bluuebunny/crossref_metadata_2025 huggingface dataset:
Polyamines affect histamine synthesis during early stages of IL‐3‐induced bone marrow cell differentiation
Authors: García‐Faroldi Gianni , Correa‐Fiz Florencia , Abrighach Hicham , Berdasco María , Fraga Mario F. , Esteller Manel , Urdiales José L. , Sánchez‐Jiménez Francisca , Fajardo Ignacio
Published: June 2009

Mast cells synthesize and store histamine, a key immunomodulatory mediator. Polyamines are essential for every living cell. Previously, we detected an antagonistic relationship between the metabolisms of these amines in established mast cell and basophilic cell lines. Here, we used the IL‐3‐driven mouse bone marrow‐derived mast cell (BMMC) culture system to further investigate this antagonism in a mast cell model of deeper physiological significance. Polyamines and histamine levels followed opposite profiles along the bone marrow cell cultures leading to BMMCs. α‐Difluoromethylornithine (DFMO)‐induced polyamine depletion resulted in an upregulation of histidine decarboxylase (HDC, the histamine‐synthesizing enzyme) expression and activity, accompanied by increased histamine levels, specifically during early stages of these cell cultures, where an active histamine synthesis process occurs. In contrast, DFMO did not induce any effect in either HDC activity or histamine levels of differentiated BMMCs or C57.1 mast cells, that exhibit a nearly inactive histamine synthesis rate. Sequence‐specific DNA methylation analysis revealed that the DFMO‐induced HDC mRNA upregulation observed in early bone marrow cell cultures is not attributable to a demethylation of the gene promoter caused by the pharmacological polyamine depletion. Taken together, the results support an inverse relationship between histamine and polyamine metabolisms during the bone marrow cell cultures leading to BMMCs and, moreover, suggest that the regulation of the histamine synthesis occurring during the early stages of these cultures depends on the concentrations of polyamines. J. Cell. Biochem. 108: 261–271, 2009. © 2009 Wiley‐Liss, Inc.
A new mechanism of gastric epithelial injury induced by acid exposure: The role of Egr‐1 and ERK signaling pathways
Authors: Abdel‐Latif Mohamed M.M. , Windle Henry J. , Davies Anthony , Volkov Yuri , Kelleher Dermot
Published: June 2009

The molecular mechanisms by which gastric acid causes epithelial injury in the stomach and initiates an inflammatory reaction are poorly understood. We aimed in the present study to investigate the role of the early growth response gene Egr‐1 and ERK in gastric epithelial cells following acid exposure, and the signaling pathways involved. Western blotting was used to assess Egr‐1 protein levels in AGS cells. A quantitative measurement of acid‐induced Egr‐1 and ERK translocation was performed using a high content analysis approach. Egr‐1 functionality was assessed by transient transfection with Egr‐1 antisense oligonucleotide. Exposure of AGS cells to acidic conditions induced Egr‐1 protein expression in a pH‐ and time‐dependent manner. Egr‐1 expression was markedly increased as the pH was reduced from pH 7.4 to 6.4. High content analysis of Egr‐1 activation showed acid‐induced Egr‐1 nuclear translocation; a maximum observed at 1–2 h followed by a decline to basal levels beyond 4 h. Acidic pH also activated ERK1/2 phosphorylation, whereas ERK1/2 inhibitors PD98059 and U0216 blocked both acid‐induced Egr‐1 and ERK translocation and expression. Moreover, acid exposure up‐regulated VEGF expression, which was inhibited by the Egr‐1 antisense oligonucleotide. Our results also demonstrate that exposure to acid induces Egr‐1 via MEK‐ERK1/2 pathway. These data suggest that Egr‐1 activation might play a crucial role in gastric mucosal inflammation and associated epithelial injury. J. Cell. Biochem. 108: 249–260, 2009. © 2009 Wiley‐Liss, Inc.
Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditions
Authors: Perrone Lorena , Devi Takhellambam S. , Hosoya Ken‐ichi , Terasaki Tetsuya , Singh Lalit P.
Published: June 2009

Chronic hyperglycemia and activation of receptor for advanced glycation end products (RAGE) are known risk factors for microvascular disease development in diabetic retinopathy. Thioredoxin‐interacting protein (TXNIP), an endogenous inhibitor of antioxidant thioredoxin (TRX), plays a causative role in diabetes and its vascular complications. Herein we investigate whether HG and RAGE induce inflammation in rat retinal endothelial cells (EC) under diabetic conditions in culture through TXNIP activation and whether epigenetic mechanisms play a role in inflammatory gene expression. We show that RAGE activation by its ligand S100B or HG treatment of retinal EC induces the expression of TXNIP and inflammatory genes such as Cox2, VEGF‐A, and ICAM1. TXNIP silencing by siRNA impedes RAGE and HG effects while stable over‐expression of a cDNA for human TXNIP in EC elevates inflammation. p38 MAPK‐NF‐κB signaling pathway and histone H3 lysine (K) nine modifications are involved in TXNIP‐induced inflammation. Chromatin immunoprecipitation (ChIP) assays reveal that TXNIP over‐expression in EC abolishes H3K9 tri‐methylation, a marker for gene inactivation, and increases H3K9 acetylation, an indicator of gene induction, at proximal Cox2 promoter bearing the NF‐κB‐binding site. These findings have important implications toward understanding the molecular mechanisms of ocular inflammation and endothelial dysfunction in diabetic retinopathy. J. Cell. Physiol. 221: 262–272, 2009. © 2009 Wiley‐Liss, Inc
Hyperglycemia and mechanical stress: Targeting the renal podocyte
Authors: Lewko Barbara , Stepinski Jan
Published: June 2009

