bluuebunny/crossref_metadata_2025 huggingface dataset:
Review of UV spectroscopic, chromatographic, and electrophoretic methods for the cholinesterase reactivating antidote pralidoxime (2‐PAM)
Authors: John Harald , Blum Marc‐Michael
Published: September 2011

Pralidoxime (2‐PAM) belongs to the class of monopyridinium oximes with reactivating potency on cholinesterases inhibited by phosphylating organophosphorus compounds (OPC), for example, pesticides and nerve agents. 2‐PAM represents an established antidote for the therapy of anticholinesterase poisoning since the late 1950s. Quite high therapeutic concentrations in human plasma (about 13 µg/ml) lead to concentrations in urine being about 100 times higher allowing the use of less sensitive analytical techniques that were used especially in the early years after 2‐PAM was introduced. In this time (mid‐1950s until the end of the 1970s) 2‐PAM was most often analyzed by either paper chromatography or simple UV spectroscopic techniques omitting any sample separation step. These methods were displaced completely after the establishment of column liquid chromatography in the early 1980s. Since then, diverse techniques including cation exchange, size‐exclusion, reversed‐phase, and ligand‐exchange chromatography have been introduced. Today, the most popular method for 2‐PAM quantification is ion pair chromatography often combined with UV detection representing more than 50% of all column chromatographic procedures published. Furthermore, electrophoretic approaches by paper and capillary zone electrophoresis have been successfully used but are seldom applied.

This review provides a commentary and exhaustive summary of analytical techniques applied to detect 2‐PAM in pharmaceutical formulations and biological samples to characterize stability and pharmacokinetics as well as decomposition and biotransformation products. Separation techniques as well as diverse detectors are discussed in appropriate detail allowing comparison of individual preferences and limitations. In addition, novel data on mass spectrometric fragmentation of 2‐PAM are provided. Copyright © 2011 John Wiley & Sons, Ltd.
Effectiveness of and challenges faced by surveillance systems
Authors: Dunn Matthew , Bruno Raimondo , Burns Lucinda , Roxburgh Amanda
Published: September 2011

Drug information or surveillance systems have been developed in an attempt to measure illicit drug use and predict new trends. In Australia, three systems are specifically designed to monitor drug use trends and related harm. These systems have their own strengths and weaknesses. This perspective offers a discussion of these facets. A series of case studies is used to highlight how surveillance systems can be effective in detecting and monitoring trends of use while highlighting the challenges these systems face. As indicated by the case study of ecstasy, such surveillance systems are effective and can provide unique information when a drug is detected and becomes ‘established’ in the market but the methodology of these systems is challenged when new drug classes emerge rapidly, as is illustrated by emerging psychotropic substances such as mephedrone. Copyright © 2011 John Wiley & Sons, Ltd.
Effects of a Randomised Reading Intervention Study: An Application of Structural Equation Modelling
Authors: Wolff Ulrika
Published: September 2011

An intensive phonics‐based intervention program for nine‐year‐old Swedish pupils with reading difficulties was performed. Pupils (N = 112) were randomly assigned to either an intervention or a control group. The training was tailored to the Swedish transparent orthography and designed for one‐to‐one‐tutoring during twelve weeks. Previously, reading speed has been shown to be hard to remediate, and one important purpose was to improve reading speed by explicit training. The intervention group showed improvements immediately after intervention in spelling, reading comprehension, reading speed, and phoneme awareness. There were also significant indirect effects from intervention to all variables one year later. Reading comprehension at immediate post‐test predicted spelling one year later, and phoneme awareness at post‐test predicted both spelling and reading comprehension one year later. The results suggest the importance of a multi‐component intervention, even in transparent orthographies, which includes phonics combined with comprehension strategies and fluency training. Copyright © 2011 John Wiley & Sons, Ltd.
Discussion about “synthetic intelligence” in dissociated culture system
Authors: Kudoh Suguru N. , Kiyohara Ai , Taguchi Takahisa
Published: September 2011

The fundamental frameworks for possessing qualia are “embodiment” and the network structures of the relationships between internal modules. We proposed “Anaplastic cognitive agent” (ACA) composed by interactions between submodules with hierarchical history functions and network structures. A dissociated culture system can discriminate several distinct spatiotemporal patterns of action potentials evoked by current inputs, and possesses kinds of history function; history properties of network dynamics, synaptic plasticity, and so on. These features are prerequisite building components of ACA. © 2011 Wiley Periodicals, Inc. Electron Comm Jpn, 94(10): 41–56, 2011; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/ecj.10328
CD22 serves as a receptor for soluble IgM
Authors: Adachi Takahiro , Harumiya Satoru , Takematsu Hiromu , Kozutsumi Yasunori , Wabl Matthias , Fujimoto Manabu , Tedder Thomas F.
Published: September 2011

CD22 (Siglec‐2) is a B‐cell membrane‐bound lectin that recognizes glycan ligands containing α2,6‐linked sialic acid (α2,6Sia) and negatively regulates signaling through the B‐cell Ag receptor (BCR). Although CD22 has been investigated extensively, its precise function remains unclear due to acting multiple phases. Here, we demonstrate that CD22 is efficiently activated in trans by complexes of Ag and soluble IgM (sIgM) due to the presence of glycan ligands on sIgM. This result strongly suggests sIgM as a natural trans ligand for CD22. Also, CD22 appears to serve as a receptor for sIgM, which induces a negative feedback loop for B‐cell activation similar to the Fc receptor for IgG (FcγRIIB).
Syntheses and Structures of Two Dimethyl Diselenide–Diiodine Adducts and the First Well Characterized Diorgano Disulfide–Nitrosonium Adduct
Authors: Mueller Birgit , Takaluoma Teemu T. , Laitinen Risto S. , Seppelt Konrad
Published: September 2011

