bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clopidogrel variability: role of plasma protein binding alterations
Authors: Ganesan Shobana , Williams Craig , Maslen Cheryl L. , Cherala Ganesh 
Published: November 2012

AimThe large inter‐individual variability in clopidogrel response is attributed to pharmacokinetics. Although, it has been used since the late 1990s the pharmacokinetic fate of clopidogrel and its metabolites are poorly explained. The variable response to clopidogrel is believed to be multi‐factorial, caused both by genetic and non‐genetic factors. In this study, we examined whether the inactive metabolite can alter the plasma protein binding of the active metabolite, thus explaining the large inter‐individual variability associated with clopidogrel response.MethodsFemale subjects (n = 28) with stable coronary disease who were not taking clopidogrel were recruited. Serial blood samples were collected following 300 mg oral dose of clopidogrel, plasma was isolated and quantified for total and free concentrations of active and inactive metabolites. Inhibition of platelet aggregation was measured using the phosphorylated vasodilator stimulated phosphoprotein (VASP) assay.ResultsA significant correlation was observed between VASP and both free (r = 0.49, P < 0.05) and total (r = 0.49, P < 0.05) concentrations of the active metabolite. Surprisingly, we observed a significant correlation with both free (r = 0.42, P < 0.05) and total (r = 0.67, P < 0.001) concentrations of the inactive metabolite as well. Free fractions of the active metabolite rose with increasing protein binding of the inactive metabolite (P < 0.05).ConclusionsThe above in vivo data suggest that the inactive metabolite displaces the active metabolite from binding sites. Thus, the inactive metabolite might increase the free concentration of the active metabolite leading to enhanced inhibition of platelet aggregation. The plasma protein binding mechanism would offer an additional therapeutic strategy to optimize clopidogrel pharmacotherapy.
The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjects
Authors: Kempsford Rodger , Allen Ann , Bal Joanne , Rubin David , Tombs Lee 
Published: November 2012

AimTo investigate the effects of the cytochrome P450 3A4 (CYP3A4) inhibitor ketoconazole on the pharmacokinetics (PK) and pharmacodynamics of fluticasone furoate (FF) and vilanterol trifenatate (VI).MethodsTwo double‐blind, randomized, placebo‐controlled, two‐way crossover studies in healthy subjects. In study 1, subjects received single doses of ketoconazole (400 mg) or placebo on days 1–6, with a single dose of inhaled VI (25 μg) on day 5. Pharmacodynamic and PK data were obtained up to 48 h following the VI dose. In study 2, subjects received once daily ketoconazole (400 mg) or placebo for 11 days, with FF/VI (200/25 μg) for the final 7 days. Pharmacodynamic and PK data were obtained up to 48 h following the day 11 dose.ResultsIn study 1, there was no effect of co‐administration of ketoconazole and VI on pharmacodynamic or PK parameters. In study 2, co‐administration of ketoconazole and FF/VI had no effect on 0–4 h maximal heart rate or minimal blood potassium {treatment difference [90% confidence interval (CI)] –0.6 beats min–1 (−5.8, 4.5) and 0.04 mmol l−1 (−0.03, 0.11), respectively}, whilst there was a 27% decrease in 24 h weighted mean serum cortisol [treatment ratio (90% CI) 0.73 (0.62, 0.86)]. Co‐administration of ketoconazole increased [percentage change (90% CI)] FF area under the curve (0‐24) and maximal plasma concentration by 36% (16, 59) and 33% (12, 58), respectively, and VI area under the curve (0–t′) and maximal plasma concentration by 65% (38, 97) and 22% (8, 38), respectively.ConclusionCo‐administration of FF/VI or VI with ketoconazole resulted in a less than twofold increase in systemic exposure to FF and VI. There was no increase in β‐agonist systemic pharmacodynamic effects, while serum cortisol was decreased by 27%. Co‐administration of FF/VI with strong CYP3A4 inhibitors has the potential to increase systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increase in the potential for adverse reactions.
Correlation of aldo‐ketoreductase (AKR) 1C3 genetic variant with doxorubicin pharmacodynamics in Asian breast cancer patients
Authors: Voon Pei Jye , Yap Hui Ling , Ma Cho‐Yee‐Thu , Lu Fan , Wong Andrea L. A. , Sapari Nur Sabrina , Soong Richie , Soh Thomas I. P. , Goh Boon‐Cher , Lee How‐Sung , Lee Soo‐Chin 
Published: November 2012