Hyperglycemia and deriving from glomerular hypertension mechanical stress are the key factors underlying pathogenesis of diabetic nephropathy (DN). Multiple direct and secondary effects of both these factors are mediated by complex signaling pathways with extensive interactions. The common signaling pathways stimulated by high glucose and mechanical insult may act in an additive manner, thereby accelerating the cell damage. Podocytes, the cells covering the outer aspect of glomerular basement membrane (GBM), are subjected not only to the load of filtered glucose but also to diverse mechanical forces. Bulging into the Bowman's space, they have no support from the apical side, which makes them particularly susceptible to the effects of mechanical strain. Both high glucose and mechanical stress may impair the protein systems anchoring the podocyte foot processes in GBM, therefore blunting resistance of these cells to mechanical forces. Modulation by these factors of expression and activity of numerous structural and functional proteins results in the (auto)inflammatory responses, dysfunction, apoptosis or necrosis of the podocytes. Loss of the podocytes is irreversible due to their inability to proliferate and to replenish damaged cells. Podocytes are injured early in the course of DN, which, most likely, underlies further glomerular and renal damage in diabetes. This review summarizes the effects of elevated glucose and mechanical stress that seem to be involved in podocyte impairment in diabetes, with particular focus on the possible interactions between these factors. J. Cell. Physiol. 221: 288–295, 2009. © 2009 Wiley‐Liss, Inc.
Non‐selective cation channel activity is required for lysophosphatidylcholine‐induced monocyte migration
Authors: Schilling Tom , Eder Claudia
Published: June 2009

Lysophosphatidylcholine (LPC) is a major atherogenic lipid which stimulates the recruitment of monocytes to atherosclerotic lesions. The physiological mechanisms underlying LPC‐induced monocyte migration are poorly understood. Here we demonstrate that LPC activates non‐selective cation channels, which are significantly involved in LPC‐induced chemotaxis of monocytes. External LPC elicited the activation of non‐selective cation currents in THP‐1 monocytes, which occurred in a G protein and phospholipase C‐independent manner. LPC‐activated currents were almost completely inhibited by Gd3+, La3+, and TRAM‐34. Furthermore, currents were partially reduced by either 2‐aminoethoxydiphenyl borate (2‐APB) or ruthenium red, while combined application of 2‐APB and ruthenium red abolished LPC‐activated currents. The 2‐APB‐sensitive current component was potentiated by flufenamic acid and Ca2+‐free extracellular solution, while the ruthenium red‐sensitive current component was abolished by capsazepine. This pharmacological profile suggests that LPC simultaneously activates TRPC6 and TRPV1 channels in monocytes. Furthermore, in the presence of Gd3+, La3+, TRAM‐34, 2‐APB, ruthenium red or capsazepine, LPC‐induced chemotaxis of monocytes was substantially inhibited, indicating that activation of both channel types is required for optimal migration of LPC‐stimulated monocytes. Thus, ion channel inhibition may represent a powerful strategy to attenuate the progression of atherosclerosis by reducing monocyte infiltration. J. Cell. Physiol. 221: 325–334, 2009. © 2009 Wiley‐Liss, Inc.
Cl‐IB‐MECA enhances TRAIL‐induced apoptosis via the modulation of NF‐κB signalling pathway in thyroid cancer cells
Authors: Morello Silvana , Sorrentino Rosalinda , Porta Amalia , Forte Giovanni , Popolo Ada , Petrella Antonello , Pinto Aldo
Published: June 2009

Apoptosis is an endogenous process that can be a useful anti‐cancer tool. This study aimed to investigate the effect of Cl‐IB‐MECA, adenosine receptor A3 agonist, on TRAIL‐induced apoptosis of thyroid carcinoma cells. Cl‐IB‐MECA enhanced TRAIL‐mediated apoptosis in FRO but not in ARO cells. This effect was correlated to higher expression levels of DR5 on FRO than ARO cells, that instead presented higher levels of decoy receptors, DcR1 and DcR2. To understand the cross‐talk between the effect of Cl‐IB‐MECA and TRAIL, we evaluated the nuclear translocation of p65 and c‐Rel. Since the dependency by NF‐κB, TRAIL promoted the nuclear translocation of both p65 and c‐Rel subunits. However, the addition of Cl‐IB‐MECA led to the predominant translocation of c‐Rel after TRAIL addition. Furthermore, Bcl‐2, cFLIP and pAkt were lower induced than caspase‐3 and ‐9 in FRO cells. To discriminate a specific effect of TRAIL, we used tumour necrosis factor‐alpha (TNF‐α) with Cl‐IB‐MECA. In this case, no synergism was observed. In addition, the effect of Cl‐IB‐MECA was not A3 receptor‐dependent since its antagonists, MRS1191 and FA385, failed to block Cl‐IB‐MECA activity on TRAIL‐treated FRO cells. In conclusion, Cl‐IB‐MECA enhanced TRAIL‐mediated apoptosis via NF‐κB/c‐Rel activation and DR5‐dependent manner. This study may shed light on a potential drug cocktail that may prove useful as anti‐cancer in an in vivo animal model. J. Cell. Physiol. 221: 378–386, 2009. © 2009 Wiley‐Liss, Inc.
Upregulation of peroxisome proliferator‐activated receptor‐γ and NADPH oxidases are involved in restenosis after balloon injury
Authors: Qin Hai‐Dong , Huang Dan , Weng Xiao‐Dan , Xu Feng
Published: June 2009

