bluuebunny/crossref_metadata_2025 huggingface dataset:
Current status of radiotherapy with proton and light ion beams
Authors: Greco Carlo , Wolden Suzanne
Published: February 2007

Several model studies have shown potential clinical advantages with charged particles (protons and light ions) compared with 3D‐conformal radiotherapy (3D‐CRT) and intensity‐modulated radiotherapy (IMRT) in many disease sites. The newly developed intensity‐modulated proton therapy (IMPT) often yields superior dose distributions to photon IMRT, with the added advantage of a significant reduction in the volume of healthy normal tissues exposed to low‐to‐medium doses. Initially, the major emphasis in clinical research for proton and light ion therapy was dose escalation for inherently radioresistant tumors, or for lesions adjacent to critical normal structures that constrained the dose that could be safely delivered with conventional x‐ray therapy. Since the advent of IMRT the interest in particle therapy has gradually shifted toward protocols aimed at morbidity reduction. Lately the emphasis has mostly been placed on the potential for reduced risk of radiation‐induced carcinogenesis with protons. Compared with 3D‐CRT, a 2‐fold increase has been theoretically estimated with the use of IMRT due to the larger integral volumes. In the pediatric setting, due to a higher inherent susceptibility of tissues, the risk could be significant, and the benefits of protons have been strongly emphasized in the literature. There is a significant expansion of particle therapy facilities around the world. Increasing public awareness of the potential benefits of particle therapy and wider accessibility for patients require that treating physicians stay abreast of the clinical indications of this radiotherapy modality. The article reviews the available literature for various disease sites in which particle therapy has traditionally been considered to offer clinical advantages and to highlight current lines of clinical research. The issue of radiation‐induced second malignancies is examined in the light of the controversial epidemiological evidence available. The cost‐effectiveness of particle therapy is also discussed. Cancer 2007. © 2007 American Cancer Society.
Detection of circulating urothelial cancer cells in the blood using the CellSearch System
Authors: Naoe Michio , Ogawa Yoshio , Morita Jun , Omori Kei , Takeshita Kumiko , Shichijyo Takeshi , Okumura Taisuke , Igarashi Atsushi , Yanaihara Atsushi , Iwamoto Sanju , Fukagai Takashi , Miyazaki Akira , Yoshida Hideki
Published: February 2007

BACKGROUND.

Circulating tumor cells (CTCs) have been shown to aid in the therapeutic management of patients. But, only a few attempts have been made at the detection of urothelial cancer cells in the blood. The purpose of this study was to test the hypothesis that CTCs are detected in patients with urothelial cancers using newly developed CellSearch Assay.

METHODS.

Firstly, the bladder cancer cell lines were used to evaluate the reagents for immunocytochemical detection. After, mixed with peripheral blood mononuclear cells (PBMCs) of healthy volunteers, bladder cancer cells were stained with antibodies then multiparameter flow cytometric analysis was performed for the identification of bladder cancer cells in the PBMCs. Secondary, recovery of known numbers of spiked bladder cancer cells from whole blood was examined using CellSearch Assay. Finally, blood samples from nonmetastatic and metastatic urothelial cancer patients were investigated for CTC detection using CellSearch Assay.

RESULTS.

1: Flow cytometric analysis revealed that it is possible to identify bladder cancer cells in PBMCs. 2: Sensitivity examination for detection of urothelial cancer cells with CellSearch Assay: Single regression analysis of the spiked number of cells vs. the recovered number of cells yielded a good correlation in this experiment. 3: Urothelial cancer cells were detected in 8 of fourteen patients (57.1%) with distant metastasis. Despite, no patient with nonmetastatic urothelial cancers showed positive result for this assay.

CONCLUSION.

