross-sectionally compared 60 patients with ADPKD with 57 patients with non-ADPKD chronic kidney disease (CKD). The two groups were matched by sex, estimated glomerular filtration rate (eGFR), blood pressure, and RAAS inhibitor use. Despite similar plasma levels of angiotensinogen and renin, urinary angiotensinogen and renin excretion were five- to sixfold higher in ADPKD ( P < 0.001). These differences persisted when adjusting for group differences and were present regardless of RAAS inhibitor use. In multivariable analyses, ADPKD, albuminuria, and the respective plasma concentrations were independent predictors for urinary angiotensinogen and renin excretion. In ADPKD, both plasma and urinary renin correlated negatively with eGFR. Total kidney volume correlated with plasma renin and albuminuria but not with urinary renin or angiotensinogen excretions. Albuminuria correlated positively with urinary angiotensinogen and renin excretions in ADPKD and CKD. In three ADPKD patients who underwent nephrectomy, the concentrations of albumin and angiotensinogen were highest in plasma, followed by cyst fluid and urine; urinary renin concentrations were higher than cyst fluid. In conclusion, this study shows that, despite similar circulating RAAS component levels, higher urinary excretions of angiotensinogen and renin are a unique feature of ADPKD. Future studies should address the underlying mechanism and whether this may contribute to hypertension or disease progression in ADPKD.
Unbounded evidence accumulation characterizes subjective visual vertical forced-choice perceptual choice and confidence
Authors: Lim Koeun , Wang Wei , Merfeld Daniel M.
Published: July 2017

Humans can subjectively yet quantitatively assess choice confidence based on perceptual precision even when a perceptual decision is made without an immediate reward or feedback. However, surprisingly little is known about choice confidence. Here we investigate the dynamics of choice confidence by merging two parallel conceptual frameworks of decision making, signal detection theory and sequential analyses (i.e., drift-diffusion modeling). Specifically, to capture end-point statistics of binary choice and confidence, we built on a previous study that defined choice confidence in terms of psychophysics derived from signal detection theory. At the same time, we augmented this mathematical model to include accumulator dynamics of a drift-diffusion model to characterize the time dependence of the choice behaviors in a standard forced-choice paradigm in which stimulus duration is controlled by the operator. Human subjects performed a subjective visual vertical task, simultaneously reporting binary orientation choice and probabilistic confidence. Both binary choice and confidence experimental data displayed statistics and dynamics consistent with both signal detection theory and evidence accumulation, respectively. Specifically, the computational simulations showed that the unbounded evidence accumulator model fits the confidence data better than the classical bounded model, while bounded and unbounded models were indistinguishable for binary choice data. These results suggest that the brain can utilize mechanisms consistent with signal detection theory—especially when judging confidence without time pressure.

NEW & NOTEWORTHY We found that choice confidence data show dynamics consistent with evidence accumulation for a forced-choice subjective visual vertical task. We also found that the evidence accumulation appeared unbounded when judging confidence, which suggests that the brain utilizes mechanisms consistent with signal detection theory to determine choice confidence.
Feasibility of Reprocessing Natural Fiber Filled Poly(lactic acid) Composites: An In-Depth Investigation
Authors: Bhattacharjee Sujal , Bajwa Dilpreet S.
Published: July 2017

Poly(lactic acid) (PLA) based composites are biodegradable; their disposal after single use may be needless and uneconomical. Prodigal disposal of these composites could also create an environmental concern and additional demand for biobased feedstock. Under these circumstances, recycling could be an effective solution, since it will widen the composite service life and prevent the excessive use of natural resources. This research investigates an in-depth impact of recycling on the mechanical and thermomechanical properties of oak wood flour based PLA composites. Two composite formulations (30 and 50 wt% filler), each with 3 wt% coupling agent (PLA-g-MA), were produced and reprocessed six times by extrusion followed by injection molding. Measurements of fiber length and molecular weight of polymer were, respectively, carried out by gel permeation chromatography (GPC). Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FTIR) tools were used to study morphological and molecular alterations. With consecutive recycling, PLA composites showed a gradual decrease in strength and stiffness properties and an increase in strain properties. The 50% and 30% filler concentration of fibers in the composite showed an abrupt decrease in strength properties after six and two reprocessing cycles, respectively.
A CAD/CAM Zirconium Bar as a Bonded Mandibular Fixed Retainer: A Novel Approach with Two-Year Follow-Up
Authors: Zreaqat Maen , Hassan Rozita , Hanoun Abdul Fatah
Published: July 2017

