bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Toll-Like Receptor 1/2 Agonist Augments Contractility in Rat Corpus Cavernosum
Authors: Stallmann-Jorgensen Inger , Ogbi Safia , Szasz Theodora , Webb R. Clinton 
Published: July 2015

ABSTRACT

Introduction
Activation of the innate immune Toll-like receptor 2 (TLR2) initiates inflammation and has been implicated in vascular dysfunction. Increased contraction and decreased relaxation responses in the penile vasculature lead to erectile dysfunction, a condition associated with inflammation. However, whether TLR2 activation plays a role in penile vascular function has not been established.

Aim
We hypothesized that activation of the TLR 1/2 heterodimer (TLR1/2) augments contractile and impairs relaxation responses of corpus cavernosum and that these perturbations of vascular function are mediated by low nitric oxide (NO) availability and enhanced activity of the RhoA/Rho-kinase pathway.

Methods
Contraction and relaxation responses were measured in rat cavernosal strips using a myograph after incubation with a TLR1/2-activating ligand Pam3CSK4 (Pam3), the TLR1/2 inhibitor CuCPT 22 (CuCPT), and inhibitors of NO synthase (LNAME) and Rho-kinase (Y27632). TLR2 protein expression was assessed by immunohistochemistry.

Main Outcome Measures
Cumulative concentration response curves, sensitivity (pEC50), and maximal response (Emax) of cavernosal strips to vasodilatory and vasocontractile agonists were compared between treatments.

Results
Pam3-treated cavernosal strips exhibited greater pEC50 and higher Emax to phenylephrine (PE) than control tissues. Inhibition of NO synthase increased Emax to PE in Pam3-treated cavernosal strips. Pam3 treatment reduced relaxation to Y27632 compared with control tissues. Inhibition of TLR1/2 activation with CuCPT returned the augmented contraction to PE and the decreased relaxation to Y27632 of Pam3-treated cavernosal strips to control values.

Conclusions
The TLR1/2 heterodimer mediates augmented contraction and reduced relaxation in rat cavernosal strips. Thus, TLR1/2 activation antagonizes vascular responses crucial for normal erectile function and implicates immune activation in vasculogenic erectile dysfunction. Immune signaling via TLR2 may offer novel targets for treating inflammation-mediated vascular dysfunction in the penis.
Liver‐infiltrating CD8+ lymphocytes as prognostic factor for tumour recurrence in hepatitis C virus‐related hepatocellular carcinoma
Authors: Ramzan Muhammad , Sturm Nathalie , Decaens Thomas , Bioulac‐Sage Paulette , Bancel Brigitte , Merle Philippe , Tran Van Nhieu Jeanne , Slama Rémy , Letoublon Christian , Zarski Jean‐Pierre , Jouvin‐Marche Evelyne , Marche Patrice N. , Leroy Vincent 
Published: July 2015

AbstractBackgroundChronic liver inflammation and immune/inflammatory response promote hepatocellular carcinoma. The aim of this study was to characterize the immune status of HCV‐related cirrhosis in patients with hepatocellular carcinoma (HCV‐HCC) as compared to HCV patients without hepatocellular carcinoma.MethodImmune markers (CD3, CD4, CD8, CD20, CD56, TCRγδ, FoxP3) and gene expression profiles (CD8α, CD8β, FoxP3, IL‐6, IFN‐γ, perforin, RANTES) were analysed in a test cohort by immunohistochemistry and quantitative RT‐PCR analysis on serial non‐tumorous and tumorous tissues.ResultsImmune micro‐environment was more inflammatory in HCV‐HCC than HCV cirrhotic livers. The number of CD3+, CD4+, CD8+ and CD20+ liver‐infiltrating lymphocytes was significantly higher, whereas the number of CD56+ cells was significantly lower in HCV‐HCC compared to HCV cirrhotic parenchyma. These differences were restricted to fibrous septa for CD4+ and CD20+ cells and to nodular parenchyma for CD8+ cells. Gene expressions of CD8α, FoxP3 and RANTES were also significantly higher in HCV‐HCC than in HCV cirrhosis. Interestingly, in a large cohort of 63 HCV‐HCC patients. The number of CD8+ cells ≥100/field was associated with significant higher tumour recurrence (P = 0.003) and lower overall survival (P = 0.05) at 5 years.ConclusionHigh densities of liver‐infiltrating lymphocytes in HCV‐HCC cirrhotic parenchyma prevail inflammatory conditions and could contribute to tumorigenesis and tumour recurrence. These results could contribute towards better clinical evaluation of patients susceptible for HCC recurrence after curative surgery.
Esophagogastric junction contractility for clinical assessment in patients with GERD: a real added value?
Authors: Tolone S. , De Bortoli N. , Marabotto E. , de Cassan C. , Bodini G. , Roman S. , Furnari M. , Savarino V. , Docimo L. , Savarino E. 
Published: July 2015