Restenosis is a major complication of percutaneous transluminal coronary angioplasty (PTCA) and is characterized by increased superoxide formation and accumulation of smooth muscle cells (SMCs). The mechanisms through which peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) modulates the pathological process are incompletely defined. In this study, balloon injury of porcine coronary arteries in vivo and cell scraping model in vitro were used to elucidate the pathway via this molecule. PPAR‐γ and NADPH oxidase expression significantly increased both in neointimal hyperplasia after balloon injury or in the cultured SMCs after scraping injury. In vitro, PPAR‐γ agonist 15‐deoxy‐Δ12,14‐prostagladlin J2 (15d‐PGJ2) decreased cell‐scraping‐induced superoxide generation through suppression of NADPH oxidase activity via down‐regulation of p22phox and gp91phox. Furthermore, 15d‐PGJ2 could suppress scraping‐stimulated proliferation of SMCs. These data demonstrate that upregulation of PPAR‐γ and NADPH oxidases are involved in restenosis and activation of PPAR‐γ can inhibit the NADPH oxidase‐dependent superoxide generation in SMCs after injury. These findings will provide a new potential drug target for restenosis after balloon injury. J. Cell. Physiol. 221: 387–393, 2009. © 2009 Wiley‐Liss, Inc.
Evolution of developmental regulation in the vertebrate FgfD subfamily
Authors: Jovelin Richard , Yan Yi‐Lin , He Xinjun , Catchen Julian , Amores Angel , Canestro Cristian , Yokoi Hayato , Postlethwait John H.
Published: June 2009

Fibroblast growth factors (Fgfs) encode small signaling proteins that help regulate embryo patterning. Fgfs fall into seven families, including FgfD. Nonvertebrate chordates have a single FgfD gene; mammals have three (Fgf8, Fgf17, and Fgf18); and teleosts have six (fgf8a, fgf8b, fgf17, fgf18a, fgf18b, and fgf24). What are the evolutionary processes that led to the structural duplication and functional diversification of FgfD genes during vertebrate phylogeny? To study this question, we investigated conserved syntenies, patterns of gene expression, and the distribution of conserved noncoding elements (CNEs) in FgfD genes of stickleback and zebrafish, and compared them with data from cephalochordates, urochordates, and mammals. Genomic analysis suggests that Fgf8, Fgf17, Fgf18, and Fgf24 arose in two rounds of whole genome duplication at the base of the vertebrate radiation; that fgf8 and fgf18 duplications occurred at the base of the teleost radiation; and that Fgf24 is an ohnolog that was lost in the mammalian lineage. Expression analysis suggests that ancestral subfunctions partitioned between gene duplicates and points to the evolution of novel expression domains. Analysis of CNEs, at least some of which are candidate regulatory elements, suggests that ancestral CNEs partitioned between gene duplicates. These results help explain the evolutionary pathways by which the developmentally important family of FgfD molecules arose and the deduced principles that guided FgfD evolution are likely applicable to the evolution of developmental regulation in many vertebrate multigene families. J. Exp. Zool. (Mol. Dev. Evol.) 314B:33–56, 2010. © 2009 Wiley‐Liss, Inc.
The best probability models for dry and wet spells in Peninsular Malaysia during monsoon seasons
Authors: Deni Sayang Mohd , Jemain Abdul Aziz , Ibrahim Kamarulzaman
Published: June 2009

The identification of the most appropriate models to represent the rainfall distribution is very important as it can be utilised in various applications such as those in water resource management, agricultural planning department and hydrological sectors. Various types of probability models have been introduced and applied to the distribution of dry (wet) spells by previous researchers in the field. With the application of these probability models, this study will investigate the best probability models to describe the distribution of dry and wet spells at each of the 38 rainfall stations in Peninsular Malaysia for the period of 1975–2004. The analysis will be conducted on annual basis and also through monsoon seasons. Thirteen types of probability models with one up to three parameters including the family of geometric and log series distributions will be considered. In selecting the best models to represent the distribution of the dry (wet) spells, the Akaike's information criteria (AIC) and the Kolmogorov‐Smirnov goodness‐of‐fit (GOF) test are used. The results revealed that the modified log series (MLD) and the compound geometric (CGD) distributions were found to be the best models for the dry and wet spells respectively during the monsoon seasons. Meanwhile, the success of the mixed log series with the truncated Poisson distribution (MLTPD) was also proven in the study since this model was the most frequent best model selected in representing the observed distribution of both the annual dry and wet spells in most of the stations over the Peninsula. Copyright © 2009 Royal Meteorological Society
Analysis of phenotypic variation of sugar profile in different peach and nectarine [Prunus persica (L.) Batsch] breeding progenies
Authors: Cantín Celia M , Gogorcena Yolanda , Moreno María Ángeles
Published: June 2009

BACKGROUND: Specific sugar contents are well known for contributing to a range of quality traits of fresh fruits such as flavour, texture and health properties. Peaches and nectarines of 205 genotypes from 14 different breeding progenies cultivated under Mediterranean conditions were evaluated by high‐performance liquid chromatography for their content of these sugar traits.

RESULTS: A high contribution of cross to the phenotypic variance of all evaluated fruit quality traits was found. There were significant differences in mean sugar concentrations between peach and nectarine, yellow‐ and white‐fleshed or freestone and clingstone genotypes. Pre‐selected genotypes from the original breeding programme showed enhanced soluble solid content (SSC), total sugar and sucrose contents. A significant effect of year was found for SSC, sucrose and glucose contents, whereas no effect was found for fructose and sorbitol contents. Individual sugar contents correlated significantly with each other and with other fruit quality traits.

