bluuebunny/crossref_metadata_2025_split huggingface dataset:
What makes a species a priority for nature conservation?
Authors: Habel J. C. , Gossner M. M. , Schmitt T. 
Published: May 2019

AbstractPrioritizing species for nature conservation should follow objective ecologically and biogeographically meaningful selection criteria. In this study, we test an approach to prioritize butterfly species for nature conservation considering the following parameters: (1) geographical distribution and endemicity, (2) vulnerability and (3) ecological specialization. Following these criteria, we identified 51 species of conservation priority out of the 403 European species assessed, that is 12.7%. This list of species and those included in the annexes II and IV of the Habitats Directive (92/43/EEC) had only four species in common. The species selected by both approaches differed significantly in their traits considering their distribution and ecological specialization with the annexes of the EU Habitats Directive including many species that are neither range‐restricted nor have their core distribution within Europe, and furthermore many not threatened ecological generalists. Our results suggest that species prioritization for nature conservation should follow objective criteria, such as distribution and ecological specialization.
Modulation of CRTh2 expression on allergen‐specific T cells following peptide immunotherapy
Authors: Rudulier Christopher D. , Tonti Elena , James Eddie , Kwok William W. , Larché Mark 
Published: May 2019

AbstractBackgroundAllergen immunotherapy using synthetic peptide T‐cell epitopes (Cat‐PAD) from the major cat allergen Fel d 1 has been shown, in allergen exposure studies, to significantly reduce symptoms of allergic rhinoconjunctivitis in cat‐allergic subjects. However, the immunological mechanisms underlying clinical benefit remain only partially understood. Since previous studies of whole allergen immunotherapy demonstrated a reduction in the frequency of allergen‐specific (MHC II tetramer+) CD4+ T cells expressing the chemokine receptor CRTh2, we assessed the impact of Cat‐PAD on the frequency and functional phenotype of Fel d 1‐specific CD4+ T cells.MethodsUsing before and after treatment samples from subjects enrolled in a randomized, double‐blind, placebo‐controlled trial of Cat‐PAD, we employed Fel d 1 MHC II tetramers and flow cytometry to analyze the expression of chemokine receptors CCR3, CCR4, CCR5, CXCR3, and CRTh2, together with markers of memory phenotype (CD27 and CCR7) on Fel d 1‐specific CD4+ T cells.ResultsNo statistically significant change in the frequency of Fel d 1‐specific CD4+ T cells, nor in their expression of chemokine receptors or memory phenotype, was observed. However, a significant reduction in cell surface expression of CRTh2 was observed between the placebo and active groups (P = 0.047).ConclusionsPeptide immunotherapy with Cat‐PAD does not significantly alter the frequency or phenotype of Fel d 1‐CD4+ T cells, but may decrease their expression of CRTh2.
Propofol use in children with allergies to egg, peanut, soybean or other legumes
Authors: Sommerfield D. L. , Lucas M. , Schilling A. , Drake‐Brockman T. F. E. , Sommerfield A. , Arnold A. , von Ungern‐Sternberg B. S. 
Published: May 2019

SummaryPropofol is the most commonly administered intravenous agent for anaesthesia in children. However, there are concerns that the emulsified preparation may not be safe in children with an allergy to egg, peanut, soybean or other legumes. We conducted a retrospective study of children with immunologically confirmed egg, peanut, soybean or legume allergy and who underwent general anaesthesia at Princess Margaret Hospital for Children between 2005 and 2015. We extracted details regarding allergy diagnosis, each anaesthetic administered and any adverse events or signs of an allergic reaction in the peri‐operative period. A convenience sample of patients without any known food allergies was identified from our prospective anaesthesia research database and acted as a control group. We identified 304 food‐allergic children and 649 procedures where propofol was administered. Of these, 201 (66%) had an egg allergy, 226 (74%) had a peanut allergy, 28 (9%) had a soybean allergy and 12 (4%) had a legume allergy. These were compared with 892 allergy‐free patients who were exposed to propofol. In 10 (3%) allergy patients and 124 (14%) allergy‐free patients, criteria for a possible allergic reaction were met. In nine of the food‐allergic children and in all the controls valid non‐allergic explanations for the clinical symptoms were found. One likely mild allergic reaction was experienced by a child with a previous history of intralipid allergy. We conclude that genuine serious allergic reaction to propofol is rare and is not reliably predicted by a history of food allergy.
One‐third of school‐aged children with cerebral palsy have neuropsychiatric impairments in a population‐based study
Authors: Påhlman Magnus , Gillberg Christopher , Himmelmann Kate 
Published: May 2019

