bluuebunny/crossref_metadata_2025 huggingface dataset:
Sleep quality under mild hypoxia in men with low hypoxic ventilatory response
Authors: Hoshikawa Masako , Uchida Sunao , Ganeko Masashi , Sumitomo Junya , Totoki Masatsugu , Kojima Takuto , Nakamura Yukiko , Kawahara Takashi
Published: May 2012

The present study evaluated whether slow‐wave sleep and whole‐night delta power of the non‐rapid eye movement (NREM) sleep electroencephalogram (EEG) decrease during sleep at a simulated altitude of 2000 m, and whether such changes related to measures of hypoxic ventilatory response (HVR). This study consisted of two parts; in the first, HVR was measured in 41 subjects and each seven subjects with the lowest or the highest HVR were selected for the subsequent sleep study. In the second part, polysomnogram, arterial oxygen saturation (SpO2) and respiratory events are recorded on the selected subjects under normoxic and hypoxic conditions. Hypoxia decreased SpO2 and increased respiratory disturbances for both groups. The low HVR group, but not the high HVR group, showed decreases in the whole‐night delta power of NREM sleep EEG under hypoxia. On the other hand, two subjects in the high HVR group, who showed relatively high apnoea indices, also showed lower SpO2 nadirs and decreases in the whole‐night delta power under hypoxia. These results suggest that acute hypoxia equivalent to that at a 2000 m altitude decreases slow‐wave sleep in individuals that show low HVR. However, low HVR may not be the only, but one of some factors that decrease the whole‐night delta power under hypoxia. Therefore, it was not sufficient to identify individuals likely to be susceptible to deteriorated sleep quality at a simulated altitude of 2000 m only using the HVR test. Other factors, which relate to respiratory instabilities, should be taken into consideration to identify them.
Relative age‐related participation and dropout trends in German youth sports clubs
Authors: Wattie Nick , Tietjens Maike , Cobley Stephen , Schorer Jörg , Baker Joseph , Kurz Dietrich
Published: May 2012

Relative age describes a youth's age within their age group cohort. Compared to relatively younger peers, relatively older youth in an annual age group cohort have been found more likely to be selected to sports teams, and to receive higher grades in education. This study examined the influence of youth sport participants’ relative age on participation and dropout. Using data from the 1995 German Youth Sport Survey (N total=2612), comparisons (stratified by gender and sport type) were made between the relative age of current and former participants. Analyses also considered the type of school youths were enrolled in while exploring the influence of relative age on sport participations. No relative age effects for dropout emerged among males in team or individual sport contexts. Female dropouts were more likely to be relatively older (Q1, ORadjusted: 0.52, 95% CI: 0.34–0.80; Q2, ORadjusted: 0.55, 95% CI: 0.36–0.84; Q3, ORadjusted: 0.59, 95% CI: 0.39–0.89), an effect that was mirrored among ‘artistic’ sport participants. Boys and girls in schools that were for children of higher academic proficiency were more likely to be currently participating in sport. Findings suggest that relative age‐related dropout effects may be context sensitive and different for males and females. For the most part, relative age did not appear to have any relationship with dropout in this sample, with some notable exceptions for females. Overall, factors such as the type of school youths were enrolled in appear to be a more salient influence on sport participation than relative age.
Potent and broad neutralization of HIV-1 by a llama antibody elicited by immunization
Authors: McCoy Laura E. , Quigley Anna Forsman , Strokappe Nika M. , Bulmer-Thomas Bianca , Seaman Michael S. , Mortier Daniella , Rutten Lucy , Chander Nikita , Edwards Carolyn J. , Ketteler Robin , Davis David , Verrips Theo , Weiss Robin A.
Published: May 2012

Llamas (Lama glama) naturally produce heavy chain–only antibodies (Abs) in addition to conventional Abs. The variable regions (VHH) in these heavy chain–only Abs demonstrate comparable affinity and specificity for antigens to conventional immunoglobulins despite their much smaller size. To date, immunizations in humans and animal models have yielded only Abs with limited ability to neutralize HIV-1. In this study, a VHH phagemid library generated from a llama that was multiply immunized with recombinant trimeric HIV-1 envelope proteins (Envs) was screened directly for HIV-1 neutralization. One VHH, L8CJ3 (J3), neutralized 96 of 100 tested HIV-1 strains, encompassing subtypes A, B, C, D, BC, AE, AG, AC, ACD, CD, and G. J3 also potently neutralized chimeric simian-HIV strains with HIV subtypes B and C Env. The sequence of J3 is highly divergent from previous anti–HIV-1 VHH and its own germline sequence. J3 achieves broad and potent neutralization of HIV-1 via interaction with the CD4-binding site of HIV-1 Env. This study may represent a new benchmark for immunogens to be included in B cell–based vaccines and supports the development of VHH as anti–HIV-1 microbicides.
Study of an active hybrid gap surface plasmon polariton waveguide with nanoscale confinement size and low compensation gain
Authors: Rao Ruijian , Tang Tiantong
Published: May 2012

