bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mirabegron causes relaxation of human and rat corpus cavernosum: could it be a potential therapy for erectile dysfunction?
Authors: Gur Serap , Peak Taylor , Yafi Faysal A. , Kadowitz Philip J. , Sikka Suresh C. , Hellstrom Wayne J.G. 
Published: April 2016

ObjectiveTo examine the effects of mirabegron, a selective β3‐adrenoceptor agonist that has recently been approved for the treatment of overactive bladder (OAB), on erectile function. Stimulation of β3‐adrenoceptors localised in cavernosal smooth muscle cells may play a physiological role in mediating penile erection, and offer a beneficial pharmacological action for patients who have OAB and erectile dysfunction (ED).Materials and MethodsCorpus cavernosal (CC) specimens were obtained from patients with ED and Peyronie's disease undergoing penile prosthesis implantation. Erectile responses were also evaluated in vivo after intracavernosal injection (ICI) of mirabegron in anaesthetised rats. Mirabegron‐elicited relaxation responses (10–8–10–3 m) on phenylephrine‐induced contraction were seen in human CC (HCC) and rat CC strips in isolated organ‐bath studies. The effects of inhibitors, namely L‐NAME [NG‐nitro‐L‐arginine methyl ester, a competitive inhibitor of nitric oxide synthase (NOS), 100 μm], ODQ [1H‐(1,2,4) oxadiazolo(4,3‐α) quinoxalin‐1‐one, a soluble guanylyl cyclase (sGC) inhibitor, 30μm], methylene blue (a NOS and sGC inhibitor, 20μm), SR59230A (β3‐adrenoceptor blocker, 1 μm), and fasudil [Rho‐associated protein kinase (ROCK) inhibitor, 0.1 μm], on mirabegron‐induced relaxation responses were evaluated. Responses to mirabegron were compared with responses to isoprenaline and nebivolol. Immunohistochemistry was used to localise β3‐adrenoceptors and ROCK in CC smooth muscle cells. In vivo rat data were expressed as intracavernosal pressure (ICP)/mean arterial pressure, and total ICP.ResultsMirabegron resulted in a relaxation of phenylephrine‐evoked CC contractions in a concentration‐dependent manner and SR59230A antagonised the mirabegron‐induced relaxations in HCC and rat CC. Other inhibitors, L‐NAME, ODQ, and methylene blue, did not affect the mirabegron‐induced relaxation responses. Mirabegron relaxation responses at concentrations (0.1–10 μm) were enhanced by fasudil (ROCK inhibitor) in rat but not in HCC strips. KCl‐induced contractions in HCC and rat CC were partially inhibited by mirabegron. In vivo, ICI of mirabegron (doses of 0.1–1 mg/kg) had a minor effect on ICP when compared with vehicle administration. Immunohistochemistry data showed β3‐adrenoceptors localised in the smooth muscle cells of the HCC and rat CC.ConclusionsMirabegron markedly relaxed isolated CC strips by activating β3‐adrenoceptors independently of the NO‐cGMP pathway. There is also evidence of the existence of a close functional link between β3‐adrenoceptors and the RhoA/ROCK pathway. These results may support further clinical studies using combinations of mirabegron with ROCK and phosphodiesterase type 5 inhibitors (PDE5i) for the treatment of ED, especially in patients who do not respond to PDE5i therapy.
Testosterone undecanoate improves sexual function in men with type 2 diabetes and severe hypogonadism: results from a 30‐week randomized placebo‐controlled study
Authors: Hackett Geoffrey , Cole Nigel , Saghir Atif , Jones Peter , Strange Richards C. , Ramachandran Sudarshan 
Published: April 2016

