bluuebunny/crossref_metadata_2025 huggingface dataset:
Nationalism versus multiculturalism: the minority issue in twenty-first-century Bulgaria
Authors: Naxidou Eleonora
Published: February 2012

The paper negotiates ideas, views and beliefs of Bulgarians towards the ethnic minorities of their country published in the Bulgarian press during the period of 2005–2009. Through these aspects it becomes clear that three years after Bulgaria's accession to the European Union and despite various state attempts to integrate minorities – mostly initiated and funded by the EU and various governmental and non-governmental organizations – prejudice and racism have not been overcome, the Other is still differentiated and the way to multiculturalism is very long. The research field is limited to the Turkish and the Roma minorities, which are “visible” in the sense that they are officially recognized.
Nationalism and orthodoxy: Nichifor Crainic and the political culture of the extreme right in 1930s Romania
Authors: Clark Roland
Published: February 2012

This article explores the interplay of religion, anti-Semitism, and personal rivalries in building the ultra-nationalist movement in 1930s Romania, using the career of Nichifor Crainic as a case study. As a theologian, Crainic created and taught a synthesis of nationalism and Romanian Orthodoxy which was broadly accepted by most ultra-nationalists in interwar Romania. As a journalist, Crainic directed several newspapers which spearheaded acrimonious attacks on democratic and ultra-nationalist politicians alike. As a politician, he joined and left both Corneliu Zelea Codreanu's Legion of the Archangel Michael and A.C. Cuza's National Christian Defense League before attempting to form his own Christian Workers’ Party. Crainic's writings ultimately earned him a place as a minister in two governments and membership of the Romanian Academy. His career reveals an ultra-nationalist movement rife with division and bickering but united around a vaguely defined ideology of religious nationalism, xenophobia, and anti-Semitism.
GPI-anchor synthesis is indispensable for the germline development of the nematodeCaenorhabditis elegans
Authors: Murata Daisuke , Nomura Kazuko H. , Dejima Katsufumi , Mizuguchi Souhei , Kawasaki Nana , Matsuishi-Nakajima Yukari , Ito Satsuki , Gengyo-Ando Keiko , Kage-Nakadai Eriko , Mitani Shohei , Nomura Kazuya
Published: February 2012

Glycosylphosphatidylinositol (GPI)-anchor attachment is one of the most common posttranslational protein modifications. Using the nematode Caenorhabditis elegans, we determined that GPI-anchored proteins are present in germline cells and distal tip cells, which are essential for the maintenance of the germline stem cell niche. We identified 24 C. elegans genes involved in GPI-anchor synthesis. Inhibition of various steps of GPI-anchor synthesis by RNA interference or gene knockout resulted in abnormal development of oocytes and early embryos, and both lethal and sterile phenotypes were observed. The piga-1 gene (orthologue of human PIGA) codes for the catalytic subunit of the phosphatidylinositol N-acetylglucosaminyltransferase complex, which catalyzes the first step of GPI-anchor synthesis. We isolated piga-1–knockout worms and found that GPI-anchor synthesis is indispensable for the maintenance of mitotic germline cell number. The knockout worms displayed 100% lethality, with decreased mitotic germline cells and abnormal eggshell formation. Using cell-specific rescue of the null allele, we showed that expression of piga-1 in somatic gonads and/or in germline is sufficient for normal embryonic development and the maintenance of the germline mitotic cells. These results clearly demonstrate that GPI-anchor synthesis is indispensable for germline formation and for normal development of oocytes and eggs.
Yos9p and Hrd1p mediate ER retention of misfolded proteins for ER-associated degradation
Authors: Izawa Toshiaki , Nagai Hiroyuki , Endo Toshiya , Nishikawa Shuh-ichi
Published: February 2012

The endoplasmic reticulum (ER) has an elaborate quality control system, which retains misfolded proteins and targets them to ER-associated protein degradation (ERAD). To analyze sorting between ER retention and ER exit to the secretory pathway, we constructed fusion proteins containing both folded carboxypeptidase Y (CPY) and misfolded mutant CPY (CPY*) units. Although the luminal Hsp70 chaperone BiP interacts with the fusion proteins containing CPY* with similar efficiency, a lectin-like ERAD factor Yos9p binds to them with different efficiency. Correlation between efficiency of Yos9p interactions and ERAD of these fusion proteins indicates that Yos9p but not BiP functions in the retention of misfolded proteins for ERAD. Yos9p targets a CPY*-containing ERAD substrate to Hrd1p E3 ligase, thereby causing ER retention of the misfolded protein. This ER retention is independent of the glycan degradation signal on the misfolded protein and operates even when proteasomal degradation is inhibited. These results collectively indicate that Yos9p and Hrd1p mediate ER retention of misfolded proteins in the early stage of ERAD, which constitutes a process separable from the later degradation step.
Roles of putative Rho-GEF Gef2 in division-site positioning and contractile-ring function in fission yeast cytokinesis
Authors: Ye Yanfang , Lee I-Ju , Runge Kurt W. , Wu Jian-Qiu
Published: February 2012