The syntheses and crystal structures of two new dimethyl diselenide–iodine adducts are described as well as the synthesis and crystal structure of the first diorgano disulfide–nitrosonium adduct. The reaction of the NO+ cation with R2S2 (R = Me, Et, neo‐Pent, H, CN, CF3, 4‐pyridyl, 2‐Prop, Ph, Ad) has been investigated theoretically with DFT. Charge transfer is the main mechanism for adduct formation. Electron density is transferred from the diorgano disulfide HOMO, which is mainly composed of sulfur lone pairs, to the NO+ cation LUMO (π*).
Synthesis and Biotransformation of Plausible Biosynthetic Intermediates of Salicylaldehyde‐Type Phytotoxins of Rice Blast Fungus, Magnaporthe grisea
Authors: Tanaka Koji , Sasaki Ayaka , Cao Hai‐Qun , Yamada Teiko , Igarashi Masahiro , Komine Isao , Nakahigashi Hirokazu , Minami Naoko , Kuwahara Shigefumi , Nukina Manabu , Kiyota Hiromasa
Published: September 2011

Rice blast fungus, Magnaporthe grisea, produces a series of salicylaldehyde‐type phytotoxins such as pyriculol, pyricuol, and pyriculariol. Plausible biosynthetic intermediates of these phytotoxins were synthesized in deuterium labeled forms using the Stille coupling reaction as the key step, and subjected to biotransformation by the fungus. Heptatrienylsalicylaldehyde was converted into dihydropyriculol by the fungus by a shaking culture. A new biosynthetic pathway comprising both oxidation and reduction is proposed.
Synthesis of C40‐Symmetrical Fully Conjugated Carotenoids by Olefin Metathesis
Authors: Fontán Noelia , Domínguez Marta , Álvarez Rosana , de Lera Ángel R.
Published: September 2011

In an effort to push olefin metathesis to the limits of conjugation in reactants and products, the C40‐symmetrical carotenoids β,β‐carotene (1), lycopene (2), (3R,3′R)‐zeaxanthin (3), and rac‐isozeaxanthin (4), which are conjugated undecaenes, have been synthesized from C21‐terminal hexaenes by treatment with Grubbs' second‐generation Ru catalyst in dichloromethane at 50 °C.
Highly Sensitive Amperometric Glucose Sensors Based on Nanostructured α‐Ni(OH)2 Electrodes
Authors: Martins Paulo Roberto , Aparecida Rocha Michele , Angnes Lúcio , Eisi Toma Henrique , Araki Koiti
Published: September 2011

Stabilized α‐Ni(OH)2 nanoparticle modified fluorine doped tin oxide (FTO) electrodes were shown to be excellent glucose amperometric FIA sensors exhibiting high specific sensitivity (446 µA mM−1 cm−2), low limit of detection (3 µM) and high analytical frequency (128 analyses/hour). The electrodes were constituted by ∼20 nm nanoparticles and the limit of detection was only slightly improved in hydrodynamic as compared to diffusional conditions reflecting the enhanced surface area and the moderate heterogeneous electron transfer rates at the nanostructured α‐Ni(OH)2/solution interface.
Genotoxicity of acute and chronic gamma-irradiation on zebrafish cells and consequences for embryo development
Authors: Pereira Sandrine , Bourrachot Stéphanie , Cavalie Isabelle , Plaire Delphine , Dutilleul Morgan , Gilbin Rodolphe , Adam-Guillermin Christelle
Published: September 2011

The effects of radiation on biological systems have been studied for many years, and it is now accepted that direct damage to DNA from radiation is the triggering event leading to biological effects. In the present study, DNA damage induced by acute or chronic irradiation was compared at the cellular (zebrafish [Danio rerio] cell line ZF4) and developmental (embryo) levels. Zebrafish ZF4 cells and embryos (at 3 h postfertilization) were exposed within ranges of acute doses (0.3–2 Gy/d) or chronic dose rates (0.1–0.75 Gy/d). DNA damage was assessed by immunodetection of γ-H2AX and DNA-PK (DNA double-strand breaks) and the alkaline comet assay (DNA single-strand breaks). Zebrafish embryo development and DNA damage were examined after 120 h. At low doses, chronic irradiation induced more residual DNA damage than acute irradiation, but embryo development was normal. From 0.3 Gy, a hyper-radiosensitivity phenomenon compared to other species was shown for acute exposure with an increase of DNA damage, an impairment of hatching success, and larvae abnormalities. These results suggest a dose-dependent correlation between unrepaired DNA damage and abnormalities in embryo development, supporting the use of DNA repair proteins as predictive biomarkers of ionizing radiation exposure. This could have important implications for environmental protection. Environ. Toxicol. Chem. 2011;30:2831–2837. © 2011 SETAC
Spatial and temporal variations of total and methylmercury concentrations in plankton from a mercury-contaminated and eutrophic reservoir in Guizhou Province, China
Authors: Wang Qing , Feng Xinbin , Yang Yufeng , Yan Haiyu
Published: September 2011