ObjectiveTo evaluate the sexual function response to 30 weeks’ treatment with long‐acting testosterone undecanoate (TU) or placebo in 199 men with type 2 diabetes and either severe or mild hypogonadism (HG).Patients and MethodsMen with HG were identified from seven primary care type 2 diabetes registers. A 30‐week randomized placebo‐controlled study of TU was carried out in 199 of these men (placebo, n = 107, TU, n = 92). The patient‐reported outcome measure was the 15‐item International Index of Erectile Function score. Men completing the study (n=189) were stratified, firstly, by baseline total testosterone (TT) or free testosterone (FT) into mild HG (TT 8.1–12 nmol/L or FT 0.18–0.25 nmol/L) and severe HG groups (TT ≤8 nmol/L and FT ≤0.18 nmol/L), and secondly, by intervention (placebo or TU), thereby creating four groups: mild HG/placebo; mild HG/TU; severe HG/placebo and severe HG/TU.Statistical AnalysisChanges in sexual function score (a secondary outcome of the study) at each visit within group (from baseline) and between groups (TU vs placebo) at each assessment (6, 18 and 30 weeks) were compared using a Wilcoxon signed‐rank and Wilcoxon rank‐sum test, respectively.ResultsSignificant improvement in erectile function was evident only in the severe HG group after 30 weeks of TU treatment; this finding persisted when TU was compared with placebo. Intercourse satisfaction and sexual desire scores were also improved at 6, 18 and 30 weeks in the severe HG group after TU treatment; this increase in scores was also evident when compared with placebo. TU did not appear to alter orgasmic function significantly in any of the patient groups.ConclusionsThe present study suggests that benefit in sexual symptoms after TU treatment is evident principally in patients with HG with TT levels ≤8 nmol/L and FT levels ≤0.18 nmol/L. We also suggest that 30 weeks of treatment is necessary before evaluating improvement in erectile function.
Reconstruction of an Extensive Midfacial Defect Using Additive Manufacturing Techniques
Authors: Fernandes Nelson , van den Heever Jacobus , Hoogendijk Christiaan , Botha Sarel , Booysen Gerrie , Els Johan 
Published: April 2016

AbstractMalignant peripheral nerve sheath tumors are extremely rare tumors arising in peripheral nerves. Only 17 cases involving the trigeminal nerve have ever been reported. These tumors have a very poor prognosis and very high rates of recurrence and metastases. Their recommended treatment involves complete tumor resection followed by radiation. This can be problematic in the head and neck region. We present a clinical case involving a 33‐year‐old female patient presenting with a slow‐growing, exophytic mass of the anterior maxilla. Incisional biopsy and subsequent histological examination revealed a diagnosis of a malignant peripheral nerve sheath tumor. Surgical resection involved a complete maxillectomy, rhinectomy, and resection of the upper lip and aspects of the left and right cheeks. Reconstruction of the subsequent defect incorporated the placement of four zygomatic oncology implants to aid in retention of a facial prosthesis. These implants, however, were subsequently lost; and an anatomical model of the hard tissues was manufactured via 3D printing. This model was used to design and manufacture a titanium frame (customized implant) for the patient. The frame was then fixated and secured intraoperatively with 21 cortical screws. A maxillary denture and silicone facial prosthesis were also made to fit onto this frame. This is the first known case where additive manufacturing, via the use of rapid prototyping and 3D printing, was employed to manufacture a facial prosthesis.
Human Nature and Moral Sprouts: Mencius on the Pollyanna Problem
Authors: Kim Richard T. 
Published: April 2016

AbstractThis article responds to a common criticism of Aristotelian naturalism known as the Pollyanna Problem, the objection that Aristotelian naturalism, when combined with recent empirical research, generates morally unacceptable conclusions. In developing a reply to this objection, I draw upon the conception of human nature developed by the ancient Chinese philosopher Mencius, and build up an account of ethical naturalism that provides a satisfying response to the Pollyanna Problem while also preserving what is most attractive about Aristotelian naturalism.
Full-Genome Sequences of Seven Fatal Enterovirus 71 Strains Isolated in Shenzhen, China, in 2014
Authors: Chen Long , He Ya-Qing , Meng Jun , Xiong Ling-Hong , Wang Chao , Yao Xiang-Jie , Zhang Hai-Long , Zhang Ren-Li , Yang Hong 
Published: April 2016

ABSTRACT
The whole-genome sequences of seven fatal enterovirus 71 (EV71) strains, isolated in southern China, in 2014, were determined. The complete genome sequences of these strains displayed close relationships to native EV71 strains and showed 94.2% to 99.8% identity to each other. All of these strains were assigned to subgenotype C4a based on phylogenetic analysis of the VP1 gene.
COAGULATION SCREENS REQUESTED IN AN EMERGENCY DEPARTMENT: CLINICALLY INDICATED OR NOT?
Authors: Park K , Ahmed N , Probst F , Mitra A , Ajayi A , Zafar K 
Published: April 2016

