bluuebunny/crossref_metadata_2025_split huggingface dataset:
5-[4-(Diethoxyphosphoryl)-2,3,5,6-tetrafluorophenyl]-10,15,20-tris(pentafluorophenyl)porphyrin
Authors: Pereira Carla F. , Fernandes José A. , Rodrigues João M. M. , Vilela Sérgio M. F. , Tomé João P. C. , Almeida Paz Filipe A. 
Published: February 2012

The title compound, C48H20F19N4O3P, prepared by the nucleophilic attack of triethyl phosphite on one of the 4-fluoro atoms of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin, contains a single molecule in the asymmetric unit. The porphyrin unit is almost planar [largest non-H atom deviation = 0.174 (6) Å], and has the planes of the neighbouring benzene rings oriented at angles ranging from 64.3 (2) to 89.6 (3)° relative to the porphyrin core. The P=O group is almost coplanar with the attached benzene ring, subtending an angle of 4.0 (3)°. Several weak supramolecular interactions, namely C—H...π, C—F...π, P=O...π, C—H...(O,F) and F...F contacts, contribute to the crystal packing.
Ber‐EP4 is a useful marker for follicular germinative cell differentiation of cutaneous epithelial neoplasms
Authors: ANSAI Shin‐ichi , TAKAYAMA Ryoko , KIMURA Tetsunori , KAWANA Seiji 
Published: February 2012

AbstractBer‐EP4 is a monoclonal antibody that recognizes 34‐kDa and 39‐kDa non‐covalently linked glycopolypeptides expressed by most human epithelial cells and carcinomas. In this study, we performed immunohistochemical staining of 31 cases of basal cell carcinoma (BCC); 20 cases of trichoblastoma (TB), including ten cases of nodular type, eight cases of cribriform type (trichoepithelioma) and two cases of columnar type (desmoplastic trichoepithelioma); 16 cases of actinic keratosis (AK); and 10 cases each of Bowen’s disease, poroma and seborrheic keratosis. Six cases of BCC and AK were co‐lesions of both neoplasms. In normal skin tissue, Ber‐EP4 reacted positively with the secretory portion of eccrine glands and follicular germinative cells at the lower end of catagen hairs. Neoplastic cells in 97% of cases with BCC reacted positively with Ber‐EP4 in at least 5% of neoplastic cells. Those in 90% with nodular type TB and 50% with trichoepithelioma also reacted positively in at least 5% of neoplastic cells. No cases of poroma, seborrheic keratosis, AK or Bowen’s disease were immunohistochemically positive for Ber‐EP4 in neoplastic cells. In all six cases with co‐lesions of BCC and AK, neoplastic cells of BCC reacted positively with Ber‐EP4 and those of AK were negative. Immunohistochemical examination using the Ber‐EP4 antibody is a useful tool for diagnosing neoplasms with follicular germinative differentiation, such as TB, TE or BCC, and for differentiating those from squamous cell carcinoma in situ, poroma or seborrheic keratosis.
Serum leptin, adiponectin, resistin and ghrelin levels in psoriatic patients treated with cyclosporin
Authors: ÖZDEMIR Mustafa , YÜKSEL Mavişe , GÖKBEL Hakkı , OKUDAN Nilsel , MEVLITOĞLU İnci 
Published: February 2012

AbstractCyclosporin has various effects on adipose tissue and glucose metabolism. This situation may lead to changes in serum levels of adipocyte‐derived cytokines which have influence on the pathogenesis of psoriasis. The aim of this study was to evaluate the effect of cyclosporin treatment on some adipocyte‐derived cytokines in psoriatic patients. This case–control study was performed between June 2009 and March 2010, at the Department of Dermatology of Meram School of Medicine. Serum leptin, adiponectin, resistin and ghrelin levels were assessed in 26 patients with psoriasis before and after cyclosporin treatment and body mass index‐matched 26 healthy control subjects. The adipokines levels were compared between the groups. Serum leptin, ghrelin, resistin and adiponectin levels in patients with psoriasis before the treatment were higher than those of the control group but the differences were not statistically significant. A positive correlation between serum leptin and family history of psoriasis was detected (r = 0.398, P = 0.044). A strong negative correlation between the Psoriasis Area and Severity Index and serum ghrelin levels was seen (r = −0.52, P = 0.001) and there was a strong positive correlation between the Nail Psoriasis Severity Index and serum resistin levels (r = 0.62, P = 0.001). Following the treatment, a significant increase was seen in the serum level of adiponectin (P = 0.02) and resistin (P = 0.003). The correlations between the adipokines and the disease parameters before the treatment were lost after the treatment. Our results suggest that levels of some adipocyte‐derived cytokines in psoriatic patients are affected by cyclosporin treatment.
UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients
Authors: Ramachandran P. , Fraser A. , Agarwal K. , Austin A. , Brown A. , Foster G. R. , Fox R. , Hayes P. C. , Leen C. , Mills P. R. , Mutimer D. J. , Ryder S. D. , Dillon J. F. 
Published: February 2012

SummaryBackgroundThe nonstructural 3 serine protease inhibitors (PIs), boceprevir and telaprevir, represent the first in a new generation of directly acting antivirals against genotype 1 hepatitis C (HCV) infection. When used in combination with pegylated interferon and ribavirin, these drugs greatly improve sustained virological response rates in both treatment‐naïve patients and patients who have had previous virological failure on treatment. However, the addition of these new agents will increase the complexity of therapeutic regimens, the rates of side‐effects and costs.AimsTo review concisely the current evidence and to suggest current best practice, for the use of telaprevir and boceprevir in the management of chronic genotype 1 HCV infection.MethodsThese guidelines for the use of boceprevir and telaprevir have been formulated following extensive review of the current literature, are based on the consensus opinion of a panel of national experts, and have been openly discussed and debated at a national meeting of HCV care providers.ResultsWe have made recommendations on a number of the key practical issues facing HCV care providers: (i) Which patients to treat?; (ii) Standards for the provision of care; (iii) Pre‐treatment considerations; (iv) Which treatment regimens to use?; (v) Stopping rules; and (vi) Management of adverse effects. Finally, we have produced suggested algorithms for the assessment and treatment of these patients.ConclusionsThese UK Consensus guidelines indicate the current best practice for the use of boceprevir and telaprevir in the management of genotype 1 chronic HCV infection.
Integration of data from multiple sources for simultaneous modelling analysis: experience from nevirapine population pharmacokinetics
Authors: Svensson Elin , van der Walt Jan‐Stefan , Barnes Karen I. , Cohen Karen , Kredo Tamara , Huitema Alwin , Nachega Jean B. , Karlsson Mats O. , Denti Paolo 
Published: February 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Integrating individual data from multiple sources in one simultaneous population analysis (sometimes called a mega‐model) can address novel research questions and add power for covariate detection without requiring new clinical studies. However, the development of this type of model can be challenging and time consuming.• Nevirapine is a non‐nucleoside reverse transcriptase inhibitor commonly used for treatment of human immunodeficiency virus infection in resource‐limited settings.WHAT THIS STUDY ADDS• This study outlines a strategy for integration of data from multiple sources for modelling analysis. It provides suggestions on handling of missing covariates in the context of several data sources and a starting point for development of a multinational nevirapine mega‐model.AIMS To propose a modelling strategy to efficiently integrate data from different sources in one simultaneous analysis, using nevirapine population pharmacokinetic data as an example.METHODS Data from three studies including 115 human immunodeficiency virus‐infected South African adults were used. Patients were on antiretroviral therapy regimens including 200 mg nevirapine twice daily and sampled at steady state. A development process was suggested, implemented in NONMEM7 and the final model evaluated with an external data set.RESULTS A stepwise approach proved efficient. Model development started with the intensively sampled data. Data were added sequentially, using visual predictive checks for inspecting their compatibility with the existing model. Covariate exploration was carried out, and auxiliary regression models were designed for imputation of missing covariates. Nevirapine pharmacokinetics was described by a one‐compartment model with absorption through two transit compartments. Body size was accounted for using allometric scaling. The model included a mixture of two subpopulations with different typical values of clearance, namely fast (3.12 l h−1) and slow metabolizers (1.45 l h−1), with 17% probability of belonging to the latter. Absorption displayed large between‐occasion variability, and food slowed the absorption mean transit time from 0.6 to 2.5 h. Concomitant antitubercular treatment including rifampicin typically decreased bioavailability by 39%, with significant between‐subject variability. Visual predictive checks of external validation data indicated good predictive performance.CONCLUSIONS The development strategy succeeded in integrating data from different sources to produce a model with robust parameter estimates. This work paves the way for the creation of a nevirapine mega‐model, including additional data from numerous diverse sources.