Total mercury (THg) and methylmercury (MeHg) concentrations in four size fractions of plankton from three sampling stations in the Hg-contaminated and eutrophic Baihua Reservoir, Guizhou, China, were investigated for biomagnification and trophic transfer of Hg at different sites with various proximity to the major point sources of nutrients and metals. Total Hg concentrations in plankton of the various size fractions varied from 49 to 5,504 ng g−1 and MeHg concentrations ranged from 3 to 101 ng g−1. The percentage of Hg as MeHg varied from 0.16 to 70%. Total Hg and MeHg concentrations in plankton samples differed among the three sampling stations with different proximities from the major point sources. The plankton from the site closest to the dam contained the highest concentrations of MeHg. The successive increase of the ratios of MeHg to Hg from seston to macroplankton at all sites indicated that biomagnification is occurring along the plankton food web. However, biomagnification factors (BMF) for MeHg were low (1.5–2.0) between trophic levels. Concentrations of THg in seston decreased with an increase of chlorophyll concentrations, suggesting a significant dilution effect by the algae bloom for Hg. Eutrophication dilution may be a reason for lower MeHg accumulation by the four size classes of plankton in this Hg-contaminated reservoir. Environ. Toxicol. Chem. 2011;30:2739–2747. © 2011 SETAC
Geomorphologic assessment of relative tectonic activity in the Maharlou Lake Basin, Zagros Mountains of Iran
Authors: Faghih Ali , Samani Babak , Kusky Timothy , Khabazi Saman , Roshanak Reihaneh
Published: September 2011

Spatial differences of Quaternary deformation and intensity of tectonic activity are assessed through a detailed quantitative geomorphic study of the fault‐generated mountain fronts and alluvial/fluvial systems around the Maharlou Lake Basin in the Zagros Fold–Thrust Belt of Iran. The Maharlou Lake Basin is defined as an approximately northwest–southeast trending, linear, topographic depression located in the central Zagros Mountains of Iran. The lake is located in a tectonically active area delineated by the Ghareh and Maharlou faults. Combined geomorphic and morphometric data reveal differences between the Ghareh and Maharlou mountain front faults indicating different levels of tectonic activity along each mountain front. Geomorphic indices show a relatively high degree of tectonic activity along the Ghareh Mountain Front in the southwest, in contrast with less tectonic activity along the Ahmadi Mountain Front northeast of the lake which is consistent with field evidence and seismotectonic data for the study area. A ramp valley tectonic setting is proposed to explain the tectonosedimentary evolution of the lake. Copyright © 2011 John Wiley & Sons, Ltd.
The GPR17 receptor in NG2 expressing cells: Focus on in vivocell maturation and participation in acute trauma and chronic damage
Authors: Boda Enrica , Viganò Francesca , Rosa Patrizia , Fumagalli Marta , Labat‐Gest Vivien , Tempia Filippo , Abbracchio Maria P. , Dimou Leda , Buffo Annalisa
Published: September 2011

NG2‐expressing cells comprise a population of cycling precursors that can exit the cell cycle and differentiate into mature oligodendrocytes. As a whole, they display heterogeneous properties and behaviors that remain unresolved at the molecular level, although partly interpretable as distinct maturation stages. To address this issue, we analyzed the expression of the GPR17 receptor, recently shown to decorate NG2‐expressing cells and to operate as an early sensor of brain damage, in immature and adult oligodendrocyte progenitors in the intact brain and after injury. In both the early postnatal and adult cerebral cortex, distinct GPR17 protein localizations and expression levels define different stages of oligodendroglial maturation, ranging from the precursor phase to the premyelinating phenotype. As soon as cells exit mitosis, a fraction of NG2‐expressing cells displays accumulation of GPR17 protein in the Golgi apparatus. GPR17 expression is subsequently upregulated and distributed to processes of cells that stop dividing, progressively lose NG2 positivity and assume premyelinating features. Absence of colabeling with mature markers or myelin proteins indicates that GPR17 is downregulated when cells complete their final maturation. BrdU‐based fate‐mapping demonstrated that a significant fraction of newly generated oligodendrocyte progenitors transiently upregulates GPR17 during maturation. Importantly, we also found that GPR17 does not participate to the early reaction of NG2‐expressing cells to damage, while it is induced at postacute stages after injury. These findings identify GPR17 as a marker for progenitor progression within the oligodendroglial lineage and highlight its participation to postacute reactivity of NG2 cells in different injury paradigms. © 2011 Wiley‐Liss, Inc.
Subjective memory complaints in community dwelling healthy older people: the influence of brain and psychopathology
Authors: Bartley M. , Bokde A. L. , Ewers M. , Faluyi Y. O. , Tobin W. O. , Snow A. , Connolly J. , Delaney C. , Coughlan T. , Collins D. R. , Hampel H. , O'Neill D.
Published: September 2011

Objectives

Subjective memory complaints (SMC) are common. We aimed to characterize the relationship between psychiatric illness and white matter disease to SMC in a sample of healthy older people.

Measurements

Cognitively normal subjects between 55 and 90 years had age‐adjusted and education‐adjusted Consortium to Establish a Registry for Alzheimer's disease (CERAD) scores ≤1.5 SD from standard mean. ApoE genotyping was performed using polymerase chain reaction. Sixty subjects (30 SMC, 30 controls) underwent 3T MRI, which was rated by two raters blinded to the diagnosis, for periventricular (PVH) and deep white matter hyperintensities (DWMH) using the Fazekas scale. Subjective memory was assessed by asking the participant, Do you feel like your memory or thinking is becoming worse?

Results

Two hundred and fifteen volunteers were assessed. Ninety‐six were cognitively normal (mean age 62.5 years). SMC were reported by 52/96 subjects (54%). These were compared with subjects who denied SMC. Participants with a history of depression or anxiety were more likely to have SMC (p = 0.02). The frequency distribution of ApoE4 allele and CERAD scores were similar. White matter load was similar (p ≤ 0.47), with a high prevalence of PVH and DWMH seen (100% and 88% of scans, respectively).