CONCLUSION: A significant effect of cross, year and qualitative traits on the sugar profile of peaches and nectarines was found. Moreover, the differences shown in sugar traits between the breeding population and the pre‐selected genotypes indicated the importance of sugar profile in the global quality of peaches and nectarines. Copyright © 2009 Society of Chemical Industry
Worldwide market screening of saffron volatile composition
Authors: Maggi Luana , Carmona Manuel , del Campo C Priscila , Kanakis Charalabos D , Anastasaki Eirini , Tarantilis Petros A , Polissiou Moschos G , Alonso Gonzalo L
Published: June 2009

BACKGROUND: Saffron (Crocus sativus L.) is one of the most valuable spices and nowadays its main use is as a foodstuff. Numerous papers have been published on saffron aroma and its volatile content, but nothing has been written about the aroma quality of samples available on the market to consumers. The aim of this study was to analyse and compare 418 commercial samples of saffron belonging to different ISO categories. Ultrasound‐assisted extraction (USAE) with an organic solvent and dynamic headspace desorption (DHD) followed by gas chromatography/mass spectrometry were used to screen for saffron volatile composition.

RESULTS: For both methods the saffron aromatic profile was characterised by spicy aromatic notes due to safranal, the most abundant volatile component, by a floral contribution attributable to isophorone and 2,2,6‐trimethyl‐1,4‐cyclohexanedione, together with citrus and spicy notes from 4‐ketoisophorone and 2‐hydroxy‐4,4,6‐trimethyl‐2,5‐cyclohexadien‐1‐one respectively.

CONCLUSION: USAE allowed the detection of a greater number of compounds, whereas DHD was faster and a smaller amount of saffron was required. Compared with the USAE method, the DHD method defined the samples as having a spicier and more floral aromatic contribution, thus corroborating that the extraction method considerably changes the aromatic fingerprint of saffron samples. Copyright © 2009 Society of Chemical Industry
1 mm ID poly(styrene‐co‐divinylbenzene) monolithic columns for high‐peak capacity one‐ and two‐dimensional liquid chromatographic separations of intact proteins
Authors: Eeltink Sebastiaan , Dolman Sebastiaan , Detobel Frederik , Desmet Gert , Swart Remco , Ursem Mario
Published: June 2009

The LC performance of a 1×50 mm polymer monolithic column format was demonstrated with high‐peak capacity one‐ (1D) and offline two dimensional (2D) LC separations of intact proteins. After optimizing the RP 1D‐LC conditions, including column temperature, flow rate and gradient time, a peak capacity of 475 was achieved within a 2‐h analysis. The suitability of the monolithic column was also demonstrated for fast 1 min protein separations yielding 1 s peak widths determined at half peak height. In addition, an offline 2D‐LC method was developed using the micro‐fraction collection capabilities of the autosampler allowing automatic fractionation of intact proteins after the weak‐ion‐exchange (WAX) separation, and re‐injection of the fractions onto the second‐dimension RP monolithic column. The best peak capacity‐to‐analysis time ratio was obtained when applying 10 min second‐dimension RP gradients. At optimized conditions, the WAX/×/RPLC separation of intact Escherichia coli proteins was performed within 6 h yielding a maximum theoretical peak capacity of 4880.
Chiral separation of amides of amino acid on a (S)‐N‐(3,5‐dinitrobenzoyl)leucine‐N‐phenyl‐N‐propylamide‐bonded silica using nonaqueous capillary electrochromatography
Authors: Jin Juhyeon , Hyun Myung Ho , Park Jung Hag
Published: June 2009

(S)‐N‐(3,5‐dinitrobenzoyl)leucine‐N‐phenyl‐N‐propylamine‐bonded silica was used as a chiral stationary phase for separation of a set of racemic π‐acidic and π‐basic α‐amino acid amides in electrolyteless ACN‐water eluents by CEC in the RP and polar organic (PO) modes. The effect of the amount of water in the ACN‐water eluent on chiral separation was examined. As water is added to ACN, retention was shortened but resolution and selectivity deteriorated severely. Retention, enantioselectivity, and resolution factors obtained in 100% ACN were compared with those in an n‐hexane‐isopropanol eluent with a small amount of water by normal phase (NP) CEC. Much shorter retention times with comparable enantioselectivities were observed with 100% ACN, demonstrating the advantage of separation on (S)‐N‐(DNB)leucine‐N‐phenyl‐N‐propylamine‐bonded silica in PO‐CEC over NP‐CEC.
Microwave‐assisted extraction with water for fast extraction and simultaneous RP‐HPLC determination of phenolic acids in Radix Salviae Miltiorrhizae
Authors: Fang Xinsheng , Wang Jianhua , Zhou Hongying , Jiang Xingkai , Zhu Lixiang , Gao Xin
Published: June 2009

An optimized microwave‐assisted extraction method using water (MAE‐W) as the extractant and an efficient HPLC analysis method were first developed for the fast extraction and simultaneous determination of D(+)‐(3,4‐dihydroxyphenyl) lactic acid (Dla), salvianolic acid B (SaB), and lithospermic acid (La) in Radix Salviae Miltiorrhizae. The key parameters of MAE‐W were optimized. It was found that the degradation of SaB was inhibited when using the optimized MAE‐W and the stable content of Dla, La, and SaB in danshen was obtained. Furthermore, compared to the conventional extraction methods, the proposed MAE‐W is a more rapid method with higher yield and lower solvent consumption with a reproducibility (RSD <6%). In addition, using water as extractant is safe and helpful for environment protection, which could be referred to as green extraction. The separation and quantitative determination of the three compounds was carried out by a developed reverse‐phase high‐performance liquid chromatographic (RP‐HPLC) method with UV detection. Highly efficient separation was obtained using gradient solvent system. The optimized HPLC analysis method was validated to have specificity, linearity, precision, and accuracy. The results indicated that MAE‐W followed by HPLC–UV determination is an appropriate alternative to previously proposed method for quality control of Radix Salviae Miltiorrhizae.
Capillary electrophoresis of intact basic proteins using noncovalently triple‐layer coated capillaries
Authors: Haselberg Rob , de Jong Gerhardus J. , Somsen Govert W.
Published: June 2009