Cytokinesis is crucial for integrating genome inheritance and cell functions. In multicellular organisms, Rho-guanine nucleotide exchange factors (GEFs) and Rho GTPases are key regulators of division-plane specification and contractile-ring formation during cytokinesis, but how they regulate early steps of cytokinesis in fission yeast remains largely unknown. Here we show that putative Rho-GEF Gef2 and Polo kinase Plo1 coordinate to control the medial cortical localization and function of anillin-related protein Mid1. The division-site positioning defects of gef2∆ plo1-ts18 double mutant can be partially rescued by increasing Mid1 levels. We find that Gef2 physically interacts with the Mid1 N-terminus and modulates Mid1 cortical binding. Gef2 localization to cortical nodes and the contractile ring depends on its last 145 residues, and the DBL-homology domain is important for its function in cytokinesis. Our data suggest the interaction between Rho-GEFs and anillins is an important step in the signaling pathways during cytokinesis. In addition, Gef2 also regulates contractile-ring function late in cytokinesis and may negatively regulate the septation initiation network. Collectively, we propose that Gef2 facilitates and stabilizes Mid1 binding to the medial cortex, where the localized Mid1 specifies the division site and induces contractile-ring assembly.
The Ankrd 13 family of UIM-bearing proteins regulates EGF receptor endocytosis from the plasma membrane
Authors: Tanno Hidetaka , Yamaguchi Teppei , Goto Eiji , Ishido Satoshi , Komada Masayuki
Published: February 2012

The mechanism of ubiquitin-dependent endocytosis of cell surface proteins is not completely understood. Here we examine the role of the ankyrin repeat domain (Ankrd) 13A, 13B, and 13D proteins, which constitute a functionally unknown family of ubiquitin-interacting motif (UIM)–bearing proteins, in the process. Stimulation of human HeLa cells with epidermal growth factor (EGF) rapidly induced direct binding of Ankrd 13 proteins to ubiquitinated EGF receptor (EGFR) via the UIMs. The binding was inhibited when the Ankrd 13 proteins underwent UIM-dependent monoubiquitination, suggesting that their activity is regulated by ubiquitination of themselves. Ankrd 13 proteins bound specifically to Lys-63–linked ubiquitin chains, which was consistent with a previous report that EGFR mainly undergoes Lys-63–linked polyubiquitination. Ankrd 13 proteins were anchored, via the central region and UIMs, to the plasma membrane, where they colocalized with EGFR. Finally, overexpression of wild-type as well as truncated-mutant Ankrd 13 proteins strongly inhibited rapid endocytosis of ubiquitinated EGFR from the surface in EGF-treated cells. We conclude that by binding to the Lys-63–linked polyubiquitin moiety of EGFR at the plasma membrane, Ankrd 13 proteins regulate the rapid internalization of ligand-activated EGFR.
A gene-based test of association using canonical correlation analysis
Authors: Tang Clara S. , Ferreira Manuel A. R.
Published: February 2012

Motivation: Canonical correlation analysis (CCA) measures the association between two sets of multidimensional variables. We reasoned that CCA could provide an efficient and powerful approach for both univariate and multivariate gene-based tests of association without the need for permutation testing.

Results: Compared with a commonly used permutation-based approach, CCA (i) is faster; (ii) has appropriate type-I error rate for normally distributed quantitative traits; (iii) provides comparable power for small to medium-sized genes (<100 kb); (iv) provides greater power when the causal variants are uncommon; (v) provides considerably less power for larger genes (≥100 kb) when the causal variants have a broad minor allele frequency (MAF) spectrum. Application to a GWAS of leukocyte levels identified SAFB and a histone gene cluster as novel putative loci harboring multiple independent variants regulating lymphocyte and neutrophil counts.

