bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non‐Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics and First‐in‐Human Dose Selection for CNTO 5825, an Anti‐Interleukin‐13 Monoclonal Antibody
Authors: Nnane Ivo P. , Xu Zhenhua , Zhou Honghui , Davis Hugh M. 
Published: February 2015

AbstractCNTO 5825 is a human anti‐interleukin‐13 (IL‐13) monoclonal antibody (mAb) that inhibits binding of human IL‐13 to IL‐13Rα1 and IL‐13Rα2. The purpose of this investigation was to predict human pharmacokinetics (PK) of CNTO 5825 using different allometric approaches and non‐clinical PK data in order to select the right and safe doses for first‐in‐human (FIH) study. After intravenous (IV) administration of CNTO 5825, clearance (CL) ranged from 9.98 to 11.49 ml/day/kg in rats and from 5.78 to 7.19 ml/day/kg in cynomolgus monkeys. The volume of distribution at steady‐state (Vss) in rats was large (151.52–155.64 ml/kg) compared to cynomolgus monkey (49.77–61.10 ml/kg). The terminal half‐life (T1/2) ranged from 12.29 to 14.15 days in rats and from 6.61 to 7.73 days in cynomolgus monkeys. The PK of CNTO 5825 was linear in 1–10 mg/kg dose range in both species. The bioavailability after subcutaneous (SC) administration was 94% and 79% in rats and cynomolgus monkeys, respectively. The predicted CL and Vss based on allometric methods and PK data from rats and monkeys were within twofold of observed CL and Vss in human beings; the predicted CL and Vss in human beings (70 kg) based on time‐invariant method with combined PK data from rats and monkeys were 4.84 ± 1.13 ml/day/kg and 68.93 ± 35.55 ml/kg, respectively. The selected doses for the FIH study based on time‐invariant method and no observed adverse effect level in toxicity studies in rats and monkeys provided exposures that were subsequently shown to be well tolerated and safe in human beings.
Fear of Childbirth and Risk of Cesarean Delivery: A Cohort Study in Six European Countries
Authors: Ryding Elsa Lena , Lukasse Mirjam , Parys An‐Sophie Van , Wangel Anne‐Marie , Karro Helle , Kristjansdottir Hildur , Schroll Anne‐Mette , Schei Berit ,   the Bidens Group
Published: February 2015

AbstractBackgroundFew studies have examined the mode of birth among women with fear of childbirth, and the results are conflicting. The objective of this study was to assess the association between fear of childbirth and cesarean delivery in North European women.MethodsA longitudinal cohort study was conducted among 6,422 pregnant women from Belgium, Iceland, Denmark, Estonia, Norway, and Sweden. Fear of childbirth was measured by the Wijma Delivery Expectancy Questionnaire during pregnancy and linked to obstetric information from hospital records.ResultsAmong 3,189 primiparous women, those reporting severe fear of childbirth were more likely to give birth by elective cesarean, (OR, 1.66 [95% CI 1.05–2.61]). Among 3,233 multiparous women, severe fear of childbirth increased the risk of elective cesarean (OR1.87 [95% CI 1.30–2.69]). Reporting lack of positive anticipation, one of six dimensions of fear of childbirth, was most strongly associated with elective cesarean (OR2.02 [95% CI 1.52–2.68]). A dose–effect pattern was observed between level of fear and risk of emergency cesarean in both primiparous and multiparous women. Indications for cesarean were more likely to be reported as “nonmedical” among those with severe fear of childbirth; 16.7 versus 4.6 percent in primiparous women, and 31.7 versus 17.5 percent in multiparous women.ConclusionHaving severe fear of childbirth increases the risk of elective cesarean, especially among multiparous women. Lack of positive anticipation of the upcoming childbirth seems to be an important dimension of fear associated with cesarean delivery. Counseling for women who do not look forward to vaginal birth should be further evaluated.
Robson Ten Group Classification System Applied to Women with Severe Maternal Morbidity
Authors: Ferreira Elton Carlos , Costa Maria Laura , Cecatti José Guilherme , Haddad Samira M. , Parpinelli Mary Angela , Robson Michael S. ,   the Brazilian Network for Surveillance of Severe Maternal Morbidity Study Group
Published: February 2015