The usefulness of a noncovalent, positively charged capillary coating for the efficient analysis of intact basic proteins with CE was studied. Capillaries were coated by subsequent flushing with solutions of 10% w/v Polybrene (PB), 3% w/v dextran sulfate (DS), and again 10% w/v PB. Coating characterization studies showed that stable coatings could be produced which exhibited a pH‐independent and highly reproducible EOF. The PB–DS–PB coating was evaluated with Tris phosphate BGEs of various pH using the four basic model proteins: α‐chymotrypsinogen A, ribonuclease A, cytochrome c, and lysozyme. Typical migration time RSDs for the proteins were less than 0.85%, and apparent plate numbers were above 125 000 using a capillary length of 40 cm. The high separation efficiency allowed detection of several minor impurities in the model proteins. Using a BGE of medium pH, the CE system with triple‐layer coating appeared to be useful for the repeatable profiling of recombinant humanized mouse monoclonal immunoglobulin G1 showing a characteristic pattern of glycoforms. The CE system was also applied to the characterization of two llama antibodies, which were produced in Saccharomyces cerevisiae, revealing the presence of a side product in one of the antibodies. The high migration time stability allowed the reliable determination of antibody–antigen binding by monitoring migration time shifts. Finally, the feasibility of using the PB–DS–PB coated capillaries for CE with mass spectrometric detection was shown by the characterization of the impure llama antibody sample.
Worse Recent Efficacy of Antiviral Therapy in Liver Transplant Recipients with Recurrent Hepatitis C: Impact of Donor Age and Baseline Cirrhosis
Authors: Berenguer Marina , Aguilera Victoria , Prieto Martín , Ortiz Cecilia , Rodríguez Maria , Gentili Federica , Risalde Blas , Rubin Angel , Cañada Raquel , Palau Antonio , Rayón Jose-Miguel
Published: June 2009

Abstract

We hypothesized that antiviral efficacy [sustained virologic response (SVR)] has improved in recent years in the transplant setting. Our aim was to assess whether the efficacy of pegylated interferon (PegIFN)–ribavirin (Rbv) has improved over time. One hundred seven liver transplant patients [74% men, 55.5 years old (range: 37.5–69.5), 86% genotype 1a or 1b] were treated with PegIFN-Rbv for 355 (16–623) days at 20.1 (1.7–132.6) months after transplantation. Tacrolimus was used in 61%. Sixty-seven percent had baseline F3–F4 (cirrhosis: 20.5%). Donor age was 49 (12–78) years. SVR was achieved in 39 (36.5%) patients, with worse results achieved in recent years (2001–2003: n = 27, 46.5%; 2004: n = 23, 43.5%; 2005: n = 21, 35%; 2006 to January 2007: n = 36, 24%; P = 0.043). Variables associated with SVR in the univariate analysis included donor age, baseline viremia and cirrhosis, bilirubin levels, rapid virologic response and early virologic response (EVR), premature discontinuation of PegIFN or Rbv, and accumulated Rbv dose. In the multivariate analysis, the variables in the model were EVR [odds ratio (OR): 0.08, 95% confidence interval (CI): 0.016–0.414, P = 0.002] and donor age (OR: 1.039, 95% CI: 1.008–1.071, P = 0.01). Variables that had changed over time included donor age, baseline viremia, disease severity (cirrhosis, baseline bilirubin, and leukocyte and platelet counts), interval between transplantation and therapy, and use of growth factors. In the multivariate analysis, variables independently changing were donor age (OR: 1.041, 95% CI: 1.013–1.071, P = 0.004), duration from transplantation to antiviral therapy (OR: 1.001, 95% CI: 1.000–1.001, P = 0.013), and baseline leukocyte count (OR: 1.000, 95% CI: 1.000–1.000, P = 0.034). In conclusion, the efficacy of antiviral therapy with PegIFN-Rbv has worsened over time, at least in our center. The increase in donor age and greater proportion of patients treated at advanced stages of disease are potential causes. Liver Transpl 15:738–746, 2009. © 2009 AASLD.
Quantification of Liver Perfusion by Dynamic Magnetic Resonance Imaging: Experimental Evaluation and Clinical Pilot Study
Authors: Zapletal Christina , Jahnke Cosima , Mehrabi Arianeb , Heß Thomas , Mihm David , Angelescu Michaela , Stegen Peter , Fonouni Hamidreza , Esmaeilzadeh Majid , Gebhard Martha Maria , Klar Ernst , Golling Markus
Published: June 2009

Abstract

Changes in liver microcirculation are considered essential in assessing ischemia-reperfusion injury, which in turn has an impact on liver graft function and outcome following liver transplantation (LTx). The aim of this study was to introduce dynamic magnetic resonance imaging (dMRI) as a new technique for overall quantification of hepatic microcirculation and compare it to perfusion measured by laser Doppler flowmetry (LDF; hepatic artery/portal vein) and thermal diffusion (TD). The study included 3 groups, measuring hepatic blood flow and microcirculation with the help of TD, LDF, and dMRI. In group I (9 landrace pigs; 26 ± 5 kg), the native liver before and after partial portal occlusion was studied; in group II (6 landrace pigs; 25.5 ± 4.4 kg), the liver 24 hours after LTx was studied; and in group III (14 patients), the liver on days 4 to 7 following LTx was studied. A close correlation was found between dMRI measurements and TD (r = 0.7–0.9, P < 0.01) in 4 defined regions of interest. Portal blood flow and partial occlusion of the portal vein were accurately detected by LDF flowmetry and correlated well with dMRI (r = 0.95, P < 0.01). In the clinical setting, representative TD measurements in segment 4b of the transplanted liver correlated well with dMRI analysis in other segments. Quantification of the portal blood flow and imaging of the whole liver could be performed simultaneously by dMRI. In conclusion, dMRI has been proved to be a sensitive modality for the quantification of liver microcirculation and hepatic blood flow in experimental and clinical LTx. It allows for a synchronous, noninvasive assessment of macrocirculation and microcirculation of the liver and could become a valuable diagnostic tool in advanced liver surgery and transplantation. Liver Transpl 15:693–700, 2009. © 2009 AASLD.
Early High Peak Hepatitis C Viral Load Levels Independently Predict Hepatitis C–Related Liver Failure Post–Liver Transplantation
Authors: Shackel Nicholas A. , Jamias Jade , Rahman Wassim , Prakoso Emilia , Strasser Simone I. , Koorey David J. , Crawford Michael D. , Verran Deborah J. , Gallagher James , McCaughan Geoffrey W.
Published: June 2009

