bluuebunny/crossref_metadata_2025 huggingface dataset:
Sliding Window-Based Region of Interest Extraction for Finger Vein Images
Authors: Yang Lu , Yang Gongping , Yin Yilong , Xiao Rongyang
Published: March 2013

Region of Interest (ROI) extraction is a crucial step in an automatic finger vein recognition system. The aim of ROI extraction is to decide which part of the image is suitable for finger vein feature extraction. This paper proposes a finger vein ROI extraction method which is robust to finger displacement and rotation. First, we determine the middle line of the finger, which will be used to correct the image skew. Then, a sliding window is used to detect the phalangeal joints and further to ascertain the height of ROI. Last, for the corrective image with certain height, we will obtain the ROI by using the internal tangents of finger edges as the left and right boundary. The experimental results show that the proposed method can extract ROI more accurately and effectively compared with other methods, and thus improve the performance of finger vein identification system. Besides, to acquire the high quality finger vein image during the capture process, we propose eight criteria for finger vein capture from different aspects and these criteria should be helpful to some extent for finger vein capture.
Some aspects of radical chemistry in the assembly of complex molecular architectures
Authors: Quiclet-Sire Béatrice , Zard Samir Z
Published: March 2013

This review article describes briefly some of the radical processes developed in the authors’ laboratory as they pertain to the concise assembly of complex molecular scaffolds. The emphasis is placed on the use of nitrogen-centred radicals, on the degenerate addition–transfer of xanthates, especially on its potential for intermolecular carbon–carbon bond formation, and on the generation and capture of radicals through electron transfer processes.
Prevalence and Determinants of Virological Failure in HIV-Infected Children on Antiretroviral Therapy in Rural Cameroon: A Cross-Sectional Study
Authors: Zoufaly Alexander , Fillekes Quirine , Hammerl Raffaela , Nassimi Nilofar , Jochum Johannes , Drexler Jan F , Awasom Charles N , Sunjoh Frida , Burchard Gerd D , Burger David M , Van Lunzen Jan , Feldt Torsten
Published: March 2013

Background

In Africa, success of antiretroviral treatment (ART) seems to lag behind in children compared with adults, and high therapeutic failure rates have been reported. We aimed to identify prevalence and determinants of virological failure in HIV-infected children treated under programmatic conditions.

Methods

All patients <18 years on ART presenting to the HIV clinic at the Bamenda Regional Hospital, a secondary referral hospital in rural Cameroon, from September 2010 to August 2011, were enrolled in this cross-sectional study. Clinical data, self-reported adherence, CD4+ T-cell counts and viral load were recorded. Therapeutic drug monitoring was performed on stored plasma samples. Determinants of virological failure were identified using descriptive statistics and logistic regression.

Results

A total of 230 children with a mean age of 8.9 years (sd 3.7) were included. At the time of analysis, the mean duration of HAART was 3.5 years (sd 1.7) and 12% had a CD4+ T-cell count <200 cells/μl. In total, 53% of children experienced virological failure (>200 copies/ml). Among children on nevirapine (NVP), plasma levels were subtherapeutic in 14.2% and supratherapeutic in 42.2%. Determinants of virological failure included male sex, lower CD4+ T-cell counts, subtherapeutic drug levels, longer time on ART and a deceased mother. Poor adherence was associated with subtherapeutic NVP plasma levels and advanced disease stages (WHO stage 3/4).

Conclusions

This study demonstrates high virological failure rates and a high variability of NVP plasma levels among HIV-infected children in a routine ART programme in rural Cameroon. Strategies to improve adherence to ART in HIV-infected children are urgently needed.
Classification, Diagnosis, and Management of Idiopathic Inflammatory Myopathies
Authors: Lazarou Ilias N. , Guerne Pierre-André
Published: March 2013

The detection and characterization of a large array of autoantibodies, including at least 8 different antisynthetase, anti-SRP, -200/100 (HMGCR), -Mi-2, -CADM-140 (MDA5), -SAE, -p155, -MJ (NXP-2), and -PMS1, frequently associated with distinct and well-defined clinicopathological features, allowed for significant improvement in the definition and diagnosis of idiopathic inflammatory myopathies (IIM). Classification remains difficult, with lingering divergence between the different specialties involved in IIM care, but several categories clearly stand out, including dermatomyositis (DM), overlap myositis (OM), polymyositis, necrotizing myositis, and sporadic inclusion body myositis (s-IBM). Biopsy and histological analysis remain crucial, particularly in the absence of autoantibodies, to accurately specify the diagnosis and rule out mimics such as muscular dystrophies and metabolic myopathies. Numerous infectious agents (in particular human immunodeficiency virus and human T cell lymphotrophic virus-1) and drugs (statins, tumor necrosis factor inhibitors, and proton pump inhibitors) can cause mimic IIM that must also be excluded. Pharmacological treatment, in addition to glucocorticoids and immunoglobulins, now includes mycophenolate mofetil and rituximab, which proved helpful in resistant cases, particularly rituximab in DM and OM. Exercise, initially seen as potentially deleterious, recently was shown to be efficacious and safe. IIM can thus be reasonably well controlled in most cases, although aggressive disease remains refractory to treatment, including some cases of necrotizing myopathy. Sporadic IBM still seems resistant to all medications tested to date.
The Downregulation of microRNA let-7a Contributes to the Excessive Expression of Type I Collagen in Systemic and Localized Scleroderma
Authors: Makino Katsunari , Jinnin Masatoshi , Hirano Ayaka , Yamane Keitaro , Eto Mitsuhiko , Kusano Takamitsu , Honda Noritoshi , Kajihara Ikko , Makino Takamitsu , Sakai Keisuke , Masuguchi Shinichi , Fukushima Satoshi , Ihn Hironobu
Published: March 2013