This is the first report of attempt to detect circulating urothelial cancer cells in the peripheral blood of the patients with metastatic and nonmetastatic urothelial cancers by CellSearch Assay. Cancer 2007. © 2007 American Cancer Society.
Conditional survival in head and neck squamous cell carcinoma
Authors: Fuller Clifton D. , Wang Samuel J. , Thomas Charles R. , Hoffman Henry T. , Weber Randal S. , Rosenthal David I.
Published: February 2007

BACKGROUND.

Survival statistics for patients with head and neck squamous cell carcinomas (HNSCC) are commonly calculated from the time of diagnosis. The less commonly employed conditional survival (CS) analyzes survival for patients who have survived a period of time after diagnosis. Useful prognostic information for cancer survivors is provided by CS analysis. Estimated baseline CS parameters for HNSCC were sought using large‐scale cancer registry data.

METHODS.

HNSCC cases identified from the Surveillance, Epidemiology, and End Results (SEER) Program were accessed to identify those diagnosed between 1973 and 1998. Five‐year observed, relative, and cumulative CS calculations were performed, with secondary stratification by site, extent of disease, and age.

RESULTS.

The overall 5‐year observed survival for all sites increased from 47.8% for 76,181 included patients from the time of diagnosis to 64.4% for those 43,985 patients alive at 3 years, and thereafter plateaus. The greatest increase in CS was for oropharyngeal cancers, which more than doubled over the first decade of surveillance (26.5%–60%). Distant disease showed a 10‐year increase in CS (17.4%–60.4%), whereas localized disease CS was essentially static, ranging from 66.1% to 68.5%; for those over 65 at diagnosis it ranged from 39.9–52.9%, whereas patients <65 years at diagnosis ranged from 53.8–73.5%.

CONCLUSIONS.

Benchmark CS estimates for domestic HNSCC cohorts were developed from the SEER database. CS is a useful tool to assist clinicians in predicting the probability of demise from HNSCC for patients surviving 1 or more year after diagnosis. Cancer 2007. © 2007 American Cancer Society.
Color‐emotion associations and color preferences: A case study for residences
Authors: Manav Banu
Published: February 2007

This study examines existing beliefs about “color” focusing on color‐emotion associations by discussing how color can be used as a way of communicator to fulfill human needs in residences. Fifty people from various age groups participated in the study. They were asked to match a list of adjectives with the proper color samples from the catalogue of a quite popular color producer firm in Turkey. Results indicate that there is a strong dependency between the choice and use of green at residences. Emotional responses to colors change with value and saturation levels. According to the test results, gender and age are determining factors in the selection of achromatic black. © 2007 Wiley Periodicals, Inc. Col Res Appl, 32, 144 – 150, 2007
Optimal fluorescent colors
Authors: Couzin Dennis
Published: February 2007

This article poses and discusses a maximization problem: for a given chromaticity, and in a given illumination, how light a fluorescent color is possible. The article does not present a solution, but does offer a conjecture that for many illuminants and many chromaticities the greatest lightness is achieved by a simple form of bispectral function. The output is in two points plus a tail, so we call it a “PPT” function. © 2007 Wiley Periodicals, Inc. Col Res Appl, 32, 85 – 91, 2007
Development of the idea of simple colors in the 16th and early 17th centuries
Authors: Kuehni Rolf G.
Published: February 2007

The development of the idea of simple or fundamental colors in Western culture from classical Greece to the early 17th century is shown, with particular emphasis on writers in the 16th and early 17th centuries. Four streams of thought are found: (1) Aristotle's seven colors, congruent with seven tastes and seven tones, thus symptomatic of an underlying general harmony; (2) Four‐basic‐color sequences where colors are emblematic of the four classical elements; (3) Spectral sequences; (4) Three simple chromatic colors between white and black, based on colorant mixture. In the late 16th century seven‐color sequences came to represent categorical sequences, in addition to shorter fundamental color sequences. © 2007 Wiley Periodicals, Inc. Col Res Appl, 32, 92 – 99, 2007
Changes in fluorescence intensity of selected leukocyte surface markers following fixation
Authors: Stewart Judith C. , Villasmil Michelle L. , Frampton Mark W.
Published: February 2007

Background:

Immunophenotyping of blood leukocytes often involves fixation with paraformaldehyde prior to cytometry analysis. However, the influence of cell type and marker specificity on the stability of fluorescence intensity after fixation has not been well studied.

