bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Placebo‐Controlled Clinical Trial of a Chewable Formulation of Amlodipine for the Treatment of Hypertension in Client‐Owned Cats
Authors: Huhtinen M. , Derré G. , Renoldi H.J. , Rinkinen M. , Adler K. , Aspegrén J. , Zemirline C. , Elliott J. 
Published: April 2015

BackgroundThere is an unmet clinical need for a cat‐specific formulation of amlodipine to treat hypertensive cats.ObjectivesTo assess the efficacy of chewable amlodipine tablets in reducing systolic blood pressure (SBP) in cats diagnosed with systemic arterial hypertension.AnimalsSeventy‐seven client‐owned cats with systemic hypertension were included (median age 14 years).MethodsThe study was randomized, double‐blinded, and placebo‐controlled. Forty‐two cats received 0.125–0.50 mg/kg amlodipine once daily for 28 days; 35 cats received placebo. After 28 days all cats continued with amlodipine for 2–3 months in an open‐label phase. Blood pressure was measured using high definition oscillometry. A responder was defined as a cat showing a decrease of SBP to <150 mmHg at 28 days or a decrease from baseline ≥15%.ResultsSixty‐one cats completed the study. The responder rate was 63% in amlodipine group and 18% in placebo group. Cats receiving amlodipine were 7.9 (95% CI 2.6–24.1) times more likely to be classified as responders when compared to those receiving placebo (P < .001). From a mean (±SD) baseline value of 181 (±12) mmHg, SBP decreased to 154 (±17) mmHg with amlodipine and to 170 (±21) mmHg with placebo (P < .001). The voluntary acceptance rate of amlodipine formulation was 73%.Conclusions and Clinical ImportanceThe chewable amlodipine tablet effectively reduced SBP compared with placebo in hypertensive cats, and was well‐tolerated. It can be used concomitantly with angiotensin‐converting enzyme inhibitors and in cats with chronic kidney disease.
Prevalence of and Risk Factors for Degenerative Mitral Valve Disease in Dogs Attending Primary‐care Veterinary Practices in England
Authors: Mattin M.J. , Boswood A. , Church D.B. , López‐Alvarez J. , McGreevy P.D. , O'Neill D.G. , Thomson P.C. , Brodbelt D.C. 
Published: April 2015

BackgroundTo date, epidemiological studies on degenerative mitral valve disease (DMVD) in dogs have largely reported referral caseloads or been limited to predisposed breeds. Analysis of primary‐care data to identify factors associated with DMVD would help clinicians identify high‐risk individuals and improve understanding.ObjectivesTo estimate the prevalence of and identify risk factors for DMVD in dogs attending primary‐care veterinary practices in England.AnimalsCases were identified within the electronic patient records of 111,967 dogs attending 93 practices. Four hundred and 5 dogs were diagnosed with DMVD (diagnosed cases) and a further 3,557 dogs had a heart murmur (HM) consistent with DMVD (possible cases).MethodsRetrospective cross‐sectional study design. Prevalence was adjusted for the sampling approach. Mixed effects logistic regression models identified factors associated with DMVD.ResultsPrevalence estimates of diagnosed DMVD and HMs consistent with DMVD (both diagnosed and possible cases) were 0.36% (95% confidence interval [CI]: 0.29–0.45) and 3.54% (95% CI: 3.26–3.84) respectively. In the multivariable analysis, males had higher odds of diagnosed DMVD than did females (odds ratio [OR] 1.40, 95% CI: 1.12–1.74). Insured dogs had increased odds of DMVD compared with noninsured dogs (OR 3.56, 95% CI: 2.79–4.55) and dogs ≥20 kg had approximately half the odds of DMVD diagnosis compared with dogs <20 kg (OR 0.51, 95% CI: 0.36–0.74). Strong associations between a DMVD diagnosis and individual breeds and age were identified.Conclusions and Clinical ImportanceDegenerative mitral valve disease was a common disorder in practice‐attending dogs. Knowledge of identified risk factors for DMVD could improve clinical diagnosis and direct future research.
Stride frequency in relation to allometric growth in ghost crabs
Authors: Whittemore S. B. , Hoglin B. , Green M. A. , Medler S. 
Published: April 2015