Stainless steel alloys containing 8% to 12% nickel and 17% to 22% chromium are generally used in orthodontic appliances. A major concern has been the performance of alloys in the environment in which they are intended to function in the oral cavity. Biodegradation and metal release increase the risk of hypersensitivity and cytotoxicity. This case report describes for the first time a CAD/CAM zirconium bar as a bonded mandibular fixed retainer with 2-year follow-up in a patient who is subjected to long-term treatment with fixed orthodontic appliance and suspected to have metal hypersensitivity as shown by the considerable increase of nickel and chromium concentrations in a sample of patient’s unstimulated saliva. The CAD/CAM design included a 1.8 mm thickness bar on the lingual surface of lower teeth from canine to canine with occlusal rests on mesial side of first premolars. For better retention, a thin layer of feldspathic ceramic was added to the inner surface of the bar and cemented with two dual-cured cement types. The patient’s complaint subsided 6 weeks after cementation. Clinical evaluation appeared to give good functional value where the marginal fit of digitized CAD/CAM design and glazed surface offered an enhanced approach of fixed retention.
Development of Poly Lactic/Glycolic Acid (PLGA) Microspheres for Controlled Release of Rho-Associated Kinase Inhibitor
Authors: Koda Sho , Okumura Naoki , Kitano Junji , Koizumi Noriko , Tabata Yasuhiko
Published: July 2017

Purpose. The purpose of this study was to investigate the feasibility of poly lactic/glycolic acid (PLGA) as a drug delivery carrier of Rho kinase (ROCK) inhibitor for the treatment of corneal endothelial disease. Method. ROCK inhibitor Y-27632 and PLGA were dissolved in water with or without gelatin (W1), and a double emulsion [(W1/O)/W2] was formed with dichloromethane (O) and polyvinyl alcohol (W2). Drug release curve was obtained by evaluating the released Y-27632 by using high performance liquid chromatography. PLGA was injected into the anterior chamber or subconjunctiva in rabbit eyes, and ocular complication was evaluated by slitlamp microscope and histological analysis. Results. Y-27632 incorporated PLGA microspheres with different molecular weights, and different composition ratios of lactic acid and glycolic acid were fabricated. A high molecular weight and low content of glycolic acid produced a slower and longer release. The Y-27632 released from PLGA microspheres significantly promoted the cell proliferation of cultured corneal endothelial cells. The injection of PLGA did not induce any evident eye complication. Conclusions. ROCK inhibitor-incorporated PLGA microspheres were fabricated, and the microspheres achieved the sustained release of ROCK inhibitor over 7–10 days in vitro. Our data should encourage researchers to use PLGA microspheres for treating corneal endothelial diseases.
Comparison of Efficacy of Self-Expandable Metallic Stent Placement in the Unresectable Esophageal Cancer Patients
Authors: Uesato Masaya , Akutsu Yasunori , Murakami Kentarou , Muto Yorihiko , Kagaya Akiko , Nakano Akira , Aikawa Mizuho , Tamachi Tomohide , Arasawa Takahiro , Amagai Hiroyuki , Muto Yasuhide , Matsubara Hisahiro
Published: July 2017

This is a retrospective study to evaluate the prevention of complications of metallic stent placement in patients with unresectable advanced esophageal cancer. A total of 87 patients were treated with 4 types of metal stents in the esophagus over a period of 18 years. Stent placement was technically successful. The most common prior treatment was chemoradiotherapy. There were no significant differences in the rate of patients with no complications among the prior treatments. Approximately, 30% of patients had the most common chest pain in complications. Stent placement within one month after the completion of chemoradiotherapy should be avoided for the prevention of the chest pain. There was no significant difference in the rate of patients with no complications by lesion location. The rate of no complications was higher for the Niti-S stent than the Gianturco Z-stent or Ultraflex stent. Of note, no complications were noted for the Niti-S ultrathin stent at all. Among cases of stent-related death, the most common type of complication was respiratory disorder caused by the stent that seems to be thick and hard. Therefore, the stent with thin and flexible characteristics like the Niti-S ultrathin stent will solve the various problems of esophageal stent placement.
Modifying Cement Hydration with NS@PCE Core-Shell Nanoparticles
Authors: Gu Yue , Ran Qianping , She Wei , Liu Jiaping
Published: July 2017