Availability:  http://genepi.qimr.edu.au/staff/manuelF/gene/main.html

Contact:  manuel.ferreira@qimr.edu.au

Supplementary information:  Supplementary material is available at Bioinformatics online.
Predicting relapse prior to transplantation in chronic myeloid leukemia by integrating expert knowledge and expression data
Authors: Yeung K. Y. , Gooley T. A. , Zhang A. , Raftery A. E. , Radich J. P. , Oehler V. G.
Published: February 2012

Motivation: Selecting a small number of signature genes for accurate classification of samples is essential for the development of diagnostic tests. However, many genes are highly correlated in gene expression data, and hence, many possible sets of genes are potential classifiers. Because treatment outcomes are poor in advanced chronic myeloid leukemia (CML), we hypothesized that expression of classifiers of advanced phase CML when detected in early CML [chronic phase (CP) CML], correlates with subsequent poorer therapeutic outcome.

Results: We developed a method that integrates gene expression data with expert knowledge and predicted functional relationships using iterative Bayesian model averaging. Applying our integrated method to CML, we identified small sets of signature genes that are highly predictive of disease phases and that are more robust and stable than using expression data alone. The accuracy of our algorithm was evaluated using cross-validation on the gene expression data. We then tested the hypothesis that gene sets associated with advanced phase CML would predict relapse after allogeneic transplantation in 176 independent CP CML cases. Our gene signatures of advanced phase CML are predictive of relapse even after adjustment for known risk factors associated with transplant outcomes.

Availability: The source codes and data sets used are available from the web site http://expression.washington.edu/publications/kayee/integratedBMA.

Contact:  kayee@u.washington.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
WegoLoc: accurate prediction of protein subcellular localization using weighted Gene Ontology terms
Authors: Chi Sang-Mun , Nam Dougu
Published: February 2012

Summary: We present an accurate and fast web server, WegoLoc for predicting subcellular localization of proteins based on sequence similarity and weighted Gene Ontology (GO) information. A term weighting method in the text categorization process is applied to GO terms for a support vector machine classifier. As a result, WegoLoc surpasses the state-of-the-art methods for previously used test datasets. WegoLoc supports three eukaryotic kingdoms (animals, fungi and plants) and provides human-specific analysis, and covers several sets of cellular locations. In addition, WegoLoc provides (i) multiple possible localizations of input protein(s) as well as their corresponding probability scores, (ii) weights of GO terms representing the contribution of each GO term in the prediction, and (iii) a BLAST E-value for the best hit with GO terms. If the similarity score does not meet a given threshold, an amino acid composition-based prediction is applied as a backup method.

Availability: WegoLoc and User's guide are freely available at the website http://www.btool.org/WegoLoc

Contact:  smchiks@ks.ac.kr; dougnam@unist.ac.kr

Supplementary information:  Supplementary data is available at http://www.btool.org/WegoLoc.
Oxford Handbook of Oral and Maxillofacial Surgery
Authors: Cascarini Luke , Schilling Clare , Gurney Ben , Brennan Peter
Published: February 2012

Practical and based on the latest clinical evidence and guidelines, the Oxford Handbook of Oral and Maxillofacial Surgery is the definitive guide for anyone working in oral and maxillofacial departments or covering the specialty during their surgical rotation.
Overview
Authors: Cascarini Luke , Schilling Clare , Gurney Ben , Brennan Peter
Published: February 2012

Using this book 2

OMFS—the speciality 3

Legal aspects of OMFS 4

Duties of an OMFS doctor 6

The future of OMFS 7

Career pathways in OMFS 8

• This book has been primarily written for junior doctors working in OMFS. We hope that it will appeal to both junior medical and junior dental practitioners. We realize that the medical undergraduate curriculum contains very little exposure to OMFS, so we apologize in advance to our dentally qualified readers if some of the dentally based chapters appear very basic!...
In the clinic
Authors: Cascarini Luke , Schilling Clare , Gurney Ben , Brennan Peter
Published: February 2012

OMFS clinics 106

Mandible fractures 108

Orbital floor fractures 110

Zygoma fractures 112

Maxillary fractures 114

Nose, naso-ethmoidal, and frontal bone fractures 116

Face and scalp soft tissue injuries 118

Dento-alveolar: impacted teeth 122

Dento-alveolar: jaw pathologies 124

Temporomandibular joint problems 126

Oral and facial pain ...
In theatre
Authors: Cascarini Luke , Schilling Clare , Gurney Ben , Brennan Peter
Published: February 2012