Methods:

Human whole blood was stained using a panel of fluorescein isothiocyanate‐labeled antibodies to surface markers. Unfixed and fixed samples were analyzed by flow cytometry at 0, 2, 4, 6, 24, 48, and 96 h after staining. Fluorescence measurements were converted to molecules of equivalent soluble fluorochrome for comparison.

Results:

Fixation caused a significant decrease in both forward and side scatter at 48 h which required gating adjustments to achieve resolution of cell populations. The autofluorescence increased progressively in fixed samples (ninefold at 96 h for monocytes). Variable decreases in marker‐associated fluorescence became apparent after correction for autofluorescence. The magnitude of the decrease at 96 h varied with cell type and marker, from 5% for CD32 on monocytes to 39% for CD16 on neutrophils.

Conclusion:

The change in fluorescence intensity following staining and fixation of leukocytes varies with cell type and surface marker. Fluorescence stability should be determined for each cell type and marker used, and the confounding effects of fixation on cell autofluorescence should be considered. © 2007 International Society for Analytical Cytology.
BMP and FGF regulatory pathways in semilunar valve precursor cells
Authors: Zhao Bin , Etter Laura , Hinton Robert B. , Benson D. Woodrow
Published: February 2007

In the developing atrioventricular (AV) valve, limb bud, and somites, cartilage cell lineage differentiation is regulated by bone morphogenetic protein (BMP), while fibroblast growth factor (FGF) controls tendon cell fate. We observed aggrecan and sox9, characteristic of cartilage cell types, and scleraxis and tenascin, characteristic of tendon cell types, in developing avian semilunar valves. Addition of BMP4 to outflow tract (OFT) precursor cells of young (E4.5) but not older (E6) chick embryos activated Smad1/5/8 and induced sox9 and aggrecan expression, while FGF4 treatment increased phosphorylated MAPK (dpERK) signaling and promoted expression of scleraxis and tenascin. These results identify BMP and FGF pathways that promote expression of cartilage‐ or tendon‐like characteristics in semilunar valve precursor cells. In contrast to AV valve precursor cells, which diversify into leaflets (cartilage‐like) or chordae tendineae (tendon‐like), semilunar valve cells exhibit both cartilage‐ and tendon‐like characteristics in the developing and mature valve cusp. Developmental Dynamics 236:971–980, 2007. © 2007 Wiley‐Liss, Inc.
Microarray analysis of homocysteine‐responsive genes in cardiac neural crest cells in vitro
Authors: Rosenquist T.H. , Bennett G.D. , Brauer P.R. , Stewart M.L. , Chaudoin T.R. , Finnell R.H.
Published: February 2007

The amino acid homocysteine increases in the serum when there is insufficient folic acid or vitamin B12, or with certain mutations in enzymes important in methionine metabolism. Elevated homocysteine is related to increased risk for cardiovascular and other diseases in adults and elevated maternal homocysteine increases the risk for certain congenital defects, especially those that result from abnormal development of the neural crest and neural tube. Experiments with the avian embryo model have shown that elevated homocysteine perturbs neural crest/neural tube migration in vitro and in vivo. Whereas there have been numerous studies of homocysteine‐induced changes in gene expression in adult cells, there is no previous report of a homocysteine‐responsive transcriptome in the embryonic neural crest. We treated neural crest cells in vitro with exogenous homocysteine in a protocol that induces significant changes in neural crest cell migration. We used microarray analysis and expression profiling to identify 65 transcripts of genes of known function that were altered by homocysteine. The largest set of effected genes (19) included those with a role in cell migration and adhesion. Other major groups were genes involved in metabolism (13); DNA/RNA interaction (11); cell proliferation/apoptosis (10); and transporter/receptor (6). Although the genes identified in this experiment were consistent with prior observations of the effect of homocysteine upon neural crest cell function, none had been identified previously as response to homocysteine in adult cells. Developmental Dynamics 236:1044–1054, 2007. © 2007 Wiley‐Liss, Inc.
Computerized screening for visual stress in children with dyslexia
Authors: Singleton Chris , Henderson Lisa‐Marie
Published: February 2007