AimsAldo‐ketoreductases have been implicated in the metabolism of doxorubicin. We sought to assess the influence of AKR1C3 genetic variants on doxorubicin metabolism.MethodsWe sequenced AKR1C3 exon 5 and genotyped seven functional single nucleotide polymorphisms in CBR3, ABCB1 and SLC22A16 involved in doxorubicin pharmacology in 151 Asian breast cancer patients treated with doxorubicin‐containing chemotherapy, and correlated these genotypes with doxorubicin pharmacokinetics and pharmacodynamics.ResultsTwo previously reported AKR1C3 intronic variants, IVS4–212 C>G and IVS4+218 G>A, were detected. The AKR1C3 IVS4–212 GG genotype was associated with significantly lower cycle 1 day 15 leucocyte (mean leucocytes 2.49 ± 1.57 × 109 vs. 3.85 ± 3.42 × 109 l−1, P = 0.007) and neutrophil counts (mean neutrophils 0.70 ± 1.01 × 109 vs. 1.56 ± 2.80 × 109 l−1, P = 0.008) and significant improvement of progression‐free survival [PFS, mean PFS 49.0 (95% confidence interval 42.2–55.8) vs. 31.0 (95% confidence interval 20.7–41.2) months, P = 0.017] and overall survival [OS; mean OS 64.4 (95% confidence interval 58.3–70.5) vs. 46.3 (95% confidence interval 35.1–57.5) months, P = 0.006] compared with those carrying at least one C allele. There was no significant association between AKR1C3 IVS4–212 C>G and doxorubicin pharmacokinetics. Of the other seven single nucleotide polymorphisms genotyped, CBR3 G11A correlated with doxorubicinol area under the concentration–time curve and OS, ABCB1 G2677T/A correlated with doxorubicin clearance and platelet toxicity, while ABCB1 IVS26+59 T>G correlated with OS. The AKR1C3 IVS4–212 C<G genotype remained significantly correlated with both PFS and OS on multivariate analysis with clinical prognosticators.ConclusionsThe AKR1C3 IVS4–212 GG genotype was associated with greater haematological toxicity and longer progression‐free survival and overall survival after doxorubicin‐based therapy, suggesting potential interaction of this variant with doxorubicin metabolism.
Identification of autoantibodies expressed in acquired aplastic anaemia
Authors: Goto Maki , Kuribayashi Kageaki , Takahashi Yusuke , Kondoh Takashi , Tanaka Maki , Kobayashi Daisuke , Watanabe Naoki 
Published: November 2012

SummaryAcquired aplastic anaemia (aAA) is recognized as an autoimmune disorder; however, the autoantigens and target cells involved remain elusive. Expression of autoantibodies and their target cells were examined using the haematopoietic cell line K562 and bone marrow stromal cell line hTS‐5; 43·5% and 21·7% of aAA expressed autoantibody against K562 and hTS‐5 cells, respectively. The autoantigens were identified by serological identification of antigens through recombinant cDNA expression cloning. This study indicates that haematopoietic cells are the targets of immune abnormality in aAA. These autoantibodies may be utilized to distinguish patients associated with immune abnormality from bone marrow failure syndrome.
Girls in detail, boys in shape: Gender differences when drawing cubes in depth
Authors: Lange‐Küttner C. , Ebersbach M. 
Published: November 2012

The current study tested gender differences in the developmental transition from drawing cubes in two‐ versus three dimensions (3D), and investigated the underlying spatial abilities. Six‐ to nine‐year‐old children (N = 97) drew two occluding model cubes and solved several other spatial tasks. Girls more often unfolded the various sides of the cubes into a layout, also called diagrammatic cube drawing (object design detail). In girls, the best predictor for drawing the cubes was Mental Rotation Test (MRT) accuracy. In contrast, boys were more likely to preserve the optical appearance of the cube array. Their drawing in 3D was best predicted by MRT reaction time and the Embedded Figures Test (EFT). This confirmed boys' stronger focus on the contours of an object silhouette (object shape). It is discussed whether the two gender‐specific approaches to drawing in three dimensions reflect two sides of the appearance–reality distinction in drawing, that is graphic syntax of object design features versus visual perception of projective space.
Differential Contributions of Development and Learning to Infants' Knowledge of Object Continuity and Discontinuity
Authors: Bertenthal Bennett I. , Gredebäck Gustaf , Boyer Ty W. 
Published: November 2012