AbstractAimTo describe motor function and associated impairments, particularly autism spectrum disorder (ASD) and attention‐deficit/hyperactivity disorder (ADHD), in school‐aged children with cerebral palsy (CP).MethodsPopulation‐based study of all children with CP born 1999–2006 from the county of Västra Götaland, Sweden; 264 children (141 males, 123 females). Information was obtained from the CP Register of western Sweden (data collected at 4–8 years of age) and all medical records at 10–17 years of age.ResultsCerebral palsy was spastic in 76%, dyskinetic in 17% and ataxic in 7% of all children. Sixty‐three per cent were independent walkers. Associated impairments were present in 75%. Vision was impaired in 19%, hearing in 8% and speech in 54%. Intellectual disability (ID) was present in 53% and epilepsy in 41%. ID had increased from 42% to 53% since preschool‐age. Neuropsychiatric impairments were present in 32% of the children; ASD in 18%; and ADHD in 21%. All impairments, except for ASD and ADHD, increased with more severe motor impairment.ConclusionThree in four school‐aged children with CP have associated impairments, underscoring the need to broadly assess every child. The high rate of ASD and ADHD points to the importance of in‐depth studies of such impairments in CP.
A synthetic epoxyeicosatrienoic acid analogue prevents the initiation of ischemic acute kidney injury
Authors: Hoff Uwe , Bubalo Gordana , Fechner Mandy , Blum Maximilian , Zhu Ye , Pohlmann Andreas , Hentschel Jan , Arakelyan Karen , Seeliger Erdmann , Flemming Bert , Gürgen Dennis , Rothe Michael , Niendorf Thoralf , Manthati Vijaya L. , Falck John R. , Haase Michael , Schunck Wolf‐Hagen , Dragun Duska 
Published: May 2019

AbstractAimImbalances in cytochrome P450 (CYP)‐dependent eicosanoid formation may play a central role in ischemic acute kidney injury (AKI). We reported previously that inhibition of 20‐hydroxyeicosatetraenoic acid (20‐HETE) action ameliorated ischemia/reperfusion (I/R)‐induced AKI in rats. Now we tested the hypothesis that enhancement of epoxyeicosatrienoic acid (EET) actions may counteract the detrimental effects of 20‐HETE and prevent the initiation of AKI.MethodsMale Lewis rats underwent right nephrectomy and ischemia was induced by 45 min clamping of the left renal pedicle followed by up to 48 h of reperfusion. Circulating CYP‐eicosanoid profiles were compared in patients who underwent cardiac surgery with (n = 21) and without (n = 38) developing postoperative AKI.ResultsIschemia induced an about eightfold increase of renal 20‐HETE levels, whereas free EETs were not accumulated. To compensate for this imbalance, a synthetic 14,15‐EET analogue was administered by intrarenal infusion before ischemia. The EET analogue improved renal reoxygenation as monitored by in vivo parametric MRI during the initial 2 h reperfusion phase. The EET analogue improved PI3K‐ as well as mTORC2‐dependent rephosphorylation of Akt, induced inactivation of GSK‐3β, reduced the development of tubular apoptosis and attenuated inflammatory cell infiltration. The EET analogue also significantly alleviated the I/R‐induced drop in creatinine clearance. Patients developing postoperative AKI featured increased preoperative 20‐HETE and 8,9‐EET levels.ConclusionsPharmacological interventions targeting the CYP‐eicosanoid pathway could offer promising new options for AKI prevention. Individual differences in CYP‐eicosanoid formation may contribute to the risk of developing AKI in clinical settings.
Therapeutic concentration achievement and allograft survival comparing usage of conventional tacrolimus doses and CYP3A5 genotype‐guided doses in renal transplantation patients
Authors: Anutrakulchai Sirirat , Pongskul Cholatip , Kritmetapak Kittrawee , Limwattananon Chulaporn , Vannaprasaht Suda 
Published: May 2019

