bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spectra Optia granulocyte apheresis collections result in higher collection efficiency of viable, functional neutrophils in a randomized, crossover, multicenter trial
Authors: Cancelas Jose A. , Padmanabhan Anand , Le Tuan , Ambruso Daniel R. , Rugg Neeta , Worsham D. Nicole , Pinkard Susan L. , Graminske Sharon , Buck Jennifer , Goldberg Julie , Bill Jerry 
Published: November 2014

BackgroundGranulocyte transfusion from healthy donors is used in the treatment of patients with granulocyte function defects, or transient neutropenia and severe bacterial or fungal infections resistant to maximal antimicrobial treatment.Study Design and MethodsThis study evaluated the performance and safety of the newly developed granulocyte collection protocol of the Spectra Optia in a prospective, multicenter, open‐label, randomized, paired crossover trial compared with the COBE Spectra apheresis system in a population of 32 evaluable healthy subjects. All subjects received granulocyte–colony‐stimulating factor and dexamethasone before collection.ResultsGranulocyte procedures from Spectra Optia apheresis procedures had an approximately 23% higher polymorphonuclear (PMN) collection efficiency (CE) than the COBE Spectra collections (mean, 53.7% vs. 43.2%; p < 0.01), while the platelet CE (10.9% vs. 10.8%, respectively) and hematocrit (7.4% vs. 7.4%) were comparable between collections on both devices. Spectra Optia collections generated a higher total PMN yield per liter of blood processed than those produced by the COBE Spectra (with means of 8.6 × 1010 vs. 6.8 × 1010, respectively). Granulocyte viability was more than 99% with both devices, and chemotaxic and bacterial killing activities of circulating versus collected granulocytes were similarly preserved. Fewer operator adjustments were required with Spectra Optia and there was no significant difference in the number or intensity of adverse events between instruments.ConclusionCE of the granulocyte collection procedure with the Spectra Optia was approximately 10 percentage points higher than with the COBE Spectra, required less operator involvement, and is safe for clinical implementation.
Transfusion‐associated Anaplasma phagocytophilum infection in a pregnant patient with thalassemia trait: a case report
Authors: Shields Kelsey , Cumming Melissa , Rios Jorge , Wong Michael T. , Zwicker Jeffrey I. , Stramer Susan L. , Alonso Carolyn D. 
Published: November 2014

BackgroundHuman granulocytic anaplasmosis (HGA) is an acute nonspecific febrile illness caused by the bacterium Anaplasma phagocytophilum. Although usually transmitted via tick bite, HGA may rarely also be acquired through transfusion. HGA during pregnancy may pose significant gestational risks due to altered maternal immune status and the potential for perinatal transmission.Case ReportA pregnant 34‐year‐old Massachusetts woman with β‐thalassemia trait was diagnosed at 32 weeks of gestation with transfusion‐associated HGA (TAHGA) after receiving nine leukoreduced red blood cell transfusions. She was successfully treated with rifampin therapy and gave birth to a healthy child who tested negative for HGA after delivery. An implicated blood donor was subsequently identified through physician collaboration with the regional American Red Cross and Massachusetts Department of Public Health.DiscussionThis is the 11th reported case of HGA in pregnancy and is at least the sixth known case in which leukoreduction did not prevent TAHGA. As seen in this case, nonspecific symptomatology of variable onset can impede diagnosis and treatment. This may increase risk of poor outcomes in maternal HGA patients. Cases of TAHGA, although currently uncommon, may increase as the incidence of HGA in certain parts of the country increases.ConclusionHeightened cross‐institutional awareness of the potential risk of TAHGA is warranted. Clinicians need to consider transfusion‐associated infections when fever occurs in a transfusion recipient. This case provides additional evidence that leukoreduction does not obviate risk of A. phagocytophilum contamination of donated blood components.
Glucose metabolism in pigs expressing human genes under an insulin promoter
Authors: Wijkstrom Martin , Bottino Rita , Iwase Hayoto , Hara Hidetaka , Ekser Burcin , van der Windt Dirk , Long Cassandra , Toledo Frederico G. S. , Phelps Carol J. , Trucco Massimo , Cooper David K. C. , Ayares David 
Published: November 2014