AbstractBackgroundThe role of esophagogastric junction contractile integral (EGJ‐CI) as assessed by high‐resolution manometry (HRM) is unclear. We aimed to correlate the EGJ‐CI with impedance‐pH findings in gastro‐esophageal reflux disease (GERD) patients.MethodsConsecutive patients with GERD symptoms were enrolled. All patients underwent upper endoscopy, HRM, and impedance‐pH testing. The EGJ‐CI was calculated using the distal contractile integral tool box during three consecutive respiratory cycles. The value was then divided by the duration of these cycles. A value below 13 was considered as a defective EGJ‐CI. We also assessed EGJ morphology, esophageal acid exposure time (AET), number of reflux episodes (NRE), and symptom association analysis (SAA). A positive impedance‐pH monitoring was considered in case of abnormal AET and/or NRE and/or positive SAA.Key ResultsAmong 130 patients we enrolled, 91 had GERD (abnormal AET and/or elevated NRE and/or positive SAA) and 39 had functional heartburn (FH) (negative endoscopy, normal AET, normal NRE, and negative SAA). The GERD patients had a lower median value of EGJ‐CI (11 [3.1–20.7] vs 22 [9.9–41], p < 0.02) compared to FH patients. Patients with a defective EGJ‐CI had, more frequently, a positive impedance‐pH monitoring or esophageal mucosal lesions at endoscopy (p < 0.05 and p < 0.05, respectively) than patients with a normal EGJ‐CI. An EGJ‐CI cut‐off value of 5 mmHg cm yielded the optimal performance in identifying GERD at impedance‐pH (sensitivity 89%–specificity 63%).Conclusions & InferencesA defective EGJ‐CI at HRM is clearly associated with evidence of GERD at impedance‐pH monitoring. Evaluating EGJ‐CI may be useful to predict an abnormal impedance‐pH testing.
The GPR55 antagonist CID16020046 protects against intestinal inflammation
Authors: Stančić A. , Jandl K. , Hasenöhrl C. , Reichmann F. , Marsche G. , Schuligoi R. , Heinemann A. , Storr M. , Schicho R. 
Published: July 2015

AbstractBackgroundG protein‐coupled receptor 55 (GPR55) is a lysophospholipid receptor responsive to certain cannabinoids. The role of GPR55 in inflammatory processes of the gut is largely unknown. Using the recently characterized GPR55 inhibitor CID16020046, we determined the role of GPR55 in experimental intestinal inflammation and explored possible mechanisms of action.MethodsColitis was induced by either 2.5% dextran sulfate sodium (DSS) supplemented in the drinking water of C57BL/6 mice or by a single intrarectal application of trinitrobenzene sulfonic acid (TNBS).Key ResultsDaily application of CID16020046 (20 mg/kg) significantly reduced inflammation scores and myeloperoxidase (MPO) activity. In the DSS colitis model, levels of tumor necrosis factor alpha (TNF‐α) and interleukin 1 beta (IL‐1β), and the expression of cyclooxygenase (Cox)‐2 and signal transducer and activator of transcription 3 (STAT‐3) were reduced in colon tissues while in TNBS‐induced colitis, levels of Cox‐2, IL‐1β and IL‐6 were significantly lowered. Evaluation of leukocyte recruitment by flow cytometry indicated reduced presence of lymphocytes and macrophages in the colon following GPR55 inhibition in DSS‐induced colitis. In J774A.1 mouse macrophages, inhibition of GPR55 revealed reduced migration of macrophages and decreased CD11b expression, suggesting that direct effects of CID16020046 on macrophages may have contributed to the improvement of colitis. GPR55−/− knockout mice showed reduced inflammation scores as compared to wild type mice in the DSS model suggesting a pro‐inflammatory role in intestinal inflammation.Conclusions & InferencesPharmacological blockade of GPR55 reduces experimental intestinal inflammation by reducing leukocyte migration and activation, in particular that of macrophages. Therefore, CID16020046 represents a possible drug for the treatment of bowel inflammation.
Root aquaporins contribute to whole plant water fluxes under drought stress in rice (Oryza sativa L.)
Authors: Grondin Alexandre , Mauleon Ramil , Vadez Vincent , Henry Amelia 
Published: July 2015