AimsAlthough cytochromeP450(CYP)3A5 gene polymorphism affects personalized tacrolimus doses, there is no consensus as to whether CYP3A5 genotypes should be determined to adjust the doses. The aims were to compare the therapeutic ranges and clinical outcomes between the conventional and genotype‐guided tacrolimus doses.MethodsThis randomized controlled study compared 63 cases of the conventional tacrolimus dose group (0.1 mg/kg/day) with 62 cases of the genotype‐guided doses group of 0.125, 0.1 and 0.08 mg/kg for CYP3A5*1/*1, *1/*3, and *3/*3 genotypes for the initial 3 days of kidney transplantation. After day 3, dose adjustment occurred in both groups to achieve therapeutic concentrations.ResultsThe genotype‐guided group had an increased proportion of patients with tacrolimus concentrations in the therapeutic range at the steady state on day 3 (40.3 vs 23.8%, P = .048). A lower proportion of over‐therapeutic concentration patients was noted in the genotype‐guided group in the CYP3A5*3/*3 genotype (9.7 vs 27%, P = .013). Unexpectedly, more delayed graft functions (DGFs) were in the genotype‐guided group (41.9 vs 22.2%, P = .018) especially in the CYP3A5*1/*1 participants who might have had an aggravated DGF by a longer ischaemic time and higher serum donor creatinine levels than in the control group. There were no significant differences of glomerular filtration rates or graft or patient survivals over a median 37‐month follow‐up period.ConclusionsDetermination of the CYP3A5 genotype improved therapeutic range achievement. CYP3A5*1/*1 patients who have high risks of DGF should be closely monitored because of an increased risk of DGF and reduced glomerular filtration rate with high tacrolimus doses.
Comparison of pharmacokinetics and the exposure–response relationship of dapagliflozin between adolescent/young adult and adult patients with type 1 diabetes mellitus
Authors: Busse David , Tang Weifeng , Scheerer Markus , Danne Thomas , Biester Torben , Sokolov Viktor , Boulton David , Parkinson Joanna 
Published: May 2019

AimsTo quantitatively compare pharmacokinetics (PK) and the exposure–response (ER) relationship of the sodium‐glucose cotransporter‐2 inhibitor, dapagliflozin, between adolescents/young adults and adults with type 1 diabetes mellitus (T1DM).MethodsData from 2 clinical studies for dapagliflozin were analysed using a non‐linear mixed‐effects approach. The PK and the relationship between dapagliflozin exposure and response (24‐hour urinary glucose excretion) were characterized. PK was evaluated using a 2‐compartment model with first‐order absorption while the exposure response‐relationship was analysed using a sigmoidal maximal‐effect model. The 24‐hour median blood glucose, estimated glomerular filtration rate (eGFR), sex, age and body weight were evaluated as covariates.ResultsA 2‐compartment model with first order absorption provided a reasonable fit to the dapagliflozin PK data. Body weight was found to be a significant covariate on dapagliflozin exposure. The ER relationship was best described by a sigmoidal maximal effect model with 24‐hour median blood glucose and eGFR as significant covariates on maximal effect. In accordance with the observed data, model‐predicted urinary glucose excretion response following 10 mg dapagliflozin dose was higher in the study in adolescents/young adults (138.0 g/24 h) compared to adults (70.5 g/24 h) with T1DM. This is linked to higher eGFR and 24‐hour median blood glucose in this trial.ConclusionsDapagliflozin PK and ER relationship were similar in the 2 analysed studies after accounting for covariate effects. These results suggest that no dose adjustment is required for adolescent patients with T1DM.
Pharmacotherapies for co‐occurring substance use and bipolar disorders: A systematic review
Authors: Coles Alexandria S. , Sasiadek Julia , George Tony P. 
Published: May 2019

AbstractObjectivesSubstance use disorders (SUDs), including those for alcohol, stimulants, tobacco, opioids and cannabis, in patients with bipolar disorder are a major clinical and public health problem, and are present in the majority of these patients. Nonetheless, the development of effective pharmacological treatments for co‐occurring SUDs in bipolar illness have not been well‐developed and may be an important practical reason for the reduced effectiveness of these medications in community practice.MethodsWe conducted a systematic review of the literature (PubMed, Medline, Google Scholar), and identified N = 29 clinical studies, which evaluated both mental health and SUD outcomes in patients with co‐occurring bipolar disorders and SUDs.ResultsOur findings suggest the potential of valproate sodium and lamotrigine as preferred pharmacological agents for the treatment of co‐occurring psychiatric and substance use outcomes in these patients. However, many of the reviewed studies are of open‐label designs and of modest sample sizes.ConclusionsThus, given the gaps in our knowledge, recommendations for treatment of this common and important co‐morbidity are preliminary. Accordingly, the conduct of larger, randomized controlled trials for this co‐morbidity is clearly needed.
Health‐related quality of life around the time of diagnosis in patients with bladder cancer
Authors: Yu Evan Yi‐Wen , Nekeman Duncan , Billingham Lucinda J. , James Nicholas D. , Cheng KK , Bryan Richard T. , Wesselius Anke , Zeegers Maurice P. 
Published: May 2019