Systemic and localized scleroderma (SSc and LSc) is characterized by excessive deposition of collagen and tissue fibrosis in the skin. Although they have fundamental common characteristics including autoimmunity, little is known about the exact mechanism that mediates the excessive collagen expression in these disorders. In the current study, we tried to evaluate the possibility that microRNAs (miRNAs) play some roles in the pathogenesis of fibrosis seen in these diseases. miRNA expression patterns were evaluated by miRNA array analysis, real-time PCR, and in situ hybridization. The function of miRNAs in dermal fibroblasts was assessed using miRNA inhibitors, precursors, or protectors. In the mouse model of bleomycin-induced dermal sclerosis, the overexpression of miRNAs was performed by i.p. miRNA injection. We demonstrated let-7a expression was downregulated in SSc and LSc skin both in vivo and in vitro, compared with normal or keloid skin. The inhibition or overexpression of let-7a in human or mouse skin fibroblasts affected the protein expression of type I collagen or luciferase activity of collagen 3′-untranslated region. Also, we found let-7a was detectable and quantitative in the serum and investigated serum let-7a levels in patients with SSc or LSc. let-7a concentration was significantly decreased in these patients, especially in LSc patients. Moreover, we revealed that the intermittent overexpression of let-7a in the skin by i.p. miRNA injection improved the skin fibrosis induced by bleomycin in mice. Investigation of more detailed mechanisms of miRNA-mediated regulation of collagen expression may lead to new therapeutic approaches against SSc and LSc.
Polyinosinic-Polycytidylic Acid Is the Most Effective TLR Adjuvant for SIV Gag Protein–Induced T Cell Responses In Nonhuman Primates
Authors: Park Haesun , Adamson Lauren , Ha Tae , Mullen Karl , Hagen Shoko I. , Nogueron Arys , Sylwester Andrew W. , Axthelm Michael K. , Legasse Al , Piatak Michael , Lifson Jeffrey D. , McElrath Juliana M. , Picker Louis J. , Seder Robert A.
Published: March 2013

Prime-boost immunization with heterologous vaccines elicits potent cellular immunity. In this study, we assessed the influence of various TLR ligands on SIV Gag–specific T cell immunity and protection following prime-boost immunization. Rhesus macaques (RMs) were primed with SIV Gag protein emulsified in Montanide ISA51 with or without TLR3 (polyinosinic-polycytidylic acid [poly-IC]), TLR4 (monophosphoryl lipid A), TLR7/8 (3M-012), TLR9 (CpG), or TLR3 (poly-IC) combined with TLR7/8 ligands, then boosted with replication defective adenovirus 5 expressing SIV Gag (rAd5-Gag). After priming, RMs that received SIV Gag protein plus poly-IC developed significantly higher frequencies of SIV Gag–specific CD4+ Th1 responses in blood and bronchoalveolar lavage (BAL) fluid lymphocytes compared with all other adjuvants, and low-level SIV Gag–specific CD8+ T cell responses. After the rAd5-Gag boost, the magnitude and breadth of SIV Gag–specific CD8+ T cell responses were significantly increased in RM primed with SIV Gag protein plus poly-IC, with or without the TLR7/8 ligand, or CpG. However, the anamnestic, SIV Gag–specific CD8+ T cell response to SIVmac251 challenge was not significantly enhanced by SIV Gag protein priming with any of the adjuvants. In contrast, the anamnestic SIV Gag–specific CD4+ T cell response in BAL was enhanced by SIV Gag protein priming with poly-IC or CpG, which correlated with partial control of early viral replication after SIVmac251 challenge. These results demonstrate that prime-boost vaccination with SIV Gag protein/poly-IC improves magnitude, breadth, and durability of CD4+ T cell immune responses, which could have a role in the control of SIV viral replication.
Precambrian Geology of parts of Tavani, Marble Island, and Chesterfield Inlet map Areas, District of Keewatin: a Progress Report
Authors: Tella S , Annesley I R , Borradaile G J , Henderson J R
Published: March 2013

The region is predominantly underlain by the Rankin Inlet Group, an (?) Archean greenstone­metasedimentary sequence comprising at least two major cycles of volcanism with intervening turbidite deposition. Ultramafic and gabbroic sills occur within the volcanic
sequence. Three periods of deformation and one event of metamorphism can be recognized within the Rankin Inlet Group. The rocks within the group form an east dipping F 1 homocline that is folded into a southeast plunging F 2 upright syncline. Shallow, northeast and southwest plunging pre-F 2 mineral
stretching lineations are developed in the metavolcanic rocks on the limbs of the F 2 syncline. Strain ratios based on selvage thicknesses from deformed lava pillows of the Rankin Inlet Group range from 2.0 to 6.0; the high ratios commonly coincide with northwest trending, southwest verging ductile
shear zones - tentatively interpreted as high angle (? thrust) faults. Paleohorizontal markers such as "lava-shelves" are reliable bedding and facing markers where axial ratios in pillows are less than 4:1. Stratigraphic and structural facing reversals suggest two structural discordances, not
coincident with ductile shear zones, within the upper volcanic cycle of the Rankin Inlet Group. The discordances may be interpreted as two thrusts with opposing vergence (northeast and southwest) that juxtapose rocks of different structural geometry. The orientation of pre F 2 mineral lineations
supports the model, but further field testing is required. Migmatitic paragneiss with kyanite, sillimanite, and staurolite assemblages, mafic and felsic schists, and metamorphosed iron formation are exposed in the region north and northeast of Rankin Inlet. They are believed to be the metamorphic
equivalents of the Rankin Inlet Group. A weakly deformed two-mica granite intrudes the gneiss complex. A (?) Lower Proterozoic orthoquartzite sequence, tentatively correlated with the Hurwitz Group, is exposed on Kudlulik Peninsula and on Marble Island 45 km east of Rankin Inlet in Hudson Bay. The
contact with the older rocks on Marble Island is a high-strain zone, and is interpreted to be a low angle, south verging fault.
Current Research, Part C, Canadian Shield
Authors:   Geological Survey of Canada
Published: March 2013