Abstract

The aim of this study was to examine the importance of the serum hepatitis C viral load within the first year post–liver transplant in determining posttransplant survival. A retrospective analysis of 118 consecutive hepatitis C virus–positive liver transplant recipients who received an allograft from January 1997 to September 2005 was undertaken with a median duration of follow-up of 32.4 months. Univariate and multivariate analyses were used to examine the effects of recipient, donor, surgical, and viral factors on posttransplant outcomes. A total of 620 viral load estimations were undertaken in the first 12 months following transplantation. Patient and graft survival rates at 1, 3, and 5 years were 87.8%, 79.9%, and 70.1% and 87.0%, 79.2%, and 68.2%, respectively. According to multivariate analysis, a peak viral load ≥ 107 IU/mL (P = 0.004; hazard ratio, 8.68; 95% confidence interval, 2.04–37.02) and exposure to antirejection therapy (P = 0.05; hazard ratio, 2.26; 95% confidence interval, 1.01–5.38) were both independent predictors of diminished patient and graft survival and hepatitis C–related allograft failure. The only other independent predictor of hepatitis C virus–related outcome after transplant was azathioprine use, which was associated with improved outcomes (P = 0.04; hazard ratio, 0.25; 95% confidence interval, 0.07–0.91). A peak viral load in the first year after transplant of >108, 107 to 108, and <107 IU/mL was associated with a mean survival of 11.8, 70.6, and 89.1 months respectively (P ≤ 0.03). The results emphasize the importance of high viral loads in the early posttransplant period as an independent predictor of recipient outcomes. Liver Transpl 15:709–718, 2009. © 2009 AASLD.
Impaired Autophagic Clearance After Cold Preservation of Fatty Livers Correlates with Tissue Necrosis Upon Reperfusion and Is Reversed by Hypothermic Reconditioning
Authors: Minor Thomas , Stegemann Judith , Hirner Andreas , Koetting Martina
Published: June 2009

Abstract

Fatty livers are particularly susceptible to mitochondrial alterations after cold preservation. We thus aimed to improve graft integrity by brief hypothermic oxygenation prior to warm reperfusion. Macrovesicular steatosis was induced in rat livers by fasting and subsequent feeding of a fat-free diet enriched with carbohydrates. Fatty livers were retrieved and stored ischemically at 4°C for 20 hours in histidine-tryptophan-ketoglutarate solution. Hypothermic reconditioning (HR) was performed in some livers by insufflation of gaseous oxygen via the caval vein during the last 90 minutes of preservation. Viability was assessed upon isolated reperfusion. HR resulted in a significant (approximately 5-fold) reduction of parenchymal (alanine aminotransferase and lactate dehydrogenase) and mitochondrial (glutamate dehydrogenase) enzyme release. Functional recovery (bile production, oxygen consumption, and tissue levels of adenosine triphosphate) was significantly improved by HR. In untreated grafts, cellular autophagy (cleavage of LC3B and protein expression of beclin-1) was significantly impaired (<50% of baseline) after preservation/reperfusion but was restored to normal values by HR. HR also increased cleavage of caspase 9 (P < 0.5) and caspase 3 enzyme activity (by a factor of 1.5). In contrast, histological signs of tissue necrosis were abundant after reperfusion in untreated livers and largely abrogated in reconditioned livers. In conclusion, HR limits mitochondrial defects and restores basal rates of cellular autophagy. This may represent a rescue mechanism for maintaining cellular homeostasis and tissue survival. Liver Transpl 15:798–805, 2009. © 2009 AASLD.
Volumes of Liver Transplant and Partial Hepatectomy Procedures Are Independently Associated with Lower Postoperative Mortality Following Resection for Hepatocellular Carcinoma
Authors: Nguyen Geoffrey C. , Thuluvath Nimisha P. , Segev Dorry L. , Thuluvath Paul J.
Published: June 2009