AbstractObjectiveTo evaluate the distribution of women with severe maternal morbidity according to Robson Ten Group Classification System (RTGCS).MethodsSecondary analysis of a multicenter cross‐sectional study in 27 obstetric units in Brazil, using RTGCS. Cases were classified into potentially life‐threatening condition or a maternal near miss or death, according to severity. Certain groups were subdivided for further analysis. Cesarean delivery (CD) rates were reported.ResultsAmong 7,247 women with severe maternal morbidity, 73.2 percent underwent CD. Group 10 (single, cephalic, preterm) was the most prevalent (33.9%). Groups mostly associated with a severe maternal outcome were: 7 (multiparous, breech), 9 (all abnormal lies, single, term), 8 (all multiple), and 10. Groups 1 (nulliparous, single, cephalic, term, spontaneous) and 3 (multiparous, single, cephalic, term, spontaneous) were associated with better maternal outcome. Group 3 had one severe maternal morbidity to 29 cases of potentially life‐threatening, but the ratio was 1:10 for women undergoing CD, indicating a worse outcome. Group 4a (multiparous, no previous CD, single, cephalic, term, induced labor) had a better maternal outcome than those delivered by CD before labor (group 4b). Hypertension was the most common condition of severity.ConclusionsThe RTGCS was useful to consider severe maternal morbidity, showing groups with higher CD rates and worse maternal outcomes.
Coping with structural disadvantage: Overcoming negative effects of perceived barriers through bonding identities
Authors: Bakouri Mouna , Staerklé Christian 
Published: February 2015

Members of socially disadvantaged groups often experience societal devaluation, material hardship, and restricted opportunities, especially during critical life‐course transitions. In this study, we investigate whether what we term ‘bonding identities’, that is identities connecting the self to significant persons whether in terms of social relationships (e.g., family relations) or in terms of categorical collective identities, help individuals negotiate structural constraints on life‐course opportunities. We develop and test a model according to which greater perceived barriers to one's life projects are psychologically harmful. We then test whether bonding identities function as a buffer against these stressors' negative psychological effects. Data were collected with a standardized questionnaire from pre‐apprentices, apprentices, and young employees in two institutions (N = 365). Results confirm that perceiving barriers to one's life project was harmful for self‐esteem. However, for participants who defined themselves in terms of bonding identities, greater perceived barriers did not decrease their perceived coping efficacy and were less harmful for their self‐esteem. These findings point to the empowering role of bonding identities (and the social relationships that they imply) for disadvantaged group members.
Inhibiting endocannabinoid biosynthesis: a novel approach to the treatment of constipation
Authors: Bashashati M , Nasser Y , Keenan C M , Ho W , Piscitelli F , Nalli M , Mackie K , Storr M A , Di Marzo V , Sharkey K A 
Published: February 2015

Background and PurposeEndocannabinoids are a family of lipid mediators involved in the regulation of gastrointestinal (GI) motility. The expression, localization and function of their biosynthetic enzymes in the GI tract are not well understood. Here, we examined the expression, localization and function of the enzyme diacylglycerol lipase‐α (DAGLα), which is involved in biosynthesis of the endocannabinoid 2‐arachidonoylglycerol (2‐AG).Experimental ApproachCannabinoid CB1 receptor‐deficient, wild‐type control and C3H/HeJ mice, a genetically constipated strain, were used. The distribution of DAGLα in the enteric nervous system was examined by immunohistochemistry. Effects of the DAGL inhibitors, orlistat and OMDM‐188 on pharmacologically induced GI hypomotility were assessed by measuring intestinal contractility in vitro and whole gut transit or faecal output in vivo. Endocannabinoid levels were measured by mass spectrometry.Key ResultsDAGLα was expressed throughout the GI tract. In the intestine, unlike DAGLβ, DAGLα immunoreactivity was prominently expressed in the enteric nervous system. In the myenteric plexus, it was colocalized with the vesicular acetylcholine transporter in cholinergic nerves. In normal mice, inhibiting DAGL reversed both pharmacologically reduced intestinal contractility and pharmacologically prolonged whole gut transit. Moreover, inhibiting DAGL normalized faecal output in constipated C3H/HeJ mice. In colons incubated with scopolamine, 2‐AG was elevated while inhibiting DAGL normalized 2‐AG levels.Conclusions and ImplicationsDAGLα was expressed in the enteric nervous system of mice and its inhibition reversed slowed GI motility, intestinal contractility and constipation through 2‐AG and CB1 receptor‐mediated mechanisms. Our data suggest that DAGLα inhibitors may be promising candidates for the treatment of constipation.
Pharmacological and electrophysiological characterization of AZSMO‐23, an activator of the hERG K+ channel
Authors: Mannikko R , Bridgland‐Taylor M H , Pye H , Swallow S , Abi‐Gerges N , Morton M J , Pollard C E 
Published: February 2015