Visual stress—a condition in which unpleasant visual symptoms are experienced when reading—has been reported to be more prevalent in dyslexic individuals but at the present time the relationship between dyslexia and visual stress remains controversial. ViSS, a computerized visual stress screener that incorporates reading‐like visual search, has recently shown promise in studies with unselected samples of primary and secondary school children. This study investigated the use of ViSS with dyslexic children. Dyslexic children identified as having high visual stress showed significantly higher per cent increases in reading rate with a coloured overlay and reported significantly higher critical symptoms of visual stress, compared to dyslexic children with low visual stress. The same results were found for reading‐age controls, indicating that ViSS can be equally effective with normal readers as well as with children with dyslexia. Compared to reading‐age controls, dyslexic children were found to have significantly higher susceptibility to visual stress, significantly larger per cent increases in reading rate with an overlay, and significantly higher critical and non‐critical symptoms of visual stress. Extrapolated to unselected population samples, the data also suggest that visual stress is more likely to be found in people with dyslexia than in people who do not have dyslexia. These results, which point to an important link between the two conditions, are discussed in relation to current theories that attribute visual stress to either a magnocellular dysfunction or cortical hyperexcitability. Copyright © 2007 John Wiley & Sons, Ltd.
Highly variable expression of tissue‐restricted self‐antigens in human thymus: Implications for self‐tolerance and autoimmunity
Authors: Taubert Richard , Schwendemann Jochen , Kyewski Bruno
Published: February 2007

Induction of T cell tolerance in the thymus (central tolerance) is essential for preventing organ‐specific autoimmunity. This apparent paradox is in part explained by promiscuous expression of numerous tissue‐restricted self‐antigens (TRA) in medullary thymic epithelial cells (mTEC), which is highly conserved between mice and man. In animal models, the threshold of central tolerance towards such TRA is surprisingly sensitive towards minor shifts in antigen expression levels and this might also be the case in humans. To precisely assess the inter‐individual variability of TRA expression in man, we determined the level of transcription of several auto‐antigens in purified human mTEC and subsets thereof by quantitative RT‐PCR. We detected two expression patterns: first, high variability (>20‐fold) correlated with autoimmune regulator (Aire) expression and mTEC differentiation, and secondly, non‐correlated low variability. Importantly, our approach revealed a significantly higher Aire–correlated insulin transcription in mTEC of carriers of the protective insulin‐dependent diabetes mellitus locus 2 haplotype compared to the non‐protective haplotype. The considerable, yet selective variability in thymic expression levels of target auto‐antigen expression might constitute a hitherto underestimated risk factor for the susceptibility of autoimmune diseases in man.

See accompanying commentary: http://dx.doi.org/10.1002/eji200737152
Aire‐ing self antigen variability and tolerance
Authors: Holmdahl Rikard
Published: February 2007

Positional cloning of the underlying genes for the rare syndrome autoimmune polyendocrinopathy candidadiasis extrodermal dystrophy (APECED) opened a new venue of research on the role of central tolerance in autoimmunity. The associated autoimmune regulator gene (AIRE), was found to be expressed in medullary thymus epithelial cells (mTEC) in both man and mice, and to control promiscuous expression of sets of self antigens. The lack of AIRE in both mice and man led to the development of a quite specific, but also an inter‐individual variable, set of autoimmune and infectious diseases. An article in this issue of the European Journal of Immunology demonstrates that several autoantigens controlled by AIRE are variably expressed in different human individuals. Most importantly it is shown that carriers of the type 1 diabetes (T1D) associated locus IDDM2 show lower expression of insulin in mTEC, as controlled by AIRE. The genetic variability of autoantigen expression in the thymus thus seems to determine the variable predisposition to autoimmunity.