Sixty infants divided evenly between 5 and 7 months of age were tested for their knowledge of object continuity versus discontinuity with a predictive tracking task. The stimulus event consisted of a moving ball that was briefly occluded for 20 trials. Both age groups predictively tracked the ball when it disappeared and reappeared via occlusion, but not when it disappeared and reappeared via implosion. Infants displayed high levels of predictive tracking from the first trial in the occlusion condition, and showed significant improvement across trials in the implosion condition. These results suggest that infants possess embodied knowledge to support differential tracking of continuously and discontinuously moving objects, but this tracking can be modified by visual experience.
Different immunosuppressive mechanisms in multi-drug-resistant tuberculosis and non-tuberculous mycobacteria patients
Authors: Pinheiro R O , de Oliveira E B , dos Santos G , Sperandio da Silva G M , de Andrade Silva B J , Teles R M B , Milagres A , Sarno E N , Dalcolmo M P , Sampaio E P 
Published: November 2012

SummaryPrevious studies have demonstrated that cells from both multi-drug-resistant tuberculosis (MDR-TB) and non-tuberculous mycobacteria (NTM) patients respond poorly to mycobacterial antigens in vitro. In the present study, we compared the in vitro response of cells isolated from sensitive TB (NR-TB)-, MDR-TB- and NTM-infected patients. Analysis of T cell phenotype ex vivo revealed that both MDR-TB and NTM patients present an increased percentage of CD4+CD25+- forkhead box protein 3 (FoxP3)+ and CD4+CD25+CD127− regulatory T (Treg) cells when compared to NR-TB. Increased numbers of Treg cells and interleukin (IL)-10 serum levels were detected in MDR-TB, whereas elevated serum transforming growth factor (TGF)-β was found in the NTM group. Cells of MDR-TB patients stimulated with early secretory antigenic target (ESAT)-6, but not purified protein derivative (PPD), showed a lower frequency of CD4+/interferon (IFN)-γ+ T cells and enhanced CD4+CD25+FoxP3+, CD4+CD25+CD127− and CD4+CD25+IL-10+ T cell population. In addition, increased IL-10 secretion was observed in cultured MDR-TB cells following ESAT-6 stimulation, but not in NR-TB or NTM patients. In vitro blockade of IL-10 or IL-10Rα decreased the CD4+CD25+FoxP3+ frequencies induced by ESAT-6 in MDR-TB, suggesting a role of IL-10 on impaired IFN-γ responses seen in MDR-TB. Depletion of CD4+CD25+ T lymphocytes restored the capacity of MDR-TB T cells to respond to ESAT-6 in vitro, which suggests a potential role for Treg/T regulatory 1 cells in the pathogenesis of MDR-TB. Together, our results indicate that although the similarities in chronicity, NTM- and MDR-TB-impaired antigenic responses involve different mechanisms.
Predicting non‐native fish dispersal under conditions of climate change: case study in England of dispersal and establishment of pumpkinseed Lepomis gibbosus in a floodplain pond
Authors: Fobert Emily , Zięba Grzegorz , Vilizzi Lorenzo , Godard Michael J. , Fox Michael G. , Stakėnas Saulius , Copp Gordon H. 
Published: November 2012

AbstractPredictions of future climate change include shifts in patterns of precipitation, evapotranspiration and water run‐off, resulting in increased periods of drought as well as variability and intensity of rainfall events. In the United Kingdom, the non‐native North American sunfish, pumpkinseed Lepomis gibbosus (L.), is expected to benefit from these changes. We examine how hydrological variability induced by predicted changes in climate will affect the dispersal and spread of pumpkinseed in England by: (i) determining the relationship between discharge regime and pumpkinseed propagule pressure; (ii) examining a newly‐established pumpkinseed population following a flood event in 2007; and (iii) comparing the growth and life‐history traits of this new population with fish collected from the source population to demonstrate how the pumpkinseed's life‐history plasticity contributes to its success as a coloniser. Using Bayesian modelling, we determined that the number of pumpkinseed escapees is likely to increase with increasing discharge. The newly‐established pumpkinseed population showed fast juvenile growth, early age at maturity and small size at maturity. These traits differed significantly from the source population, specifically total length (TL) means at ages 1 and 2 were significantly greater in the new population, whereas TL at age 4 was significantly greater in the source population, and a significantly higher proportion of mature females were found at smaller size classes in the newly established pumpkinseed population. This study demonstrates the potential link between hydrological variability (current and future) and the dispersal of non‐native pumpkinseed, leading to the establishment of new populations.
Molecular cloning of IGλ rearrangements using long‐distance inverse PCR (LDI‐PCR)
Authors: Shimanuki Masaya , Sonoki Takashi , Hosoi Hiroki , Watanuki Jyuri , Murata Shogo , Kawakami Keiki , Matsuoka Hiroshi , Hanaoka Nobuyoshi , Nakakuma Hideki 
Published: November 2012