A silicon-based hybrid gap surface plasmon polariton (SPP) waveguide consisting of an active InP/GaInAsP/InP double heterostructure layer, a silver cladding with a rectangular bump and a gap between them is presented. Based on this waveguide, all the SPP waveguides and even the SPP components share a common planar active medium layer in the whole photonic integration circuit chip, so not only can both the waveguide structure width and the mode lateral confinement width be of nanoscale simultaneously, but optical pumping can also be easily realized for compensating the propagation loss of all the SPP waveguides and components. By means of thickening the active GaInAsP layer and thinning the gap, the threshold gain coefficient is reduced to an achievable range and the mode confinement size is dropped to the nanoscale. Numerical simulation suggests that when the gap size is 50 nm × 10 nm and the GaInAsP height is 350 nm, by adjusting the metal bump height, the effective mode area is

at λ0 = 1550 nm and the full-width at half-maximum of the Poynting vector magnitude is 66 nm and the threshold gain coefficient is 158.5 cm−1 or 850.9 cm−1 for different Ag permittivities coming from two sources.
Femtosecond laser ablation of dentin
Authors: Alves S , Oliveira V , Vilar R
Published: May 2012

The surface morphology, structure and composition of human dentin treated with a femtosecond infrared laser (pulse duration 500 fs, wavelength 1030 nm, fluences ranging from 1 to 3 J cm−2) was studied by scanning electron microscopy, x-ray diffraction, x-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. The average dentin ablation threshold under these conditions was 0.6 ± 0.2 J cm−2 and the ablation rate achieved in the range 1 to 2 µm/pulse for an average fluence of 3 J cm−2. The ablation surfaces present an irregular and rugged appearance, with no significant traces of melting, deformation, cracking or carbonization. The smear layer was entirely removed by the laser treatment. For fluences only slightly higher than the ablation threshold the morphology of the laser-treated surfaces was very similar to the dentin fracture surfaces and the dentinal tubules remained open. For higher fluences, the surface was more porous and the dentin structure was partially concealed by ablation debris and a few resolidified droplets. Independently on the laser processing parameters and laser processing method used no sub-superficial cracking was observed. The dentin constitution and chemical composition was not significantly modified by the laser treatment in the processing parameter range used. In particular, the organic matter is not preferentially removed from the surface and no traces of high temperature phosphates, such as the β-tricalcium phosphate, were observed. The achieved results are compatible with an electrostatic ablation mechanism. In conclusion, the high beam quality and short pulse duration of the ultrafast laser used should allow the accurate preparation of cavities, with negligible damage of the underlying material.
Phylogeny versus body size as determinants of food web structure
Authors: Naisbit Russell E. , Rohr Rudolf P. , Rossberg Axel G. , Kehrli Patrik , Bersier Louis-Félix
Published: May 2012

Food webs are the complex networks of trophic interactions that stoke the metabolic fires of life. To understand what structures these interactions in natural communities, ecologists have developed simple models to capture their main architectural features. However, apparently realistic food webs can be generated by models invoking either predator–prey body-size hierarchies or evolutionary constraints as structuring mechanisms. As a result, this approach has not conclusively revealed which factors are the most important. Here we cut to the heart of this debate by directly comparing the influence of phylogeny and body size on food web architecture. Using data from 13 food webs compiled by direct observation, we confirm the importance of both factors. Nevertheless, phylogeny dominates in most networks. Moreover, path analysis reveals that the size-independent direct effect of phylogeny on trophic structure typically outweighs the indirect effect that could be captured by considering body size alone. Furthermore, the phylogenetic signal is asymmetric: closely related species overlap in their set of consumers far more than in their set of resources. This is at odds with several food web models, which take only the view-point of consumers when assigning interactions. The echo of evolutionary history clearly resonates through current food webs, with implications for our theoretical models and conservation priorities.
Rhabdom evolution in butterflies: insights from the uniquely tiered and heterogeneous ommatidia of the Glacial Apollo butterfly,Parnassius glacialis
Authors: Matsushita Atsuko , Awata Hiroko , Wakakuwa Motohiro , Takemura Shin-ya , Arikawa Kentaro
Published: May 2012

The eye of the Glacial Apollo butterfly,Parnassius glacialis, a ‘living fossil’ species of the family Papilionidae, contains three types of spectrally heterogeneous ommatidia. Electron microscopy reveals that the Apollo rhabdom is tiered. The distal tier is composed exclusively of photoreceptors expressing opsins of ultraviolet or blue-absorbing visual pigments, and the proximal tier consists of photoreceptors expressing opsins of green or red-absorbing visual pigments. This organization is unique because the distal tier of other known butterflies contains two green-sensitive photoreceptors, which probably function in improving spatial and/or motion vision. Interspecific comparison suggests that the Apollo rhabdom retains an ancestral tiered pattern with some modification to enhance its colour vision towards the long-wavelength region of the spectrum.
Outsourcing punishment to God: beliefs in divine control reduce earthly punishment
Authors: Laurin Kristin , Shariff Azim F. , Henrich Joseph , Kay Aaron C.
Published: May 2012

The sanctioning of norm-transgressors is a necessary—though often costly—task for maintaining a well-functioning society. Prior to effective and reliable secular institutions for punishment, large-scale societies depended on individuals engaging in ‘altruistic punishment’—bearing the costs of punishment individually, for the benefit of society. Evolutionary approaches to religion suggest that beliefs in powerful, moralizing Gods, who can distribute rewards and punishments, emerged as a way to augment earthly punishment in large societies that could not effectively monitor norm violations. In five studies, we investigate whether such beliefs in God can replace people's motivation to engage in altruistic punishment, and their support for state-sponsored punishment. Results show that, although religiosity generally predicts higher levels of punishment, the specific belief in powerful, intervening Gods reduces altruistic punishment and support for state-sponsored punishment. Moreover, these effects are specifically owing to differences in people's perceptions that humans are responsible for punishing wrongdoers.
A Middle Jurassic abelisaurid from Patagonia and the early diversification of theropod dinosaurs
Authors: Pol Diego , Rauhut Oliver W. M.
Published: May 2012