Conclusion

Both SMC and white matter disease were common. SMC were associated with a history of depression or anxiety but not with white matter disease. Evaluation for a history of depression and anxiety in people with SMC is supported by these findings. Copyright © 2011 John Wiley & Sons, Ltd.
Patterns of failure and histopathologic outcome predictors following definitive radiotherapy and planned neck dissection with residual disease
Authors: Huang Shao Hui , O'Sullivan Brian , Weinreb Ilan , Perez–Ordonez Bayardo , Irish Jonathan , Waldron John , Gullane Patrick , Gilbert Ralph , Brown Dale , Cummings Bernard , Kim John , Freeman Jeremy , Witterick Ian , Goldstein David
Published: September 2011

Background

Our aim was to report patterns of failure and histopathological predictors in patients with head and neck cancer treated by planned neck dissection.

Methods

We reviewed all new patients with head and neck cancer who underwent a planned neck dissection in our institution from 1998 to 2007. Patterns of failure after positive planned neck dissection were reported. The frequency and predictive value of histopathologic features were analyzed.

Results

Fifty positive planned neck dissection and 144 negative planned neck dissection cases were identified. The positive planned neck dissection cohort had lower 5‐year overall survival (OS; 33% vs 77%; p < .01), a significantly higher distant metastasis (DM; 44% vs 11%; p < .01), a moderately lower local (86% vs 96%; p < .01), and a similar regional control (94% vs 99%; p = .07) compared to the negative planned neck dissection cohort. Extracapsular extension/carcinoma within soft tissue and lymphovascular invasion were adverse survival predictors for patients with positive planned neck dissection on univariate and multivariate analysis.

Conclusion

Positive planned neck dissection is associated with lower survival, predominantly attributed to significantly increased DM rather than reduced locoregional control. © 2011 Wiley Periodicals, Inc. Head Neck, 2012
Successful Isolation of Liver Progenitor Cells by Aldehyde Dehydrogenase Activity in Na"ve Mice
Authors: Dollé Laurent , Best Jan , Empsen Christophe , Mei Jie , Van Rossen Elke , Roelandt Philip , Snykers Sarah , Najimi Mustapha , Al Battah Feras , Theise Neil D. , Streetz Konrad , Sokal Etienne , Leclercq Isabelle A. , Verfaillie Catherine , Rogiers Vera , Geerts Albert , van Grunsven Leo A.
Published: September 2011

The role of progenitor cells in liver repair and fibrosis has been extensively described, but their purification remains a challenge, hampering their characterization and use in regenerative medicine. To address this issue, we developed an easy and reproducible liver progenitor cell (LPC) isolation strategy based on aldehyde dehydrogenase (ALDH) activity, a common feature shared by many progenitor cells. We demonstrate that a subset of nonparenchymal mouse liver cells displays high levels of ALDH activity, allowing the isolation of these cells by fluorescence-activated cell sorting. Immunocytochemistry and qPCR analyses on freshly isolated ALDH+ cells reveal an enrichment in cells expressing liver stem cell markers such as EpCAM, CK19, CD133, and Sox9. In culture, the ALDH+ population can give rise to functional hepatocyte-like cells as illustrated by albumin and urea secretion and cytochrome P450 activity. ALDH1A1 expression can be detected in canals of Hering and bile duct epithelial cells and is increased on liver injury. Finally, we showed that the isolation and differentiation toward hepatocyte-like cells of LPCs with high ALDH activity is also successfully applicable to human liver samples.

Conclusion :

High ALDH activity is a feature of LPCs that can be taken advantage of to isolate these cells from untreated mouse as well as human liver tissues. This novel protocol is practically relevant, because it provides an easy and nontoxic method to isolate liver stem cells from normal tissue for potential therapeutic purposes. (Hepatology 2012)
“Normal” Liver Stiffness Measure (LSM) Values Are Higher in Both Lean and Obese Individuals: A Population-Based Study From a Developing Country
Authors: Das Kausik , Sarkar Rajib , Ahmed Sk. Mahiuddin , Mridha Asit R. , Mukherjee Partha S. , Das Kshaunish , Dhali Gopal K. , Santra Amal , Chowdhury Abhijit
Published: September 2011

The liver stiffness measure (LSM) needs to be explored in ethnically and anthropometrically diverse healthy subjects (to derive an acceptable normal range) and also in patients with liver disease. In view of this objective, LSM was performed by transient elastography (TE) using FibroScan in 437 healthy subjects with normal alanine aminotransferase (ALT) levels, recruited from a free-living population of the Birbhum Population Project (BIRPOP;
www.shds.in
), a Health and Demographic Surveillance System (HDSS), and from 274 patients with liver disease attending the Hepatology Clinic of the School of Digestive and Liver Diseases (SDLD; Institute of Post Graduate Medical Education & Research [IPGME&R], Kolkata, India) including 188 with nonalcoholic fatty liver disease (NAFLD) and 86 with chronic hepatitis of viral and other etiologies. Liver biopsy was performed in 125 patients. The range of normal values for LSM, defined by 5th and 95th percentile values in healthy subjects, was 3.2 and 8.5 kPa, respectively. Healthy subjects with a lower body mass index (BMI; < <18.5 kg/m2) had a higher LSM compared with subjects who had a normal BMI; this LSM value was comparable to that of obese subjects (6.05 ± 1.78 versus 5.51 ± 1.59 and 6.60 ± 1.21,

P

= 0.016 and 0.349, respectively). Liver disease patients without histologic fibrosis had significantly higher LSM values compared with healthy subjects (7.52 ± 5.49 versus 5.63 ± 1.64,

P

< 0.001). Among the histologic variables, stage of fibrosis was the only predictor for LSM. LSM did not correlate with inflammatory activity and ALT in both NAFLD and chronic hepatitis groups.