Scaling of pharmacokinetics across paediatric populations: the lack of interpolative power of allometric models
Authors: Cella Massimo , Knibbe Catherijne , de Wildt Saskia N. , Van Gerven Joop , Danhof Meindert , Della Pasqua Oscar 
Published: February 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• No consensus has been reached so far on the suitability of different methodologies for dose selection in children.• In paediatric drug development, initial estimation of the paediatric dose is obtained by extrapolation. This is usually performed using the dosing regimen in another population as reference. This approach also implies the possibility of using interpolations across age groups.• Midazolam, the paradigm compound selected for the purposes of our investigation, is a short‐acting imidazobenzodiazepine used for inducing sedation before medical procedures.WHAT THIS STUDY ADDS• The results of this analysis show that the use of allometric models to interpolate pharmacokinetics between paediatric subpopulations has limitations and drawbacks.• Estimation of covariate effects is critical, but not sufficient to interpolate parameter distributions and drug exposures from a reference population to another population.• The covariate–parameter relationship does not remain constant beyond the range of observations. Exponential relationships used by allometry do not correct for these discrepancies.AIM The objective of this investigation was to assess the performance of an allometric model as the basis for interpolating drug exposure in the context of pharmacokinetic bridging across paediatric subpopulations.METHODS Midazolam was selected as a paradigm compound. Two nonlinear mixed effects models were developed to describe midazolam pharmacokinetics in infants, toddlers and adults (model 1) and in children and adolescents (model 2). Subsequently, systemic drug exposure, expressed in terms of the area under the concentration vs. time curve (AUC), in children and adolescents was interpolated based on pharmacokinetic parameter distributions obtained from the model describing infants, toddlers and adults (model 1). Results were compared with the values obtained from modelling of the data in the corresponding population (model 2).RESULTS The two pharmacokinetic models accurately described midazolam exposure in the population on which they were built. However, the model based on data from infants, toddlers and adults failed to predict the exposure observed in children and adolescents: the mean difference between the predicted and estimated AUC0–180 was of −17.8%, with a range of −6.8 to −38.4%.The discrepancy between estimated and interpolated exposure increased proportionally with body weight.CONCLUSIONS The current results indicate that irrespective of whether extrapolation or interpolation methods are to be applied during paediatric drug development, model predictions beyond the range of the data used for parameter estimation may be biased. For accurate inter‐ or extrapolation to different populations, the assumption of identical parameter–covariate correlations across age groups may not be taken for granted.
Disease progress and response to treatment as predictors of survival, disability, cognitive impairment and depression in Parkinson's disease
Authors: Vu Thuy C. , Nutt John G. , Holford Nicholas H. G. 