Anorthosite has been discovered at the margin of the M'Clure Bay granite, a large rapakivi granite intrusion (1703 Ma old) in northwestem Somerset Island. It appears to form a sheet, 20 m thick, and is probably cogenetic with the granite. Substantial sequences of
the Proterozoic Aston Formation lie nonconformably on basement adjacent to the Paleozoic terranes on eastem Prince of Wales Island and Prescott and Pandora islands. A representative section measured on Prince of Wales Island comprises 700 m of shallow-marine rocks: a thin breccia-conglomerate
resting on gneiss, 200 m of reddish arkose, and a 500 m-thick succession mainly of more mature quartz sandstone. A 200 m-thick gabbro sill (1268 Ma) has intruded the section. The section terminates at the high-angle reverse fault juxtaposing Proterozoic and Paleozoic strata at the margin of the
Boothia Uplift. The intense deformation evident in rocks on both sides of the fault is consistent with a compressive tectonic regime.
Multi-temporal SAR interferometry reveals acceleration of bridge sinking before collapse
Authors: Sousa J. J. , Bastos L.
Published: March 2013

Abstract. On the night of 4 March 2001, at Entre-os-Rios (Northern Portugal), the Hintze Ribeiro centennial bridge collapsed killing 59 people traveling in a bus and three cars that were crossing the Douro River. According to the national authorities, the collapse was due to two decades of uncontrolled sand extraction which compromised the stability of the bridge's pillars, together with underestimating the warnings from divers and technicians. In this work we do not intend to corroborate or contradict the official version of the accident's causes, but only demonstrate the potential of Multi-Temporal Interferometric techniques for detection and monitoring of deformations in structures such as bridges, and consequently the usefulness of the derived information in some type of early warning system to help prevent new catastrophic events. Based on the analysis of 52 ERS-1/2 covering the period from May 1995 to the fatal occurrence, we were able to detect significant movements, reaching rates of 20 mm yr−1, in the section of the bridge that fell into the Douro River, which are obvious signs of the bridge's instability. These promising results demonstrate that with the new high-resolution synthetic aperture radar satellite scenes it is possible to develop interferometric based methodologies for structural health monitoring.
Mucin-Related Molecular Responses of Bronchial Epithelial Cells in Rats Infected with the NematodeNippostrongylus brasiliensis
Authors: Soga Koichi , Yamada Minoru , Naito Yuji , Yoshikawa Toshikazu , Arizono Naoki
Published: March 2013

Although mucins are essential for the protection of internal epithelial surfaces, molecular responses involving mucin production and secretion in response to various infectious agents in the airway have not been fully elucidated. The present study analysed airway goblet cell mucins in rats infected with the nematodeNippostrongylus brasiliensis, which migrates to the lungs shortly after infection. Goblet cell hyperplasia occurred in the bronchial epithelium 3–10 days after infection. The high iron diamine-alcian blue staining combined with neuraminidase treatment showed that sialomucin is the major mucin in hyperplastic goblet cells. Immunohistochemical studies demonstrated that goblet cell mucins were immunoreactive with both the major airway mucin core peptide, Muc5AC, and the major intestinal mucin core peptide Muc2. Reverse transcription real-time PCR studies demonstrated upregulation of gene transcription levels of Muc5AC, Muc2, the sialyltransferase St3gal4, and the resistin-like molecule beta (Retnlb) in the lungs. These results showed that nematode infection induces airway epithelial responses characterised by the production of sialomucin with Muc5AC and Muc2 core peptides. These mucins, as well as Retnlb, might have important roles in the protection of mucosa from migrating nematodes in the airway.
O ensino de História nos anos iniciais: como se pensa, como se faz
Authors: Abud Kátia Maria
Published: March 2013

O texto traz à discussão algumas questões relativas ao ensino de História nos anos iniciais e busca demonstrar a permanência de alguns conceitos e de algumas concepções, nos currículos e propostas curriculares desde o início da segunda metade do século XX. Com informações extraídas de relatórios e projetos de estagiários da disciplina Metodologia do Ensino de História, analisou-se a construção, pelos professores, de projetos e planejamentos de ensino de História nos anos iniciais. Procurou-se estabelecer também quais os temas e conceitos são valorizados para a disciplina e como são desenvolvidos em sala de aula.
Three Years After Transplants in Human Mandibles, Histological and In-Line Holotomography Revealed That Stem Cells Regenerated a Compact Rather Than a Spongy Bone: Biological and Clinical Implications
Authors: Giuliani Alessandra , Manescu Adrian , Langer Max , Rustichelli Franco , Desiderio Vincenzo , Paino Francesca , De Rosa Alfredo , Laino Luigi , d'Aquino Riccardo , Tirino Virginia , Papaccio Gianpaolo
Published: March 2013

