bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three‐dimensional organotypic culture of human salivary glands: the slice culture model
Authors: Su X , Fang D , Liu Y , Ramamoorthi M , Zeitouni A , Chen W , Tran SD 
Published: May 2016

ObjectiveA challenge in studying human salivary glands is to maintain the cells ex vivo in their three‐dimensional (3D) morphology with an intact native extracellular matrix (ECM) environment. This paper established a human salivary 3D organotypic slice culture model that could maintain its physiological functions as well as allowing a direct visualization of the cells.MethodsHuman salivary biopsies from six patients were embedded in agarose and submerged in cold buffer for thin (50 μm) sectioning using a vibratome. ‘Salivary slices’ were mechanically supported by a porous membrane insert that allowed an air–liquid interface and cultured in serum‐free culture media. Cell viability, proliferation, apoptosis, physiological functions, and gene expression were assessed during 14 days of culture.ResultsHuman salivary slices maintained cell survival (70–40%) and proliferation (6–17%) for 14 days ex vivo. The protein secretory (amylase) function decreased, but fluid (intracellular calcium mobilization) function was maintained. Acinar, ductal, and myoepithelial cell populations survived and maintained their 3D organization within the slice culture model.ConclusionThe human salivary slice culture model kept cells alive ex vivo for 14 days as well as maintaining their 3D morphology and physiological functions.
The STBUR questionnaire for identifying children at risk for sleep‐disordered breathing and postoperative opioid‐related adverse events
Authors: Tait Alan R. , Bickham Rebecca , O'Brien Louise M. , Quinlan Megan , Voepel‐Lewis Terri 
Published: May 2016

SummaryBackgroundChildren with symptoms of sleep‐disordered breathing (SDB) appear to be at risk for perioperative respiratory events (PRAE). Furthermore, these children may be more sensitive to the respiratory‐depressant effects of opioids compared with children without SDB.AimsThe aim of this prospective observational study was to confirm that otherwise healthy children with symptoms of SDB are at greater risk for PRAE compared with children with no symptoms and to determine if these children are also at increased risk for postoperative opioid‐related adverse events (ORAE).MethodsSix hundred and seventy‐eight parents of children scheduled for surgery completed the Snoring, Trouble Breathing, and Un‐Refreshed (STBUR) questionnaire preoperatively. Data regarding the incidence of PRAE were collected prospectively. Postoperative pulse oximetry desaturation alarm events were downloaded from the institutional secondary alarm notification system.ResultsChildren with symptoms of SDB per STBUR (≥3 symptoms) had a two‐fold increased likelihood of PRAE compared with children without SDB (52.8% vs 27.9% respectively, LR+ = 2.00, 95% CI = 1.60–2.49, P = 0.0001). A subset analysis of children undergoing airway procedures requiring hospital admittance (n = 179) showed that those with SDB were given the same postoperative opioid doses as children without SDB. However, children with SDB symptoms generated a greater number of postoperative oxygen desaturation alarms (14.14 ± 29.3 vs 7.12 ± 13.2, mean difference = 7.02, 95% CI = 0.39–13.64, P = 0.038) and more frequently required escalation of care (15.3% vs 7.1%, LR+ = 1.67, 95% CI = 1.22–2.16, P = 0.001) compared with children with no SDB symptoms.ConclusionsChildren presenting for surgery with SDB symptoms are at increased risk for PRAE. Children undergoing airway‐related procedures also appear to be at increased risk for ORAE. Furthermore, regardless of the preoperative assessment of risk using the STBUR questionnaire, children received the same doses of opioids postoperatively. Given the increased incidence of postoperative oxygen desaturations among children with SDB symptoms, it would seem prudent to consider titration of opioid doses according to identified risk.
Fiscal Uncertainty and Currency Crises
Authors: Gumus Inci 
Published: May 2016