ObjectivesTo quantify the health‐related quality of life (HRQoL) of patients with bladder cancer around the time of diagnosis and to test the hypotheses of a two‐factor model for the HRQoL questionnaire QLQ‐C30.MethodsFrom participants in the Bladder Cancer Prognoses Programme, a multicentre cohort study, sociodemographic data were collected using semi‐structured face‐to‐face interviews. Answers to the QLQ‐C30 were transformed into a scale from 0 to 100. HRQoL data were analysed in multivariate analyses. The hypothesized two‐factor (Physical and Mental Health) domain structure of the QLQ‐C30 was also tested with confirmatory factor analyses (CFA).ResultsA total of 1160 participants (78%) completed the questionnaire after initial visual diagnosis and before pathological confirmation. Despite non‐muscle‐invasive bladder cancer (NMIBC) being associated with a higher HRQoL than carcinoma invading bladder muscle, only the domain Role Functioning was clinically significantly better in patients with NMIBC. Age, gender, bladder cancer stage and comorbidity all had a significant influence on QLQ‐C30 scores. The CFA showed an overall good fit of the hypothesized two‐factor model.ConclusionThis study identified a baseline reference value for HRQoL for patients with bladder cancer, which allows better evaluation of any changes in HRQoL as disease progresses or after treatment. In addition, a two‐factor (Physical and Mental Health) model was developed for the QLQ‐C30.
New‐onset metabolic risk factors and the incidence of kidney stones: a prospective cohort study
Authors: Ping Hao , Lu Na , Wang Mingshuai , Lu Jiapeng , Liu Yuexin , Qiao Ludong , Wang Yun , Jiang Lixin , Zhang Xiaodong 
Published: May 2019

ObjectiveTo examine the association of kidney stones with new‐onset hypertension, diabetes and obesity.Participants and MethodsThis prospective cohort study included participants in the Qingdao Port Cardiovascular Health Study who were aged ≥18 years and had abdominal ultrasonography results in 2013 that were negative for kidney stones. Multivariable Cox regression models with time‐dependent covariates were used to estimate the effects of new‐onset hypertension, diabetes and obesity on the incidence of kidney stones.ResultsThere were 9667 participants without kidney stones in 2013 (mean age 46.2 years; 75.6% men). During a mean (range) follow‐up of 33.5 (6–42) months, 676 (7.0%) incident cases of kidney stones were identified. Kidney stones were more frequent among those who had new‐onset of a metabolic factor vs those who did not (hypertension: 7.7 vs 6.0%; diabetes: 8.4 vs 6.6%; obesity: 7.4 vs 6.8%). Adjusted Cox models identified that increased risk of kidney stones was associated with new‐onset hypertension (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.25–2.27), new‐onset diabetes (HR 1.78, 95% CI 1.07–2.96), and new‐onset obesity (HR 1.78, 95% CI 1.15–2.74).ConclusionsNew‐onset of hypertension, diabetes and obesity were all strongly associated with an increased risk of kidney stones in this prospective cohort study. Results suggest that a substantial proportion of kidney stones are potentially preventable by appropriate control of these metabolic risk factors.
Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions
Authors: Desai Radha , Campanella Michelangelo 
Published: May 2019