Background and PurposeWe aimed to characterize the pharmacology and electrophysiology of N‐[3‐(1H‐benzimidazol‐2‐yl)‐4‐chloro‐phenyl]pyridine‐3‐carboxamide (AZSMO‐23), an activator of the human ether‐a‐go‐go‐related gene (hERG)‐encoded K+ channel (Kv11.1).Experimental ApproachAutomated electrophysiology was used to study the pharmacology of AZSMO‐23 on wild‐type (WT), Y652A, F656T or G628C/S631C hERG, and on other cardiac ion channels. Its mechanism of action was characterized with conventional electrophysiology.Key ResultsAZSMO‐23 activated WT hERG pre‐pulse and tail current with EC50 values of 28.6 and 11.2 μM respectively. At 100 μM, pre‐pulse current at +40 mV was increased by 952 ± 41% and tail current at −30 mV by 238 ± 13% compared with vehicle values. The primary mechanism for this effect was a 74.5 mV depolarizing shift in the voltage dependence of inactivation, without any shift in the voltage dependence of activation. Structure–activity relationships for this effect were remarkably subtle, with close analogues of AZSMO‐23 acting as hERG inhibitors. AZSMO‐23 blocked the mutant channel, hERG Y652A, but against another mutant channel, hERG F656T, its activator activity was enhanced. It inhibited activity of the G628C/S631C non‐inactivating hERG mutant channel. AZSMO‐23 was not hERG selective, as it blocked hKv4.3‐hKChIP2.2, hCav3.2 and hKv1.5 and activated hCav1.2/β2/α2δ channels.Conclusion and ImplicationsThe activity of AZSMO‐23 and those of its close analogues suggest these compounds may be of value to elucidate the mechanism of type 2 hERG activators to better understand the pharmacology of this area from both a safety perspective and in relation to treatment of congenital long QT syndrome.
Mammal Browsers and Rainfall Affect Acacia Leaf Nutrient Content, Defense, and Growth in South African Savannas
Authors: Wigley Benjamin J. , Bond William J. , Fritz Hervé , Coetsee Corli 
Published: February 2015

AbstractFive sets of herbivore exclosures situated in mesic and semi‐arid savannas in Hluhluwe‐iMfolozi Park, South Africa were used to investigate the effects of mammal browsers and savanna type on plant traits relating to leaf nutrient content, defense, and growth in seven Acacia species. Mostly, browsing did not significantly affect leaf nutrient content but for a few species (i.e., increasing foliar N and P, decreasing C/N, and total polyphenols). Browser effects on structural defenses tended to be more pronounced than for leaf nutrient content and chemical defenses, particularly for semi‐arid species, resulting in longer, thicker, and denser spines, and a lower bite size index on browsed plants for most semi‐arid species. Browsing had no significant effect on growth rates for all species. Secondly, we investigated the effect of savanna type (mesic vs. semi‐arid) on the same set of plant traits and growth rates. A trade‐off in defense strategy was evident where mesic species had lower quality leaves and invested more heavily in growth and chemical defenses, while semi‐arid species generally had higher nutrient content leaves and invested more in structural defenses and higher levels of ramification. These findings suggest that the previously documented trade‐off in plant growth, resprouting ability and architecture between herbivore versus fire‐adapted savanna woody species can possibly be extended to include browse quality and defense type.
The Dominance of Introduced Plant Species in the Diets of Migratory Galapagos Tortoises Increases with Elevation on a Human‐Occupied Island
Authors: Blake Stephen , Guézou Anne , Deem Sharon L. , Yackulic Charles B. , Cabrera Fredy 
Published: February 2015