OMFS operations 146

Overview of maxillofacial trauma surgery 148

Mandibular fractures 150

Zygomatic fractures 154

Orbital floor fractures 158

Other fractures 160

Dento-alveolar surgery 162

Head and neck oncology and reconstructive surgery 164

Salivary gland surgery 166

Orthognathic surgery 168

Facial plastic surgery 170

Miscellaneous operations ...
Essential skills
Authors: Cascarini Luke , Schilling Clare , Gurney Ben , Brennan Peter
Published: February 2012

Local anaesthesia 190

Intra-oral suturing 193

Managing the bleeding socket 194

Managing the dry socket 195

Suturing facial lacerations 196

Packing the nose and midface for bleeding 198

Re-implanting and splinting teeth 199

Temporomandibular joint relocation 200

Bridle wiring and intermaxillary fixation 201

Incision and drainage of intra- and extra-oral abscesses ...
Oral medicine
Authors: Cascarini Luke , Schilling Clare , Gurney Ben , Brennan Peter
Published: February 2012

Common dental diseases 212

Oral mucosal infections 216

Oral ulceration 218

Blistering diseases 220

White, red, and pigmented lesions 222

Oral cancer 224

Oral manifestations of systemic diseases 226

Miscellaneous oral conditions 228

Dental caries is the result of acid-producing bacteria (Streptococcus mutans and others) creating a microenvironment, dental plaque, where sugar is metabolized and acid is a by-product. The acid demineralizes the tooth. The process is reversible when the pH rises and saliva, which is rich in Ca...
Eponyms and maxillofacial syndromes
Authors: Cascarini Luke , Schilling Clare , Gurney Ben , Brennan Peter
Published: February 2012

Apert syndrome is a craniosynostosis plus syndactyly leading to lack of anterior growth of the midface, raised intracranial pressure, and blindness due subluxation and lack of corneal cover of the eye.

Behçet syndrome is a multisystem autoimmune condition associated with HLA-B5. Patients have oral and genital ulceration and uveitis. Treatment is highly specialized; mainly immunosuppressant....
Dynamic noise, chaos and parameter estimation in population biology
Authors: Stollenwerk N. , Aguiar M. , Ballesteros S. , Boto J. , Kooi B. , Mateus L.
Published: February 2012

We revisit the parameter estimation framework for population biological dynamical systems, and apply it to calibrate various models in epidemiology with empirical time series, namely influenza and dengue fever. When it comes to more complex models such as multi-strain dynamics to describe the virus–host interaction in dengue fever, even the most recently developed parameter estimation techniques, such as maximum likelihood iterated filtering, reach their computational limits. However, the first results of parameter estimation with data on dengue fever from Thailand indicate a subtle interplay between stochasticity and the deterministic skeleton. The deterministic system on its own already displays complex dynamics up to deterministic chaos and coexistence of multiple attractors.
A gauge-theoretical approach to elasticity with microrotations
Authors: Böhmer C. G. , Obukhov Yu. N.
Published: February 2012

We formulate elasticity theory with microrotations using the framework of gauge theories, which has been developed and successfully applied in various areas of gravitation and cosmology. Following this approach, we demonstrate the existence of particle-like solutions. Mathematically, this is due to the fact that our equations of motion are of sine-Gordon type and thus have soliton-type solutions. Similar to Skyrmions and Kinks in classical field theory, we can show explicitly that these solutions have a topological origin.
E2F1, ARID3A/Bright and Oct-2 factors bind to the Epstein–Barr virus C promoter, EBNA1 and oriP, participating in long-distance promoter–enhancer interactions
Authors: Boreström Cecilia , Forsman Alma , Rüetschi Ulla , Rymo Lars
Published: February 2012