The pharmacological targeting of cholesterol levels continues to generate interest due to the undoubted success of therapeutic agents, such as statins, in extending life expectancy by modifying the prognosis of diseases associated with the impairment of lipid metabolism. Advances in our understanding of mitochondrial dysfunction in chronic age‐related diseases of the brain have disclosed an emerging role for mitochondrial cholesterol in their pathophysiology, thus delineating an opportunity to provide mechanistic insights and explore strategies of intervention. This review draws attention to novel signalling mechanisms in conditions linked with impaired metabolism associated with impaired handling of cholesterol and its oxidized forms (oxysterols) by mitochondria. By emphasizing the role of mitochondrial cholesterol in neurological diseases, we here call for novel approaches and new means of assessment.Linked ArticlesThis article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc
Spermidine‐enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting the AMPK/mTOR signalling pathway
Authors: Yan Jing , Yan Jian‐Yun , Wang Yu‐Xi , Ling Yuan‐Na , Song Xu‐Dong , Wang Si‐Yi , Liu Hai‐Qiong , Liu Qi‐Cai , Zhang Ya , Yang Ping‐Zhen , Wang Xian‐Bao , Chen Ai‐Hua 
Published: May 2019

Background and PurposeSpermidine, a natural polyamine, is abundant in mammalian cells and is involved in cell growth, proliferation, and regeneration. Recently, oral spermidine supplements were cardioprotective in age‐related cardiac dysfunction, through enhancing autophagic flux. However, the effect of spermidine on myocardial injury and cardiac dysfunction following myocardial infarction (MI) remains unknown.Experimental ApproachWe determined the effects of spermidine in a model of MI, Sprague–Dawley rats with permanent ligation of the left anterior descending artery, and in cultured neonatal rat cardiomyocytes (NRCs) exposed to angiotensin II (Ang II). Cardiac function in vivo was assessed with echocardiography. In vivo and in vitro studies used histological and immunohistochemical techniques, along with western blots.Key ResultsSpermidine improved cardiomyocyte viability and decreased cell necrosis in NRCs treated with angiotensin II. In rats post‐MI, spermidine reduced infarct size, improved cardiac function, and attenuated myocardial hypertrophy. Spermidine also suppressed the oxidative damage and inflammatory cytokines induced by MI. Moreover, spermidine enhanced autophagic flux and decreased apoptosis both in vitro and in vivo. The protective effects of spermidine on cardiomyocyte apoptosis and cardiac dysfunction were abolished by the autophagy inhibitor chloroquine, indicating that spermidine exerted cardioprotective effects at least partly through promoting autophagic flux, by activating the AMPK/mTOR signalling pathway.Conclusions and ImplicationsOur findings suggest that spermidine improved MI‐induced cardiac dysfunction by promoting AMPK/mTOR‐mediated autophagic flux.
Second M3 muscarinic receptor binding site contributes to bronchoprotection by tiotropium
Authors: Kistemaker Loes E.M. , Elzinga Carolina R.S. , Tautermann Christofer S. , Pieper Michael P. , Seeliger Daniel , Alikhil Suraya , Schmidt Martina , Meurs Herman , Gosens Reinoud 
Published: May 2019

Background and PurposeThe bronchodilator tiotropium binds not only to its main binding site on the M3 muscarinic receptor but also to an allosteric site. Here, we have investigated the functional relevance of this allosteric binding and the potential contribution of this behaviour to interactions with long‐acting β‐adrenoceptor agonists, as combination therapy with anticholinergic agents and β‐adrenoceptor agonists improves lung function in chronic obstructive pulmonary disease.Experimental ApproachACh, tiotropium, and atropine binding to M3 receptors were modelled using molecular dynamics simulations. Contractions of bovine and human tracheal smooth muscle strips were studied.Key ResultsMolecular dynamics simulation revealed extracellular vestibule binding of tiotropium, and not atropine, to M3 receptors as a secondary low affinity binding site, preventing ACh entry into the orthosteric binding pocket. This resulted in a low (allosteric binding) and high (orthosteric binding) functional affinity of tiotropium in protecting against methacholine‐induced contractions of airway smooth muscle, which was not observed for atropine and glycopyrrolate. Moreover, antagonism by tiotropium was insurmountable in nature. This behaviour facilitated functional interactions of tiotropium with the β‐agonist olodaterol, which synergistically enhanced bronchoprotective effects of tiotropium. This was not seen for glycopyrrolate and olodaterol or indacaterol but was mimicked by the interaction of tiotropium and forskolin, indicating no direct β‐adrenoceptor–M3 receptor crosstalk in this effect.Conclusions and ImplicationsWe propose that tiotropium has two binding sites at the M3 receptor that prevent ACh action, which, together with slow dissociation kinetics, may contribute to insurmountable antagonism and enhanced functional interactions with β‐adrenoceptor agonists.