Conclusion:

LSM varies between 3.2 and 8.5 kPa in healthy subjects of South Asian origin. Both lean and obese healthy subjects have higher LSM values compared with subjects with normal BMI. Liver stiffness begins to increase even before fibrosis appears in patients with liver disease. (Hepatology 2012)
Patients With Minimal Hepatic Encephalopathy Show Impaired Mismatch Negativity Correlating With Reduced Performance in Attention Tests
Authors: Felipo Vicente , Ordoño Juan F. , Urios Amparo , El Mlili Nisrin , Giménez-Garzó Carla , Aguado Carolina , González-Lopez Olga , Giner-Duran Remedios , Serra Miguel A. , Wassel Abdallah , Rodrigo Jose M. , Salazar José , Montoliu Carmina
Published: September 2011

Attention deficit is an early event in the cognitive impairment of patients with minimal hepatic encephalopathy (MHE). The underlying mechanisms remain unclear. Mismatch negativity (MMN) is an auditory event-related potential that reflects an attentional trigger. Patients with schizophrenia show impaired attention and cognitive function, which are reflected in altered MMN. We hypothesized that patients with MHE, similarly to those with schizophrenia, should show MMN alterations related with attention deficits. The aims of this work were to assess whether (1) MMN is altered in cirrhotic patients with MHE, compared to those without MHE, (2) MMN changes in parallel with performance in attention tests and/or MHE in a longitudinal study, and (3) MMN predicts performance in attention tests and/or in the Psychometric Hepatic Encephalopathy Score (PHES). We performed MMN analysis as well as attention and coordination tests in 34 control subjects and in 37 patients with liver cirrhosis without MHE and 23 with MHE. Patients with MHE show reduced performance in selective and sustained attention tests and in visuomotor and bimanual coordination tests. The MMN wave area was reduced in patients with MHE, but not in those without MHE. In the longitudinal study, MMN area improved in parallel with performance in attention tests and PHES in 4 patients and worsened in parallel in another 4. Logistic regression analyses showed that MMN area predicts performance in attention tests and in PHES, but not in other tests or critical flicker frequency. Receiver operating characteristic curve analyses showed that MMN area predicts attention deficits in the number connection tests A and B, Stroop tasks, and MHE, with sensitivities of 75%-90% and specificities of 76%-83%.

Conclusion :

MMN area is useful to diagnose attention deficits and MHE in patients with liver cirrhosis. (Hepatology 2012;)
Human Leukocyte Antigen Class II Molecules Confer Both Susceptibility and Progression in Japanese Patients With Primary Biliary Cirrhosis
Authors: Umemura Takeji , Joshita Satoru , Ichijo Tetsuya , Yoshizawa Kaname , Katsuyama Yoshihiko , Tanaka Eiji , Ota Masao
Published: September 2011

Along with twin and family studies, recent genome-wide association studies suggest that genetic factors contribute to the susceptibility and severity of primary biliary cirrhosis (PBC). Although several reports have demonstrated that the human leukocyte antigen (HLA)

DRB1*08:03

allele is associated with disease susceptibility in Japan, the precise analysis of HLA haplotypes and the role of amino acid alignment have not been fully clarified. We investigated HLA class I A, B, and C and HLA class II DRB1 and DQB1 alleles and haplotypes in 229 Japanese patients with PBC and compared them with the published data of 523 healthy subjects. Significant associations were found with PBC susceptibility for the

DRB1*08:03-DQB1*06:01

(13% versus 6%;

P

= 0.000025; odds ratio [OR] = 2.22) and

DRB1*04:05-DQB1*04:01

haplotypes (17% versus 13%;

P

= 0.044; OR = 1.38). Conversely, there were significant protective associations with the

DRB1*13:02-DQB1*06:04

(2% versus 5%;

P

= 0.00093; OR = 0.27) and

DRB1*11:01-DQB1*03:01

haplotypes (1% versus 4%;

P

= 0.03; OR = 0.37). The frequency of the

DRB1*09:01-DQB1*03:03

haplotype was significantly higher in patients who had received orthotopic liver transplantation (33% versus 11%;

P

= 0.0012; OR = 3.96). Furthermore, the frequency of serine at position 57 (

P

= 0.0000015; OR = 1.83) of the DRβchain differed the most in patients with PBC, compared with healthy subjects.

Conclusion :

This study established the role of HLA haplotypes in determining PBC susceptibility and progression in the Japanese population. Further resequencing of the HLA region is required to more precisely identify the genetic components of PBC. (Hepatology 2012)
Regulation of Hepatic Lipin-1 by Ethanol: Role of AMP-Activated Protein Kinase/Sterol Regulatory Element-Binding Protein 1 Signaling in Mice
Authors: Hu Ming , Wang Fengming , Li Xin , Rogers Christopher Q. , Liang Xiaomei , Finck Brian N. , Mitra Mayurranjan S. , Zhang Ray , Mitchell Dave A. , You Min
Published: September 2011

Lipin-1 is a protein that exhibits dual functions as a phosphatidic acid phosphohydrolase enzyme in the triglyceride synthesis pathways and a transcriptional coregulator. Our previous studies have shown that ethanol causes fatty liver by activation of sterol regulatory element-binding protein 1 (SREBP-1) and inhibition of hepatic AMP-activated protein kinase (AMPK) in mice. Here, we tested the hypothesis that AMPK-SREBP-1 signaling may be involved in ethanol-mediated up-regulation of lipin-1 gene expression. The effects of ethanol on lipin-1 were investigated in cultured hepatic cells and in the livers of chronic ethanol-fed mice. Ethanol exposure robustly induced activity of a mouse lipin-1 promoter, promoted cytoplasmic localization of lipin-1, and caused excess lipid accumulation, both in cultured hepatic cells and in mouse livers. Mechanistic studies showed that ethanol-mediated induction of lipin-1 gene expression was inhibited by a known activator of AMPK or overexpression of a constitutively active form of AMPK. Importantly, overexpression of the processed nuclear form of SREBP-1c abolished the ability of 5-aminoimidazole-4-carboxamide ribonucleoside to suppress ethanol-mediated induction of lipin-1 gene-expression level. Chromatin immunoprecipitation assays further revealed that ethanol exposure significantly increased the association of acetylated histone H3 at lysine 9 with the SRE-containing region in the promoter of the lipin-1 gene.