The Epstein–Barr virus (EBV) C promoter (Cp) regulates several genes required for B-cell proliferation in latent EBV infection. The family of repeats (FR) region of the latent origin of plasmid replication (oriP) functions as an Epstein–Barr nuclear antigen 1 (EBNA1)-dependent distant enhancer of Cp activity, and the enhancer–promoter interaction is mediated by a higher-order multi-protein complex containing several copies of EBNA1. Using DNA-affinity purification with a 170 bp region of the Cp in combination with mass spectrometry, we identified the cell cycle-regulatory protein E2F1, the E2F-binding protein ARID3A, and the B-cell-specific transcription factor Oct-2 as components of this multi-protein complex. Binding of the three factors to the FR region oforiPwas determined by DNA-affinity and immunoblot analysis. Co-immunoprecipitation and proximity ligation analysis revealed that the three factors, E2F1, ARID3A and Oct-2, interact with each other as well as with EBNA1 in the nuclei of EBV-positive cells. Using the chromatin immunoprecipitation assay, we showed that E2F1 and Oct-2 interacted with the FR part oforiPand the Cp, but the ARID3A interaction was, however, only detected at the Cp. Our findings support the hypothesis that EBNA1 initiates transcription at the Cp via interactions between multiple EBNA1 homodimers and cellular transcription factors in a large molecular machinery that forms a dynamic interaction between Cp and FR.
Role of Itk signalling in the interaction between influenza A virus and T-cells
Authors: Fan Kewei , Jia Yinping , Wang Song , Li Hua , Wu Defeng , Wang Guoshun , Chen Ji-Long
Published: February 2012

Although the T-cell-mediated immune response to influenza virus has been studied extensively, little information is available on the direct interaction between influenza virus and T-cells that pertains to severe diseases in humans and animals. To address these issues, we utilized the BALB/c mouse model combined with primary T-cells infected with A/WSN/33 influenza virus to investigate whether influenza virus has an affinity for T-cellsin vivo. We observed that small proportions of CD4+T-cells and CD8+T-cells in spleen and thymus expressed viral proteins in infected mice. A significant proportion of mouse primary T-cells displayed expression of α-2,6 sialic acid-linked influenza virus receptor and were infected directly by influenza A virus. These experiments reveal that there exists a population of T-cells that is susceptible to influenza A virus infection. Furthermore, we employed human Jurkat T-cells to investigate the virus–T-cell interaction, with particular emphasis on understanding whether Itk (interleukin-2-inducible T-cell kinase), a Tec family tyrosine kinase that regulates T-cell activation, is involved in virus infection of T-cells. Interestingly, influenza virus infection resulted in an increased recruitment of Itk to the plasma membrane and an increased level of phospholipase C-γ1 (PLC-γ1) phosphorylation, suggesting that Itk/PLC-γ1 signalling is activated by the virus infection. We demonstrated that depletion of Itk inhibited the replication of influenza A virus, whereas overexpression of Itk increased virus replication. These results indicate that Itk is required for efficient replication of influenza virus in infected T-cells.
Transcriptional Profiling of ESTs from the Biocontrol FungusChaetomium cupreum
Authors: Zhang Haiyan , Li Min
Published: February 2012

Comparative analysis was applied to two cDNA/ESTs libraries (C1 and C2) fromChaetomium cupreum. A total of 5538 ESTs were sequenced and assembled into 2162 unigenes including 585 contigs and 1577 singletons. BlastX analysis enabled the identification of 1211 unigenes with similarities to sequences in the public databases. MFS monosaccharide transporter was found as the gene expressed at the highest level in library C2, but no expression in C1. The majority of unigenes were library specific. Comparative analysis of the ESTs further revealed the difference ofC. cupreumin gene expression and metabolic pathways between libraries. Two different sequences similar to the 48-KDa endochitinase and 46-KDa endochitinase were identified in libraries C1 and C2, respectively.
Evaluation of the Oxidative Effect of Long-Term Repetitive Hyperbaric Oxygen Exposures on Different Brain Regions of Rats
Authors: Simsek Kemal , Ozler Mehmet , Yildirim Ali Osman , Sadir Serdar , Demirbas Seref , Oztosun Muzaffer , Korkmaz Ahmet , Ay Hakan , Oter Sukru , Yildiz Senol
Published: February 2012

Hyperbaric oxygen (HBO2) exposure affects both oxidative and antioxidant systems. This effect is positively correlated with the exposure time and duration of the treatment. The present study aims enlightening the relation of HBO2with oxidative/antioxidant systems when administered in a prolonged and repetitive manner in brain tissues of rats. Sixty rats were divided into 6 study (n=8for each) and 1 control (n=12) group. Rats in the study groups were daily exposed 90-min HBO2sessions at 2.8 ATA for 5, 10, 15, 20, 30 and 40 days. One day after the last session, animals were sacrificed; their whole brain tissue was harvested and dissected into three different regions as the outer grey matter (cortex), the inner white matter and cerebellum. Levels of lipid peroxidation and protein oxidation and activities of superoxide dismutase and glutathione peroxidase were measured in these tissues. Malondialdehyde, carbonylated protein and glutathione peroxidase levels were found to be insignificantly increased at different time-points in the cerebral cortex, inner white matter and cerebellum, respectively. These comparable results provide evidence for the safety of HBO treatments and/or successful adaptive mechanisms at least in the brain tissue of rats, even when administered for longer periods.
Yeast as a Tool to Study Signaling Pathways in Mitochondrial Stress Response and Cytoprotection
Authors: Ždralević Maša , Guaragnella Nicoletta , Antonacci Lucia , Marra Ersilia , Giannattasio Sergio
Published: February 2012