AbstractFiscal deficits have been put forward as the main factor in the occurrence of currency crises by the first‐generation currency crisis models. While most papers within this framework consider a fiscal deficit that occurs with certainty, in reality an increase in the government's fiscal burden may be an uncertain outcome. This paper introduces a model where there is uncertainty about the occurrence of a fiscal deficit for a finite number of periods, and studies the effects of such uncertainty on the evolution of currency crises. If the fiscal deficit materializes, the government has to abandon the fixed exchange rate regime, as in the standard case. However, the paper shows that the peg becomes unsustainable even if the fiscal deficit never materializes. Therefore, a speculative attack occurs and the fixed exchange rate regime collapses with the mere possibility of a deficit, independently of whether this outcome actually occurs or not.
Institutional Determinants of Financial Development in MENA countries
Authors: Cherif Mondher , Dreger Christian 
Published: May 2016

AbstractDeveloped and well regulated financial markets are usually seen as a precondition for an efficient allocation of resources and can foster long term economic growth. This paper explores the institutional determinants for financial development in the countries of the Middle East and North African (MENA) region. Institutional conditions are from the International Country Risk Guide. Panel‐econometric techniques are applied to assess the development in the banking sector and the stock market. As a main finding, institutional conditions are important in both financial segments, even after controlling for standard macroeconomic determinants and fixed effects. For the banking sector, corruption seems to be most decisive. For the stock market, the impact of corruption and law and order appear to be relevant. While per capita income and inflation do not seem to play a vital role, openness to foreign trade is quite important for all areas of financial development. Hence, overall, faster real economic integration is of key policy priority to improve financial development as a condition for higher GDP growth. Better law and enforcement practices and anti‐corruption policies are strategies to accompany this process.
Why are rods more sensitive than cones?
Authors: Ingram Norianne T. , Sampath Alapakkam P. , Fain Gordon L. 
Published: May 2016

AbstractOne hundred and fifty years ago Max Schultze first proposed the duplex theory of vision, that vertebrate eyes have two types of photoreceptor cells with differing sensitivity: rods for dim light and cones for bright light and colour detection. We now know that this division is fundamental not only to the photoreceptors themselves but to the whole of retinal and visual processing. But why are rods more sensitive, and how did the duplex retina first evolve? Cells resembling cones are very old, first appearing among cnidarians; the emergence of rods was a key step in the evolution of the vertebrate eye. Many transduction proteins have different isoforms in rods and cones, and others are expressed at different levels. Moreover rods and cones have a different anatomy, with only rods containing membranous discs enclosed by the plasma membrane. These differences must be responsible for the difference in absolute sensitivity, but which are essential? Recent research particularly expressing cone proteins in rods or changing the level of expression seem to show that many of the molecular differences in the activation and decay of the response may have each made a small contribution as evolution proceeded stepwise with incremental increases in sensitivity. Rod outer‐segment discs were not essential and developed after single‐photon detection. These experiments collectively provide a new understanding of the two kinds of photoreceptors and help to explain how gene duplication and the formation of rod‐specific proteins produced the duplex retina, which has remained remarkably constant in physiology from amphibians to man.
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Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment
Authors: Custodio Joseph M. , Fordyce Marshall , Garner William , Vimal Mona , Ling Kah Hiing J. , Kearney Brian P. , Ramanathan Srinivasan 
Published: May 2016