It is generally accepted that fine particles could accelerate cement hydration process, or, more specifically, this accelerating effect can be attributed to additional surface area introduced by fine particles. In addition to this view, the surface state of fine particles is also an important factor, especially for nanoparticles. In the previous study, a series of nano-SiO2-polycarboxylate superplasticizer core-shell nanoparticles (NS@PCE) were synthesized, which have a similar particle size distribution but different surface properties. In this study, the impact of NS@PCE on cement hydration was investigated by heat flow calorimetry, mechanical property measurement, XRD, and SEM. Results show that, among a series of NS@PCE, NS@PCE-2 with a moderate shell-core ratio appeared to be more effective in accelerating cement hydration. As dosage increases, the efficiency of NS@PCE-2 would reach a plateau which is quantified by various characteristic values. Compressive strength results indicate that strength has a linear correlation with cumulative heat release. A hypothesis was proposed to explain the modification effect of NS@PCE, which highlights a balance between initial dispersion and pozzolanic reactivity. This paper provides a new understanding for the surface modification of supplementary cementitious materials and their application and also sheds a new light on nano-SiO2 for optimizing cement-based materials.
Incidental Finding of an Undiagnosed Coarctation of the Aorta Causing Dilated Cardiomyopathy in an Adult
Authors: Ibrahim Abdalla , Satti Zahir , Curtin Ronan
Published: July 2017

31-year-old male with no past medical history apart from high blood pressure noted by GP one week prior to admission presented with a three-week history of a flu-like illness and symptoms of heart failure with severe global left ventricular dilation and dysfunction on Transthoracic Echocardiography (TTE). Two weeks following admission he complained of left arm pain and CT upper limb confirmed embolic occlusion of the left brachial artery and incidental severe coarctation of the proximal descending aorta after the origin of the left subclavian artery. Follow-up TTE suggested the presence of coarctation of the aorta on a suprasternal view which was not performed at the time of his first TTE. His heart failure and blood pressure responded very well to medical therapy and he has been referred for surgical correction of his aortic coarctation.
Contemporary Antiplatelet Treatment in Acute Coronary Syndrome Patients with Impaired Renal Function Undergoing Percutaneous Coronary Intervention
Authors: Davlouros Periklis , Xanthopoulou Ioanna , Goudevenos John , Hamilos Michalis , Vavuranakis Emmanouil , Sitafidis George , Kanakakis Ioannis , Deftereos Spyridon , Alexopoulos Dimitrios
Published: July 2017

Objectives: To assess the clinical impact of impaired renal function (IRF), in “real-world” acute coronary syndrome (ACS) patients, receiving clopidogrel, prasugrel, or ticagrelor. Methods: This was a prospective, observational, multicenter, cohort study of ACS patients undergoing percutaneous coronary interventions (PCI) with IRF (creatinine clearance <60 mL/min by Cockroft-Gault equation), who were recruited into the Greek Antiplatelet Registry (GRAPE). Patients were followed-up until 1 year for major adverse cardiovascular events (MACE; a composite of death, nonfatal myocardial infarction, urgent revascularization, and stroke) and BARC (Bleeding Academic Research Consortium) bleeding. Results: Out of 2,047 registered patients, there were 344 (16.8%) with IRF. At the 1-year follow-up, MACE occurred in 18.6 and 6.2% of those patients with and without IRF, respectively: adjusted hazard ratio (HR) = 2.13 (95% confidence interval, CI 1.16-3.91), p = 0.02. IRF patients were also at higher risk of death and BARC type ≥2 and ≥3 bleeding: adjusted HR = 3.55 (95% CI 1.73-7.27), p = 0.001; HR = 2.75 (95% CI 1.13-6.68), p = 0.03; and HR = 6.02 (95% CI 2.30-15.77), p < 0.001, respectively. Combined MACE and BARC type ≥2 bleeding occurred in 34.0 and 14.0% of those with and without IRF, respectively: adjusted HR = 2.65 (95% CI 1.36-5.16), p = 0.004. At discharge, clopidogrel was more frequently prescribed in IRF patients (61.0 vs. 33.1%, p < 0.001). Conclusions: Real-world ACS patients with IRF subjected to PCI demonstrate higher thrombotic and bleeding risks than patients with normal renal function.
A Practical Approach to Tumor Heterogeneity in Clinical Research and Diagnostics
Authors: Stanta Giorgio , Bonin Serena
Published: July 2017