AbstractBackgroundXenotransplantation of porcine islets can reverse diabetes in non‐human primates. The remaining hurdles for clinical application include safe and effective T‐cell‐directed immunosuppression, but protection against the innate immune system and coagulation dysfunction may be more difficult to achieve. Islet‐targeted genetic manipulation of islet‐source pigs represents a powerful tool to protect against graft loss. However, whether these genetic alterations would impair islet function is unknown.MethodsOn a background of α1,3‐galactosyltransferase gene‐knockout (GTKO)/human (h)CD46, additional genes (hCD39, human tissue factor pathway inhibitor, porcine CTLA4‐Ig) were inserted in different combinations under an insulin promoter to promote expression in islets (confirmed by immunofluorescence). Seven pigs were tested for baseline and glucose/arginine‐challenged levels of glucose, insulin, C‐peptide, and glucagon.ResultsThis preliminary study did not show definite evidence of β‐cell deficiencies, even when three transgenes were expressed under the insulin promoter. Of seven animals, all were normoglycemic at fasting, and five of seven had normal glucose disposal rates after challenge. All animals exhibited insulin, C‐peptide, and glucagon responses to both glucose and arginine challenge; however, significant interindividual variation was observed.ConclusionsMultiple islet‐targeted transgenic expression was not associated with an overtly detrimental effect on islet function, suggesting that complex genetic constructs designed for islet protection warrants further testing in islet xenotransplantation models.
Dominant role of interstitial cells of Cajal in nitrergic relaxation of murine lower oesophageal sphincter
Authors: Groneberg Dieter , Zizer Eugen , Lies Barbara , Seidler Barbara , Saur Dieter , Wagner Martin , Friebe Andreas 
Published: November 2014

Key points
Nitric oxide (NO) is an important inhibitory neurotransmitter in the gastrointestinal tract. Oesophageal achalasia may result from impairment of nitrergic relaxation.
Smooth muscle cells (SMCs) have been accepted to be the major targets for neuronal NO to mediate relaxation. However, besides SMCs, the receptor for NO, NO‐sensitive guanylyl cyclase (NO‐GC), has been shown in interstitial cells of Cajal (ICC).
Using cell‐specific knockout mice, this study shows that NO‐GC in SMC and ICC modulates lower oesophagus sphincter tone in vitro and in vivo.
More importantly, NO‐GC in ICC possesses a dominant role in mediating swallowing‐induced relaxation. Lack of functional nitrergic signalling, thus, results in deficits in relaxation of the lower oesophagus sphincter as seen in achalasic patients.
AbstractOesophageal achalasia is a disease known to result from reduced relaxation of the lower oesophageal sphincter (LES). Nitric oxide (NO) is one of the main inhibitory transmitters. NO‐sensitive guanylyl cyclase (NO‐GC) acts as the key target of NO and, by the generation of cGMP, mediates nitrergic relaxation in the LES. To date, the exact mechanism of nitrergic LES relaxation is still insufficiently elucidated. To clarify the role of NO‐GC in LES relaxation, we used cell‐specific knockout (KO) mouse lines for NO‐GC. These include mice lacking NO‐GC in smooth muscle cells (SMC‐GCKO), in interstitial cells of Cajal (ICC‐GCKO) and in both SMC/ICC (SMC/ICC‐GCKO). We applied oesophageal manometry to study the functionality of LES in vivo. Isometric force studies were performed to monitor LES responsiveness to exogenous NO and electric field stimulation of intrinsic nerves in vitro. Cell‐specific expression/deletion of NO‐GC was monitored by immunohistochemistry. Swallowing‐induced LES relaxation is strongly reduced by deletion of NO‐GC in ICC. Basal LES tone is affected by NO‐GC deletion in either SMC or ICC. Lack of NO‐GC in both cells leads to a complete interruption of NO‐induced relaxation and, therefore, to an achalasia‐like phenotype similar to that seen in global GCKO mice. Our data indicate that regulation of basal LES tone is based on a dual mechanism mediated by NO‐GC in SMC and ICC whereas swallow‐induced LES relaxation is mainly regulated by nitrergic mechanisms in ICC.
Pannexin channels and ischaemia
Authors: Thompson Roger J. 
Published: November 2014