Mesenchymal stem cells deriving from dental pulp differentiate into osteoblasts capable of producing bone. In previous studies, we extensively demonstrated that, when seeded on collagen I scaffolds, these cells can be conveniently used for the repair of human mandible defects. Here, we assess the stability and quality of the regenerated bone and vessel network 3 years after the grafting intervention, with conventional procedures and in-line holotomography, an advanced phase-imaging method using synchrotron radiation that offers improved sensitivity toward low-absorbing structures. We found that the regenerated tissue from the graft sites was composed of a fully compact bone with a higher matrix density than control human alveolar spongy bone from the same patient. Thus, the regenerated bone, being entirely compact, is completely different from normal alveolar bone. Although the bone regenerated at the graft sites is not of the proper type found in the mandible, it does seem to have a positive clinical impact. In fact, it creates steadier mandibles, may well increase implant stability, and, additionally, may improve resistance to mechanical, physical, chemical, and pharmacological agents.
Caregiver Burden: Meeting the Needs of People who Support the Person with Multiple Sclerosis
Authors: Wollin Judy , Reiher Christine , Spencer Nancy , Madl Romana , Nutter Helen
Published: March 2013

Reliance on informal arrangements to support the person with multiple sclerosis (MS) is an increasingly common phenomenon. The focus of this Australian-based research is on the impact of the caregiver role, the identification of stressors that might prevent a continuation of the role, and the determination of resources needed by caregivers to continue in this role.

Using surveys that were sent through the mail, the views of 34 people who care for an individual with MS were collected in order to identify the caregivers’ views on the impact of their role. The results indicate that caregivers provide between 2 and 10 hours daily of physical, emotional, financial, or informational support to the person with MS. The majority of people who provide support to individuals with MS are married to them; they provide care out of love; and they are overtaxed by day-to-day tasks with reduced physical, emotional, and financial resources. Caregivers requested practical support rather than information to reduce their burden.
Coordinatable and High Charge‐Carrier‐Mobility Water‐Soluble Conjugated Copolymers for Effective Aqueous‐Processed Polymer–Nanocrystal Hybrid Solar Cells and OFET Applications
Authors: Wei Haotong , Zhang Hao , Jin Gan , Na Tianyi , Zhang Guoyan , Zhang Xue , Wang Yan , Sun Haizhu , Tian Wenjing , Yang Bai
Published: March 2013

A water‐soluble conjugated polymer (WCP) poly[(3,4‐dibromo‐2,5‐thienylene vinylene)‐co‐(p‐phenylene‐vinylene)] (PBTPV), containing thiophene rings with high charge‐carrier mobility and benzene rings with excellent solubility is designed and prepared through Wessling polymerization. The PBTPV precursor can be easily processed by employing water or alcohols as the solvents, which are clean, environmentally friendly, and non‐toxic compared with the highly toxic organic solvents such as chloroform and chlorobenzene. As a novel photoelectric material, PBTPV presents excellent hole‐transport properties with a carrier mobility of 5 × 10−4 cm2 V−1 s−1 measured in an organic field‐effect transistor device. By integrating PBTPV with aqueous CdTe nanocrystals (NCs) to produce the active layer of water‐processed hybrid solar cells, the devices exhibit effective power conversion efficiency up to 3.3%. Moreover, the PBTPV can form strong coordination interactions with the CdTe NCs through the S atoms on the thiophene rings, and effective coordination with other nanoparticles can be reasonably expected.
Fe(PyTACN)‐Catalyzed cis‐Dihydroxylation of Olefins with Hydrogen Peroxide
Authors: Prat Irene , Font David , Company Anna , Junge Kathrin , Ribas Xavi , Beller Matthias , Costas Miquel
Published: March 2013

A family of iron complexes with general formula [Fe(II)(R,Y,XPyTACN)(CF3SO3)2], where R,Y,XPyTACN=1‐[2′‐(4‐Y‐6‐X‐pyridyl)methyl]‐4,7‐dialkyl‐1,4,7‐triazacyclononane, X and Y refer to the groups at positions 4 and 6 of the pyridine, respectively, and R refers to the alkyl substitution at N‐4 and N‐7 of the triazacyclononane ring, are shown to be catalysts for efficient and selective alkene oxidation (epoxidation and cis‐dihydroxylation) employing hydrogen peroxide as oxidant. Complex [Fe(II)(Me,Me,HPyTACN)(CF3SO3)2] (7), was identified as the most efficient and selective cis‐dihydroxylation catalyst among the family. The high activity of 7 allows the oxidation of alkenes to proceed rapidly (30 min) at room temperature and under conditions where the olefin is not used in large amounts but instead is the limiting reagent. In the presence of 3 mol% of 7, 2 equiv. of H2O2 as oxidant and 15 equiv. of water, in acetonitrile solution, alkenes are cis‐dihydroxylated reaching yields that might be interesting for synthetic purposes. Competition experiments show that 7 exhibits preferential selectivity towards the oxidation of cis olefins over the trans analogues, and also affords better yields and high [syn‐diol]/[epoxide] ratios when cis olefins are oxidized. For aliphatic substrates, reaction yields attained with the present system compare favourably with state of the art Fe‐catalyzed cis‐dihydroxylation systems, and it can be regarded as an attractive complement to the iron and manganese systems described recently and which show optimum activity against electron‐deficient and aromatic olefins.
One‐Pot Synthesis of Allylamine Derivatives by Iodine‐ Catalyzed Three‐Component Reaction of N‐Heterocycles, Paraformaldehyde and Styrenes
Authors: Quan Zheng‐Jun , Hu Wang‐Hua , Zhang Zhang , Da Yu‐Xia , Jia Xiao‐Dong , Wang Xi‐Cun
Published: March 2013

The molecular iodine‐catalyzed three‐component reaction of amides or amide derivatives, paraformaldehyde and styrenes allows for the clean generation of allylamine derivatives in good yields and high regioselectivities. The reaction, forming water as the sole co‐product, is an experimentally easy to conduct transformation in the absence of transition metals under mild conditions.
Regio‐ and Stereoselective Synthesis of Tri‐ and Tetrasubstituted Enamides via Palladium‐Catalyzed Silaboration of Ynamides
Authors: Saito Nozomi , Saito Keiichi , Sato Hiroyasu , Sato Yoshihiro
Published: March 2013