Conclusion:

In conclusion, ethanol-induced up-regulation of lipin-1 gene expression is mediated through inhibition of AMPK and activation of SREBP-1. (Hepatology 2012)
Translationally Controlled Tumor Protein Induces Mitotic Defects and Chromosome Missegregation in Hepatocellular Carcinoma Development
Authors: Chan Tim Hon Man , Chen Leilei , Liu Ming , Hu Liang , Zheng Bo-jian , Poon Vincent Kwok-Man , Huang Pinzhu , Yuan Yun-Fei , Huang Jian-dong , Yang Jie , Tsao George Sai-wah , Guan Xin-Yuan
Published: September 2011

Emerging evidence implicates the chromodomain helicase/ATPase DNA binding protein 1–like gene (

CHD1L

) as a specific oncogene in human hepatocellular carcinoma (HCC). To better understand the molecular mechanisms underlying HCC cases carrying

CHD1L

amplification (>50% HCCs), we identified a CHD1L target, translationally controlled tumor protein (

TCTP

), and investigated its role in HCC progression. Here, we report that CHD1L protein directly binds to the promoter region (nt −

733

to −

1,027

) of

TCTP

and activates

TCTP

transcription. Overexpression of TCTP was detected in 40.7% of human HCC samples analyzed and positively correlated with CHD1L overexpression. Clinically, overexpression of

TCTP

was significantly associated with the advanced tumor stage (

P

= 0.037) and overall survival time of HCC patients (

P

= 0.034). In multivariate analyses, TCTP was determined to be an independent marker associated with poor prognostic outcomes.

In vitro

and

in vivo

functional studies in mice showed that

TCTP

has tumorigenic abilities, and overexpression of

TCTP

induced by CHD1L contributed to the mitotic defects of tumor cells. Further mechanistic studies demonstrated that TCTP promoted the ubiquitin-proteasome degradation of Cdc25C during mitotic progression, which caused the failure in the dephosphorylation of Cdk1 on Tyr15 and decreased Cdk1 activity. As a consequence, the sudden drop of Cdk1 activity in mitosis induced a faster mitotic exit and chromosome missegregation, which led to chromosomal instability. The depletion experiment proved that the tumorigenicity of

TCTP

was linked to its role in mitotic defects.

Conclusion:

Collectively, we reveal a novel molecular pathway (CHD1L/TCTP/Cdc25C/Cdk1), which causes the malignant transformation of hepatocytes with the phenotypes of accelerated mitotic progression and the production of aneuploidy. (Hepatology 2012)
Hepatocellular Carcinoma Confirmation, Treatment, and Survival in Surveillance, Epidemiology, and End Results Registries, 1992-2008
Authors: Altekruse Sean F. , McGlynn Katherine A. , Dickie Lois A. , Kleiner David E.
Published: September 2011

Approaches to the diagnosis and management of hepatocellular carcinoma (HCC) are improving survival. In the Surveillance, Epidemiology, and End Results-13 registries, HCC stage, histological confirmation, and first-course surgery were examined. Among 21,390 HCC cases diagnosed with follow-up of vital status during 1998-2008, there were 4,727 (22%) with reported first-course invasive liver surgery, local tumor destruction, or both. The proportion with reported liver surgery or ablation was 39% among localized stage cases and only 4% among distant/unstaged cases. Though 70% of cases had histologically confirmed diagnoses, the proportion with confirmed diagnoses was higher among cases with reported invasive surgery (99%), compared to cases receiving ablation (81%) or no reported therapy (65%). Incidence rates of histologically unconfirmed HCC increased faster than those of confirmed HCC from 1992 to 2008 (8% versus 3% per year). Two encouraging findings were that incidence rates of localized-stage HCC increased faster than rates of regional- and distant-stage HCC combined (8% versus 4% per year), and that incidence rates of reported first-course surgery or tumor destruction increased faster than incidence rates of HCC without such therapy (11% versus 7%). Between 1975-1977 and 1998-2007, 5-year cause-specific HCC survival increased from just 3% to 18%. Survival was 84% among transplant recipients, 53% among cases receiving radiofrequency ablation at early stage, 47% among cases undergoing resection, and 35% among cases receiving local tumor destruction. Asian or Pacific Islander cases had significantly better 5-year survival (23%) than white (18%), Hispanic (15%), or black cases (12%).

Conclusion:

HCC survival is improving, because more cases are diagnosed and treated at early stages. Additional progress may be possible with continued use of clinical surveillance to follow individuals at risk for HCC, enabling early intervention. (Hepatology 2012;)
Mature Hepatocytes Exhibit Unexpected Plasticity by Direct Dedifferentiation Into Liver Progenitor Cells in Culture
Authors: Chen Yixin , Wong Philip P. , Sjeklocha Lucas , Steer Clifford J. , Sahin Behnan M.
Published: September 2011

Although there have been numerous reports describing the isolation of liver progenitor cells from the adult liver, their exact origin has not been clearly defined; and the role played by mature hepatocytes as direct contributors to the hepatic progenitor cell pool has remained largely unknown. Here, we report strong evidence that mature hepatocytes in culture have the capacity to dedifferentiate into a population of adult liver progenitors without genetic or epigenetic manipulations. By using highly purified mature hepatocytes, which were obtained from untreated, healthy rat liver and labeled with fluorescent dye PKH2, we found that hepatocytes in culture gave rise to a population of PKH2-positive liver progenitor cells. These cells, liver-derived progenitor cells, which share phenotypic similarities with oval cells, were previously reported to be capable of forming mature hepatocytes, both in culture and in animals. Studies done at various time points during the course of dedifferentiation cultures revealed that hepatocytes rapidly transformed into liver progenitors within 1 week through a transient oval cell-like stage. This finding was supported by lineage-tracing studies involving double-transgenic AlbuminCreXRosa26 mice expressing β-galactosidase exclusively in hepatocytes. Cultures set up with hepatocytes obtained from these mice resulted in the generation of β-galactosidase-positive liver progenitor cells, demonstrating that they were a direct dedifferentiation product of mature hepatocytes. Additionally, these progenitors differentiated into hepatocytes

in vivo

when transplanted into rats that had undergone retrorsine pretreatment and partial hepatectomy.