See accompanying article: http://dx.doi.org/10.1002/eji.200636962
Monohydrocalcite and Its Relationship to Hydrated Amorphous Calcium Carbonate in Biominerals
Authors: Neumann Markus , Epple Matthias
Published: February 2007

Calcium carbonate monohydrate (monohydrocalcite) is prepared and structurally characterised by X‐ray diffraction, X‐ray absorption spectroscopy (EXAFS), thermal analysis, IR spectroscopy, and scanning electron microscopy. It is compared to hydrated phases of amorphous calcium carbonate (ACC) that have frequently been observed in biomineralisation. The crystal water is more strongly bound than in hydrated ACC phases, and monohydrocalcite can be distinguished from ACC by its IR spectrum. The EXAFS results suggest that monohydrocalcite is a suitable model for some biogenic and synthetic ACC phases, although not for all of them. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Protonation of Tris(iminocatecholato) Complexes of Gallium(III) and Titanium(IV)
Authors: Albrecht Markus , Burk Simon , Stoffel Ralf , Lüchow Arne , Fröhlich Roland , Kogej Michael , Schalley Christoph A.
Published: February 2007

The coordination behaviour of the chiral tren‐type tripodal ligand 3‐H6 with gallium(III) and titanium(IV) ions was investigated and it was found that only mononuclear complexes are formed. In the presence of Na+, one of the cations acts as a template and is bound inside the “cap” of [Na(3)M]n– (M = Ga, n = 2; M = Ti, n = 1). If no such cation is present, three protons are bound to the iminocatechol units in order to prevent repulsion between lone pairs at nitrogen and oxygen. To minimize the charge repulsion between the protonated imines of [H3(3)M]n+ (M = Ga, n = 0; M = Ti, n = 1), an enaminone/chinomethine mesomeric structure becomes important. The adoption of this unusual mesomeric form by the iminocatecholates was supported by computational methods. In further investigations, we found, that the addition of protons (H2SO4) to the dinuclear (catecholimine)titanium helicate K4[(4)3Ti2] leads to protonation of the imine part of the iminocatechol. An excess of acid results in the hydrolysis of the complexes as well as of the imine units. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Assessing Guest Selectivity within Metallacrown Host Compartments
Authors: Lim Choong‐Sun , Van Noord Annabel Cutland , Kampf Jeff W. , Pecoraro Vincent L.
Published: February 2007

15‐MC‐5 complexes associate in the solid state to form chiral compartments capable of binding guests. Using small molecular yardsticks, we are able to assess the size restrictions of these structures. Dicarboxylate guests that are too short to span the GdIII ions are stabilized by solvates that hydrogen bond to the uncoordinated carboxylate, while guests that are too long destroy the weakly associated structure. We also demonstrate that all that is required for guest encapsulation is unsaturation of the chain connection carboxylates rather than necessitating the presence of aromaticity. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Estimating joint tail probabilities of river discharges through the logistic copula
Authors: de Waal D. J. , van Gelder P. H. A. J. M. , Nel A.
Published: February 2007