The palladium‐catalyzed silaboration of ynamides is demonstrated. The silaboration proceeds in a highly regioselective manner to give the corresponding tri‐ and tetrasubstituted enamide derivatives having both a silyl group and a boryl group on the alkene. Furthermore, the silaborated enamide could be utilized as a coupling partner in Suzuki–Miyaura coupling with aryl iodides to give the corresponding cross‐coupling product in good yield.
Numerical simulation of particle breakage in dry impact pulverizer
Authors: Takeuchi Hirohisa , Nakamura Hideya , Watano Satoru
Published: March 2013

A novel method to simultaneously simulate particle motion and its breakage in a dry impact pulverizer was developed. The motion of particles in the pulverizer was calculated using a discrete phase model (DPM)‐computational fluid dynamics (CFD) coupling model. When the particle impacts against a vessel wall, impact stress acting on the particle is calculated from Hertz's theory as a function of the impact velocity. At the same time, the particle strength as a function of the particle size is calculated from Griffith's theory. If the impact stress is larger than the particle strength, the particle is broken and replaced with smaller fragments. The size distribution of the fragments is obtained from a breakage function proposed. The motion of the fragments is calculated again by using the DPM‐CFD coupling model. By repeating the above calculations over the whole particles, the grinding phenomenon can be simulated. The calculated results showed good agreement with the experimental one, and validity of the proposed method was confirmed. © 2013 American Institute of Chemical Engineers AIChE J, 59: 3601–3611, 2013
Sex dependent influence of a functional polymorphism in steroid 5‐α‐reductase type 2 (SRD5A2) on post‐traumatic stress symptoms
Authors: Gillespie Charles F. , Almli Lynn M. , Smith Alicia K. , Bradley Bekh , Kerley Kimberly , Crain Daniel F. , Mercer Kristina B. , Weiss Tamara , Phifer Justine , Tang Yilang , Cubells Joseph F. , Binder Elisabeth B. , Conneely Karen N. , Ressler Kerry J.
Published: March 2013

A non‐synonymous, single nucleotide polymorphism (SNP) in the gene coding for steroid 5‐α‐reductase type 2 (SRD5A2) is associated with reduced conversion of testosterone to dihydrotestosterone (DHT). Because SRD5A2 participates in the regulation of testosterone and cortisol metabolism, hormones shown to be dysregulated in patients with PTSD, we examined whether the V89L variant (rs523349) influences risk for post‐traumatic stress disorder (PTSD). Study participants (N = 1,443) were traumatized African‐American patients of low socioeconomic status with high rates of lifetime trauma exposure recruited from the primary care clinics of a large, urban hospital. PTSD symptoms were measured with the post‐traumatic stress symptom scale (PSS). Subjects were genotyped for the V89L variant (rs523349) of SRD5A2. We initially found a significant sex‐dependent effect of genotype in male but not female subjects on symptoms. Associations with PTSD symptoms were confirmed using a separate internal replication sample with identical methods of data analysis, followed by pooled analysis of the combined samples (N = 1,443, sex × genotype interaction P < 0.002; males: n = 536, P < 0.001). These data support the hypothesis that functional variation within SRD5A2 influences, in a sex‐specific way, the severity of post‐traumatic stress symptoms and risk for diagnosis of PTSD. © 2013 Wiley Periodicals, Inc.
The Teratogenic Effect of Dofetilide during Rat Limb Development and Association with Drug‐Induced Bradycardia and Hypoxia in the Embryo
Authors: Ritchie Helen E. , Ababneh Deena H. , Oakes Diana J. , Power Carl A. , Webster William S.
Published: March 2013

BACKGROUND

Dofetilide is an antiarrhythmic drug that blocks the cardiac repolarizing current IKr ((IKr, rapid component of the delayed rectifying potassium current). Previous studies have shown that (a) IKr is essential for normal cardiac function of the embryonic heart and (b) dofetilide is teratogenic in rodents. This study was undertaken to examine the mechanism by which dofetilide causes limb defects on gestational day 13 (GD 13) in the rat.

METHODS

Rats were treated with dofetilide (single oral dose, 5 mg/kg) on GD 13 and embryonic heart rates assessed by ultrasound (Vevo770, VisualSonics, Toronto, Ontario, Canada) 2 hr later. Fetuses were examined for malformations on GD 20. In a separate experiment, dofetilide treatment of GD 13 rats was followed 2, 4, 12, or 24 hr with iv dosing with the hypoxia marker, pimonidazole (60 mg/kg). Embryos were collected and heart rates were assessed in vitro and hypoxia in embryo limbs analyzed.

RESULTS

A teratogenic dose of dofetilide at a susceptible stage of development (GD 13) resulted in a period of bradycardia and arrhythmia of the embryonic heart and hypoxia in the developing limbs (GD 13) resulting in limb malformations (GD 20).