This Pathobiology issue tries to better define the complex phenomenon of intratumor heterogeneity (ITH), mostly from a practical point of view. This topic has been chosen because ITH is a central issue in tumor development and has to be investigated directly in patient tissue and immediately applied in the treatment of the presenting patient. Different types of ITH should be considered: clonal genetic and epigenetic evolution, morphological heterogeneity, and tumor sampling, heterogeneity resulting from microenvironmental autocrine and paracrine interaction, and stochastic plasticity related to different functional cell efficiencies. For a higher level of reproducibility in clinical research and diagnostics, it is necessary to establish standardized analytical methods, including microdissection. In situ techniques can be pivotal to explore tumor microenvironment and can be improved with associated digital analysis. Liquid biopsies for plasma DNA analysis are at present the best method to study recurrent tumors with treatment adaptation, and widespread clinical use could be beneficial. The different types of tumor genomic instabilities could have pragmatic applications to rank ITH for clinical applications: treatment approaches differ in patients with a high nucleotide mutation rate and patients with high copy number alterations.
Chancengleichheit in der ambulanten Therapie: Ein Experiment zur Bereitschaft von niedergelassenen Psychotherapeuten, Patienten mit Schizophrenie zu behandeln
Authors: Schlier Björn , Wiese Salome , Frantz Inga , Lincoln Tania M.
Published: July 2017

Hintergrund: Seit 2014 ist Psychotherapie bei psychotischen Störungen uneingeschränkt indiziert. Patienten mit psychotischen Störungen erhalten jedoch weiterhin selten eine ambulante Psychotherapie. Unklar ist, ob eine höhere Ablehnungsquote durch ambulante Psychotherapeuten dazu beiträgt. In einem Feldexperiment prüften wir, ob Patienten mit psychotischen Störungen auf Therapieplatzsuche häufiger von Therapeuten abgelehnt werden als andere Patientengruppen. Methode: Die Experimentatorin kontaktierte niedergelassene Psychotherapeuten mit dem Schwerpunkt «Verhaltenstherapie» (N = 60) und gab sich entweder als Patientin mit Schizophrenie oder als Patientin mit Depression aus. Wir erfassten die Zu- oder Absage der Therapeuten zu einem Erstgespräch, die voraussichtliche Wartezeit und Vorerfahrungen mit Schizophrenie sowie erwartete Herausforderungen bei der Schizophreniebehandlung. Ergebnisse: Dabei zeigten sich keine statistisch signifikanten Unterschiede hinsichtlich der Zusagen zu einem Erstgespräch (Schizophrenie: 60%; Depression: 53%) und der durchschnittlichen Wartezeit (Schizophrenie: M = 1,6 Monate; Depression: M = 0,8 Monate). Therapeuten, die im Nachgespräch angaben, grundsätzlich keine Patienten mit Schizophrenie zu behandeln, beklagten häufiger das Fehlen spezialisierter Supervisionsangebote und waren eher der Ansicht, Patienten mit psychotischen Störungen seien unzureichend zu rationalem Denken befähigt. Schlussfolgerung: Patienten mit psychotischen Störungen scheinen auf Therapieplatzsuche ebenso häufig ein Erstgesprächsangebot zu erhalten wie andere Patientengruppen. Mögliche Unterschiede in der Wartezeit sollten mit größeren Stichproben getestet werden. Eine spezialisierte Weiterbildung und Supervision könnten das Engagement in der Versorgung dieser Patientengruppe steigern.
A Case of Lipoprotein Glomerulopathy with apoE Chicago and apoE (Glu3Lys) Treated with Fenofibrate
Authors: Kodera Hitoshi , Mizutani Yasuhide , Sugiyama Satoshi , Miyata Toshio , Ehara Takashi , Matsunaga Akira , Saito Takao
Published: July 2017