ABSTRACT

Tenofovir alafenamide (TAF) is an oral prodrug of tenofovir (TFV) that has greater stability in plasma than TFV disoproxil fumarate (TDF) and circulates as intact TAF, resulting in the direct and higher lymphatic loading of and exposure to TFV diphosphate, the active moiety. Unlike TFV, TAF is minimally eliminated in urine. The pharmacokinetics (PK) of TAF and TFV in HIV-uninfected subjects with severe renal impairment and matched healthy controls were evaluated. Subjects with severe renal impairment (RI; estimated glomerular filtration rate [eGFR], 15 to 29 ml/min) and controls (eGFR, ≥90 ml/min) matched for age, gender, and body mass index received a single dose of TAF at 25 mg. Blood and urine samples for TAF and TFV PK determinations were collected over 7 days postdosing, and subjects were followed up at 14 days. A total of 14 renally impaired subjects and 13 control subjects enrolled and completed the study. The TAF maximum observed concentration in plasma (
C
max
) and the area under the concentration-versus-time curve (AUC) extrapolated to infinite time (AUC
inf
) were 79% and 92% higher, respectively, in subjects with severe RI than the controls, primarily due to higher absorption. The TFV
C
max
and AUC
inf
were 2.8-fold and 5.7-fold higher, respectively, in subjects with severe RI than the controls. In subjects with severe RI, TAF at 25 mg provided a TFV AUC 10 to 40% lower than that from historical TDF-based TFV exposures in subjects with normal renal function. There were no discontinuations due to adverse events. In subjects with severe RI receiving TAF at 25 mg, TAF exposures were higher than those for the controls; these differences are unlikely to be clinically meaningful. TFV exposures were higher than those for the controls but lower than the exposures in nonrenally impaired subjects on TDF-based regimens.
In Vitro
Synergism between Azithromycin or Terbinafine and Topical Antimicrobial Agents against Pythium insidiosum
Authors: Itaqui Sabrina R. , Verdi Camila M. , Tondolo Juliana S. M. , da Luz Thaisa S. , Alves Sydney H. , Santurio Janio M. , Loreto Érico S. 
Published: May 2016

ABSTRACT

We describe here
in vitro
activity for the combination of azithromycin or terbinafine and benzalkonium, cetrimide, cetylpyridinium, mupirocin, triclosan, or potassium permanganate. With the exception of potassium permanganate, the remaining antimicrobial drugs were active and had an MIC
90
between 2 and 32 μg∕ml. The greatest synergism was observed for the combination of terbinafine and cetrimide (71.4%).
In vivo
experimental evaluations will clarify the potential of these drugs for the topical treatment of lesions caused by
Pythium insidiosum
.
Simultaneous Determination of Eight β-Lactam Antibiotics, Amoxicillin, Cefazolin, Cefepime, Cefotaxime, Ceftazidime, Cloxacillin, Oxacillin, and Piperacillin, in Human Plasma by Using Ultra-High-Performance Liquid Chromatography with Ultraviolet Detection
Authors: Legrand Tiphaine , Vodovar Dominique , Tournier Nicolas , Khoudour Nihel , Hulin Anne 
Published: May 2016

ABSTRACT
A simple and rapid ultra-high-performance liquid chromatography (UHPLC) method using UV detection was developed for the simultaneous determination of eight β-lactam antibiotics in human plasma, including four penicillins, amoxicillin (AMX), cloxacillin (CLX), oxacillin (OXA), and piperacillin (PIP), and four cephalosporins, cefazolin (CFZ), cefepime (FEP), cefotaxime (CTX), and ceftazidime (CAZ). One hundred-microliter samples were spiked with thiopental as an internal standard, and proteins were precipitated by acetonitrile containing 0.1% formic acid. Separation was achieved on a pentafluorophenyl (PFP) column with a mobile phase composed of phosphoric acid (10 mM) and acetonitrile in gradient elution mode at a flow rate of 500 μl/min. Detection was performed at 230 nm for AMX, CLX, OXA, and PIP and 260 nm for CFZ, FEP, CTX, and CAZ. The total analysis time did not exceed 13 min. The method was found to be linear at concentrations ranging from 2 to 100 mg/liter for each compound, and all validation parameters fulfilled international requirements. Between- and within-run accuracy errors ranged from −5.2% to 11.4%, and precision was lower than 14.2%. This simple method requires small-volume samples and can easily be implemented in most clinical laboratories to promote the therapeutic drug monitoring of β-lactam antibiotics. The simultaneous determination of several antibiotics considerably reduces the time to results for clinicians, which may improve treatment efficiency, especially in critically ill patients.
Cefazolin versus Nafcillin for Methicillin-Sensitive Staphylococcus aureus Bloodstream Infection in a California Tertiary Medical Center
Authors: Pollett S. , Baxi S. M. , Rutherford G. W. , Doernberg S. B. , Bacchetti P. , Chambers H. F. 
Published: May 2016