Abelisaurids are a clade of large, bizarre predatory dinosaurs, most notable for their high, short skulls and extremely reduced forelimbs. They were common in Gondwana during the Cretaceous, but exceedingly rare in the Northern Hemisphere. The oldest definitive abelisaurids so far come from the late Early Cretaceous of South America and Africa, and the early evolutionary history of the clade is still poorly known. Here, we report a new abelisaurid from the Middle Jurassic of Patagonia,Eoabelisaurus mefigen. et sp. nov., which predates the so far oldest known secure member of this lineage by more than 40 Myr. The almost complete skeleton reveals the earliest evolutionary stages of the distinctive features of abelisaurids, such as the modification of the forelimb, which started with a reduction of the distal elements. The find underlines the explosive radiation of theropod dinosaurs in the Middle Jurassic and indicates an unexpected diversity of ceratosaurs at that time. The apparent endemism of abelisauroids to southern Gondwana during Pangean times might be due to the presence of a large, central Gondwanan desert. This indicates that, apart from continent-scale geography, aspects such as regional geography and climate are important to reconstruct the biogeographical history of Mesozoic vertebrates.
Phylogenomic datasets provide both precision and accuracy in estimating the timescale of placental mammal phylogeny
Authors: dos Reis Mario , Inoue Jun , Hasegawa Masami , Asher Robert J. , Donoghue Philip C. J. , Yang Ziheng
Published: May 2012

The fossil record suggests a rapid radiation of placental mammals following the Cretaceous–Paleogene (K–Pg) mass extinction 65 million years ago (Ma); nevertheless, molecular time estimates, while highly variable, are generally much older. Early molecular studies suffer from inadequate dating methods, reliance on the molecular clock, and simplistic and over-confident interpretations of the fossil record. More recent studies have used Bayesian dating methods that circumvent those issues, but the use of limited data has led to large estimation uncertainties, precluding a decisive conclusion on the timing of mammalian diversifications. Here we use a powerful Bayesian method to analyse 36 nuclear genomes and 274 mitochondrial genomes (20.6 million base pairs), combined with robust but flexible fossil calibrations. Our posterior time estimates suggest that marsupials diverged from eutherians 168–178 Ma, and crown Marsupialia diverged 64–84 Ma. Placentalia diverged 88–90 Ma, and present-day placental orders (except Primates and Xenarthra) originated in a ∼20 Myr window (45–65 Ma) after the K–Pg extinction. Therefore we reject a pre K–Pg model of placental ordinal diversification. We suggest other infamous instances of mismatch between molecular and palaeontological divergence time estimates will be resolved with this same approach.
The “Bringing into Cultivation” Phase of the Plant Domestication Process and Its Contributions toIn SituConservation of Genetic Resources in Benin
Authors: Vodouhè R. , Dansi A.
Published: May 2012

All over the world, plant domestication is continually being carried out by local communities to support their needs for food, fibre, medicine, building materials, etc. Using participatory rapid appraisal approach, 150 households were surveyed in 5 villages selected in five ethnic groups of Benin, to investigate the local communities’ motivations for plant domestication and the contributions of this process toin situconservation of genetic resources. The results indicated differences in plant domestication between agroecological zones and among ethnic groups. People in the humid zones give priority to herbs mainly for their leaves while those in dry area prefer trees mostly for their fruits. Local communities were motivated to undertake plant domestication for foods (80% of respondents), medicinal use (40% of respondents), income generation (20% of respondents) and cultural reasons (5% of respondents). 45% of the species recorded are still at early stage in domestication and only 2% are fully domesticated. Eleven factors related to the households surveyed and to the head of the household interviewed affect farmers’ decision making in domesticating plant species. There is gender influence on the domestication: Women are keen in domesticating herbs while men give priority to trees.
Screening for Depression, Sleep-Related Disturbances, and Anxiety in Patients with Adenocarcinoma of the Pancreas: A Preliminary Study
Authors: Boyd Andrew D. , Brown Doris , Henrickson Chris , Hampton Janet , Zhu Bin , Almani Farideh , Ben-Josef Edgar , Zalupski Mark , Simeone Diane M. , Taylor Jeremy M. G. , Armitage Roseanne , Riba Michelle
Published: May 2012

Purpose. Screening for depression, sleep-related disturbances, and anxiety in patients with diagnosed adenocarcinoma of the pancreas.Materials and Methods. Patients were evaluated at initial consultation and subsequent visits at the multidisciplinary pancreatic cancer clinic at our University Cancer Center. Cross-sectional and longitudinal psychosocial distress was assessed utilizing Personal Health Questionnaire 9 (PHQ9) to screen for depression and monitor symptoms, the Penn State Worry Questionnaire (PSWQ) for generalized anxiety, and the University of Michigan Sleep Questionnaire to monitor sleep symptoms.Results. Twenty-two patients diagnosed with pancreatic cancer participated during the 6-month pilot study with longitudinal followup for thirteen patients. In this study, mild-to-moderate depressive symptoms, anxiety, and potential sleep problems were common. The main finding of the study was 23% of the patients who were part of this pilot project screened positive for moderately severe major depressive symptoms, likely anxiety disorder or a potential sleep disorder during the study. One patient screened positive for moderately severe depressive symptoms in longitudinal followup.Conclusions. Depression, anxiety, and sleep problems are evident in patients with pancreatic cancer. Prospective, longitudinal studies, with larger groups of patients, are needed to determine if these comorbid symptoms impact outcome and clinical course.
Process Evaluation of a Positive Youth Development Program in Hong Kong Based on Different Cohorts
Authors: Law Ben M. F. , Shek Daniel T. L.
Published: May 2012