Lipoprotein glomerulopathy (LPG) is characterized by the accumulation of lipoprotein thrombi within glomerular capillaries. This rare disorder is associated with various types of mutations in the apolipoprotein E gene (apoE). Herein, we present a case of LPG with a combination of apoE Chicago (Arg147Pro) and apoE (Glu3Lys) mutations. A 51-year-old Japanese woman presented with severe (3+) proteinuria. The initial renal biopsy showed glomerular capillary dilation and occlusion with lipid granules, a specific characteristic of LPG. Phenotype, genotype, and apoE DNA sequence analyses detected 2 mutations as described above within the same allele. Although both mutations had already been reported in 1 case of LPG each, this is the first time that the combination of the 2 mutations was identified in the same case. Familial analysis detected the same mutations in the patient’s mother. However, she has not suffered LPG thus far. In addition, a re-analysis of the previous LPG case with apoE (Glu3Lys) also identified the apoE Chicago mutation, as was observed in our case. Treatment with fenofibrate and irbesartan was initiated, and urinary protein excretion ceased within 1 year; recurrence was not observed after an additional 2 years of follow-up. A second biopsy after 2 years showed great improvement, with lipoprotein thrombi identified only in 2 of 18 glomeruli.
Loss of the Protein Cystathionine β-Synthase During Kidney Injury Promotes Renal Tubulointerstitial Fibrosis
Authors: Yuan Xiangning , Zhang Jin , Xie Feifei , Tan Wenqing , Wang Shuting , Huang Ling , Tao Lijian , Xing Qiqi , Yuan Qiongjing
Published: July 2017

Background/Aims: Renal tubulointerstitial fibrosis (TIF) is the common pathway of progressive chronic kidney disease. Inflammation has been widely accepted as the major driving force of TIF. Cystathionine β-synthase (CBS) is the first and rate-limiting enzyme in the transsulfuration pathway. CBS is considered to play protective role in liver and pulmonary fibrosis, but its role in TIF remains unknown. The purpose of this study was to investigate the potential role and mechanism of CBS in renal inflammation and TIF. Methods: Renal function, tubulointerstitium damage index score, extracellular matrix (ECM) deposition, and the expressions of collagen I, collagen III, fibronectin, CD3, CD68, IL-1β, TNF-α were measured in sham operation and unilateral ureteral obstruction (UUO) rats. Proteomics and gene array analysis were performed to screen differentially expressed molecules in the development of renal inflammation and TIF in UUO rats. The expression of CBS was detected in patients with obstructive nephropathy and UUO rats. We confirmed the expression of CBS using western blot and real-time PCR in HK-2 cells. Overexpression plasmid and siRNA were transfected specifically to study the possible function of CBS in HK-2 cells. Results: Abundant expression of CBS, localized in renal tubular epithelial cells, was revealed in human and rat renal tissue, which correlated negatively with the progression of fibrotic disease. Expression of CBS was dramatically decreased in the obstructed kidney from UUO rats as compared with the sham group (SHM). In addition, knocking down CBS exacerbated extracellular matrix (ECM) deposition, whereas CBS overexpression attenuated TGF-β1-induced ECM deposition in vitro. Inflammatory and chemotactic factors were also increased in CBS knockdown HK-2 cells stimulated by IL-1β. Conclusions: These findings establish CBS as a novel inhibitor in renal fibrosis and as a new therapeutic target in patients with chronic kidney disease.
Ablation of the Cl-/HCO3- Exchanger Pendrin Enhances Hydrochlorothiazide-Induced Diuresis
Authors: Alshahrani Saeed , Soleimani Manoocher
Published: July 2017