CONCLUSIONS

Drugs that induce periods of bradycardia and/or arrhythmia of the embryonic heart and cause the embryo to become hypoxic are potential human teratogens.
Diverse Effects of Macromolecular Crowding on the Sequential Glycan‐Processing Pathway Involved in Glycoprotein Quality Control
Authors: Matsushima Hikaru , Hirano Makoto , Ito Yukishige , Totani Kiichiro
Published: March 2013

Compared with in vitro conditions, the intracellular environment is highly crowded with biomolecules; this has numerous effects on protein functions, including enzymatic activity. We examined the effects of macromolecular crowding on glycan processing of N‐glycoprotein in the endoplasmic reticulum as a model sequential metabolic pathway. Experiments with synthetic substrates of physiological glycan structure clearly showed that the first half of the pathway (glucose trimming) was accelerated, whereas the second (mannose trimming) was decelerated under molecular crowding conditions. Furthermore, calreticulin, a lectin‐like molecular chaperone, bound more strongly to a glycan‐processing intermediate under these conditions. This study demonstrates the diverse effects of molecular crowding on sequential enzymatic processing, and the importance of the effects of macromolecular crowding on in vitro assays for understanding sequential metabolic pathways.
Optical/Magnetic Multimodal Bioprobes Based on Lanthanide‐Doped Inorganic Nanocrystals
Authors: Tu Datao , Liu Yongsheng , Zhu Haomiao , Chen Xueyuan
Published: March 2013

Multimodal bioprobes, which integrate the advantages of different diagnostic modes into one single particle, can overcome the current limitations of sensitivity and resolution in medical assays and significantly improve the outcome of existing therapeutics. Lanthanide‐doped inorganic multimodal bioprobes, which are emerging as a promising new class of optical/magnetic multimodal bioprobes, have been long sought‐after and have recently attracted revived interest owing to their distinct optical and magnetic properties. In this concept article, we introduce the controlled synthesis of lanthanide‐doped inorganic multimodal bioprobes, including core–shell structured and single‐phase nanoparticles, and demonstrate different design strategies for achieving dual‐modal functionalization of nanoprobes. In particular, we highlight the most recent advances in biodetection, bioimaging, targeted drug delivery, and therapy based on these nanoparticles.
Health‐related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3, randomized, controlled, BOLERO‐2 trial
Authors: Burris Howard A. , Lebrun Fabienne , Rugo Hope S. , Beck J. Thaddeus , Piccart Martine , Neven Patrick , Baselga Jose , Petrakova Katarina , Hortobagyi Gabriel N. , Komorowski Anna , Chouinard Edmond , Young Robyn , Gnant Michael , Pritchard Kathleen I. , Bennett Lee , Ricci Jean‐Francois , Bauly Hounayda , Taran Tetiana , Sahmoud Tarek , Noguchi Shinzaburo
Published: March 2013

BACKGROUND:

The randomized, controlled BOLERO‐2 (Breast Cancer Trials of Oral Everolimus) trial demonstrated significantly improved progression‐free survival with the use of everolimus plus exemestane (EVE + EXE) versus placebo plus exemestane (PBO + EXE) in patients with advanced breast cancer who developed disease progression after treatment with nonsteroidal aromatase inhibitors. This analysis investigated the treatment effects on health‐related quality of life (HRQOL).

METHODS:

Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 (EORTC QLQ‐C30) questionnaire, HRQOL was assessed at baseline and every 6 weeks thereafter until disease progression and/or treatment discontinuation. The 30 items in 15 subscales of the QLQ‐C30 include global health status wherein higher scores (range, 0‐100) indicate better HRQOL. This analysis included a protocol‐specified time to definitive deterioration (TDD) analysis at a 5% decrease in HRQOL versus baseline, with no subsequent increase above this threshold. The authors report additional sensitivity analyses using 10‐point minimal important difference decreases in the global health status score versus baseline. Treatment arms were compared using the stratified log‐rank test and Cox proportional hazards model adjusted for trial stratum (visceral metastases, previous hormone sensitivity), age, sex, race, baseline global health status score and Eastern Cooperative Oncology Group performance status, prognostic risk factors, and treatment history.

RESULTS:

Baseline global health status scores were found to be similar between treatment groups (64.7 vs 65.3). The median TDD in HRQOL was 8.3 months with EVE + EXE versus 5.8 months with PBO + EXE (hazard ratio, 0.74; P = .0084). At the 10‐point minimal important difference, the median TDD with EVE + EXE was 11.7 months versus 8.4 months with PBO + EXE (hazard ratio, 0.80; P = .1017).

CONCLUSIONS:

In patients with advanced breast cancer who develop disease progression after treatment with nonsteroidal aromatase inhibitors, EVE + EXE was associated with a longer TDD in global HRQOL versus PBO + EXE. Cancer 2013. © 2013 American Cancer Society.
Elucidation of target muscle and detailed development of dorsal motor neurons in chick embryo spinal cord
Authors: Kobayashi Nobumi , Homma Shunsaku , Okada Tomoaki , Masuda Tomoyuki , Sato Noboru , Nishiyama Keiji , Sakuma Chie , Shimada Takako , Yaginuma Hiroyuki
Published: March 2013

The avian cervical spinal cord includes motoneurons (MNs) that send their axons through the dorsal roots. They have been called dorsal motoneurons (dMNs) and assumed to correspond to MNs of the accessory nerve that innervate the cucullaris muscle (SAN‐MNs). However, their target muscles have not been elucidated to date. The present study sought to determine the targets and the specific combination of transcription factors expressed by dMNs and SAN‐MNs and to describe the detailed development of dMNs. Experiments with tracing techniques confirmed that axons of dMNs innervated the cucullaris muscle. Retrogradely labeled dMNs were distributed in the ventral horn of C3 and more caudal segments. In most cases, some dMNs were also observed in the C2 segment. It was also demonstrated that SAN‐MNs existed in the ventral horn of the C1–2 segments and the adjacent caudal hindbrain. Both SAN‐MNs and dMNs expressed Isl1 but did not express Isl2, MNR2, or Lhx3. Rather, these MNs expressed Phox2b, a marker for branchial motoneurons (brMNs), although the intensity of expression was weaker. Dorsal MNs and SAN‐MNs were derived from the Nkx2.2‐positive precursor domain and migrated dorsally. Dorsal MNs remain in the ventral domain of the neural tube, unlike brMNs in the brainstem. These results indicate that dMNs and SAN‐MNs belong to a common MN population innervating the cucullaris muscle and also suggest that they are similar to brMNs of the brainstem, although there are differences in Phox2b expression and in the final location of each population. J. Comp. Neurol. 521: 2987–3002, 2013. © 2013 Wiley Periodicals, Inc.
Socially regulated reproductive development: Analysis of GnRH‐1 and kisspeptin neuronal systems in cooperatively breeding naked mole‐rats (Heterocephalus glaber)
Authors: Zhou Shuzhi , Holmes Melissa M. , Forger Nancy G. , Goldman Bruce D. , Lovern Matthew B. , Caraty Alain , Kalló Imre , Faulkes Christopher G. , Coen Clive W.
Published: March 2013