AbstractBody size has significant impacts on fundamental processes of locomotion, including the operational frequency of skeletal muscle contraction, which declines systematically with increasing size. Although this shift in operation frequency and contractile kinetics is well documented in the literature, the mechanisms responsible for these changes are still incompletely understood. One important factor is that the mechanical properties of the musculoskeletal system possess resonant properties that favor higher frequencies in small animals. Another significant element is the physiological properties of the skeletal muscles, which may be tuned for faster contractions in smaller animals. These two components are interrelated, but precisely how muscle physiology and musculoskeletal mechanics interact to shape patterns of locomotion is complex. Ghost crabs Ocypode quadrata present an interesting model to study these processes because they are proficient runners that exhibit systematic changes in stride frequency as they grow. In the current study, we focused on anatomical changes that might occur with allometric growth in ghost crabs to test the hypothesis that changes in mechanical parameters contribute to the slowing of stride frequency. We paired basic anatomical measurements with kinematic analyses of crabs running at top speeds on a treadmill and experimentally weighted crabs to determine if the relative mass of larger crabs affects running frequency. We found that biologically relevant mechanics of the leg joints do not change with growth, as mechanical advantage and muscle fiber length relative to joint moment arm were unaffected by body size. Loading crabs had similar effects on stride frequency in both large and small animals alike. In contrast, muscle shortening velocity, estimated directly from angular velocity of the leg joints, decreased significantly with increasing body size. These data suggest that fundamental changes to the contractile properties of skeletal muscles during growth are primarily responsible for the changes in stride frequency observed in ghost crabs.
Volaemic status and dyspepsia in end‐stage renal disease patients
Authors: Santos Paulo Roberto , Monteiro Diego Levi Silveira , de Paula Paulo Henrique Alexandre , Monte Neto Vicente Lopes , Coelho Maria Leilah Ponte Monte , Arcanjo Cecília Costa , Aragão Sânkia Maria Lopes , Gondim Camila Barbosa , Tapeti Janaína Teixeira Pereira Carneiro , Mendes Hyngridd Soares , Vieira Luise Vasconcelos , Prado Rita de Cássia Parente 
Published: April 2015

AbstractAimStudies in animals show a relationship between extracellular volume and gastrointestinal motility. End‐stage renal disease (ESRD) patients present fluid overload and frequent dyspeptic symptoms. We looked for an association between volaemic status and dyspepsia among ESRD patients undergoing haemodialysis (HD).MethodsWe studied 155 ESRD patients on HD. Their volaemic status was evaluated using bioimpedance analysis. Fluid overload (FO) in litres and relative fluid overload (rFO) in percentage were calculated. rFO > 15% was classified as hypervolaemia. Dyspepsia was assessed through the Porto Alegre Dyspeptic Symptoms Questionnaire (PADYQ). PADYQ scores equal to or greater than 6 classified patients as dyspeptic. Characteristics of patients with and without dyspepsia were compared. Pearson's test was used to test the correlation between continuous variables. Multivariate linear and logistic regressions were performed to test FO as predictor of dyspepsia score and the presence of dyspepsia.ResultsThere were 64 (41.2%) patients with dyspepsia. Dyspeptics presented higher FO (2.5 ± 1.8 L vs 1.0 ± 1.8 L; P < 0.001) and higher rFO (16 ± 9.9% vs 4.8 ± 12.0%; P < 0.001). Dyspepsia score was positively correlated with FO (r = 0.300; P < 0.001) and with rFO (r = 0.256; P = 0.001). There were more patients with hypervolaemia among dyspeptics compared to non‐dyspeptics (65.6% vs 17.6%; P < 0.001). FO was an independent predictor of dyspepsia score (b = 1.036; P < 0.001) and the presence of dyspepsia (OR = 2.00, 95% CI = 1.55–2.50; P < 0.001).ConclusionHypervolaemia is associated with dyspepsia among ESRD patients on HD.
The broad‐spectrum receptor tyrosine kinase inhibitor dovitinib suppresses growth of BRAF‐mutant melanoma cells in combination with other signaling pathway inhibitors
Authors: Langdon Casey G. , Held Matthew A. , Platt James T. , Meeth Katrina , Iyidogan Pinar , Mamillapalli Ramanaiah , Koo Andrew B. , Klein Michael , Liu Zongzhi , Bosenberg Marcus W. , Stern David F. 
Published: April 2015