Conclusion :

Our studies provide strong evidence for the unexpected plasticity of mature hepatocytes to dedifferentiate into progenitor cells in culture, and this may potentially have a significant effect on the treatment of liver diseases requiring liver or hepatocyte transplantation. (Hepatology 2012;)
A Mouse Model of Accelerated Liver Aging Caused by a Defect in DNA Repair
Authors: Gregg Siobhán Q. , Gutiérrez Verónica , Rasile Robinson Andria , Woodell Tyler , Nakao Atsunori , Ross Mark A. , Michalopoulos George K. , Rigatti Lora , Rothermel Carrie E. , Kamileri Irene , Garinis George , Beer Stolz Donna , Niedernhofer Laura J.
Published: September 2011

The liver changes with age, leading to an impaired ability to respond to hepatic insults and increased incidence of liver disease in the elderly. Therefore, there is critical need for rapid model systems to study aging-related liver changes. One potential opportunity is murine models of human progerias or diseases of accelerated aging.

Ercc1

−/Δ mice model a rare human progeroid syndrome caused by inherited defects in DNA repair. To determine whether hepatic changes that occur with normal aging occur prematurely in

Ercc1

−/Δ mice, we systematically compared liver from 5-month-old progeroid

Ercc1

−/Δ mice to old (24-36-month-old) wild-type (WT) mice. Both displayed areas of necrosis, foci of hepatocellular degeneration, and acute inflammation. Loss of hepatic architecture, fibrosis, steatosis, pseudocapillarization, and anisokaryosis were more dramatic in

Ercc1

−/Δ mice than in old WT mice. Liver enzymes were significantly elevated in serum of

Ercc1

−/Δ mice and old WT mice, whereas albumin was reduced, demonstrating liver damage and dysfunction. The regenerative capacity of

Ercc1

−/Δ liver after partial hepatectomy was significantly reduced. There was evidence of increased oxidative damage in

Ercc1

−/Δ and old WT liver, including lipofuscin, lipid hydroperoxides and acrolein, as well as increased hepatocellular senescence. There was a highly significant correlation in genome-wide transcriptional changes between old WT and 16-month-old, but not 5-week-old,

Ercc1

−/Δ mice, emphasizing that the

Ercc1

−/Δ mice acquire an aging profile in early adulthood.

Conclusion:

There are strong functional, regulatory, and histopathological parallels between accelerated aging driven by a DNA repair defect and normal aging. This supports a role for DNA damage in driving aging and validates a murine model for rapidly testing hypotheses about causes and treatment for aging-related hepatic changes. (Hepatology 2012)
Electrophysiological indices of altered working memory processes in long‐term ecstasy users
Authors: Nulsen Claire , Fox Allison , Hammond Geoff
Published: September 2011

Objective

The aim of this study was to determine the effect of light long‐term ecstasy consumption on verbal short‐term and working memory and to identify the cognitive processes contributing to task performance.

Method

Electroencephalogram was recorded while ecstasy users (N = 11), polydrug users (N = 13), and non‐users (N = 13) completed forward and backward serial recognition tasks designed to engage verbal short‐term memory and verbal working memory, respectively.

Results

All three groups displayed significantly lower digit‐backward span than digit‐forward span with ecstasy users displaying the greatest difference. The parietally distributed P3b was significantly smaller in the digits backward task than in the digits forward task in non‐ecstasy‐using controls. Ecstasy users did not show the reduced P3b component in the backward task that was seen in both non‐ecstasy‐using control groups.

Conclusions

Ecstasy users' performance was suppressed more by the concurrent processing demands of the working memory task than that of the non‐ecstasy‐using controls. Non‐ecstasy‐using controls showed differential event‐related potential wave forms in the short‐term and working memory tasks, and this pattern was not seen in the ecstasy users. This is consistent with a reduction in the cognitive resources allocated to processing in working memory in ecstasy users. Copyright © 2011 John Wiley & Sons, Ltd.
Developmental Improvements in Perceptual Restoration: Can Young Children Reconstruct Missing Sounds in Noisy Environments?
Authors: Winstone Naomi , Davis Alyson , Bruyn Bart De
Published: September 2011

Young children are frequently exposed to sounds such as speech and music in noisy listening conditions, which have the potential to disrupt their learning. Missing input that is masked by louder sounds can, under the right conditions, be ‘filled in’ by the perceptual system using a process known as perceptual restoration. This experiment compared the ability of 4‐ to 6‐year‐old children, 9‐ to 11‐year‐old children and adults to complete a melody identification task using perceptual restoration. Melodies were presented either intact (complete input), with noise‐filled gaps (partial input; perceptual restoration can occur) or with silence‐filled gaps (partial input; perceptual restoration cannot occur). All age groups could use perceptual restoration to help them interpret partial input, yet perception was the most detrimentally affected by the presentation of partial input for the youngest children. This implies that they might have more difficulty perceiving sounds in noisy environments than older children or adults. Young children had particular difficulty using partial input for identification under conditions where perceptual restoration could not occur. These findings suggest that perceptual restoration is a crucial mechanism in young children, where processes that fill in missing sensory input represent an important part of the way meaning is extracted from a complex sensory world. Copyright © 2011 John Wiley & Sons, Ltd.
Fourteen‐Month‐Olds' Imitation of Differently Aged Models
Authors: Zmyj Norbert , Daum Moritz M. , Prinz Wolfgang , Nielsen Mark , Aschersleben Gisa
Published: September 2011