In naked mole‐rat (NMR) colonies, breeding is monopolized by the queen and her consorts. Subordinates experience gonadal development if separated from the queen. To elucidate the neuroendocrine factors underlying reproductive suppression/development in NMRs, we quantified plasma gonadal steroids and GnRH‐1‐ and kisspeptin‐immunoreactive (ir) neurons in subordinate adults and in those allowed to develop into breeders, with or without subsequent gonadectomy. In males and females, respectively, plasma testosterone and progesterone are higher in breeders than in subordinates. No such distinction occurs for plasma estradiol; its presence after gonadectomy and its positive correlation with adrenal estradiol suggest an adrenal source. Numbers of GnRH‐1‐ir cell bodies do not differ between gonad‐intact breeders and subordinates within or between the sexes. As in phylogenetically related guinea pigs, kisspeptin‐ir processes pervade the internal and external zones of the median eminence. Their distribution is consistent with actions on GnRH‐1 neurons at perikaryal and/or terminal levels. In previously investigated species, numbers of kisspeptin‐ir cell bodies vary from substantial to negligible according to sex and/or reproductive state. NMRs are exceptional: irrespective of sex, reproductive state, or presence of gonads, substantial numbers of kisspeptin‐ir cell bodies are detected in the rostral periventricular region of the third ventricle (RP3V) and in the anterior periventricular (PVa), arcuate, and dorsomedial hypothalamic nuclei. Nevertheless, the greater number in the RP3V/PVa of female breeders compared with female subordinates or male breeders suggests that emergence from a hypogonadotrophic state in females may involve kisspeptin‐related mechanisms similar to those underlying puberty or seasonal breeding in other species. J. Comp. Neurol. 521: 3003–3029, 2013. © 2013 Wiley Periodicals, Inc.
Seasonal changes in RFamide‐related peptide‐3 neurons in the hypothalamus of a seasonally breeding marsupial species, the brushtail possum (Trichosurus vulpecula)
Authors: Harbid Anan A. , McLeod Bernie J. , Caraty Alain , Anderson Greg M.
Published: March 2013

RFamide‐related peptide‐3 (RFRP‐3) neurons have been shown to inhibit gonadotropin‐releasing hormone (GnRH) neuronal activity and hence reproduction in birds and eutherian mammals. They have also been proposed to have a direct hypophysiotropic effect on pituitary gonadotropin release. We used a new RFRP‐3 antibody to characterize the cell body distribution and fiber projections of RFRP‐3 neurons in the adult female brushtail possum brain. RFRP‐3‐immunoreactive cell bodies were found scattered within the dorsomedial hypothalamus and the dorsomedial half of the ventromedial hypothalamus, while GnRH neurons were observed scattered rostrocaudally along the lateral septum, rostral to the medial septum. There was a significant 2‐fold increase in the RFRP‐3 cell body number during the nonbreeding season (summer) compared to the breeding season (winter). Immunoreactive RFRP‐3 fibers were distributed throughout the thalamus, preoptic area, and hypothalamus. Very few fibers were observed in the median eminence, especially in the external zone. Intraperitoneal injection of the retrograde tracer Fluoro‐Gold resulted in the labeling of 40% of hypophysiotropic tuberoinfundibular dopaminergic (tyrosine hydroxylase‐positive) neurons; however, <10% of zona incerta dopaminergic neurons (which are not hypophysiotropic) or RFRP‐3 neurons were labeled with this tracer. These observations suggest that RFRP‐3 exhibits a seasonal fluctuation in cell numbers, as seen in sheep and birds, which is consistent with an increased inhibitory tone during the nonbreeding season. The lack of RFRP‐3 fibers in the median eminence and of Fluoro‐Gold uptake from the periphery imply that the actions of this peptide occur primarily centrally rather than at the anterior pituitary gland. J. Comp. Neurol. 521: 3030–3041, 2013. © 2013 Wiley Periodicals, Inc.
Adipocyte‐derived lipids modulate CD4+ T‐cell function
Authors: Ioan‐Facsinay Andreea , Kwekkeboom Joanneke C. , Westhoff Sanne , Giera Martin , Rombouts Yoann , van Harmelen Vanessa , Huizinga Tom W. J. , Deelder André , Kloppenburg Margreet , Toes René E. M.
Published: March 2013