ABSTRACT

Recent observational studies have suggested possible reductions in mortality in patients receiving cefazolin versus antistaphylococcal penicillins. We examined 90-day mortality in patients receiving cefazolin compared to nafcillin for methicillin-susceptible
Staphylococcus aureu
s (MSSA) bloodstream infection (BSI). We identified persons with MSSA BSI admitted to San Francisco General Hospital from January 2008 to July 2013 through a hospital-wide infection surveillance system and confirmed 90-day mortality using U.S. national vital registries. We included persons receiving cefazolin or nafcillin as the predominant intravenous antimicrobial agent; all participants received inpatient Infectious Diseases service consultation. We estimated the association between receipt of cefazolin and 90-day risk of death by multivariate logistic regression, including a propensity score for receiving cefazolin as the second predictor. Of 230 MSSA BSI cases, 30 received nafcillin and 70 received cefazolin as the predominant antimicrobial; 10 died within 90 days, 5 from each group. Unadjusted analysis showed substantial but not statistically significant reduced odds of death in those receiving cefazolin (odds ratio, 0.38; 95% confidence interval [CI], 0.10 to 1.44). Multivariate analysis with propensity scores found a similar adjusted odds ratio (0.40; 95% CI, 0.09 to 1.74;
P
= 0.22). We found a large reduction in 90-day mortality in those receiving cefazolin compared to nafcillin for MSSA BSI, but this finding was not statistically significant. The magnitude of effect seen in this and other studies justifies further study.
Imidazo[1,2-
a
]Pyridine-3-Carboxamides Are Active Antimicrobial Agents against Mycobacterium avium Infection
In Vivo
Authors: Moraski Garrett C. , Cheng Yong , Cho Sanghyun , Cramer Jeffrey W. , Godfrey Alexander , Masquelin Thierry , Franzblau Scott G. , Miller Marvin J. , Schorey Jeffery 
Published: May 2016

ABSTRACT

A panel of six imidazo[1,2-
a
]pyridine-3-carboxamides (IAPs) were shown to have low-micromolar activity against
Mycobacterium avium
strains. Compound ND-10885 (compound 2) showed significant activity in the lung, spleen, and liver in a mouse
M. avium
infection model. A combined regimen consisting of ND-10885 (compound 2) and rifampin was additive in its anti-
M. avium
activity in the lung. Our data indicate that IAPs represent a new class of antibiotics that are active against
M. avium
and could potentially serve as an effective addition to a combined treatment regimen.
Correlation-Aware Probabilistic Timing Analysis for the Dynamic Segment of FlexRay
Authors: Tanasa Bogdan , Bordoloi Unmesh D. , Eles Petru , Peng Zebo 
Published: May 2016

We propose an analytical framework for probabilistic timing analysis of the event-triggered Dynamic segment of the FlexRay communication protocol. Specifically, our framework computes the Deadline Miss Ratio of each message. The core problem is formulated as a Mixed Integer Linear Program (MILP). Given the intractability of the problem, we also propose several techniques that help to mitigate the running times of our tool. This includes the re-engineering of the problem to run it on GPUs as well as reformulating the MILP itself.Most importantly, we also show how our framework can handle correlations between the queuing events of messages. This is challenging because one cannot apply the convolution operator in the same way as in the case of independent queuing events.
Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression
Authors: Botla Sandeep K. , Savant Soniya , Jandaghi Pouria , Bauer Andrea S. , Mücke Oliver , Moskalev Evgeny A. , Neoptolemos John P. , Costello Eithne , Greenhalf William , Scarpa Aldo , Gaida Matthias M. , Büchler Markus W. , Strobel Oliver , Hackert Thilo , Giese Nathalia A. , Augustin Hellmut G. , Hoheisel Jörg D. 
Published: May 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial–mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149–59. ©2016 AACR.
Three-Dimensional Breast Cancer Models Mimic Hallmarks of Size-Induced Tumor Progression
Authors: Singh Manjulata , Mukundan Shilpaa , Jaramillo Maria , Oesterreich Steffi , Sant Shilpa 
Published: May 2016