Objectives & BackgroundEmergency Department (ED) staff order blood tests for diagnostic work-up and to facilitate prompt treatment. However, with the emerging use of Rapid Assessment and Treatment (RAT) models aiming to provide early assessment by doctors, inappropriate investigations can be requested as a consequence. Our objectives were to establish whether coagulation screens performed in our London ED were clinically appropriate, and to determine its subsequent financial implications.MethodsRetrospective analysis of blood investigations performed was done using the ED computer system (Ascribe Symphony, UK). The first cohort was a random selection of approximately one-third of ED attendances during a one-week period in July 2013. Inclusion criteria were only patients who were seen by ED clinicians; patients seen directly by other specialties were excluded. Clinical notes were reviewed for every patient who had coagulation screens requested. A recently revised ED ‘investigation matrix’ was used as a local departmental standard.Up-to-date costs were obtained from the Pathology Department for common investigations (including a coagulation screen and D-Dimer for 2013/14). On the basis of initial results, implementations were introduced in the form of: staff teaching sessions, displaying of up-to-date cost figures, daily team read file and local posters highlighting the importance of cost prevention.The re-audit (second cohort) was performed 9 months later in May 2014 for all consecutive patients investigated by ED clinicians in a one-week period. Patients were included and excluded on the basis of the same criteria, with the same ‘blood matrix’ as a standard.Results70% of patients in the first cohort had blood tests (n=137). 54% of these patients had coagulation screens (n=74), 66% of them not being clinically indicated (n=49). From our initial findings, we projected an estimated loss of>£90,000 per year.52% patients in the second cohort had blood tests (n=370). 23% of these patients had coagulation screens (n=84), with 68% clinically inappropriate (n=57) based on our clinical criteria.ConclusionCoagulation screens are sent in the majority of patients in the absence of clinical indications. A huge financial implication is associated with the investigations. A different approach is required in the ED to avoid inappropriate use of coagulation screens.
Dietary vitamin E supplementation on cholesterol, vitamin E content, and fatty acid profile in chicken muscles
Authors: Zdanowska-Sąsiadek Ż. , Michalczuk M. , Poławska E. , Damaziak K. , Niemiec J. , Radzik-Rant A. 
Published: April 2016

The aim of the study was to determine the effect of dietary vitamin E level on cholesterol and vitamin E content and fatty acid profile in broiler chicken breast and leg muscles. Chickens (420 cocks) were randomly divided into two feeding groups (210 birds each). The control group was fed with standard diet containing 44 mg kg−1of vitamin E, whereas the experimental group was supplemented with extra 200 mg kg−1of vitamin E. The dietary addition of vitamin E caused a significant increase in its content in the muscles, with a higher value noted in the leg muscles. Meat of chickens fed with the higher dose of vitamin E was also characterized by a lower cholesterol level. The addition of vitamin E as well as type of the muscles had a significant effect on the fatty acid profile and values of atherogenicity (AI) and thrombogenicity (TI) indices. The recorded increase in the content of n-3 polyunsaturated fatty acids (PUFAs) and a decrease in the n-6/n-3 fatty acid ratio indicate a positive effect of vitamin E on the fatty acid profile. In turn, lower values of AI and TI in leg muscles of chickens with a high intake of vitamin E prove the beneficial fatty acid profile in these muscles upon such supplementation.
Comparing anesthesia with isoflurane and fentanyl/fluanisone/midazolam in a rat model of cardiac arrest
Authors: Secher Niels , Malte Christian Lind , Tønnesen Else , Østergaard Leif , Granfeldt Asger 
Published: April 2016