AbstractAquaporin activity and root anatomy may affect root hydraulic properties under drought stress. To better understand the function of aquaporins in rice root water fluxes under drought, we studied the root hydraulic conductivity (Lpr) and root sap exudation rate (Sr) in the presence or absence of an aquaporin inhibitor (azide) under well‐watered conditions and following drought stress in six diverse rice varieties. Varieties varied in Lpr and Sr under both conditions. The contribution of aquaporins to Lpr was generally high (up to 79% under well‐watered conditions and 85% under drought stress) and differentially regulated under drought. Aquaporin contribution to Sr increased in most varieties after drought, suggesting a crucial role for aquaporins in osmotic water fluxes during drought and recovery. Furthermore, root plasma membrane aquaporin (PIP) expression and root anatomical properties were correlated with hydraulic traits. Three chromosome regions highly correlated with hydraulic traits of the OryzaSNP panel were identified, but did not co‐locate with known aquaporins. These results therefore highlight the importance of aquaporins in the rice root radial water pathway, but emphasize the complex range of additional mechanisms related to root water fluxes and drought response.
Fetal Growth, Obesity, and Atopic Disorders in Adolescence: a Retrospective Birth Cohort Study
Authors: Lin Meng‐Hung , Hsieh Chia‐Jung , Caffrey James L. , Lin Yu‐Sheng , Wang I‐Jen , Ho Wen‐Chao , Chen Pau‐Chung , Wu Trong‐Neng , Lin Ruey‐Shiung 
Published: July 2015

AbstractBackgroundDevelopmental status at birth and subsequent obesity have been implicated in the development of childhood atopic dermatitis (AD) and allergic rhinitis (AR).MethodsThe current study analysed the cohort data of 74 688 junior high school students from a national retrospective birth cohort study in Taiwan. A random 10% sample was selected from singleton livebirths with complete data on the analytical variables of interest. Atopic disorders, including AD and AR, were assessed by questionnaires (International Study of Asthma and Allergies in Childhood). Logistic regression analyses were applied with adjustments for related risk factors.ResultsAmong subjects mainly 13–15 years of age, the estimated prevalence was 7.6% for AD and 22.4% for AR. While the role of fetal growth in allergic disorders was less evident, the risk of developing AD and AR were both influenced by a combination of fetal growth status and adolescent body mass index (BMI). Compared with those with normal fetal growth and school‐aged BMI, the risk of developing AD increased 64% among adolescents with both restricted fetal growth and high BMI (odds ratio 1.64, 95% confidence interval 1.37, 1.97). The risk for this combination was higher than that for either restricted fetal growth or high BMI alone. Nevertheless, the overall interaction between BMI and fetal growth status on atopic disorders did not reach statistical significance.ConclusionsExcessive weight gain could be an important risk factor related to developing atopic dermatitis and allergic rhinitis during adolescence, especially among infants born small for gestational age.
(Not So) Easy Come, (Still) Easy Go? Footloose Multinationals Revisited
Authors: Blanchard Pierre , Dhyne Emmanuel , Fuss Catherine , Mathieu Claude 
Published: July 2015

AbstractThe central question of this paper is to test whether multinational firms (MNFs) are more likely to exit the local market than domestic firms. Using firm‐level data for Belgium, we estimate a random effects probit model taking into account the endogeneity of firm size, total factor productivity (TFP) and sunk costs in firm exit. Our results highlight two features of the ‘footloose’ nature of MNFs. First, controlling for firm and sector characteristics, the exit probability of MNFs is larger than that of domestic firms. Second, MNFs have a lower sensitivity to TFP and size than do domestic firms. This means that an improvement in economic performance on the local market will not prevent a multinational from closing its local plant as much as it would for a domestic firm.
Focal metatarsal fistulae syndrome affecting a greyhound dog successfully treated with topical 0.1% tacrolimus ointment
Authors: Scholz Fiona M. , Muse Russell , Burrows Amanda K. 
Published: July 2015