Abstract
Tumor size is strongly correlated with breast cancer metastasis and patient survival. Increased tumor size contributes to hypoxic and metabolic gradients in the solid tumor and to an aggressive tumor phenotype. Thus, it is important to develop three-dimensional (3D) breast tumor models that recapitulate size-induced microenvironmental changes and, consequently, natural tumor progression in real time without the use of artificial culture conditions or gene manipulations. Here, we developed size-controlled multicellular aggregates (“microtumors”) of subtype-specific breast cancer cells by using non-adhesive polyethylene glycol dimethacrylate hydrogel microwells of defined sizes (150–600 μm). These 3D microtumor models faithfully represent size-induced microenvironmental changes, such as hypoxic gradients, cellular heterogeneity, and spatial distribution of necrotic/proliferating cells. These microtumors acquire hallmarks of tumor progression in the same cell lines within 6 days. Of note, large microtumors of hormone receptor–positive cells exhibited an aggressive phenotype characterized by collective cell migration and upregulation of mesenchymal markers at mRNA and protein level, which was not observed in small microtumors. Interestingly, triple-negative breast cancer (TNBC) cell lines did not show size-dependent upregulation of mesenchymal markers. In conclusion, size-controlled microtumor models successfully recapitulated clinically observed positive association between tumor size and aggressive phenotype in hormone receptor–positive breast cancer while maintaining clinically proven poor correlation of tumor size with aggressive phenotype in TNBC. Such clinically relevant 3D models generated under controlled experimental conditions can serve as precise preclinical models to study mechanisms involved in breast tumor progression as well as antitumor drug effects as a function of tumor progression. Cancer Res; 76(13); 3732–43. ©2016 AACR.
Copy Number Alterations in Enzyme-Coding and Cancer-Causing Genes Reprogram Tumor Metabolism
Authors: Sharma Ashwini Kumar , Eils Roland , König Rainer 
Published: May 2016

Abstract
Somatic copy number alterations frequently occur in the cancer genome affecting not only oncogenic or tumor suppressive genes, but also passenger and potential codriver genes. An intrinsic feature resulting from such genomic perturbations is the deregulation in the metabolism of tumor cells. In this study, we have shown that metabolic and cancer-causing genes are unexpectedly often proximally positioned in the chromosome and share loci with coaltered copy numbers across multiple cancers (19 cancer types from The Cancer Genome Atlas). We have developed an analysis pipeline, Identification of Metabolic Cancer Genes (iMetCG), to infer the functional impact on metabolic remodeling from such coamplifications and codeletions and delineate genes driving cancer metabolism from those that are neutral. Using our identified metabolic genes, we were able to classify tumors based on their tissue and developmental origins. These metabolic genes were similar to known cancer genes in terms of their network connectivity, isoform frequency, and evolutionary features. We further validated these identified metabolic genes by (i) using gene essentiality data from several tumor cell lines, (ii) showing that these identified metabolic genes are strong indicators for patient survival, and (iii) observing a significant overlap between our identified metabolic genes and known cancer-metabolic genes. Our analyses revealed a hitherto unknown generic mechanism for large-scale metabolic reprogramming in cancer cells based on linear gene proximities between cancer-causing and -metabolic genes. We have identified 119 new metabolic cancer genes likely to be involved in rewiring cancer cell metabolism. Cancer Res; 76(14); 4058–67. ©2016 AACR.