Adipose tissue contains several immune cells whose number and phenotype vary depending on the adiposity. In the present study, we show that IFN‐γ+ CD4+ T cells are enriched in human adipose tissue compared with in blood. To gain insight into the underlying mechanisms, we investigated the possibility that human adipocytes modulate CD4+ T‐cell cytokine production and proliferation and show that CD4+ T cells produced increased levels of IFN‐γ when activated in the presence of adipocytes. This effect was mediated by soluble mediators, as shown in transwell and adipocyte‐conditioned medium (ACM) transfer experiments. Additionally, ACM induced increased proliferation of CD4+ T cells upon activation. Intriguingly, the proliferation‐enhancing effect resided mainly in the lipid fraction of ACM, as shown upon separation of the protein and lipid fraction. Further separation of these lipids based on polarity revealed that the modulatory effect is confined to fractions containing free fatty acids. All identified fatty acids were able to individually enhance T‐cell proliferation. These data indicate that adipocytes can modulate CD4+ T‐cell function through the release of lipids. Remarkably, free fatty acids were the most prominent modulators of T‐cell proliferation, possibly leading to an accumulation of these cells in adipose tissue.
Electrophilic Cyclization of N‐Alkynyl‐2‐(organochalcogen)imidazoles: An Alternative Access to Imidazo[2,1‐b]chalcogenazoles
Authors: Grimaldi Tamíris B. , Godoi Benhur , Roehrs Juliano A. , Sperança Adriane , Zeni Gilson
Published: March 2013

We present here a practical synthesis of multifunctional imidazo[2,1‐b]chalcogenazoles through electrophilic cyclization of N‐alkynyl‐2‐(organochalcogen)imidazoles. The cyclization reaction proceeded cleanly and smoothly under mild reaction conditions in the presence of air. The methodology was highly regioselective: In a competition between the chalcogen and oxygen atoms, only S‐, and Se‐heterocycles were obtained. The resulting imidazo[2,1‐b]chalcogenazoles proved to be versatile as precursors for the synthesis of more highly functionalized imidazoselenazoles through copper‐catalyzed cross‐coupling reactions with arene‐ and alkanethiols, leading to Ullmann‐type products in good yields.
Molecular mechanism of histamine clearance by primary human astrocytes
Authors: Yoshikawa Takeo , Naganuma Fumito , Iida Tomomitsu , Nakamura Tadaho , Harada Ryuichi , Mohsen Attayeb S. , Kasajima Atsuko , Sasano Hironobu , Yanai Kazuhiko
Published: March 2013

Histamine clearance is an essential process for avoiding excessive histaminergic neuronal activity. Previous studies using rodents revealed the predominant role of astrocytes in brain histamine clearance. However, the molecular mechanism of histamine clearance has remained unclear. We detected histamine N‐methyltransferase (HNMT), a histamine‐metabolizing enzyme, in primary human astrocytes and the astrocytes of human brain specimens. Immunocytochemical analysis and subcellular fractionation assays revealed that active HNMT localized to the cytosol, suggesting that histamine transport into the cytosol is crucial for histamine inactivation. We showed that primary human astrocytes transported histamine in a time‐dependent manner. Kinetics analysis showed that two low‐affinity transporters were involved in histamine transport. Histamine uptake by primary human astrocytes was not dependent on the extracellular Na+/Cl− concentration. Histamine is reported to be a substrate for three low‐affinity and Na+/Cl−‐independent transporters: organic cation transporter 2 (OCT2), OCT3, and plasma membrane monoamine transporter (PMAT). RT‐PCR analysis revealed that OCT3 and PMAT were expressed in primary human astrocytes. Immunohistochemistry confirmed OCT3 and PMAT expression in the astrocytes of human brain specimens. Drug inhibition assays and gene knockdown assays revealed the major contribution of PMAT and the minor contribution of OCT3 to histamine transport. The present study demonstrates for the first time that the molecular mechanism of histamine clearance is by primary human astrocytes. These findings might indicate that PMAT, OCT3 and HNMT in human astrocytes play a role in the regulation of extraneuronal histamine concentration and the activities of histaminergic neurons.
Prediction Models of Long-Term Cirrhosis and Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients: Risk Scores Integrating Host and Virus Profiles
Authors: Lee Mei-Hsuan , Yang Hwai-I. , Liu Jessica , Batrla-Utermann Richard , Jen Chin-Lan , Iloeje Uchenna H. , Lu Sheng-Nan , You San-Lin , Wang Li-Yu , Chen Chien-Jen
Published: March 2013

Integrating host and HBV characteristics, this study aimed to develop models for predicting long-term cirrhosis and hepatocellular carcinoma (HCC) risk in chronic hepatitis B virus (HBV) patients. This analysis included hepatitis B surface antigen (HBsAg)-seropositive and anti-HCV-seronegative participants from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer in HBV (R.E.V.E.A.L.-HBV) cohort. Newly developed cirrhosis and HCC were ascertained through regular follow-up ultrasonography, computerized linkage with national health databases, and medical chart reviews. Two-thirds of the participants were allocated for risk model derivation and another one-third for model validation. The risk prediction model included age, gender, HBV e antigen (HBeAg) serostatus, serum levels of HBV DNA, and alanine aminotransferase (ALT), quantitative serum HBsAg levels, and HBV genotypes. Additionally, the family history was included in the prediction model for HCC. Cox's proportional hazards regression coefficients for cirrhosis and HCC predictors were converted into risk scores. The areas under receiver operating curve (AUROCs) were used to evaluate the performance of risk models. Elder age, male, HBeAg, genotype C, and increasing levels of ALT, HBV DNA, and HBsAg were all significantly associated with an increased risk of cirrhosis and HCC. The risk scores estimated from the derivation set could accurately categorize participants with low, medium, and high cirrhosis and HCC risk in the validation set (

P

< 0.001). The AUROCs for predicting 3-year, 5-year, and 10-year cirrhosis risk ranged 0.83-0.86 and 0.79-0.82 for the derivation and validation sets, respectively. The AUROC for predicting 5-year, 10-year, 15-year risk of HCC ranged 0.86-0.89 and 0.84-0.87 in the derivation and validation sets, respectively.

Conclusion

: The risk prediction models of cirrhosis and HCC by integrating host and HBV profiles have excellent prediction accuracy and discriminatory ability. They may be used for clinical management of chronic hepatitis B patients. (Hepatology 2013;58:546-554)