In flood analysis, apart from extreme precipitation or sudden snow melt, also the duration or persistence of high water levels needs proper description. The purpose of this paper is to estimate tail probabilities from the joint distribution of variables such as one‐day annual maximum river discharges and its aggregate seven‐day annual maximum discharges. An application will be shown to the river Rhine in The Netherlands. The marginal distributions of the annual maxima (AM) exceeding certain thresholds are assumed to be bounded Strict Pareto and the logistic copula is used for the joint distribution. The main methodological issue discussed is the fitting of the logistic copula within a Bayesian framework. The estimation of parameters are obtained through a Markov Chain Monte Carlo simulation. In this respect, the paper provides a method for selecting the univariate and bivariate thresholds. Copyright © 2007 John Wiley & Sons, Ltd.
Generalised algorithm of novel space vector modulation: forN‐level three‐phase voltage source inverter
Authors: Chekireb Hachemi , Berkouk El Madjid
Published: February 2007

This paper concerns the development of a generalised algorithm of a novel space vector modulation (SVM) forN‐level three‐phase voltage source inverter. It is considering that the (N−1) DC input voltages of inverter are constant. The proposed method ensures initially the determination of theN3inverter switching states, the extraction of the redundancies to obtain 3N(N‐1) + 1 independent switching states and their organisation by sector in six distinct matricesWkwithk = (1, … ,6). After that, these matricesWkwithk = (2, … ,6) are ordered as the matrixW1related to the first sector. So, the research of the three closest vectors to the reference vector is carried out only in first sector and for this purpose, the equivalent reference vector is introduced which is resulting from the rotation by −(k−1)π/3 of the reference vector. The on‐line choice of the three vectors (three switching states of the inverter) is based on the distances between the equivalent reference vector and some vectors located in its vicinity in the (α,β) plane of the first sector. Moreover, a simple method for the calculation of the duty cycles for these three switching states is proposed which exploits directly the three shortest distances associated to these three selected vectors. The sequence of these three switching states over a sampling period is investigated in view to reduce the harmonic contents of the voltage output. The application is carried out on anN‐level three‐phase voltage source inverter, whereNis an arbitrary odd integer. Finally, the phase voltage and its harmonic spectrum provided by a three‐phaseN‐level inverter withN = (3,5,7,9,13,15) are presented to confirm the generalisation of this method. Copyright © 2007 John Wiley & Sons, Ltd.
A simple simulation method for torque and speed calculation of AC motors under distorted input waveforms
Authors: Kappatou Joya C. , Zarmakoupis Konstantinos , Safacas Athanasios N.
Published: February 2007

This paper presents a method of calculating in a simple, cheap and computational efficient way the steady‐state time variables of three‐phase induction or synchronous motors when only the data of the machine and a drawn waveform of its distorted stator input are given. Such waveforms can be considered as converter output voltage or current feeding the machine. According to this method the converter part for simulation can be omitted. The method has been implemented for an induction, as well as a synchronous machine under different cases of distorted voltage waveforms in the stator. Experimental and simulation results are in good agreement. Copyright © 2007 John Wiley & Sons, Ltd.
The Neolithic of the southern Levant
Authors: Twiss Katheryn C.
Published: February 2007

The Neolithic period of the southern Levant was an era of tremendous change. Over the course of the Neolithic, the gradual transition from foraging to agriculture involved not merely economic innovations, but also profound shifts in population size, social organization, and technology. This represents possibly the earliest, and certainly one of the earliest, instances of the transition to agriculture. The advent of farming altered human demography, health, and diversity; it shaped the spread of the world's dominant cultures, genes, and languages.1, 2 It recast humans' relationship with the natural world, increasing modification of the environment. It both enabled and required the development of new social structures as humans learned how to live in increasingly large and densely packed groups.