Metatarsal fistulation is an uncommon cutaneous condition reported almost exclusively in German shepherd dogs and their cross‐breeds. To the best of the authors’ knowledge this is the first reported case of focal metatarsal fistulae syndrome affecting a greyhound. Remission was obtained within 6 weeks of commencing treatment using compounded 0.1% tacrolimus ointment twice daily and the dog remained stable for another 6 months with twice weekly application before treatment was discontinued. The dog remained in remission at the time of writing, which is 1 year after treatment withdrawal.
Effects of in vitro hemodilution with crystalloids, colloids, and plasma on canine whole blood coagulation as determined by kaolin‐activated thromboelastography
Authors: Morris Bari R. , deLaforcade Armelle , Lee Joyce , Palmisano Joseph , Meola Dawn , Rozanski Elizabeth 
Published: July 2015

AbstractObjectiveTo investigate the effects of in vitro hemodilution with lactated Ringers solution (LRS), hetastarch (HES), and fresh frozen plasma (FFP) on whole blood coagulation in dogs as assessed by kaolin‐activated thromboelastography.DesignIn vitro experimental study.SettingUniversity teaching hospital.AnimalsSix healthy client‐owned dogs.InterventionsWhole blood was collected and diluted in vitro at a 33% and 67% dilution with either LRS, HES, or FFP.Measurements and Main ResultsKaolin‐activated thromboelastography was performed on each sample as well as a control. Thromboelastographic parameters R (min), alpha (deg), K (min), and MA (mm) were measured and compared to the sample control for each dilution using mixed model methodology. Prolongation in coagulation times were seen at both dilutions with LRS and HES. There was no significant difference in R times at the 33% dilution, but R time was significantly prolonged at the 67% dilution with HES (P = 0.004). MA was significantly decreased for LRS at both dilutions (P = 0.013, P < 0.001) and more profoundly decreased for HES (P < 0.001, P = 0.006). No significant difference in any parameter was found for FFP.ConclusionsIn vitro hemodilution of whole blood with both LRS and HES but not FFP resulted in significant effects on coagulation with HES having a more profound effect. In vivo evaluation of changes in coagulation with various resuscitation fluids is warranted and may be clinically relevant.
Physiological roles for the subfornical organ: a dynamic transcriptome shaped by autonomic state
Authors: Hindmarch Charles Colin Thomas , Ferguson Alastair V. 
Published: July 2015

AbstractThe subfornical organ (SFO) is a circumventricular organ recognized for its ability to sense and integrate hydromineral and hormonal circulating fluid balance signals, information which is transmitted to central autonomic nuclei to which SFO neurons project. While the role of SFO was once synonymous with physiological responses to osmotic, volumetric and cardiovascular challenge, recent data suggest that SFO neurons also sense and integrate information from circulating signals of metabolic status. Using microarrays, we have confirmed the expression of receptors already described in the SFO, and identified many novel transcripts expressed in this circumventricular organ including receptors for many of the critical circulating energy balance signals such as adiponectin, apelin, endocannabinoids, leptin, insulin and peptide YY. This transcriptome analysis also identified SFO transcripts, the expressions of which are significantly changed by either 72 h dehydration, or 48 h starvation, compared to fed and euhydrated controls. Expression and potential roles for many of these targets are yet to be confirmed and elucidated. Subsequent validation of data for adiponectin and leptin receptors confirmed that receptors for both are expressed in the SFO, that discrete populations of neurons in this tissue are functionally responsive to these adipokines, and that such responsiveness is regulated by physiological state. Thus, transcriptomic analysis offers great promise for understanding the integrative complexity of these physiological systems, especially with development of technologies allowing description of the entire transcriptome of single, carefully phenotyped, SFO neurons. These data will ultimately elucidate mechanisms through which these uniquely positioned neurons respond to and integrate complex circulating signals.
image
Telavancin for Acute Bacterial Skin and Skin Structure Infections, a
Post Hoc
Analysis of the Phase 3 ATLAS Trials in Light of the 2013 FDA Guidance
Authors: Pushkin Richard , Barriere Steven L. , Wang Whedy , Corey G. Ralph , Stryjewski Martin E. 
Published: July 2015