Published: February 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The marked between variability in the rate of progression of Parkinson's disease severity assessed with a global functional score (Unified Parkinson' Disease Rating Scale, UPDRS) is recognized but its origin is uncertain and variously attributed to different subtypes of Parkinson's disease, life style, genetic variability and treatment. An increased risk of death in patients treated with selegiline has been reported but this is controversial.WHAT THIS STUDY ADDS• We used a hazard model approach to describe the time to clinical events (death, disability, depression and dementia). The time course of disease status changes was shown to be a key predictor of the risk of these events. Baseline motor subtype was not a predictor of outcome events. Selegiline was associated with an increased risk of death that was independent of its effect on disease status.AIM To describe the time to clinical events (death, disability, cognitive impairment and depression) in Parkinson's disease using the time course of disease status and treatment as explanatory variables.METHODS Disease status based on the Unified Parkinson's Disease Rating Scale (UPDRS) and the time to clinical outcome events were obtained from 800 patients who initially had early Parkinson's disease. Parametric hazard models were used to describe the time to the events of interest.RESULTS Time course of disease status (severity) was an important predictor of clinical outcome events. There was an increased hazard ratio for death 1.4 (95% CI 1.31, 149), disability 2.75 (95% CI 2.30, 3.28), cognitive impairment 4.35 (95% CI 1.94, 9.74), and depressive state 1.43 (95% CI 1.26, 1.63) with each 10 unit increase of UPDRS. Age at study entry increased the hazard with hazard ratios of 49.1 (95% CI 8.7, 278) for death, 4.76 (95% CI 1.10, 20.6) for disability and 90.0 (95% CI 63.3–128) for cognitive impairment at age 60 years. Selegiline treatment had independent effects as a predictor of death at 8 year follow‐up with a hazard ratio of 2.54 (95% CI 1.51, 4.25) but had beneficial effects on disability with a hazard ratio of 0.363 (95% CI 0.132, 0.533) and depression with a hazard ratio of 0.372 (95% CI 0.12, 0.552).CONCLUSIONS Our findings show that the time course of disease status based on UPDRS is a much better predictor of future clinical events than any baseline disease characteristic. Continued selegiline treatment appears to increase the hazard of death.
Urinary pharmacokinetic methodology to determine the relative lung bioavailability of inhaled beclometasone dipropionate
Authors: Said Amira S. A. , Harding Lindsay P. , Chrystyn Henry 
Published: February 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Urinary pharmacokinetic methodology can be used to identify the relative bioavailability to the lungs and the systemic circulation after an inhalation but has not yet been extended to corticosteroids.• Two (Qvar® and Clenil®) HFA (CFC‐free) metered dose inhaler formulations of beclometasone dipropionate are now available. The recommended dose of Qvar is half that of Clenil but the two have yet to be compared.WHAT THIS STUDY ADDS• The urinary excretion of beclometasone dipropionate and its main metabolites (beclometasone‐17‐ monopropionate and beclometasone) in the first 30 min post inhalation represents the relative bioavailability to the lungs after an inhalation.• Similarly the 24 h urinary excretion of the main metabolites can be used to identify the relative bioavailability to the systemic circulation after an inhalation.• The relative lung and systemic bioavailability between Qvar and Clenil confirms the two fold difference in their recommended doses.AIM Urinary pharmacokinetic methods have been identified to determine the relative lung and systemic bioavailability after an inhalation. We have extended this methodology to inhaled beclometasone dipropionate (BDP).METHOD Ethics Committee approval was obtained and all subjects gave consent. Twelve healthy volunteers received randomized doses, separated by >7 days, of 2000 µg BDP solution with (OralC) and without (Oral) 5 g oral charcoal, 10 100 µg inhalations from a Qvar® Easibreathe metered dose inhaler (pMDI) with (QvarC) and without (Qvar) oral charcoal and eight 250 µg inhalations from a Clenil® pMDI (Clenil). Subjects provided urine samples at 0, 0.5, 1, 2, 3, 5, 8, 12 and 24 h post study dose. Urinary concentrations of BDP and its metabolites, beclometasone‐17‐monopropionate (17‐BMP) and beclometasone (BOH) were measured.RESULTS No BDP, 17‐BMP or BOH were detected in any samples post OralC dosing. Post oral dosing no BDP was detected in all urine samples and no 17‐BMP or BOH was excreted in the first 30 min. Significantly more (P < 0.001) BDP, 17‐BMP and BOH were excreted in the first 30 min and the cumulative 24 h urinary excretions post Qvar and Clenil compared with Oral. The mean ratio (90% confidence interval) of the 30 min urinary excretions for Qvar compared with Clenil was 231.4 (209.6, 255.7) %.CONCLUSION The urinary pharmacokinetic methodology to determine the relative lung and systemic bioavailability post inhalation, using 30 min and cumulative 24 h post inhalation samples, applies to BDP. The ratio between Qvar and Clenil is consistent with related clinical and lung deposition studies.