There are only a few process evaluation studies on positive youth development programs, particularly in the Chinese context. This study aims to examine the quality of implementation of a positive youth development program (the Project P.A.T.H.S.: Positive Adolescent Training through Holistic Social Programmes) and investigate the relationships among program adherence, process factors, implementation quality, and perceived program success. Process evaluation of 97 classroom-based teaching units was conducted in 62 schools from 2005 to 2009. Findings based on different cohorts generally showed that there were high overall program adherence and implementation quality. Program adherence and implementation process were highly correlated with quality and success of the program. Multiple regression analyses further showed that both implementation process and program adherence are significant predictors of program quality and success. Theoretical and practical implications of the findings are discussed.
In vitro characterization of calcium transport along the gastrointestinal tract of freshwater rainbow trout Oncorhynchus mykiss
Authors: Klinck J. S. , Singh A. , Wood C. M.
Published: May 2012

Using an in vitro gut‐sac technique, this study examined the mechanisms of calcium (Ca) uptake along the gastrointestinal tract (GIT) of rainbow trout Oncorhynchus mykiss. Ca uptake into three different compartments (mucous‐bound, mucosal epithelium and blood space) of four distinct GIT segments (stomach, anterior intestine, mid intestine and posterior intestine) was monitored after luminal exposure to 10 mM Ca saline (radiolabelled with 45Ca). Ca transport was determined to be both time‐dependent and concentration‐dependent. The concentration‐dependent kinetics of Ca uptake was investigated using varying luminal concentrations of Ca (1, 10, 30, 60 and 100 mM). In the blood‐space compartment, Ca uptake was saturable at high Ca concentrations in the mid intestine (suggesting mediated transport), while linear uptake was found in the other gut segments. In the mucous‐bound and mucosal epithelium compartments, however, saturation kinetics were found for most GIT segments, also suggesting mediated transport. Manipulation of serosal saline osmotic pressure with mannitol demonstrated that Ca uptake was not greatly affected by solvent drag. Elevated mucosal cadmium (Cd) did not appear to inhibit Ca uptake into the blood space in any of the GIT sections, and Ca uptake did not appear to be sodium dependent. Maximum transport capacities for Ca and Cd were found to be comparable between the gills and gut, but affinities were much higher at the gills (up to 3000 times).
Morphological and physiological changes of female tropical eels, Anguilla celebesensis and Anguilla marmorata, in relation to downstream migration
Authors: Hagihara S. , Aoyama J. , Limbong D. , Tsukamoto K.
Published: May 2012

The morphological and physiological characteristics of migrating and non‐migrating female tropical eels, Anguilla celebesensis and Anguilla marmorata were examined in relation to their downstream migration on central Sulawesi Island, Indonesia. Migrating eels (64 A. celebesensis and 37 A. marmorata) were obtained from weirs set near the outlet area of Poso Lake and non‐migrating eels (21 A. celebesensis and 21 A. marmorata) were sampled by set‐lines and eel pots in Poso Lake, its inlet rivers, and in the La River system during February 2009 to October 2010. In both species, values of eye index, pectoral‐fin length index, gonado‐somatic index (IG), hepato‐somatic index, swimbladder‐somatic index and cardio‐somatic index of migrating eels were significantly higher than those of non‐migrating eels and the gut‐somatic index values of the migrating eels were significantly lower than that of non‐migrating eels. When silvering stages of eels were classified by the silvering index for Anguilla japonica, in A. celebesensis, all non‐migrating eels were Y1 stage and the migrating eels consisted of Y2, S1 and S2 stages eels. In A. marmorata, the non‐migrating eels consisted of Y1 and Y2 eels, and the migrating eels consisted of Y2 and S1 eels, but there were no S2 eels. Results of principal component analysis (PCA) of morphological and physiological variables suggested that these characteristics changed drastically between the Y1 and Y2 stages in A. celebesensis, while A. marmorata showed a gradual change with silvering, which differs from the temperate species A. japonica. The mean ±s.d. IG value of migrating A. celebesensis (6·9 ± 1·8, 3·3–11·4) was very high and that of A. marmorata (3·1 ± 0·8, 1·8–5·7) was comparatively low. The very different rates of maturation that were found between these two species provide support for the hypothesis that the reproductive characteristics of silver eels can reflect their migration scale.
Partial migration in fishes: causes and consequences
Authors: Chapman B. B. , Hulthén K. , Brodersen J. , Nilsson P. A. , Skov C. , Hansson L.‐A. , Brönmark C.
Published: May 2012