Background/Aims: The Cl-/HCO3- exchanger pendrin and the thiazide-sensitive Na-Cl cotransporter NCC are expressed in the kidney distal nephron and mediate salt absorption. We hypothesized that deletion of pendrin leaves NCC as the major salt absorbing transporter in the distal nephron and therefore enhances salt excretion by hydrochlorothiazide (HCTZ). Methods: Metabolic cage studies were performed in wild type, pendrin KO and NCC KO mice at baseline and following HCTZ treatment. In parallel studies, systemic blood pressure was measured in mice treated with HCTZ with the tail cuff method. Results: Urine output, salt excretion and water intake were comparable in all groups under baseline condition. Urine output and water intake increased significantly only in pendrin KO mice in response to HCTZ, but not in WT or NCC KO mice. Sodium and chloride excretion increased in HCTZ-treated pendrin KO mice, but they remained unchanged in WT or NCC KO mice. Pendrin KO mice treated with HCTZ developed volume depletion, as determined by increased expression of renin mRNA and protein. The expression of ENaC and pendrin increased in HCTZ-treated WT mice. HCTZ treatment did not significantly modify blood pressure in any of the experimental group. Conclusion: The ablation of the Cl-/HCO3- exchanger Pendrin enhances the magnitude of salt wasting by HCTZ.
TIMP-2*IGFBP7 (Nephrocheck®) Measurements at Intensive Care Unit Admission After Cardiac Surgery are Predictive for Acute Kidney Injury Within 48 Hours
Authors: Oezkur Mehmet , Magyar Attila , Thomas Phillip , Stork Tabea , Schneider Reinhard , Bening Constanze , Störk Stefan , Heuschmann Peter U. , Leyh Rainer G. , Wagner Martin
Published: July 2017

Background/Aims: Acute kidney injury (AKI) is a postoperative complication after cardiac surgery with a high impact on mortality and morbidity. Nephrocheck® [TIMP-2*IGFBP7] determines markers of tubular stress, which occurs prior to tubular damage. It is unknown at which time-point [TIMP-2*IGFBP7] measurement should be performed to ideally predict AKI. We investigated the association of [TIMP-2*IGFBP7] at various time-points with the incidence of AKI in patients undergoing elective cardiac surgery including cardio-pulmonary bypass. Methods: In a prospective cohort study, serial blood and urine samples were collected from 150 patients: pre-operative, at ICU-admission, 24h and 48h post-surgery. AKI was defined as Serum-Creatinine rise >0.3 mg/dl within 48hrs. Urinary [TIMP-2*IGFBP7] was measured at pre-operative, ICU-admission and 24h post-surgery; medical staff was kept blinded to these results. Results: A total of 35 patients (23.5%) experienced AKI, with a higher incidence in those with high [TIMP-2*IGFBP7] values at ICU admission (57.1% vs. 10.1%, p<0.001). In logistic regression [TIMP-2*IGFBP7] at ICU admission was independently associated with the occurrence of AKI (Odds Ratio 11.83; p<0.001, C-statistic= 0.74) after adjustment for EuroSCORE II and CBP-time. Conclusions: Early detection of elevated [TIMP-2*IGFBP7] at ICU admission was strongly predictive for postoperative AKI and appeared to be more precise as compared to subsequent measurements.
Carbon Monoxide Preserves Circadian Rhythm to Reduce the Severity of Subarachnoid Hemorrhage in Mice
Authors: Schallner Nils , Lieberum Judith-Lisa , Gallo David , LeBlanc Robert H. , Fuller Patrick M. , Hanafy Khalid A. , Otterbein Leo E.
Published: July 2017

Background and Purpose—

Subarachnoid hemorrhage (SAH) is associated with a temporal pattern of stroke incidence. We hypothesized that natural oscillations in gene expression controlling circadian rhythm affect the severity of neuronal injury. We moreover predict that heme oxygenase-1 (HO-1/
Hmox1
) and its product carbon monoxide (CO) contribute to the restoration of rhythm and neuroprotection.

Methods—

Murine SAH model was used where blood was injected at various time points of the circadian cycle. Readouts included circadian clock gene expression, locomotor activity, vasospasm, neuroinflammatory markers, and apoptosis. In addition, cerebrospinal fluid and peripheral blood leukocytes from SAH patients and controls were analyzed for clock gene expression.