SummaryBRAF inhibitors have revolutionized treatment of mutant BRAF metastatic melanomas. However, resistance develops rapidly following BRAF inhibitor treatment. We have found that BRAF‐mutant melanoma cell lines are more sensitive than wild‐type BRAF cells to the small molecule tyrosine kinase inhibitor dovitinib. Sensitivity is associated with inhibition of a series of known dovitinib targets. Dovitinib in combination with several agents inhibits growth more effectively than either agent alone. These combinations inhibit BRAF‐mutant melanoma and colorectal carcinoma cell lines, including cell lines with intrinsic or selected BRAF inhibitor resistance. Hence, combinations of dovitinib with second agents are potentially effective therapies for BRAF‐mutant melanomas, regardless of their sensitivity to BRAF inhibitors.
Mining wild barley for powdery mildew resistance
Authors: Ames N. , Dreiseitl A. , Steffenson B. J. , Muehlbauer G. J. 
Published: April 2015

Powdery mildew, caused by Blumeria graminis f. sp. hordei (Bgh), is a worldwide disease problem on barley (Hordeum vulgare) with potentially severe impact on yield. Historically, resistance genes have been identified chiefly from cultivated lines and landraces; however, wild barley (H. vulgare subsp. spontaneum) accessions have proven to be extraordinarily rich sources of powdery mildew resistance. This study describes the characterization of a collection of 316 wild barley accessions, known as the Wild Barley Diversity Collection (WBDC), for resistance to powdery mildew and the genetic location of powdery mildew resistance loci. The WBDC was phenotyped for reaction to 40 different Bgh isolates at the seedling stage and genotyped with 10 508 molecular markers. Accessions resistant to all 40 isolates of Bgh were not found; however, three accessions (WBDC 053, 085 and 089) exhibited resistance to 38 of the isolates. Gene postulation analyses revealed that many accessions, while resistant, contained none of the 12 genes present in the Pallas near‐isogenic lines Mla1, Mla3, Mla6, Mla7, Mla9, Mla12, Mla13, Mlk1, MlLa, Mlg, Mlat and Ml(Ru2), suggesting that the accessions carry novel genes or gene combinations. A genome‐wide association study of powdery mildew resistance in the WBDC identified 21 significant marker‐trait associations that resolved into 15 quantitative trait loci. Seven of these loci have not been previously associated with powdery mildew resistance. Taken together, these results demonstrate that the WBDC is a rich source of powdery mildew resistance, and provide genetic tools for incorporating the resistance into barley breeding programmes.
Metaphysics of Pain; Semantics of ‘Pain’
Authors: Pelman Alik 
Published: April 2015