AbstractAn ischaemic stroke occurs during loss of blood flow in the brain from the occlusion of a blood vessel. The ischaemia itself comprises a complex array of insults, including oxygen and glucose deprivation (OGD), glutamate excitotoxicity, acidification/hypercapnia, and loss of sheer forces. A substantial amount of knowledge has accumulated that define the excitotoxic cascade downstream of N‐methyl‐d‐aspartate receptors (NMDARs). While the NMDAR can influence numerous downstream elements, one critical target during ischaemia is the ion channel, pannexin‐1 (Panx1). The C‐terminal region of Panx1 appears critical for its regulation under a host of physiological and pathological stimuli. We have shown using hippocampal brain slices that Panx1 is activated by NMDARs through Src family kinases. However, it is not yet certain if this involves direct phosphorylation of Panx1 or an allosteric interaction between the channel's C‐terminal tail and Src. Interestingly, Panx1 opening during ischaemia and NMDAR over‐activation is antagonized by an interfering peptide that comprises amino acids 305–318 of Panx1. Thus, targeting the activation of Panx1 by NMDARs and Src kinases is an attractive mechanism to reduce anoxic depolarizations and neuronal death.
RNASeq‐derived transcriptome comparisons reveal neuromodulatory deficiency in the CO2 insensitive brown Norway rat
Authors: Puissant Madeleine M. , Echert Ashley E. , Yang Chun , Mouradian Gary C. , Novotny Tyler , Liu Pengyuan , Liang Mingyu , Hodges Matthew R. 
Published: November 2014

Key points
Increases in carbon dioxide (CO2) provide a major chemical stimulus to breathe through activation of the ventilatory CO2 chemoreflex, which is heavily influenced by the brainstem serotonergic (5‐HT) system.
Brown Norway (BN) rats have an inherent and extremely low ventilatory sensitivity to hypercapnia, which can be augmented with selective serotonin reuptake inhibition.
Using mRNA sequencing, we show that BN rats have reduced medullary raphé expression of multiple 5‐HT neuron‐specific genes, predictive of lower monoamine levels by informatics pathway analyses and confirmed by high‐performance liquid chromatography measurements.
BN rats also showed reduced thyrotropin‐releasing hormone (TRH) expression, where injections of the TRH analogue Taltirelin caused greater increases in baseline ventilation, body temperature and the ventilatory CO2 chemoreflex in BN rats compared to control Sprague–Dawley rats.
These data establish a molecular basis of a neuromodulatory deficiency in BN rats, and further suggest an important functional role for TRH signalling in the mammalian CO2 chemoreflex.
AbstractRaphé‐derived serotonin (5‐HT) and thyrotropin‐releasing hormone (TRH) play important roles in fundamental, homeostatic control systems such as breathing and specifically the ventilatory CO2 chemoreflex. Brown Norway (BN) rats exhibit an inherent and severe ventilatory insensitivity to hypercapnia but also exhibit relatively normal ventilation at rest and during other conditions, similar to multiple genetic models of 5‐HT system dysfunction in mice. Herein, we tested the hypothesis that the ventilatory insensitivity to hypercapnia in BN rats is due to altered raphé gene expression and the consequent deficiencies in raphé‐derived neuromodulators such as TRH. Medullary raphé transcriptome comparisons revealed lower expression of multiple 5‐HT neuron‐specific genes in BN compared to control Dahl salt‐sensitive rats, predictive of reduced central nervous system monoamines by bioinformatics analyses and confirmed by high‐performance liquid chromatography measurements. In particular, raphé Trh mRNA and peptide levels were significantly reduced in BN rats, and injections of the stable TRH analogue Taltirelin (TAL) stimulated breathing dose‐dependently, with greater effects in BN versus control Sprague–Dawley rats. Importantly, TAL also effectively normalized the ventilatory CO2 chemoreflex in BN rats, but TAL did not affect CO2 sensitivity in control Sprague–Dawley rats. These data establish a molecular basis of the neuromodulatory deficiency in BN rats, and further suggest an important functional role for TRH signalling in the mammalian CO2 chemoreflex.
Microvascular perfusion heterogeneity contributes to peripheral vascular disease in metabolic syndrome
Authors: Frisbee Jefferson C. , Goodwill Adam G. , Frisbee Stephanie J. , Butcher Joshua T. , Wu Fan , Chantler Paul D. 
Published: November 2014