Studies comparing adult and peer imitation are rare and have to date provided mixed results. The aim of the present study was to investigate 14‐month‐olds' imitation of different actions (novel versus familiar) performed by televised models of different age groups (peers, older children or adults). In two experiments, we investigated infants' imitative performance when observing a novel action (Experiment 1) and familiar actions (Experiment 2). The results showed that the likelihood of imitating a novel action increased as the age of the model increased. The opposite was true for familiar actions where infants imitated the peer more frequently than either the older child or the adult model. These findings are discussed in relation to infants' ability to take into account a model's characteristics such as age when imitating actions. Copyright © 2011 John Wiley & Sons, Ltd.
Expression of ER stress and autophagy‐related molecules in human non‐small cell lung cancer and premalignant lesions
Authors: Kim Kyoung Min , Yu Tack Keun , Chu Hyun Hee , Park Ho Sung , Jang Kyu Yun , Moon Woo Sung , Kang Myoung Jae , Lee Dong Geun , Kim Min Ho , Lee Ju Hyung , Chung Myoung Ja
Published: September 2011

Stress that impairs endoplasmic reticulum (ER) function leads to an accumulation of unfolded or misfolded proteins in the ER (ER stress). Autophagy is a lysosomal pathway involved in the turnover of cellular macromolecules and organelles, which emerging data indicate that ER stress is also a potent inducer of autophagy. ER stress and autophagy are involved in human cancer. We examined the expression of ER stress‐related proteins [GRP78 and C/EBP homologous protein (CHOP)] and autophagic proteins (Beclin‐1 and LC3) in non‐small cell lung carcinomas (NSCLCs), bronchioloalveolar carcinomas (BACs) and atypical adenomatous hyperplasias (AAHs) to understand their role in the NSCLC pathogenesis. The expression of GRP78 and CHOP, Beclin‐1 and LC3 were analyzed using immunohistochemistry on tissue sections from 133 NSCLC (69 squamous cell carcinomas, 56 adenocarcinomas (AC) and eight other NSCLCs), 21 BAC and 9 AAH. Expression of GRP78 and Beclin‐1 was correlated with low tumor stage (p < 0.001 and p = 0.019, respectively) and longer survival (p = 0.007 and p <0.001, respectively) by Kaplan–Meier analysis. However, CHOP was correlated with high tumor stage (p = 0.038) and shorter survival (p = 0.012). Expression of GRP78 and Beclin‐1 was positively correlated (p = 0.006). Our study showed that the expression of GRP78, CHOP, Beclin‐1 and LC3 in lung cancer and its relation with clinicopathologic factors and patients survival. These results suggest that GRP78, CHOP and Beclin‐1 may play an important role in tumorigenesis of lung AC and may serve as new prognostic indicators for outcome of the patients with NSCLC.
Raman spectroscopy for the non‐contact and non‐destructive monitoring of collagen damage within tissues
Authors: Votteler Miriam , Carvajal Berrio Daniel A. , Pudlas Marieke , Walles Heike , Stock Ulrich A. , Schenke‐Layland Katja
Published: September 2011

The non‐destructive and label‐free monitoring of extracellular matrix (ECM) remodeling and degradation processes is a great challenge. Raman spectroscopy is a non‐contact method that offers the possibility to analyze ECM in situ without the need for tissue processing. Here, we employed Raman spectroscopy for the detection of heart valve ECM, focusing on collagen fibers. We screened the leaflets of porcine aortic valves either directly after dissection or after treatment with collagenase. By comparing the fingerprint region of the Raman spectra of control and treated tissues (400–1800 cm–1), we detected no significant differences based on Raman shifts; however, we found that increasing collagen degradation translated into decreasing Raman signal intensities. After these proof‐of‐principal experiments, we compared Raman spectra of native and cryopreserved valve tissues and revealed that the signal intensities of the frozen samples were significantly lower compared to those of native tissues, similar to the data seen in the enzymatically‐degraded tissues. In conclusion, our data demonstrate that Raman microscopy is a promising, non‐destructive and non‐contact tool to probe ECM state in situ. (© 2012 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Interplay between long‐ and short‐range interactions drives neuritogenesis on stiff surfaces
Authors: Lamour Guillaume , Souès Sylvie , Hamraoui Ahmed
Published: September 2011

Substrate factors such as surface energy distribution can affect cell functions, such as neuronal differentiation of PC12 cells. However, the surface effects that trigger such cell responses need to be clarified and analyzed. Here we show that the total surface tension is not a critical parameter. Self‐assembled monolayers of alkylsiloxanes on glass were used as culture substrates. By changing the nanoscale structure and ordering of the monolayer, we designed surfaces with a range of dispersive (γd) and nondispersive (γnd) potentials, but with a similar value for total free‐energy (50 ≤ γd+ γnd≤ 55 mNm−1). When seeded on surfaces displaying γd/γnd≤ 3.7, PC12 cells underwent low level of neuritogenesis. On surfaces exhibiting γd/γnd≥ 5.4, neurite outgrowth was greatly enhanced and apparent by only 24 h of culture in absence of nerve growth‐factor treatment. These data indicate how the spatial distribution of surface potentials may control neuritogenesis, thus providing a new criterion to address nerve regeneration issues on rigid biocompatible surfaces. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2011.