These transformations were not easily achieved. This paper traces the development of the southern Levantine Neolithic through two thousand years of socioeconomic elaboration and expansion; a major social recalibration in the middle Neolithic; and a final millennium‐and‐a‐half of smaller‐scale and materially simpler adaptations.
Efficient multilocus association testing for whole genome association studies using localized haplotype clustering
Authors: Browning Brian L. , Browning Sharon R.
Published: February 2007

Whole genome association studies are generating data sets with hundreds of thousands of markers genotyped on thousands of cases and controls. We show that whole genome haplotypic association testing with permutation to account for multiple testing is statistically powerful and computationally feasible on such data, using an efficient software implementation of a recently proposed method. We use realistic simulations to explore the statistical properties of the method, and show that for ungenotyped disease‐susceptibility variants with population frequencies of 5% or less the haplotypic tests have markedly better power than single‐marker tests. We propose a combined single‐marker and haplotypic strategy, in which both single‐marker and haplotypic tests are applied, with the minimum P‐value adjusted for multiple testing by permutation which results in a test that is powerful for detecting both low‐and high‐frequency disease‐susceptibility variants. Genet. Epidemiol. 2007. © 2007 Wiley‐Liss, Inc.
Phylochronology of early metazoans: combined evidence from molecular and fossil data
Authors: Qun Yang , Junye Ma , Xiaoyan Sun , Peiyun Cong
Published: February 2007

Timing the evolutionary appearances of early Metazoa on Earth may rely on the combined information of fossil occurrences, molecular divergences and the geological background. Recent advances in the studies of Neoproterozoic and earliest Cambrian strata in South China and elsewhere, together with numerous works on molecular dating, provide an opportunity to draw a more precise timescale for the early metazoan evolution. This study presents a synthesis of available molecular and fossil dating results, placed in the palaeoenvironmental background, which leads to the recognition of the following time events for early metazoan cladogenesis: (1) Animal multicellularity occurred most probably during early to middle Neoproterozoic times (between ∼1000 and ∼660 Ma) during the geological period of gradual increase in oxygen content; (2) Eumetazoans and sponges (or sponge‐like organisms) parted from each other during the Neoproterozoic glaciation interval (ca. 750–580 Ma), but both experienced adaptive radiation after the glaciations as evidenced by the Doushantuo Biota (ca. 635–551 Ma); (3) A great metazoan radiation event (MRE) occurred during the late Ediacaran and earliest Cambrian periods (ca. 550–530 Ma), interpreted here as a metazoan radiation at higher taxonomic levels, as compared with the early Cambrian radiation representing one at lower taxonomic levels (lower than subphylum or class). In order to better constrain the phylochronology of early metazoans, we present evidence for the divergences of arthropod subgroups on the basis of molecular dating results and the fossil record. It is shown that the arthropod stem group diverged from its sister taxon at between ∼700 and ∼565 Ma and major arthropod subgroups originated coevally with MRE. The MRE is probably correlatable with the δ13C negative anomaly in the late Ediacaran Period.

Although the phylochronology of early Metazoa is gradually emerging, a great deal of research still will be needed in the following directions in order to reduce uncertainties in, and discrepancies among, dating results: (1) Evaluate different molecular dating techniques so as to establish a proper set of standard procedures for dating early metazoan events; (2) Set up a standard set of fossil calibration points suitable for dating early metazoan divergences; (3) Use both molecular and fossil constraints as far as possible; (4) Place the time sequence in the geological and palaeoecological background so that one can visualize a logical evolutionary scenario. We suggest that the fossil record plus the geological background should serve to construct a general timeframe for evolution, while molecular dating will supplement and probably increase the precision of the chronology. Copyright © 2007 John Wiley & Sons, Ltd.
Prevalence and correlates of disruptive behavior in patients in Norwegian nursing homes
Authors: Testad I. , Aasland A. M. , Aarsland D.
Published: February 2007

Background

Although Behavioral and Psychological Symptoms of Dementia (BPSD) increase with increasing dementia severity, and institutionalization of an individual with dementia is often caused by behavioral symptoms, relatively few studies have explored the prevalence of BPSD in nursing homes.

Objective

To study the prevalence and correlates of agitation in residents with dementia, in Norwegian nursing homes.