Only one in ten patients survives cardiac arrest (CA), underscoring the need to improve CA management. Isoflurane has shown cardio- and neuroprotective effects in animal models of ischemia-reperfusion injury. Therefore, the beneficial effect of isoflurane should be tested in an experimental CA model. We hypothesize that isoflurane anesthesia improves short-term outcome following resuscitation from CA compared with a subcutaneous fentanyl/fluanisone/midazolam anesthesia. Male Sprague-Dawley rats were randomized to anesthesia with isoflurane ( n = 11) or fentanyl/fluanisone/midazolam ( n = 11). After 10 min of asphyxial CA, animals were resuscitated by mechanical chest compressions, ventilations, and epinephrine and observed for 30 min. Hemodynamics, including coronary perfusion pressure, systemic O2consumption, and arterial blood gases, were recorded throughout the study. Plasma samples for endothelin-1 and cathecolamines were drawn before and after CA. Compared with fentanyl/fluanisone/midazolam anesthesia, isoflurane resulted in a shorter time to return of spontaneous circulation (ROSC), less use of epinephrine, increased coronary perfusion pressure during cardiopulmonary resusitation, higher mean arterial pressure post-ROSC, increased plasma levels of endothelin-1, and decreased levels of epinephrine. The choice of anesthesia did not affect ROSC rate or systemic O2consumption. Isoflurane reduces time to ROSC, increases coronary perfusion pressure, and improves hemodynamic function, all of which are important parameters in CA models.NEW & NOTEWORTHY The preconditioning effect of volatile anesthetics in studies of ischemia-reperfusion injury has been demonstrated in several studies. This study shows the importance of anesthesia in experimental cardiac arrest studies as isoflurane raised coronary perfusion pressure during resuscitation, reduced time to return of spontaneous circulation, and increased arterial blood pressure in the post-cardiac arrest period. These effects on key outcome measures in cardiac arrest research are important in the interpretation of results from animal studies.
Antibody-Targeted Chemotherapy for the Treatment of Melanoma
Authors: Nevala Wendy K. , Buhrow Sarah A. , Knauer Daniel J. , Reid Joel M. , Atanasova Elena A. , Markovic Svetomir N. 
Published: April 2016

AbstractAntibody-directed chemotherapy (ADC) offers an advantage over conventional chemotherapy because it provides antibody-directed targeting, with resultant improvement in therapeutic efficacy and reduced toxicity. Despite extensive research, with notable exceptions, broad clinical application of ADC remains elusive; major hurdles include the instability of antibody–chemotherapy linkers and reduced tumor toxicity of the chemotherapy when bound to the antibody. To address these challenges, we have developed a platform technology that utilizes the nab-paclitaxel formulation of paclitaxel, Abraxane, in which hydrophobic paclitaxel is suspended in 130-nm albumin nanoparticles and thus made water-soluble. We have developed a method to noncovalently coat the Abraxane nanoparticle with recombinant mAbs (anti-VEGF, bevacizumab) and guide Abraxane delivery into tumors in a preclinical model of human A375 melanoma. Here, we define the binding characteristics of bevacizumab and Abraxane, demonstrate that the chemotherapy agent retains its cytotoxic effect, while the antibody maintains the ability to bind its ligand when the two are present in a single nanoparticle (AB160), and show that the nanoparticle yields improved antitumor efficacy in a preclinical human melanoma xenograft model. Further data suggest that numerous therapeutic monoclonal IgG1 antibodies may be utilized in this platform, which has implications for many solid and hematologic malignancies. Cancer Res; 76(13); 3954–64. ©2016 AACR.
A Synthetic Cell-Penetrating Dominant-Negative ATF5 Peptide Exerts Anticancer Activity against a Broad Spectrum of Treatment-Resistant Cancers
Authors: Karpel-Massler Georg , Horst Basil A. , Shu Chang , Chau Lily , Tsujiuchi Takashi , Bruce Jeffrey N. , Canoll Peter , Greene Lloyd A. , Angelastro James M. , Siegelin Markus D. 
Published: April 2016

Abstract
Purpose: Despite significant progress in cancer research, many tumor entities still have an unfavorable prognosis. Activating transcription factor 5 (ATF5) is upregulated in various malignancies and promotes apoptotic resistance. We evaluated the efficacy and mechanisms of the first described synthetic cell-penetrating inhibitor of ATF5 function, CP-d/n-ATF5-S1.
Experimental Design: Preclinical drug testing was performed in various treatment-resistant cancer cells and in vivo xenograft models.
Results: CP-d/n-ATF5-S1 reduced the transcript levels of several known direct ATF5 targets. It depleted endogenous ATF5 and induced apoptosis across a broad panel of treatment-refractory cancer cell lines, sparing non-neoplastic cells. CP-d/n-ATF5-S1 promoted tumor cell apoptotic susceptibility in part by reducing expression of the deubiquitinase Usp9X and led to diminished levels of antiapoptotic Bcl-2 family members Mcl-1 and Bcl-2. In line with this, CP-d/n-ATF5-S1 synergistically enhanced tumor cell apoptosis induced by the BH3-mimetic ABT263 and the death ligand TRAIL. In vivo, CP-d/n-ATF5-S1 attenuated tumor growth as a single compound in glioblastoma, melanoma, prostate cancer, and triple receptor–negative breast cancer xenograft models. Finally, the combination treatment of CP-d/n-ATF5-S1 and ABT263 significantly reduced tumor growth in vivo more efficiently than each reagent on its own.
Conclusions: Our data support the idea that CP-d/n-ATF5-S1, administered as a single reagent or in combination with other drugs, holds promise as an innovative, safe, and efficient antineoplastic agent against treatment-resistant cancers. Clin Cancer Res; 22(18); 4698–711. ©2016 AACR.
Clinical Scales Do Not Reliably Identify Acute Ischemic Stroke Patients With Large-Artery Occlusion
Authors: Turc Guillaume , Maïer Benjamin , Naggara Olivier , Seners Pierre , Isabel Clothilde , Tisserand Marie , Raynouard Igor , Edjlali Myriam , Calvet David , Baron Jean-Claude , Mas Jean-Louis , Oppenheim Catherine 
Published: April 2016