AbstractFunctionalism is often used to identify mental states with physical states. A particularly powerful case is Lewis's analytical functionalism. Kripke's view seriously challenges any such identification. The dispute between Kripke and Lewis's views boils down to whether the term ‘pain’ is rigid or nonrigid. It is a strong intuition of ours that if it feels like pain it is pain, and vice versa, so that ‘pain’ should designate, with respect to every possible world, all and only states felt as pain. Hence, in order to settle the dispute, we need to check which of the two – Kripke's use of ‘pain’ as rigid, or Lewis's use of ‘pain’ as nonrigid – better meets this intuition. I show that, despite crucial differences in both their semantic and metaphysical assumptions, surprisingly, both views meet this intuition equally well. Thus it appears that this question of rigidity cannot, in principle, be solved, and so, at least with respect to this particular dispute, the jury is still out on whether mental states are identical to physical states.
The residual risk of transfusion‐transmitted cytomegalovirus infection associated with leucodepleted blood components
Authors: Seed C. R. , Wong J. , Polizzotto M. N. , Faddy H. , Keller A. J. , Pink J. 
Published: April 2015

Background and ObjectivesCytomegalovirus poses a risk to transfusion safety as its transmission to an immunocompromised recipient may lead to significant clinical sequelae. Once infection is established, it is lifelong and generally asymptomatic. Strategies to reduce the risk of transfusion‐transmitted CMV (TT‐CMV) include donor serological testing and blood component leucodepletion to deplete the transmissible reservoir. We estimate the residual risk for non‐CMV antibody screened, leucodepleted (LD‐only) fresh blood components.Materials and MethodsWe established an approach to estimate the risk of TT‐CMV under various scenarios. We estimated the probability of an infectious component, for both red cells and platelets, as a function of the observed WBC filter failure rate and the probability that such a unit was also contaminated with infectious virus.ResultsUsing this model, the estimated combined residual risk of LD‐only red cell and platelet units was very low, 1 in 13 575 000 (95%CI:1 in 1 344 167 000–1 in 1 730 000) as was the individual residual risk estimate for LD‐only red cells, 1 in 7 790 000 (95%CI: 1 in 771 307 000–1 in 993 000) and LD‐only platelets, where a zero risk was estimated (95%CI: 0–1 in 1 074 000).ConclusionWe describe a novel approach to assess the residual risk of LD‐only components. This can be applied generally using local data. Our risk estimate for LD‐only blood components in Australia is below the threshold of 1 in 1 million, generally considered negligible. This provides a useful indicator of the relative safety of LD‐only components to assist clinical decisions when serologically screened inventory is unavailable.
Cardioprotective effect of hyperthyroidism on the stunned rat heart during ischaemia–reperfusion: energetics and role of mitochondria
Authors: Ragone María Inés , Bonazzola Patricia , Colareda Germán A. , Consolini Alicia E. 
Published: April 2015

New Findings

What is the central question of this study?
Hyperthyroidism is a cardiac risk factor, but thyroid therapy is used on myocardial stunning. What is the consequence of hyperthyroidism for mitochondrial metabolism and Ca2+ handling of the postischaemic stunned heart?

What is the main finding and its importance?
Hyperthyroidism reduced stunning and improved muscle economy of the postischaemic rat heart. The activities of the mitochondrial sodium–calcium exchanger and mitochondrial K+ channel in hyperthyroid rat hearts were different from those in the euthyroid rat hearts. These findings contribute to the understanding of mitochondrial bioenergetics in pathology and support thyroid therapy in the stunning induced by ischaemia.