AbstractObjectivesMalignant cells of mature B‐cell origin show tumor‐specific clonal immunoglobulin gene (IG) rearrangements, including V(D)J recombinations, nucleotide mutations, or translocations. Rapid molecular cloning of the breakpoint sequence by long‐distance inverse PCR (LDI‐PCR) has so far been applied to rearrangements targeted to IGH joining, IGH switch, and IGκ regions. We tended to apply LDI‐PCR method for cloning of IGλ rearrangements.MethodsTo identify which IGλ isotype segment was rearranged, we performed Southern blot analysis using isotype‐specific probes. We set inverse primers on the telomeric side of each joining region and amplified rearranged bands detected by Southern blot analysis as corresponding PCR products.ResultsAll germline IGλ segments were successfully amplified as expected PCR products. We determined breakpoint sequences of five chromosome translocations involving IGλ locus: three novel t(8;22)(q24;q11), one known t(3;22)(q27;q11), and one partially known t(11;22)(q13;q11). Two of the three t(8;22)(q24;q11) were involved in Jλ with a recombination signal sequence and one of three in the first exon of IGLL5, which lies upstream of Jλ1. Three 8q24 breakpoints were widespread at 132, 260 and 366 kb downstream of MYC locus. The t(3;22)(q27;q11) showed a juxtaposition of Jλ2 and the first intron of BCL6, as previously reported. In t(11;22)(q13;q11), 3′UTR of cyclin D1 fused to the constant region of λ7 with nucleotide mutations. We also amplified four Vλ/Jλ recombination sequences.ConclusionOur method is a useful tool for molecular analysis of genetic events in IGλ.
Comparison of 6‐hydroxydopamine lesions of the substantia nigra and the medial forebrain bundle on a lateralised choice reaction time task in mice
Authors: Heuer Andreas , Smith Gaynor A. , Dunnett Stephen B. 
Published: November 2012

AbstractParkinson's disease is most commonly modelled via unilateral infusion of the neurotoxin 6‐hydroxydopamine (6‐OHDA) in the rat, but recent work has been aimed to translate the reproducibility and reliability of the model to the mouse. Here we present the effects of unilateral 6‐OHDA lesions to either the medial forebrain bundle or the substantia nigra (SN) in mice, which were trained on a lateralised choice reaction time (RT) task. This task measures response accuracy as well as RT and movement time latencies, and offers the opportunity for a more fine‐grained analysis of the precise nature of the movement deficit, motor learning and functional recovery than can be achieved using classical tests of simple motor asymmetry. Both lesion types caused impaired response accuracy, which was more pronounced when responses had to be directed contralateral to the lesion. Furthermore, movement times were increased for both lesion groups, whereas only the bundle lesion group displayed a RT deficit. The lesions were stable over three consecutive weeks of testing, therefore lesion‐type and behavioural assessment on the operant task are suitable to investigate the dopaminergic system in parkinsonian mice. Both lesions were stable over time, and were more pronounced when responses were directed in contralateral space; the mice with more complete bundle lesions displayed a greater deficit than mice that received lesions to the SN. The translation of this choice RT task will be beneficial for the assessment of therapeutics in mouse models of the disease.
Freeze‐drying as a preserving preparation technique for in vitro testing of human skin
Authors: Franzen Lutz , Vidlářová Lucie , Kostka Karl‐Heinz , Schaefer Ulrich F. , Windbergs Maike 
Published: November 2012

AbstractIn vitro testing of drugs with excised human skin is a valuable prerequisite for clinical studies. However, the analysis of excised human skin presents several obstacles. Ongoing drug diffusion, microbial growth and changes in hydration state influence the results of drug penetration studies. In this work, we evaluate freeze‐drying as a preserving preparation method for skin samples to overcome these obstacles. We analyse excised human skin before and after freeze‐drying and compare these results with human skin in vivo. Based on comprehensive thermal and spectroscopic analysis, we demonstrate comparability to in vivo conditions and exclude significant changes within the skin samples due to freeze‐drying. Furthermore, we show that freeze‐drying after skin incubation with drugs prevents growth of drug crystals on the skin surface due to drying effects. In conclusion, we introduce freeze‐drying as a preserving preparation technique for in vitro testing of human skin.
Skewed distribution of natural killer cells in psoriasis skin lesions
Authors: Batista Mariana D. , Ho Emily L. , Kuebler Peter J. , Milush Jeffrey M. , Lanier Lewis L. , Kallas Esper G. , York Vanessa A. , Chang David , Liao Wilson , Unemori Patrick , Leslie Kieron S. , Maurer Toby , Nixon Douglas F. 
Published: November 2012