AbstractA major challenge facing public health is the increased incidence and prevalence of the metabolic syndrome, a clinical condition characterized by excess adiposity, impaired glycaemic control, dyslipidaemia and moderate hypertension. The greatest concern for this syndrome is the profound increase in risk for development of peripheral vascular disease (PVD) in afflicted persons. However, ongoing studies suggest that reductions in bulk blood flow to skeletal muscle may not be the primary contributor to the premature muscle fatigue that is a hallmark of PVD. Compelling evidence has been provided suggesting that an increasingly spatially heterogeneous and temporally stable distribution of blood flow at successive arteriolar bifurcations in metabolic syndrome creates an environment where a large number of the pre‐capillary arterioles have low perfusion, low haematocrit, and are increasingly confined to this state, with limited ability to adapt perfusion in response to a challenged environment. Single pharmacological interventions are unable to significantly restore function owing to a divergence in their spatial effectiveness, although combined therapeutic approaches to correct adrenergic dysfunction, elevated oxidant stress and increased thromboxane A2improve perfusion‐based outcomes. Integrated, multi‐target therapeutic interventions designed to restore healthy network function and flexibility may provide for superior outcomes in subjects with metabolic syndrome‐associated PVD.
The Effect of Honeycomb Core Geometry on the Sound Transmission
Performance of Sandwich Panels
Authors: Griese David , Summers Joshua D. , Thompson Lonny 
Published: November 2014

Abstract
The authors present numerical results for a systematic parametric study of the effect of honeycomb core geometry on the sound transmission and vibration properties of in-plane loaded honeycomb core sandwich panels using structural acoustic finite element analysis (FEA). Honeycomb cellular structures offer many distinct advantages over homogenous materials because their effective material properties depend on both their constituent material properties and their geometric cell configuration. From these structures, a wide range of targeted effective material properties can be achieved thus supporting forward design-by-tailoring honeycomb cellular structures for specific applications. One area that has not been fully explored is the set of acoustic properties of honeycomb and understanding of how designers can effectively tune designs in different frequency ranges. One such example is the insulation of target sound frequencies to prevent sound transmission through a panel. This work explored the effect of geometry of in-plane honeycomb cores in sandwich panels on the acoustic properties the panel. The two acoustic responses of interest are the general level of sound transmission loss (STL) of the panel and the location of the resonance frequencies that exhibit high levels of sound transmission, or low sound pressure transmission loss. Constant mass honeycomb core models were studied with internal cell angles ranging in increments from −45 deg to +45 deg. Effective honeycomb moduli based on static analysis of honeycomb unit cells are calculated and correlated to the shift in resonance frequencies for the different geometries, with all panels having the same total mass. This helps explain the direction of resonance frequency shift found in the panel natural frequency solutions. Results show an interesting trend of the first resonance frequencies in relation to effective structural properties. Honeycomb geometries with smaller core internal cell angles, under constant mass constraints, shifted natural frequencies lower, and had more resonances in the 1–1000 Hz range, but exhibited a higher sound pressure transmission loss between resonant frequencies.
In Vitro
Antiviral Activity and Preclinical and Clinical Resistance Profile of Miravirsen, a Novel Anti-Hepatitis C Virus Therapeutic Targeting the Human Factor miR-122
Authors: Ottosen Søren , Parsley Todd B. , Yang Lu , Zeh Karin , van Doorn Leen-Jan , van der Veer Eva , Raney Anneke K. , Hodges Michael R. , Patick Amy K. 
Published: November 2014