Transient ischaemia and hyperthyroidism are cardiovascular risk factors. Nevertheless, 3,5,3′‐triiodothyronine/thyroxine therapy has been used to revert myocardial stunning. We studied the influence of hyperthyroidism on the role played by mitochondria in myocardial stunning consequent to ischaemia–reperfusion. Rats were injected s.c. daily with 20 μg kg−1 triiodothyronine for 15 days (HpT group). Isolated ventricles from either HpT or euthyroid (EuT) rats were perfused in a calorimeter, and left intraventricular pressure (in millimetres of mercury) and heat release (Ht; in milliwatts per gram) were measured. Stunning was evoked by 20 min of no‐flow ischaemia and 45 min reperfusion. The HpT hearts developed higher postischaemic contractile recovery (PICR) and improved total muscle economy (P/Ht) with lower diastolic contracture (ΔLVEDP) than EuT hearts. Release of Ca2+ from the sarcoplasmic reticulum during reperfusion with 10 mm caffeine in low‐[Na+] Krebs solution evoked a higher contracture in EuT than in HpT hearts. Blockade of the mitochondrial sodium–calcium exchanger with clonazepam increased ΔLVEDP and reduced P/Ht and PICR in HpT but not in EuT hearts. The clonazepam‐induced dysfunction in HpT hearts was reduced by ciclosporin, suggesting a dependance on activation of the mitochondrial permeability transition pore. Blockade of the mitochondrial Ca2+ uniporter with Ru360 reduced P/Ht and PICR to ∼10% in both HpT and EuT hearts. Blockade of mitochondrial K+ channels with 5‐hydroxydecanoate increased LVEDP and reduced PICR and P/Ht in HpT hearts, while it only increased LVEDP in EuT hearts. The results suggest that hyperthyroidism prevents the stunning with high dependence on the mitochondrial sodium–calcium exchanger and mitochondrial K+ channels. Both HpT and EuT hearts showed a similar and critical role of the uniporter. The HpT hearts have a slow sarcoplasmic reticulum Ca2+ loss and low mitochondrial Ca2+ uptake.
Comparison of Two Commercial Type 1 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Modified Live Vaccines against Heterologous Type 1 and Type 2 PRRSV Challenge in Growing Pigs
Authors: Kim Taeyeon , Park Changhoon , Choi Kyuhyung , Jeong Jiwoon , Kang Ikjae , Park Su-Jin , Chae Chanhee 
Published: April 2015

ABSTRACT
The objective of the present study was to compare the efficacy of two commercial type 1 porcine reproductive and respiratory syndrome virus (PRRSV) modified live vaccines against heterologous type 1 and type 2 PRRSV challenge in growing pigs. Vaccination with a type 1 PRRSV vaccine reduced the level of viremia after type 1 PRRSV challenge but did not reduce the level of viremia after the type 2 PRRSV challenge in pigs. Increased levels of interleukin-10 (IL-10) stimulated by type 2 PRRSV coincided with the low numbers of type 2 PRRSV-specific interferon gamma-secreting cells (IFN-γ-SC) in vaccinated pigs after type 2 PRRSV challenge, whereas low levels of IL-10 stimulated by type 1 PRRSV coincided with high numbers of type 1 PRRSV-specific IFN-γ-SC in vaccinated pigs after type 1 PRRSV challenge. Additionally, vaccination with the type 1 PRRSV vaccine effectively reduced the lung lesions and type 1 PRRSV nucleic acids in type 1 PRRSV-challenged pigs but did not reduce lung lesions and type 2 PRRSV nucleic acids in type 2 PRRSV-challenged pigs. There were no significant differences between two commercial type 1 PRRSV vaccines against type 1 and type 2 PRRSV challenge based on virological results, immunological responses, and pathological outcomes. This study demonstrates that vaccinating pigs with the type 1 PRRSV vaccine provides partial protection against respiratory disease with heterologous type 1 PRRSV challenge but no protection with heterologous type 2 PRRSV challenge.
Temperature-Sensitive Mutants in the Influenza A Virus RNA Polymerase: Alterations in the PA Linker Reduce Nuclear Targeting of the PB1-PA Dimer and Result in Viral Attenuation
Authors: Da Costa Bruno , Sausset Alix , Munier Sandie , Ghounaris Alexandre , Naffakh Nadia , Le Goffic Ronan , Delmas Bernard 
Published: April 2015