AbstractPsoriasis is a hyper‐proliferative disease of the skin in which immunological mechanisms play a direct pathogenetic role. There have been limited studies of natural killer (NK) cells in psoriasis. The aim of this study was to examine the phenotype of NK cells in skin biopsies and peripheral blood mononuclear cells from patients with psoriasis and healthy controls. CD56+CD16− and CD56+CD16+ NK cells were isolated from lesional skin, unaffected skin and PBMC of psoriasis patients, and normal skin and PBMC from healthy controls. The expression of CD57, NKG2A and NKG2C was assessed by flow cytometry. NK cells in psoriasis skin lesions were skewed in their expression of CD57, a marker of NK cell maturity, with CD57 expression significantly reduced and NKG2A expression increased on NK cells in lesional and unaffected skin compared to controls. These data suggest that in this patient cohort, NK cells could be isolated from psoriasis lesions and exhibit an immature phenotype.
Mammalian target of rapamycin complex 1 (mTORC1) may modulate the timing of anagen entry in mouse hair follicles
Authors: Kellenberger Antonia J. , Tauchi Miyuki 
Published: November 2012

AbstractMammalian target of rapamycin (mTOR) is a central regulator of cell proliferation and survival. There is limited evidence that mTOR influences hair follicles (HFs), which undergo cycles of quiescence (telogen), growth (anagen) and regression (catagen). We sought to investigate whether mTOR, in particular mTOR complex 1 (mTORC1), regulates the hair growth cycle by employing biochemical, immunohistochemical and functional approaches in vivo. Here, we demonstrate that quantitative analysis of mTORC1 kinase activity shows phase‐dependent changes, and phosphorylated mTOR at S2448 (p‐mTOR) was localized in certain sites of HFs in a phase‐dependent manner. These results were indicative of mTOR's role in hair growth initiation. Finally, in a pharmacological challenge in vivo using the specific mTORC1 inhibitor, rapamycin, hair cycle initiation was delayed, suggesting a functional relevance of mTORC1 in anagen entry. Based on our findings, we propose that mTORC1 may participate in hair cycle regulation, namely the timing of anagen initiation.
Torrefaction/biochar production by microwave and conventional slow pyrolysis – comparison of energy properties
Authors: Gronnow Mark J. , Budarin Vitaliy L. , Mašek Ondřej , Crombie Kyle N. , Brownsort Peter A. , Shuttleworth Peter S. , Hurst Peter R. , Clark James H. 
Published: November 2012

AbstractThe energy efficiency of torrefaction/pyrolysis of biomass to fuel/biochar was studied using conventional (slow) and microwave (low temperature) pyrolysis. Conventional pyrolysis is approximately three times as energy efficient as microwave pyrolysis, in terms of the energy required to process a unit of feedstock. However, this is more than compensated for by the higher energy content of the condensable and gaseous coproducts from microwave pyrolysis, as these can be utilized to generate the electricity required to drive the process. It is proposed that the most efficient method of torrefaction/biochar production is a combination of conventional heating with ‘catalytic’ amount of microwave irradiation.
At the limits: habitat suitability modelling of northern 17‐year periodical cicada extinctions (Hemiptera: Magicicada spp.)
Authors: Cooley John R. , Marshall David C. , Simon Chris , Neckermann Michael L. , Bunker Gerry 
Published: November 2012

AbstractAimAdult periodical cicadas emerge as temporally isolated, synchronized multispecies communities (‘broods’) that are for the most part geographically contiguous and that fit together in jigsaw‐puzzle‐like fashion. Some year‐classes of 17‐year cicadas have become extinct within historical times. We investigate two general causes for these extinctions – anthropogenic habitat destruction and post‐glacial climate change.LocationPeriodical cicadas are confined to the eastern United States, east of the Great Plains. We document the locations of known periodical cicada extinctions in two broods of 17‐year cicadas in Connecticut, Rhode Island, and upstate New York, USA.MethodsUsing additional distributional records of 17‐year cicadas, we develop habitat suitability models for all 17‐year periodical cicadas, using data layers that reflect both ecological and anthropogenic factors.ResultsClimatological data layers related specifically to annual mean temperature and temperature during the warmest months make the greatest contributions to our models, and data layers most specifically related to deforestation and habitat fragmentation tend to make much smaller contributions. Two well‐documented extinct populations of periodical cicadas occurred in locations where these models predict relatively low habitat suitability for 17‐year cicadas.Main conclusionsOur results and other circumstantial evidence discount the importance of anthropogenic habitat destruction in explaining these particular extinctions.