Abstract

Partial hepatectomy for hepatocellular carcinoma (HCC) is a high-risk procedure, especially in the presence of portal hypertension. We assessed whether the volume of hospital liver transplant procedures was associated with lower in-hospital mortality independently of the volume of partial hepatectomy procedures. We queried the Nationwide Inpatient Sample (1998-2005) to identify patients who had undergone partial hepatectomy for HCC and used logistic regression to assess the independent effect of volumes of hospital liver transplant and partial hepatectomy procedures on mortality while adjusting for demographic, clinical, and hospital factors. Overall in-hospital mortality was 7.7%. Patients with portal hypertension experienced higher mortality than those who did not (24.5% versus 5.8%, P < 0.0001). Postoperative mortality benefited from a higher volume of hospital liver transplants (>12 per year) and partial hepatectomy procedures (>5 resections per year). Undergoing partial hepatectomy at a center that performed an effective liver transplant volume (eLTV; >12 transplants per year) was associated with lower mortality in both the portal hypertensive group (16.4% versus 33.7%, P = 0.004) and non–portal hypertensive group (4% versus 8%, P = 0.0002). After multivariate adjustment, the odds ratio (OR) of in-hospital death for those with portal hypertension was 4.5 [95% confidence interval (CI), 2.98-6.81]. The lower mortality observed with eLTV (OR, 0.59; 95% CI, 0.37-0.93) was independent of the mortality benefit from an effective partial hepatectomy volume (>5 hepatectomies per year; OR, 0.54; 95% CI, 0.31-0.94). Postoperative complications were also fewer at centers with eLTV compared to those without eLTV (39.2% versus 29.3%, P < 0.0001). In conclusion, given the postoperative mortality benefit independent of the volume of partial hepatectomy procedures, referral to a center with eLTV should be considered for HCC resection, especially in the presence of portal hypertension. Liver Transpl 15:776–781, 2009. © 2009 AASLD.
Motor abnormalities in premanifest persons with Huntington's disease: The PREDICT‐HD study
Authors: Biglan Kevin M. , Ross Christopher A. , Langbehn Douglas R. , Aylward Elizabeth H. , Stout Julie C. , Queller Sarah , Carlozzi Noelle E. , Duff Kevin , Beglinger Leigh J. , Paulsen Jane S.
Published: June 2009

The PREDICT‐HD study seeks to identify clinical and biological markers of Huntington's disease in premanifest individuals who have undergone predictive genetic testing. We compared baseline motor data between gene‐expansion carriers (cases) and nongene‐expansion carriers (controls) using t‐tests and Chi‐square. Cases were categorized as near, mid, or far from diagnosis using a CAG‐based formula. Striatal volumes were calculated using volumetric magnetic resonance imaging measurements. Multiple linear regression associated total motor score, motor domains, and individual motor items with estimated diagnosis and striatal volumes. Elevated total motor scores at baseline were associated with higher genetic probability of disease diagnosis in the near future (partial R2 0.14, P < 0.0001) and smaller striatal volumes (partial R2 0.15, P < 0.0001). Nearly all motor domain scores showed greater abnormality with increasing proximity to diagnosis, although bradykinesia and chorea were most highly associated with diagnostic immediacy. Among individual motor items, worse scores on finger tapping, tandem gait, Luria, saccade initiation, and chorea show unique association with diagnosis probability. Even in this premanifest population, subtle motor abnormalities were associated with a higher probability of disease diagnosis and smaller striatal volumes. Longitudinal assessment will help inform whether motor items will be useful measures in preventive clinical trials. © 2009 Movement Disorder Society
Norepinephrine and cardiovascular responses to maximal exercise in Parkinson's disease on and off medication
Authors: DiFrancisco‐Donoghue Joanne , Elokda Ahmed , Lamberg Eric M. , Bono Nancy , Werner William G.
Published: June 2009

The aim of this experiment is to understand how Parkinson's disease (PD) medication affects the autonomic responses of individuals during an acute exercise stress test. Fourteen people with PD and fifteen healthy individuals age‐matched between 50 and 80 years performed a modified Bruce protocol. Subjects with PD performed the test once off medication (PD‐off) and then 1 week later on medication (PD‐on). Heart rate (HR), blood pressure (BP), VO2, and norepinephrine (NE) levels were taken at rest and at peak exercise. At peak exercise HR, BP, and NE values for the PD‐on and PD‐off group were all significantly lower than healthy controls, regardless of whether subjects were on their medication. Autonomic abnormalities during exercise in this population appear to be disease manifested and not impactedby medications used to treat PD. We can assume, both on and off medication, this population will show markedly lower BP, HR, and NE responses. © 2009 Movement Disorder Society
Comparison of three clinical rating scales in Friedreich ataxia (FRDA)
Authors: Bürk Katrin , Mälzig Ulrike , Wolf Stefanie , Heck Suzette , Dimitriadis Konstantinos , Schmitz‐Hübsch Tanja , Hering Sascha , Lindig Tobias M. , Haug Verena , Timmann Dagmar , Degen Ingrid , Kruse Bernd , Dörr Jan‐Markus , Ratzka Susanne , Ivo Anja , Schöls Ludger , Boesch Sylvia , Klockgether Thomas , Klopstock Thomas , Schulz Jörg B.
Published: June 2009

To test the validity and reliability of the scale for the assessment and rating of ataxia (SARA) in Friedreich ataxia (FRDA). SARA is limited to eight items and can be performed rapidly. Ninety‐six patients with a molecular genetic diagnosis of FRDA were rated using three different clinical scales, the FRDA Rating Scale (FARS), the International Cooperative Ataxia Rating Scale (ICARS), and SARA. Despite considerable discrepancies in scale size and subscale structure, SARA total scores were significantly correlated with ICARS (r = 0.953, P < 0.0001) and FARS (r = 0.938, P < 0.0001) total scores. SARA total scores also correlated with the activities of daily living (ADL, r = 0.929, P < 0.0001). Although originally developed for the use in dominantly inherited ataxias, which are primarily ataxias of the cerebellar type, SARA can also be used successfully to assess afferent ataxia, which is the predominant form in FRDA. Because SARA is characterized by high interrater reliability and practicability, SARA is applicable and well suited forclinical trials of FRDA. © 2009 Movement Disorder Society
Expanding the clinical phenotype of SNCA duplication carriers
Authors: Nishioka Kenya , Ross Owen A. , Ishii Kenji , Kachergus Jennifer M. , Ishiwata Kiichi , Kitagawa Mayumi , Kono Satoshi , Obi Tomokazu , Mizoguchi Koichi , Inoue Yuichi , Imai Hisamasa , Takanashi Masashi , Mizuno Yoshikuni , Farrer Matthew J. , Hattori Nobutaka
Published: June 2009