ABSTRACT

Miravirsen is a β-
d
-oxy-locked nucleic acid-modified phosphorothioate antisense oligonucleotide targeting the liver-specific microRNA-122 (miR-122). Miravirsen demonstrated antiviral activity against hepatitis C virus (HCV) genotype 1b replicons with a mean 50% effective concentration (EC
50
) of 0.67 μM. No cytotoxicity was observed up to the highest concentration tested (>320 μM) in different cell culture models, yielding a therapeutic index of ≥297. Combination studies of miravirsen with interferon α2b, ribavirin, and nonnucleoside (VX-222) and nucleoside (2′-methylcytidine) inhibitors of NS5B, NS5A (BMS-790052), or NS3 (telaprevir) indicated additive interactions. Miravirsen demonstrated broad antiviral activity when tested against HCV replicons resistant to NS3, NS5A, and NS5B inhibitors with less than 2-fold reductions in susceptibility. In serial passage studies, an A4C nucleotide change was observed in the HCV 5′ untranslated region (UTR) from cells passaged in the presence of up to 20 μM (40-fold the miravirsen EC
50
concentration) at day 72 of passage but not at earlier time points (up to 39 days of passage). Likewise, a C3U nucleotide change was observed in the HCV 5′UTR from subjects with viral rebound after the completion of therapy in a miravirsen phase 2 clinical trial. An HCV variant constructed to contain the A4C change was fully susceptible to miravirsen. A C3U HCV variant demonstrated overall reductions in susceptibility to miravirsen but was fully susceptible to all other anti-HCV agents tested. In summary, miravirsen has demonstrated broad antiviral activity and a relatively high genetic barrier to resistance. The identification of nucleotide changes associated with miravirsen resistance should help further elucidate the biology of miR-122 interactions with HCV. (The clinical trial study has been registered at ClinicalTrials.gov under registration no. NCT01200420).
The Two-Component System GrvRS (EtaRS) Regulates
ace
Expression in Enterococcus faecalis OG1RF
Authors: Roh Jung Hyeob , Singh Kavindra V. , La Rosa Sabina Leanti , Cohen Ana Luisa V. , Murray Barbara E. 
Published: November 2014

ABSTRACT

Expression of
ace
(
a
dhesin to
c
ollagen of

E
nterococcus faecalis

), encoding a virulence factor in endocarditis and urinary tract infection models, has been shown to increase under certain conditions, such as in the presence of serum, bile salts, urine, and collagen and at 46°C. However, the mechanism of
ace
/Ace regulation under different conditions is still unknown. In this study, we identified a two-component regulatory system GrvRS as the main regulator of
ace
expression under these stress conditions. Using Northern hybridization and β-galactosidase assays of an
ace
promoter-
lacZ
fusion, we found transcription of
ace
to be virtually absent in a
grvR
deletion mutant under the conditions that increase
ace
expression in wild-type OG1RF and in the complemented strain. Moreover, a
grvR
mutant revealed decreased collagen binding and biofilm formation as well as attenuation in a murine urinary tract infection model. Here we show that GrvR plays a major role in control of
ace
expression and
E. faecalis
virulence.
Psychophysiology of Refractive Accommodative Esotropia
Authors: Kim Ungsoo Samuel 
Published: November 2014

Purpose. To investigate the psychophysiologic aspects of refractive accommodative esotropia (RAE).Methods. I prospectively recruited patients aged 3–6 years with more than 3.0 diopters of hyperopia who presented at Kim’s Eye Hospital from January 2011 to March 2013. I compared Korean Child Behavior Checklist (K-CBCL) which consists of internalizing factors (social withdrawal, somatic complaints, anxiety, and depression) and externalizing factors (social problems, thought problems, attention problems, delinquent behavior, and aggressive behavior) between RAE group and control group.Results. Two out of three internalizing indexes were significantly different between groups (somatic complaints: RAE children50.1±4.6and controls46.6±5.8, P=0.026; depression/anxiety: RAE children48.8±7.9and controls43.9±6.8, P=0.024). Although there was no significant difference, RAE children scored slightly higher on the externalizing behavior index. In the RAE group, the far angle of esodeviation showed a moderate correlation with withdrawn behaviors.Conclusion. Hypermetropic children with high scores on the somatic complaint and depression/anxiety subscales of the CBCL could be at high risk for developing RAE. Psychosocial problems might be related to the pathogenesis of refractive accommodative esotropia.
Telomere Length and the Risk of Atrial Fibrillation
Authors: Roberts Jason D. , Dewland Thomas A. , Longoria James , Fitzpatrick Annette L. , Ziv Elad , Hu Donglei , Lin Jue , Glidden David V. , Psaty Bruce M. , Burchard Esteban G. , Blackburn Elizabeth H. , Olgin Jeffrey E. , Heckbert Susan R. , Marcus Gregory M. 
Published: November 2014

Background—
Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients.

Methods and Results—

Mean LTL and the
TERT
rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95% confidence interval: 0.92–1.29;
P
=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the
TERT
rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95% confidence interval: 0.88–1.04;
P
=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19±0.20 versus 1.02±0.25 [T/S ratio],
P
<0.001), a finding that remained consistent within the AF subgroup.

Conclusions—
Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.