ABSTRACT

The influenza virus RNA-dependent RNA polymerase catalyzes genome replication and transcription within the cell nucleus. Efficient nuclear import and assembly of the polymerase subunits PB1, PB2, and PA are critical steps in the virus life cycle. We investigated the structure and function of the PA linker (residues 197 to 256), located between its N-terminal endonuclease domain and its C-terminal structured domain that binds PB1, the polymerase core. Circular dichroism experiments revealed that the PA linker by itself is structurally disordered. A large series of PA linker mutants exhibited a temperature-sensitive (
ts
) phenotype (reduced viral growth at 39.5°C versus 37°C/33°C), suggesting an alteration of folding kinetic parameters. The
ts
phenotype was associated with a reduced efficiency of replication/transcription of a pseudoviral reporter RNA in a minireplicon assay. Using a fluorescent-tagged PB1, we observed that
ts
and lethal PA mutants did not efficiently recruit PB1 to reach the nucleus at 39.5°C. A protein complementation assay using PA mutants, PB1, and β-importin IPO5 tagged with fragments of the
Gaussia princeps
luciferase showed that increasing the temperature negatively modulated the PA-PB1 and the PA-PB1-IPO5 interactions or complex stability. The selection of revertant viruses allowed the identification of different types of compensatory mutations located in one or the other of the three polymerase subunits. Two
ts
mutants were shown to be attenuated and able to induce antibodies in mice. Taken together, our results identify a PA domain critical for PB1-PA nuclear import and that is a “hot spot” to engineer
ts
mutants that could be used to design novel attenuated vaccines.

IMPORTANCE
By targeting a discrete domain of the PA polymerase subunit of influenza virus, we were able to identify a series of 9 amino acid positions that are appropriate to engineer temperature-sensitive (
ts
) mutants. This is the first time that a large number of
ts
mutations were engineered in such a short domain, demonstrating that rational design of
ts
mutants can be achieved. We were able to associate this phenotype with a defect of transport of the PA-PB1 complex into the nucleus. Reversion substitutions restored the ability of the complex to move to the nucleus. Two of these
ts
mutants were shown to be attenuated and able to produce antibodies in mice. These results are of high interest for the design of novel attenuated vaccines and to develop new antiviral drugs.
Identification of vitamin C transporters in the human airways: a cross-sectional in vivo study
Authors: Larsson Nirina , Rankin Gregory D , Bicer Elif M , Roos-Engstrand Ester , Pourazar Jamshid , Blomberg Anders , Mudway Ian S , Behndig Annelie F 
Published: April 2015

ObjectivesVitamin C is an important low-molecular weight antioxidant at the air-lung interface. Despite its critical role as a sacrificial antioxidant, little is known about its transport into the respiratory tract lining fluid (RTLF), or the underlying airway epithelial cells. While several vitamin C transporters have been identified, such as sodium-ascorbate cotransporters (SVCT1/2) and glucose transporters (GLUTs), the latter transporting dehydroascorbate, knowledge of their protein distribution within the human lung is limited, in the case of GLUTs or unknown for SVCTs.Setting and participantsProtein expression of vitamin C transporters (SVCT1/2 and GLUT1-4) was examined by immunohistochemistry in endobronchial biopsies, and by FACS in airway leucocytes from lavage fluid, obtained from 32 volunteers; 16 healthy and 16 mild asthmatic subjects. In addition, antioxidant concentrations were determined in RTLF. The study was performed at one Swedish centre.Primary and secondary outcome measuresThe primary outcome measure was to establish the location of vitamin C transporters in the human airways. As secondary outcome measures, RTLF vitamin C concentration was measured and related to transporter expression, as well as bronchial epithelial inflammatory and goblet cells numbers.ResultsPositive staining was identified for SVCT1 and 2 in the vascular endothelium. SVCT2 and GLUT2 were present in the apical bronchial epithelium, where SVCT2 staining was predominately localised to goblet cells and inversely related to RTLF vitamin C concentrations.ConclusionsThis experimental study is the first to demonstrate protein expression of GLUT2 and SVCT2 in the human bronchial epithelium. A negative correlation between SVCT2-positive goblet cells and bronchial RTLF vitamin C concentrations suggests a possible role for goblet cells in regulating the extracellular vitamin C pool.