ABSTRACT

Two phase 3 ATLAS trials demonstrated noninferiority of telavancin compared with vancomycin for complicated skin and skin structure infections. Data from these trials were retrospectively evaluated according to 2013 U.S. Food and Drug Administration (FDA) guidance on acute bacterial skin and skin structure infections. This
post hoc
analysis included patients with lesion sizes of ≥75 cm
2
and excluded patients with ulcers or burns (updated all-treated population;
n
= 1,127). Updated day 3 (early) clinical response was defined as a ≥20% reduction in lesion size from baseline and no rescue antibiotic. Updated test-of-cure (TOC) clinical response was defined as a ≥90% reduction in lesion size, no increase in lesion size since day 3, and no requirement for additional antibiotics or significant surgical procedures. Day 3 (early) clinical responses were achieved in 62.6% and 61.0% of patients receiving telavancin and vancomycin, respectively (difference, 1.7%, with a 95% confidence interval [CI] of −4.0% to 7.4%). Updated TOC visit cure rates were similar for telavancin (68.0%) and vancomycin (63.3%), with a difference of 4.8% (95% CI, −0.7% to 10.3%). Adopting current FDA guidance, this analysis corroborates previous noninferiority findings of the ATLAS trials of telavancin compared with vancomycin.
Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice
Authors: Smits A. , De Cock R. F. W. , Allegaert K. , Vanhaesebrouck S. , Danhof M. , Knibbe C. A. J. 
Published: July 2015

ABSTRACT
Based on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% ≤5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization.
Effects of Zidovudine Treatment on Heart mRNA Expression and Mitochondrial DNA Copy Number Associated with Alterations in Deoxynucleoside Triphosphate Composition in a Neonatal Rat Model
Authors: Snowdin Jacob W. , Hsiung Chia-Heng , Kesterson Daniel G. , Kamath Vasudeva G. , McKee Edward E. 
Published: July 2015

ABSTRACT
The prevention of mother-to-child transmission (MTCT) of HIV is a crucial component in HIV therapy. Nucleoside reverse transcriptase inhibitors (NRTIs), primarily 3′-azido-3′-thymidine (AZT [zidovudine]), have been used to treat both mothers and neonates. While AZT is being replaced with less toxic drugs in treating mothers in MTCT prevention, it is still commonly used to treat neonates. Problems related to mitochondrial toxicity and potential mutagenesis associated with AZT treatment have been reported in treated cohorts. Yet little is known concerning the metabolism and potential toxicity of AZT on embryonic and neonatal tissues, especially considering that the enzymes of nucleoside metabolism change dramatically as many tissues convert from hyperplastic to hypertrophic growth during this period. AZT is known to inhibit thymidine phosphorylation and potentially alter deoxynucleoside triphosphate (dNTP) pools in adults. This study examines the effects of AZT on dNTP pools, mRNA expression of deoxynucleoside/deoxynucleotide metabolic enzymes, and mitochondrial DNA levels in a neonatal rat model. Results show that AZT treatment dramatically altered dNTP pools in the first 7 days of life after birth, which normalized to age-matched controls in the second and third weeks. Additionally, AZT treatment dramatically increased the mRNA levels of many enzymes involved in deoxynucleotide synthesis and mitochondrial biogenesis during the first week of life, which normalized to age-matched controls by the third week. These results were correlated with depletion of mitochondrial DNA noted in the second week. Taken together, results demonstrated that AZT treatment has a powerful effect on the deoxynucleotide synthesis pathways that may be associated with toxicity and mutagenesis.
Characterization of an Enterobacter cloacae Strain Producing both KPC and NDM Carbapenemases by Whole-Genome Sequencing
Authors: Wu Wenjing , Feng Yu , Carattoli Alessandra , Zong Zhiyong 
Published: July 2015

ABSTRACT

A carbapenem-resistant
Enterobacter cloacae
strain, WCHECl-14653, causing a fatal bloodstream infection, was characterized by genome sequencing and conjugation experiments. The strain carried two carbapenemase genes,
bla
NDM-1
and
bla
KPC-2
, on separate IncF plasmids. The coexistence of
bla
NDM-1
and
bla
KPC-2
conferred slightly higher-level carbapenem resistance compared with that of
bla
NDM-1
or
bla
KPC-2
alone, and the coexistence of two IncF plasmids may generate new platforms for spreading carbapenemase genes.