Results—

Significant elevations in the clock genes
Per-1
,
Per-2
, and
NPAS-2
were observed in the hippocampus, cortex, and suprachiasmatic nucleus in mice subjected to SAH at zeitgeber time (ZT) 12 when compared with ZT2. Clock gene expression amplitude correlated with basal expression of HO-1, which was also significantly greater at ZT12. SAH animals showed a significant reduction in cerebral vasospasm, neuronal apoptosis, and microglial activation at ZT12 compared with ZT2. In animals with myeloid-specific HO-1 deletion (
Lyz-Cre-Hmox1

fl/fl

),
Per-1, Per-2
, and
NPAS-2
expression was reduced in the suprachiasmatic nucleus, which correlated with increased injury. Treatment with low-dose CO rescued
Lyz-Cre-Hmox1

fl/fl

mice, restored
Per-1, Per-2
,
and NPAS-2
expression, and reduced neuronal apoptosis.

Conclusions—

Clock gene expression regulates, in part, the severity of SAH and requires myeloid HO-1 activity to clear the erythrocyte burden and inhibit neuronal apoptosis. Exposure to CO rescues the loss of HO-1 and thus merits further investigation in patients with SAH.
Household Education Spending in Latin America and the Caribbean: Evidence from Income and Expenditure Surveys
Authors: Acerenza Santiago , Gandelman Néstor
Published: July 2017

This paper characterizes household spending in education using microdata from income and expenditure surveys for twelve Latin American and Caribbean countries and the United States. Bahamas, Chile, and Mexico have the highest household spending in education and Bolivia, Brazil, and Paraguay have the lowest. Tertiary education is the most important form of spending, and most educational spending is performed for 18- to 23-year-old individuals. More educated and wealthier household heads spend more in the education of household members. Households with both parents present and those with a female main income provider spend more than their counterparts. Urban households also spend more than rural households. On average, education in Latin America and the Caribbean is a luxury good, whereas it may be a necessity in the United States. No gender bias is found in primary education, but at secondary school age and up households invest more in females than in males.
A new population and subspecies of the critically endangered Anatolian meadow viper Vipera anatolica Eiselt and Baran, 1970 in eastern Antalya province
Authors: Göçmen Bayram , Mebert Konrad , Karış Mert , Oğuz Mehmet Anıl , Ursenbacher Sylvain
Published: July 2017

We report on a new population ofVipera anatolicafrom the Geyik Mountain Range in eastern Antalya Province, Turkey. It represents only the second known location, and is situated in a valley about 200 km east from the terra typica at Kohu Dağ in western Antalya Province. We compare both populations and, based on marked differences in morphology, habitat, genetics, and its geographically isolated location, we describe the recently discovered population as a new subspecies. Aspects of ecology, threats, and conservation needs are discussed.
A new species of Olecryptotendipes Zorina from China (Diptera, Chironomidae)
Authors: YAN CHUNCAI , LIU TING , ZHAO GUANGJUN , SHI YAFENG , WANG XINHUA
Published: July 2017

Olecryptotendipes arienus Yan & Wang sp. n. is described and illustrated as male imago from China. The generic diagnosis of Olecryptotendipes Zorina is amended. A key to the known adult males of the genus worldwide is presented.
The neotropical stingless bee genus Nannotrigona Cockerell (Hymenoptera: Apidae: Meliponini): An illustrated key, notes on the types, and designation of lectotypes
Authors: RASMUSSEN CLAUS , GONZALEZ VICTOR H.
Published: July 2017

We provide comparative comments on the morphology and provenance of the primary types of the species in the stingless bee genus Nannotrigona Cockerell. We offer an illustrated key to workers of all presently known species and designate lectotypes for the following species to stabilize their names: N. dutrae (Friese), N. mellaria (Smith), N. punctata (Smith), and N. schultezi (Friese). The type of Melipona minuta Lepeletier de Saint Fargeau could not be located and it remains an incertae sedis, but a possible member of Nannotrigona. A distinctive new species from western Ecuador, Nannotrigona camargoi n. sp. (type locality Ecuador, Pichincha) is also described and figured.
A new species of Miroculis Edmunds, 1963 (Ephemeroptera: Leptophlebiidae) from Cerrado-Amazonian forest transition zone, Brazil
Authors: RAIMUNDI ERIKCSEN A. , CABETTE HELENA R. S. , BRASIL LEANDRO S. , SALLES FREDERICO F.
Published: July 2017

A new species of Miroculis is described based on all developmental stages (nymph, and male and female imagos). Miroculis yulieae sp. nov. is recorded from the transitional area of Cerrado-Amazonia, Brazil.