Background and Purpose—
It remains debated whether clinical scores can help identify acute ischemic stroke patients with large-artery occlusion and hence improve triage in the era of thrombectomy. We aimed to determine the accuracy of published clinical scores to predict large-artery occlusion.

Methods—
We assessed the performance of 13 clinical scores to predict large-artery occlusion in consecutive patients with acute ischemic stroke undergoing clinical examination and magnetic resonance or computed tomographic angiography ≤6 hours of symptom onset. When no cutoff was published, we used the cutoff maximizing the sum of sensitivity and specificity in our cohort. We also determined, for each score, the cutoff associated with a false-negative rate ≤10%.

Results—
Of 1004 patients (median National Institute of Health Stroke Scale score, 7; range, 0–40), 328 (32.7%) had an occlusion of the internal carotid artery, M1 segment of the middle cerebral artery, or basilar artery. The highest accuracy (79%; 95% confidence interval, 77–82) was observed for National Institute of Health Stroke Scale score ≥11 and Rapid Arterial Occlusion Evaluation Scale score ≥5. However, these cutoffs were associated with false-negative rates >25%. Cutoffs associated with an false-negative rate ≤10% were 5, 1, and 0 for National Institute of Health Stroke Scale, Rapid Arterial Occlusion Evaluation Scale, and Cincinnati Prehospital Stroke Severity Scale, respectively.

Conclusions—
Using published cutoffs for triage would result in a loss of opportunity for ≥20% of patients with large-artery occlusion who would be inappropriately sent to a center lacking neurointerventional facilities. Conversely, using cutoffs reducing the false-negative rate to 10% would result in sending almost every patient to a comprehensive stroke center. Our findings, therefore, suggest that intracranial arterial imaging should be performed in all patients with acute ischemic stroke presenting within 6 hours of symptom onset.
Toward an Algorithm for Estimating Latent Heat Release in Warm Rain Systems
Authors: Nelson Ethan L. , L’Ecuyer Tristan S. , Saleeby Stephen M. , Berg Wesley , Herbener Stephen R. , van den Heever Susan C. 
Published: April 2016

AbstractThis paper outlines an approach for estimating latent heating, surface rainfall rate, and liquid water path in warm rain from downward-viewing W-band radar observations using a Bayesian Monte Carlo algorithm. The algorithm utilizes observed vertical and path-integrated characteristics of precipitating liquid clouds to identify the most appropriate hydrometeor and latent heating structures in a large database of profiles generated using a cloud-resolving model. These characteristics are selected by applying multiple performance metrics to synthetic retrievals. Analysis of the retrievals suggests that a combination of cloud-top, rain-top, and maximum reflectivity heights; vertically integrated reflectivity and attenuation; and a measure of near-surface intensity is sufficient to constrain bulk properties and the vertical structure of warm rain systems. When applied to observations at CloudSat resolution, biases in retrieved liquid water path and surface rainfall rate are small (less than 10%). The algorithm also captures the vertical structure of latent heating, although the magnitudes of integrated heating and cooling exhibit nearly compensating low biases. Random errors are larger owing to the limitations of single-frequency radar observations in constraining drop size distributions. Uncertainties in the altitudes of peak heating and cooling at the pixel scale are typically less than one vertical level, while uncertainties in vertically resolved estimates of heating and cooling rates are on the order of a factor of 2. The utility of the technique is illustrated through application to case studies from airborne radar data from the VAMOS Ocean–Cloud–Atmosphere–Land Study field campaign and satellite observations from CloudSat.