Cell homeostasis results from the balance between cell capability to adapt or succumb to environmental stress. Mitochondria, in addition to supplying cellular energy, are involved in a range of processes deciding about cellular life or death. The crucial role of mitochondria in cell death is well recognized. Mitochondrial dysfunction has been associated with the death process and the onset of numerous diseases. Yet, mitochondrial involvement in cellular adaptation to stress is still largely unexplored. Strong interest exists in pharmacological manipulation of mitochondrial metabolism and signaling. The yeastSaccharomyces cerevisiaehas proven a valuable model organism in which several intracellular processes have been characterized in great detail, including the retrograde response to mitochondrial dysfunction and, more recently, programmed cell death. In this paper we review experimental evidences of mitochondrial involvement in cytoprotection and propose yeast as a model system to investigate the role of mitochondria in the cross-talk between prosurvival and prodeath pathways.
Poly[[diaquabis(μ2-crotonato-κ3O:O,O′)(crotonato-κ2O,O′)lanthanum(III)] adenine monosolvate monohydrate]
Authors: Atria Ana María , Garland Maria Teresa , Baggio Ricardo
Published: February 2012

The asymmetric unit of the title compound, {[La(C4H5O2)3(H2O)2]·C5H5N5·H2O}n, consists of an LaIIIcation, three crotonate (but-2-enoate) anions and two coordinated water molecules forming the neutral complex, completed by an external adenine molecule and one hydration water molecule. The LaO10coordination polyhedra, connected through the sharing of a single edge, form isolated chains running along the [100] direction. These one-dimensional structures are characterized by two different centrosymmetric La2O2loops, with La...La distances of 4.5394 (6) and 4.5036 (6) Å. The unbound adenine and water solvent molecules form a highly planar hydrogen-bonded array parallel to (110) (r.m.s. deviation from the mean plane < 0.10 Å) which intersects the isolated La–crotonate chains in a slanted fashion to form an extremely connected hydrogen-bonded three-dimensional structure.
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.
A novel three-dimensional CdIImetal–organic framework based on [Cd6(malonate)6] metallomacrocycles with zeolite SOD (sodalite) topology: poly[ammine-μ3-malonato-cadmium(II)]
Authors: Yuan Shuai , Liu Mei-Jiao , Xie Han-Yi , Xu Meng-Zhen , Sun Di
Published: February 2012

A novel CdIImetal–organic framework, [Cd(C3H2O4)(NH3)]n, was synthesized by liquid diffusion conducted in the presence of ammonia. The CdIIatom has seven-coordinate O6N pentagonal–bipyramidal geometry. Six CdIIcenters are joined by six malonate ligands to form anS6-symmetric [Cd6(malonate)6] metallomacrocycle, which is further extended through a side-on chelating malonate ligand to form a three-dimensional network. Topologically, each CdIIcenter is connected to four others to yield an infinite three-periodic four-coordinated SOD (sodalite) network with point symbol {42·64}. The overall network structure in the crystal is maintained and stabilized by the presence of N—H...O hydrogen bonds.
Validation of otolith daily increment formation for two temperate syngnathid fishes: the pipefishes Stigmatopora argus and Stigmatopora nigra
Authors: Parkinson K. L. , Booth D. J. , Lee J. E.
Published: February 2012

Otoliths were used for the first time to successfully validate the age of members of the family Syngnathidae: the spotted pipefish Stigmatopora argus and the wide‐bodied pipefish Stigmatopora nigra. Otolith increments were deposited daily in (1) known‐age juveniles ranging in age from 0 to 31 days and (2) adults that had been stained with alizarin complexone, and a hatch mark was found on all otoliths which represented day 0. Otolith increment validation will allow development of growth models for S. argus and S. nigra, essential to understanding and managing these exclusive seagrass species.
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

Ber‐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

Cyclosporin 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

Background

The 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.

Aims

To 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.

Methods

These 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.

Results

We 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.

Conclusions

These 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

Systemic 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.