SNCA duplication is a recognized cause of familial Parkinson's disease (PD). We aimed to explore the genetic and clinical variability in the disease manifestation. Molecular characterization was performed using real‐time PCR, SNP arrays, and haplotype analysis. We further studied those patients who were found to harbor SNCA duplication with olfactory function tests, polysomnography, and PET. We identified four new families and one sporadic patient with SNCA duplication. Eleven symptomatic patients from these four families presented with parkinsonism, of which three subsequently developed dementia. The lifetime estimate of overall penetrance was 43.8%. FDG–PET study of symptomatic patients showed hypometabolism in the occipital lobe, whereas asymptomatic carriers of SNCA duplication demonstrated normal glucose metabolism. Symptomatic patients showed abnormal olfactory function and polysomnography and asymptomatic carriers showed normal results. The clinical features of SNCA duplication include parkinsonism with or without dementia. Asymptomatic carriers displayed normal test results with the eldest individual aged 79 years; thus, even a carrier of SNCA duplication may escape the development of PD. This difference in age‐associated penetrance may be due to the genetic background or environmental exposures. Further studies of SNCA duplication carriers will help identify disease‐modifiers and may open novel avenues for future treatment. © 2009 Movement Disorder Society
PINK1 mutations in a Brazilian cohort of early‐onset Parkinson's disease patients
Authors: Godeiro‐Junior Clecio , de Carvalho‐Aguiar Patricia M. , Felício Andre C. , Barsottini Orlando G.P. , Silva Sonia M.A. , Borges Vanderci , Andrade Luiz Augusto F. , Ferraz Henrique Ballalai
Published: June 2009

Data on the frequency of PINK1 mutations in Brazilian patients with early‐onset Parkinson's disease (EOPD) are lacking. The aim of this report was to investigate mutations of the PINK1 gene in a cohort of Brazilian patients with EOPD. Sixty consecutive familial or sporadic EOPD patients were included. All eight PINK1 exons and exon‐intron boundaries were analyzed. We did not find any pathogenic mutation of PINK1 in our cohort. Single Nucleotide Polymorphisms (SNP) were identified in 46.7% of the patients and in 45.9% of controls (P = 0.9). The SNPs identified in our patients had already been described in previous reports. The results of our study support the hypothesis that mutations in PINK1 may not be a relevant cause of EOPD. In Brazil, if we consider only EOPD patients, it seems that parkin and LRRK2 mutations are more common. © 2009 Movement Disorder Society
Hierarchical model reduction at multiple scales
Authors: Yuan Zheng , Fish Jacob
Published: June 2009

A hierarchical model reduction approach aimed at reducing computational complexity of non‐linear homogenization at multiple scales is developed. The method consists of the following salient features: (1) formulation of non‐linear unit cell problems at multiple scales in terms of eigendeformation modes that a priori satisfy equilibrium equations at multiple scales and thus eliminating the need for costly solution of discretized non‐linear equilibrium, (2) the ability to control the discretization of the eigendeformation modes at multiple scales to maintain desired accuracy, and (3) hierarchical solution strategy that requires sequential solution of single‐scale problems.

A two‐scale formulation is verified against an one‐dimensional model problem for which an analytical solution can be obtained and a three‐scale formulation is validated against tube crash experiments. Copyright © 2009 John Wiley & Sons, Ltd.
An improved assumed strain solid–shell element formulation with physical stabilization for geometric non‐linear applications and elastic–plastic stability analysis
Authors: Abed‐Meraim Farid , Combescure Alain
Published: June 2009

In this paper, the earlier formulation of the SHB8PS finite element is revised in order to eliminate some persistent membrane and shear locking phenomena. This new formulation consists of a solid–shell element based on a purely three‐dimensional approach. More specifically, the element has eight nodes, with displacements as the only degrees of freedom, as well as an arbitrary number of integration points, with a minimum number of two, distributed along the ‘thickness’ direction. The resulting derivation, which is computationally efficient, can then be used for the modeling of thin structures, while providing an accurate description of the various through‐thickness phenomena. A reduced integration scheme is used to prevent some locking phenomena and to achieve an attractive, low‐cost formulation. The spurious zero‐energy modes due to this in‐plane one‐point quadrature are efficiently controlled using a physical stabilization procedure, whereas the strain components corresponding to locking modes are eliminated with a projection technique following the assumed strain method. In addition to the extended and detailed formulation presented in this paper, particular attention has been focused on providing full justification regarding the identification of hourglass modes in relation to rank deficiencies. Moreover, an attempt has been made to provide a sound foundation to the derivation of the co‐rotational coordinate frame, on which the calculations of the stabilization stiffness matrix and internal load vector are based. Finally to assess the effectiveness and performance of this new formulation, a set of popular benchmark problems is investigated, involving geometric non‐linear analyses as well as elastic–plastic stability issues. Copyright © 2009 John Wiley & Sons, Ltd.
Taylor‐Galerkin B‐spline finite element method for the one‐dimensional advection‐diffusion equation
Authors: Kadalbajoo Mohan K. , Arora Puneet
Published: June 2009

The advection‐diffusion equation has a long history as a benchmark for numerical methods. Taylor‐Galerkin methods are used together with the type of splines known as B‐splines to construct the approximation functions over the finite elements for the solution of time‐dependent advection‐diffusion problems. If advection dominates over diffusion, the numerical solution is difficult especially if boundary layers are to be resolved. Known test problems have been studied to demonstrate the accuracy of the method. Numerical results show the behavior of the method with emphasis on treatment of boundary conditions. Taylor‐Galerkin methods have been constructed by using both linear and quadratic B‐spline shape functions. Results shown by the method are found to be in good agreement with the exact solution. © 2009 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 2010