Partial migration, where only some individuals from a population migrate, has been widely reported in a diverse range of animals. In this paper, what is known about the causes and consequences of partial migration in fishes is reviewed. Firstly, the ultimate and proximate drivers of partial migration are reflected upon: what ecological factors can shape the evolution of migratory dimorphism? How is partial migration maintained over evolutionary timescales? What proximate mechanisms determine whether an individual is migratory or remains resident? Following this, the consequences of partial migration are considered, in an ecological and evolutionary context, and also in an applied sense. Here it is argued that understanding the concept of partial migration is crucial for fisheries and ecosystem managers, and can provide information for conservation strategies. The review concludes with a reflection on the future opportunities in this field, and the avenues of research that are likely to be fruitful to shed light on the enduring puzzle of partial migration in fishes.
Analysis of mitochondrial DNA in Bolivian llama, alpaca and vicuna populations: a contribution to the phylogeny of the South American camelids
Authors: Barreta J. , Gutiérrez‐Gil B. , Iñiguez V. , Saavedra V. , Chiri R. , Latorre E. , Arranz J. J.
Published: May 2012

The objectives of this work were to assess the mtDNA diversity of Bolivian South American camelid (SAC) populations and to shed light on the evolutionary relationships between the Bolivian camelids and other populations of SACs. We have analysed two different mtDNA regions: the complete coding region of the MT‐CYB gene and 513 bp of the D‐loop region. The populations sampled included Bolivian llamas, alpacas and vicunas, and Chilean guanacos. High levels of genetic diversity were observed in the studied populations. In general, MT‐CYB was more variable than D‐loop. On a species level, the vicunas showed the lowest genetic variability, followed by the guanacos, alpacas and llamas. Phylogenetic analyses performed by including additional available mtDNA sequences from the studied species confirmed the existence of the two monophyletic clades previously described by other authors for guanacos (G) and vicunas (V). Significant levels of mtDNA hybridization were found in the domestic species. Our sequence analyses revealed significant sequence divergence within clade G, and some of the Bolivian llamas grouped with the majority of the southern guanacos. This finding supports the existence of more than the one llama domestication centre in South America previously suggested on the basis of archaeozoological evidence. Additionally, analysis of D‐loop sequences revealed two new matrilineal lineages that are distinct from the previously reported G and V clades. The results presented here represent the first report on the population structure and genetic variability of Bolivian camelids and may help to elucidate the complex and dynamic domestication process of SAC populations.
The effect of CYP3A inhibitors and inducers on the pharmacokinetics of telaprevir in healthy volunteers
Authors: Garg Varun , Chandorkar Gurudatt , Yang Yijun , Adda Nathalie , McNair Lindsay , Alves Katia , Smith Frances , van Heeswijk Rolf P. G.
Published: May 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Telaprevir is a hepatitis C virus protease inhibitor for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease. In vitro studies indicated that CYP3A was the major cytochrome P‐450 (CYP) isozyme involved in the metabolism of telaprevir. It is important to understand the potential for drug–drug interactions of telaprevir when it is co‐administered with CYP3A inhibitors or inducers.

WHAT THIS STUDY ADDS

• CYP3A inducers, rifampicin and efavirenz, can reduce telaprevir exposure to varying degrees based on their potency. After a single dose, telaprevir exposure is increased when ketoconazole, a strong CYP3A inhibitor, is co‐administered. However, at steady‐state, telaprevir exposure is less likely to be affected by CYP3A inhibitors.

AIM To evaluate the effects of ketoconazole, rifampicin and efavirenz on the pharmacokinetics of telaprevir in healthy volunteers.

METHOD Results from three clinical studies are described. (1) Volunteers received a single 750 mg dose telaprevir with and without a single 400 mg dose ketoconazole. (2) Volunteers received (a) 1250 mg telaprevir followed by three 750 mg doses given every 8 h and (b) four 1250 mg telaprevir doses given every 8 h, with a single 400 mg dose ketoconazole given with the fourth dose of telaprevir. (3) Volunteers received either a single 750 mg dose telaprevir with or without 600 mg once daily rifampicin, or 750 mg every 8 h telaprevir with and without 600 mg once daily efavirenz.

RESULTS A single 400 mg dose of ketoconazole increased single dose telaprevir exposure: the geometric least‐squares mean ratio (GLSMR, with 90% confidence limits) was 1.24 (1.10, 1.41) for Cmax and 1.62 (1.45, 1.81) for AUC(0,∞). However, after multiple doses of telaprevir, there was no discernible effect of ketoconazole on telaprevir exposure. Co‐administration of rifampicin at steady‐state markedly reduced single dose telaprevir exposure with GLSMRs of 0.14 (0.11, 0.18) for Cmax and 0.08 (0.07, 0.11) for AUC(0,∞), whereas efavirenz had a smaller effect on telaprevir exposure when both drugs were co‐administered at steady‐state, with GLSMRs of 0.91 (0.81, 1.02) for Cmax, 0.53 (0.44, 0.65) for Cmin, and 0.74 (0.65, 0.84) for AUC(0,8 h).