AbstractThe distribution of resources and food selection are fundamental to the ecology, life history, physiology, population dynamics, and conservation of animals. Introduced plants are changing foraging dynamics of herbivores in many ecosystems often with unknown consequences. Galapagos tortoises, like many herbivores, undertake migrations along elevation gradients driven by variability in vegetation productivity which take them into upland areas dominated by introduced plants. We sought to characterize diet composition of two species of Galapagos tortoises, focussing on how the role of introduced forage species changes over space and the implications for tortoise conservation. We quantified the distribution of tortoises with elevation using GPS telemetry. Along the elevation gradient, we quantified the abundance of introduced and native plant species, estimated diet composition by recording foods consumed by tortoises, and assessed tortoise physical condition from body weights and blood parameter values. Tortoises ranged between 0 and 429 m in elevation over which they consumed at least 64 plant species from 26 families, 44 percent of which were introduced species. Cover of introduced species and the proportion of introduced species in tortoise diets increased with elevation. Introduced species were positively selected for by tortoises at all elevations. Tortoise physical condition was either consistent or increased with elevation at the least biologically productive season on Galapagos. Santa Cruz tortoises are generalist herbivores that have adapted their feeding behavior to consume many introduced plant species that has likely made a positive contribution to tortoise nutrition. Some transformed habitats that contain an abundance of introduced forage species are compatible with tortoise conservation.
A Matter of Scale: Historical and Environmental Factors Structure Anuran Assemblages from the Upper Madeira River, Amazonia
Authors: Dias‐Terceiro Randolpho G. , Kaefer Igor Luis , de Fraga Rafael , de Araújo Maria Carmozina , Simões Pedro Ivo , Lima Albertina P. 
Published: February 2015

AbstractBiogeographical history and current ecological interactions have usually been addressed separately to explain the spatial distribution of patterns of biodiversity. In this study, we evaluated the integrated effects of biogeographical and environmental factors in structuring the diurnal amphibian anuran assemblages of the upper Madeira River, southwestern Amazonia. We used a sampling design involving 98 standardized units, distributed across seven locations covering both banks of the river's course in the state of Rondônia, Brazil. We conducted searches for frogs in three campaigns between February 2010 and February 2011, aiming to: (1) evaluate the effect of the Madeira River as a biogeographic barrier at the species‐assemblage level, and (2) test the influence of seven environmental variables (vegetation structure, vegetation cover, soil nutrients, soil structure, slope, elevation, and distance from the river bank) on the spatial structure of the frog assemblages, separately on each riverbank. Thirteen species of diurnal frogs were recorded, six of which were restricted to one of the river margins. Multivariate analysis of variance indicated a significant effect of the river as a barrier. Multiple regression analyses suggested that the environmental variables structuring frog assemblages differ on either side of the river. We found that both historical elements (on a regional scale) and environmental factors (at a local scale) shaped the occurrence and distribution of frog species in the study area.
Population Viability Analysis of the Epiphytic Ghost Orchid (Dendrophylax lindenii) in Cuba
Authors: Raventós José , González Elaine , Mújica Ernesto , Doak Dan F. 
Published: February 2015

AbstractTo design feasible conservation and management policies for wild species, it is critical to understand the effects of periodic disturbances, be they natural or anthropogenic. The Caribbean Basin is characterized by high cyclonic activity that has a strong impact on the demography and population dynamics of many taxa, including epiphytic orchids. We conducted a 5‐yr study of rare ghost orchid demography, Dendrophylax lindenii, to assess the stability of a protected population of this species in Cuba. Using both stochastic and deterministic integral projection models, we found that mean annual population growth rates are negative (λ = 0.975). However, we found both population growth rate and extinction risk are highly sensitive to survival rates and reproduction, a difficult to quantify rate for many orchids including our study species. While this species is fairly long‐lived, its relatively slow increase in annual survival with increasing size may reflect the lack of a protected (i.e., subterranean) storage organ—a life‐history trait that may typify other epiphytic species and increase susceptibility to disturbance events. Hurricanes, which are predicted to increase in frequency as a result of climate change, dramatically increase adult mortality. Simulations of these effects indicate that hurricanes and similar disturbances could result in near certain extinction in short time horizons (25 yr) if their annual probability of occurrence exceeds 14 percent. These results suggest a need to better quantify recruitment rates, as well as the sensitivity of population dynamics of this and other orchid species to hurricanes and other periodic disturbances.
Entry, reputation and intellectual property rights enforcement
Authors: Che Jiahua , Qiu Larry , Zhou Wen 
Published: February 2015