Murine lupus strains differentially model unique facets of human lupus serology
Authors: Li L , Nukala S , Du Y , Han J , Liu K , Hutcheson J , Pathak S , Li Q , Mohan C 
Published: February 2012

SummarySystemic lupus erythematosus (SLE) is a polygenic autoimmune disease characterized by the production of anti-nuclear autoantibodies that lead to subsequent end organ damage. Previous array-based studies in patients with SLE have shown that high immunoglobulin (Ig)G anti-nuclear autoantibody reactivity was associated with severe renal lupus, whereas IgM polyreactivity was associated with less severe disease. To ascertain how different murine lupus strains recapitulate these different autoantibody profiles seen in patients, serum from New Zealand black (NZB)/NZ white (W) F1, Murphy Roths large (MRL)/lpr, NZ mixed (M)2410 and BXSB strains were compared using a comprehensive array-based screen. The array results were verified using enzyme-linked immunosorbent assays (ELISAs). Serum from MRL/lpr mice exhibited high levels of IgG anti-nuclear antibodies as well as anti-glomerular antibodies and variable levels of antibodies to myosin, Matrigel and thyroglobulin. Elevated anti-nuclear IgG antibodies were associated with severe nephritis in this strain. In contrast, NZM2410 mice exhibited lower IgG autoantibody levels with less severe nephritis but a significantly higher polyreactive IgM autoantibody profile. ELISA analysis confirmed these results. The NZB/NZW F1 and BXSB strains exhibited an intermediate serological profile. Hence, just as in patients with SLE, whereas strong IgG reactivity to nuclear antigens is associated with severe renal disease, a polyreactive IgM seroprofile is also less ominous in murine lupus.
Dispersal limitation and spatial scale affect model based projections of Pinus uncinata response to climate change in the Pyrenees
Authors: Martínez Isabel , González‐Taboada Fernando , Wiegand Thorsten , Camarero Jesus Julio , Gutiérrez Emilia 
Published: February 2012

AbstractSpecies Distribution Models (SDMs) were employed to assess the potential impact of climate change on the distribution of Pinus uncinata in the Pyrenees, where it is the dominant tree species in subalpine forest and alpine tree lines. Predicting forest response to climate change is a challenging task in mountain regions but also a conservation priority. We examined the potential impact of spatial scale on SDM projections by conducting all analyses at four spatial resolutions. We further examined the potential effect of dispersal constraints by applying a threshold distance of maximal advancement derived from a spatially explicit, individual‐based simulation model of tree line dynamics. Under current conditions, SDMs including climatic factors related to stress or growth limitation performed best. These models were then employed to project P. uncinata distribution under two emission scenarios, using data generated from several regional climate models. At the end of this century, P. uncinata is expected to migrate northward and upward, occupying habitat currently inhabited by alpine plant species. However, consideration of dispersal limitation and/or changing the spatial resolution of the analysis modified the assessment of climate change impact on mountain ecosystems, especially in the case of estimates of colonization and extinction at the regional scale. Our study highlights the need to improve the characterization of biological processes within SDMs, as well as to consider simultaneously different scales when assessing potential habitat loss under future climate conditions.