CONCLUSION CYP3A inducers, rifampicin and efavirenz, can reduce telaprevir exposure to varying degrees based on their potency. The effect of ketoconazole as an inhibitor of telaprevir metabolism is more pronounced after a single dose of telaprevir than after repeated administration.
The pharmacokinetics of darexaban are not affected to a clinically relevant degree by rifampicin, a strong inducer of P‐glycoprotein and CYP3A4
Authors: Groenendaal Dorien , Strabach Gregory , Garcia‐Hernandez Alberto , Kadokura Takeshi , Heeringa Marten , Mol Roelof , Eltink Charlotte , Onkels Hartmut
Published: May 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Darexaban is an oral direct factor Xa inhibitor developed as an antithrombotic for several indications. Several other new oral anticoagulants are metabolized via CYP3A4 and transported by P‐glycoprotein, displaying clinically relevant drug interactions with rifampicin and ketoconazole.

• Darexaban is almost entirely metabolized to darexaban glucuronide, which is the main active moiety. In vitro, CYP3A4 metabolism is not involved in the formation or metabolism of darexaban glucuronide; and darexaban, but not darexaban glucuronide, is a P‐glycoprotein substrate in vitro.

WHAT THIS STUDY ADDS

• The study shows that rifampicin does not affect the pharmacokinetic profiles of darexaban glucuronide and darexaban to a clinically relevant degree, suggesting that the potential for drug−drug interactions between darexaban and CYP3A4 or P‐glycoprotein‐inducing agents is low.

• This study was carried out to confirm the susceptibility of darexaban/darexaban glucuronide to CYP3A4 and P‐glycoprotein induction in vivo in humans.

AIMS We investigated the effects of rifampicin on the pharmacokinetics (PK) of the direct clotting factor Xa inhibitor darexaban (YM150) and its main active metabolite, darexaban glucuronide (YM‐222714), which almost entirely determines the antithrombotic effect.

METHODS In this open‐label, single‐sequence study, 26 healthy men received one dose of darexaban 60 mg on day 1 and oral rifampicin 600 mg once daily on days 4−14. On day 11, a second dose of darexaban 60 mg was given with rifampicin. Blood and urine were collected after study drug administration on days 1−14. The maximal plasma drug concentration (Cmax) and exposure [area under the plasma concentration–time curve from time zero to time of quantifiable measurable concentration; (AUClast) or AUClast extrapolated to infinity (AUC∞)] were assessed by analysis of variance of PK. Limits for statistical significance of 90% confidence intervals for AUC and Cmax ratios were predefined as 80−125%.

RESULTS Darexaban glucuronide plasma exposure was not affected by rifampicin; the geometric mean ratio (90% confidence interval) of AUClast with/without rifampicin was 1.08 (1.00, 1.16). The Cmax of darexaban glucuronide increased by 54% after rifampicin [ratio 1.54 (1.37, 1.73)]. The plasma concentrations of darexaban were very low (<1% of darexaban glucuronide concentrations) with and without rifampicin. Darexaban alone or in combination with rifampicin was generally safe and well tolerated.

CONCLUSIONS Overall, rifampicin did not affect the PK profiles of darexaban glucuronide and darexaban to a clinically relevant degree, suggesting that the potential for drug−drug interactions between darexaban and CYP3A4 or P‐glycoprotein‐inducing agents is low.
Allogeneic haematopoietic stem cell transplantation for chronic lymphocytic leukaemia: outcome in a 20‐year cohort
Authors: Toze Cynthia L. , Dalal Chinmay B. , Nevill Thomas J. , Gillan Tanya L. , Abou Mourad Yasser R. , Barnett Michael J. , Broady Raewyn C. , Forrest Donna L. , Hogge Donna E. , Nantel Stephen H. , Power Maryse M. , Song Kevin W. , Sutherland Heather J. , Smith Clayton A. , Narayanan Sujaatha , Young Sean S. , Connors Joseph M. , Shepherd John D.
Published: May 2012

The curative potential of allogeneic haematopoietic stem cell transplant (allo HSCT) in chronic lymphocytic leukaemia CLL is established, with a demonstrated role for graft‐versus‐leukaemia and less certainty for other factors in determining outcome. The first two decades of CLL patients proceeding to allo HSCT at the Leukaemia/Bone Marrow Transplant Program of British Columbia (n = 49 consecutive, 1991–2009) were studied to clarify factors predicting outcome. The donor was related in 29 (59%) and unrelated in 20 (41%). Conditioning was reduced‐intensity in 27 (55%) and myeloablative in 22 (45%). Thirty‐one of 49 patients survive with median follow‐up of 5 years (0·2–15). Cumulative incidence of non‐relapse mortality; complete remission (CR); clearance of fluorescence in situ hybridization (FISH) abnormality and progression at 10 years was 36%; 69%; 55% and 22%. Overall survival (OS) was 63% at 2 years; 55% at 5 years and beyond. Factors predicting OS (P value by log rank <0·05) were: comorbidity index <3, FISH rank (Dohner) and 17p deletion, alemtuzumab pre‐HSCT, achievement of CR post‐HSCT, donor chimerism >90%, clearance of FISH abnormality post‐HSCT and absence of high‐grade (3–4) graft‐versus‐host disease. Results from this province‐wide, two‐decade cohort demonstrated that a substantial proportion of patients with high‐risk CLL become long term disease‐free survivors.
What does anti‐Müllerian hormone tell you about ovarian function?
Authors: Anderson Richard A.
Published: May 2012