AbstractWe examine how reputation concerns induce a multinational to partly withhold its entry into a developing country under weak intellectual property rights (IPR) enforcement. Equilibrium IPR violations are shown to arise only in the presence of such concerns. Holding constant a multinational's incentive to innovate, better IPR enforcement encourages entry but reduces social welfare. The multinational's incentive to innovate may be inversely U‐shaped in the strength of IPR enforcement. If timed properly, however, stronger IPR enforcement can foster innovation without compromising social welfare. Testable implications concerning observable IPR violations are derived.
Occupations, fields of study and returns to education
Authors: Lemieux Thomas 
Published: February 2015

AbstractThis paper considers several possible channels behind the well‐documented effect of education on earnings. The first channel is that education makes workers more productive on a given task, as in a conventional human capital framework. The second channel is based on the idea that education helps workers get assigned to higher‐paying occupations where output is more sensitive to skill. A third and final channel is that workers are more productive and earn more when they are matched to a job related to their field of study. Using data from the 2005 National Graduate Survey and the 2006 Canadian Census, I find that channels two and three account for close to half of the conventionally measured return to education. The results indicate that the return to education varies greatly depending on occupation, field of study and the match between these two factors.
Validation study of the combined repeated‐dose toxicity and genotoxicity assay using gpt delta rats
Authors: Akagi Jun‐ichi , Toyoda Takeshi , Cho Young‐Man , Mizuta Yasuko , Nohmi Takehiko , Nishikawa Akiyoshi , Ogawa Kumiko 
Published: February 2015

Transgenic rodents carrying reporter genes to detect organ‐specific in vivo genetic alterations are useful for risk assessment of genotoxicity that causes cancer. Thus, the Organization for Economic Co‐operation and Development has established the guideline for genotoxicity tests using transgenic animals, which may be combined with repeated‐dose toxicity studies. Here, we provide evidence to support equivalence of gpt delta and wild type (WT) rats in terms of toxicological responses to a genotoxic hepatocarcinogen, N‐nitrosodiethylamine (DEN), and a non‐genotoxic hepatocarcinogen, di(2‐ethylhexyl)phthalate (DEHP). gpt delta rats treated with DEHP showed similar increases in liver and kidney weights, serum albumin, albumin/globulin ratios, and incidence of diffuse hepatocyte hypertrophy compared to WT F344 and Sprague–Dawley (SD) rats. DEN‐treated gpt delta rats showed equivalent increases in the number and area of precancerous GST‐P‐positive foci in the liver compared to WT rats. The livers of DEN‐treated gpt delta rats also showed increased frequencies of gpt and Spi− mutations; such changes were not observed in DEHP‐treated gpt delta rats. These results indicated that gpt delta rats (both F344 and SD backgrounds) showed comparable DEHP‐induced toxicity and DEN‐induced genotoxicity to those observed in WT rats. With regard to the administration period, the general toxicity of 1.2% DEHP was evident throughout the experimental period, and the genotoxicity of 10 p.p.m. DEN could be detected after 2 weeks of administration and further increased at 4 weeks. These results suggested that combined assays using gpt delta rats could detect both general toxicity and genotoxicity by the canonical 4‐week administration protocol. Therefore, this assay using gpt delta rats would be applicable for risk assessment including early detection of genotoxic carcinogens and ultimately serve to reduce cancer risks in humans from environmental chemicals.
Depressive Symptoms in Third‐Grade Teachers: Relations to Classroom Quality and Student Achievement
Authors: McLean Leigh , Connor Carol McDonald 
Published: February 2015

This study investigated associations among third‐grade teachers' (N = 27) symptoms of depression, quality of the classroom‐learning environment (CLE), and students' (N = 523, Mage = 8.6 years) math and literacy performance. teachers' depressive symptoms in the winter negatively predicted students' spring mathematics achievement. This depended on students' fall mathematics scores; students who began the year with weaker math skills and were in classrooms where teachers reported more depressive symptoms achieved smaller gains than did peers whose teachers reported fewer symptoms. teachers' depressive symptoms were negatively associated with quality of CLE, and quality of CLE mediated the association between depressive symptoms and student achievement. The findings point to the importance of teachers' mental health, with implications for policy and practice.