The measurement anti‐Müllerian hormone (AMH) is leading to new insights into ovarian function. AMH is produced by small growing follicles, thus is distinct from ovulation and is a step closer to being able to assess the true ovarian reserve. AMH is measureable from birth to near the menopause, with a peak in the mid‐20s. Changes in adolescence are likely to lead to new understanding of ovarian maturation at puberty. AMH is becoming a routine test in assisted conception, reflecting a decline in the primordial follicle pool during the later reproductive years, and also identifying women at risk of over‐response. Thus, its relationship with the ovarian reserve changes from an inverse one in the first quarter century to a positive one thereafter as both decline in parallel. AMH does not vary significantly across the menstrual cycle, but it is not fully gonadotrophin‐independent, showing delayed changes consistent with the site of production from smaller growing follicles. There is considerable interest, both professional and public, in its ability to predict remaining reproductive lifespan, which clinically may be of value in the assessment of ovarian reserve following damage, for example postchemotherapy or ovarian surgery. AMH is markedly increased in polycystic ovarian syndrome and may be of diagnostic value. The considerable promise of AMH measurement is ahead of the robustness of the data in allowing clinical interpretation in most contexts, but it is clear that it will in the future offer novel opportunities for the assessment of ovarian function in health as well as disease.
Carbon isotope evidence for recent climate‐related enhancement of CO2 assimilation and peat accumulation rates in Antarctica
Authors: Royles Jessica , Ogée Jérôme , Wingate Lisa , Hodgson Dominic A. , Convey Peter , Griffiths Howard
Published: May 2012

Signy Island, maritime Antarctic, lies within the region of the Southern Hemisphere that is currently experiencing the most rapid rates of environmental change. In this study, peat cores up to 2 m in depth from four moss banks on Signy Island were used to reconstruct changes in moss growth and climatic characteristics over the late Holocene. Measurements included radiocarbon dating (to determine peat accumulation rates) and stable carbon isotope composition of moss cellulose (to estimate photosynthetic limitation by CO
2 supply and model CO
2 assimilation rate). For at least one intensively 14C‐dated Chorisodontium aciphyllum moss peat bank, the vertical accumulation rate of peat was 3.9 mm yr−1 over the last 30 years. Before the industrial revolution, rates of peat accumulation in all cores were much lower, at around 0.6–1 mm yr−1. Carbon‐13 discrimination (Δ), corrected for background and anthropogenic source inputs, was used to develop a predictive model for CO
2 assimilation. Between 1680 and 1900, there had been a gradual increase in Δ, and hence assimilation rate. Since 1800, assimilation has also been stimulated by the changes in atmospheric CO
2 concentration, but a recent decline in Δ (over the past 50–100 years) can perhaps be attributed to documented changes in temperature and/or precipitation. The overall increase in CO
2 assimilation rate (13C proxy) and enhanced C accumulation (14C proxy) are consistent with warmer and wetter conditions currently generating higher growth rates than at any time in the past three millennia, with the decline in Δ perhaps compensated by a longer growing season.
Immunophenotyping of male breast cancer
Authors: Kornegoor Robert , Verschuur‐Maes Anoek H J , Buerger Horst , Hogenes Marieke C , de Bruin Peter C , Oudejans Joost J , Hinrichs Bernd , van Diest Paul J
Published: May 2012

Kornegoor R, Verschuur‐Maes A H J, Buerger H, Hogenes M C, de Bruin P C, Oudejans J J, Hinrichs B & van Diest P J  (2012) Histopathology Immunophenotyping of male breast cancer

Aims:  Male breast cancer is a rare disease, and knowledge of carcinogenesis is limited. Conflicting results, based on small series, have been reported for clinically relevant biomarkers.

Methods and results:  One hundred and thirty‐four cases of male breast cancer were immunohistochemically stained on tissue microarrays for oestrogen receptor (ER), progesterone receptor (PR), androgen receptor, human epidermal growth factor receptor 2 (HER2), BRST2, cyclin D1, bcl‐2, p53, p16, p21, Ki67, cytokeratin (CK) 5/6, CK14, and epidermal growth factor receptor. Data were correlated with clinicopathological features and patient outcome. High mitotic count and high grade were correlated with high Ki67, HER2 amplification/overexpression, p53 accumulation, high p21 expression, low PR expression, and low bcl‐2 expression. PR negativity (P = 0.009) and p53 accumulation (P = 0.042) were correlated with decreased 5‐year survival and were independent markers for patient outcome in Cox regression. In unsupervised hierarchical clustering, four groups were identified that were correlated with distinctive clinicopathological features. The hormone negative/ER‐positive/high‐grade cluster was significantly associated with decreased survival (P = 0.011) and was an independent prognostic factor in Cox regression.

Conclusions:  Several tissue biomarkers are associated with an aggressive phenotype in male breast cancer. PR and p53 are the most promising individual prognostic markers. On the basis of immunophenotype, four distinctive and prognostically relevant male breast cancer groups were identified, indicating that protein expression profiling may be clinically useful in male breast cancer.
Evidence for an adaptation in ROS scavenging systems in human testicular peritubular cells from infertility patients
Authors: Kampfer C. , Spillner S. , Spinnler K. , Schwarzer J. U. , Terradas C. , Ponzio R. , Puigdomenech E. , Levalle O. , Köhn F. M. , Matzkin M. E. , Calandra R. S. , Frungieri M. B. , Mayerhofer A.
Published: May 2012

Fibrosis, increased amounts of immune cells and expression of COX‐2 in the testes of infertility patients provide circumstantial evidence for a specific testicular milieu, in which reactive oxygen species (ROS) could be increased. If ROS level increase and/or ROS scavengers decrease, the resulting testicular oxidative stress may contribute to human male infertility. Primary peritubular cells of the human testis, from men with normal spermatogenesis (HTPCs) and infertile patients (HTPC‐Fs), previously allowed us to identify an end product of COX‐2 action, a prostaglandin derivative (15dPGJ2), which acts via ROS to alter the phenotype of peritubular cells, at least in vitro. Using testicular biopsies we now found 15dPGJ2 in patients and hence we started exploring the ROS scavenger systems of the human testis. This system includes catalase, DJ‐1, peroxiredoxin 1, SOD 1 and 2, glutathione‐S‐transferase and HMOX‐1, which were identified by RT‐PCR/sequencing in HTPCs and HTPC‐Fs and whole testes. Catalase, DJ‐1, peroxiredoxin 1 and SOD 2 were also detected by Western blots and in part by immunohistochemistry in testicular samples. Western blots of cultured cells further revealed that catalase levels, but not peroxiredoxin 1, SOD 2 or DJ‐1 levels, are significantly higher in HTPC‐Fs than in HTPCs. This particular difference is correlated with the improved ability of HTPC‐Fs to handle ROS, which became evident when cells were exposed to 100 μm H2O2. H2O2 induced stronger responses in HTPCs than in HTPC‐Fs, which correlates with the lower level of the H2O2‐degrading defence enzyme catalase in HTPCs. The results provide evidence for an adaptation to elevated ROS levels, which must have occurred in vivo and which persist in vitro in HTPC‐Fs. Thus, in infertile men with impaired spermatogenesis elevated ROS levels likely exist, at least in the tubular wall.
Clinical correlates of sex steroids and gonadotropins in men over the late adulthood: the Framingham Heart Study
Authors: Haring R. , Xanthakis V. , Coviello A. , Sullivan L. , Bhasin S. , Wallaschofski H. , Murabito J. M. , Vasan R. S.
Published: May 2012

Low serum concentrations of sex steroids and gonadotropins in men have been associated with increased cardiometabolic risk and mortality, but the clinical correlates of these hormones in men over late adulthood are less clearly understood. We analysed up to five serial measurements of total testosterone (TT), dehydroepiandrosterone sulphate (DHEAS), follicle stimulating hormone (FSH), luteinizing hormone (LH) and total estradiol (EST) in older men in the original cohort of the Framingham Heart Study to determine the short‐ (2‐years; 1,165 person‐observations in 528 individuals) and long‐term (up to 10‐years follow‐up; 2520 person‐observations in 835 individuals with mean baseline age: 71.2 years) clinical correlates of these sex steroids and gonadotropins using multilevel modelling and Generalized Estimating Equations. Age, body mass index and pre‐existing type 2 diabetes were inversely related to long‐term TT concentrations, whereas higher systolic blood pressure showed a positive association. Furthermore, age and pre‐existing cardiovascular disease (CVD) were inversely associated and HDL cholesterol concentrations positively associated with long‐term DHEAS concentrations respectively. Analyses of short‐term changes revealed age was inversely related to DHEAS, but positively related to FSH and LH concentrations. Our community‐based study identified modifiable correlates of decreasing TT and DHEAS concentrations in elderly men, suggesting that maintenance of a low CVD risk factor burden may mitigate the age‐related decline of these hormones over the late adulthood.
Why are there more arboreal ant species in primary than in secondary tropical forests?
Authors: Klimes Petr , Idigel Cliffson , Rimandai Maling , Fayle Tom M. , Janda Milan , Weiblen George D. , Novotny Vojtech
Published: May 2012

1. Species diversity of arboreal arthropods tends to increase during rainforest succession so that primary forest communities comprise more species than those from secondary vegetation, but it is not well understood why. Primary forests differ from secondary forests in a wide array of factors whose relative impacts on arthropod diversity have not yet been quantified.

2. We assessed the effects of succession‐related determinants on a keystone ecological group, arboreal ants, by conducting a complete census of 1332 ant nests from all trees with diameter at breast height ≥ 5 cm occurring within two (unreplicated) 0·32‐ha plots, one in primary and one in secondary lowland forest in New Guinea. Specifically, we used a novel rarefaction‐based approach to match number, size distribution and taxonomic structure of trees in primary forest communities to those in secondary forest and compared the resulting numbers of ant species.

3. In total, we recorded 80 nesting ant species from 389 trees in primary forest but only 42 species from 295 trees in secondary forest. The two habitats did not differ in the mean number of ant species per tree or in the relationship between ant diversity and tree size. However, the between‐tree similarity of ant communities was higher in secondary forest than in primary forest, as was the between‐tree nest site similarity, suggesting that secondary trees were more uniform in providing nesting microhabitats.

4. Using our rarefaction method, the difference in ant species richness between two forest types was partitioned according to the effects of higher tree density (22·6%), larger tree size (15·5%) and higher taxonomic diversity of trees (14·3%) in primary than in secondary forest. The remaining difference (47·6%) was because of higher beta diversity of ant communities between primary forest trees. In contrast, difference in nest density was explained solely by difference in tree density.

5. Our study shows that reduction in plant taxonomic diversity in secondary forests is not the main driver of the reduction in canopy ant species richness. We suggest that the majority of arboreal species losses in secondary tropical forests are attributable to simpler vegetation structure, combined with lower turnover of nesting microhabitats between trees.