Methods

This study has taken place in dementia wards in four Norwegian nursing homes. To measure agitation in residents with dementia we used the Cohen‐Mansfield Agitation Inventory (CMAI), consisting of 29 agitation items. Dementia stage was measured by Functional Assessment Staging (FAST).

Results

Two hundred and eleven patients (71% female) were included in the study: mean (SD) age 85.5 (8.4), FAST 4.7 (2.1), CMAI total sumscore 39.5 (12.6). Dementia was present in 167 (79%) subjects. Among those with dementia, weekly occurrence of at least one CMAI item (i.e. a score of 3 or higher) occurred in 75.4% (95% CI 68.4–81.4). Six of the items occurred at least weekly in 20% of the residents with dementia, and 11 of the items, including physical aggression, occurred in less than 5% of the residents. Agitation was associated with more severe dementia (p = 0.001), but not with age and gender.

Conclusion

Symptoms of agitation were common, but may nevertheless be lower compared to findings in other geographical areas. Further studies are warranted to test this hypothesis, and if confirmed, to explore possible causes for such differences. Copyright © 2007 John Wiley & Sons, Ltd.
The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells
Authors: Keitel Verena , Reinehr Roland , Gatsios Petros , Rupprecht Claudia , Görg Boris , Selbach Oliver , Häussinger Dieter , Kubitz Ralf
Published: February 2007

Sinusoidal endothelial cells (SEC) constitute a permeable barrier between hepatocytes and blood. SEC are exposed to high concentrations of bile salts from the enterohepatic circulation. Whether SEC are responsive to bile salts is unknown. TGR5, a G-protein–coupled bile acid receptor, which triggers cAMP formation, has been discovered recently in macrophages. In this study, rat TGR5 was cloned and antibodies directed against the C-terminus of rat TGR5 were developed, which detected TGR5 as a glycoprotein in transfected HepG2-cells. Apart from Kupffer cells, TGR5 was detected in SEC of rat liver. SEC expressed TGR5 over the entire acinus, whereas endothelial cells of the portal or central veins were not immunoreactive toward TGR5 antibodies. In isolated SEC, TGR5 mRNA and protein were detected by reverse transcription (RT) PCR, immunofluorescence microscopy, and Western blot analysis. Bile salts increased cAMP in isolated SEC and induced mRNA expression of endothelial NO synthase (eNOS), a known cAMP-dependent gene. In addition, bile acids activated eNOS by phosphorylation of eNOS at amino acid position 1177. In line with eNOS activation, bile acids induced NO production in liver slices. This is the first report on the expression of TGR5 in SEC.Conclusion:The data suggest that SEC are directly responsive toward specific bile salts. Regulation of eNOS in SEC by TGR5 connects bile salts with hepatic hemodynamics. This is of particular importance in cholestatic livers when bile salt concentrations are increased. (Hepatology 2007;45:695–704.)
MELD score as a predictor of liver failure and death in patients with acetaminophen-induced liver injury
Authors: Schmidt Lars E. , Larsen Fin Stolze
Published: February 2007

The Model for End-Stage Liver Disease (MELD) scoring system has been established as a reliable measure of short-term mortality risk in patients with end-stage chronic liver disease. The aim of this study was to evaluate the prognostic value of the MELD scoring as a predictor of fulminant hepatic failure (FHF) and death in patients with acetaminophen poisoning. Prospectively, serial measurements of the 3 MELD components—INR, bilirubin, and creatinine—were performed in 460 patients with acetaminophen-induced liver injury. Starting on the first day after the day of overdose, MELD score was significantly higher in patients who eventually developed hepatic encephalopathy (HE) than in those who did not. HE developed in 63 of 142 patients with a MELD score above 18 at 48-72 hours after the overdose (positive predictive value 44%) compared with 2 of 182 patients with a MELD score of 18 or below (negative predictive value 99%). Among 124 patients with FHF, a threshold MELD score of 33 on the day after the onset of HE had sensitivity of 60%, specificity of 69%, positive predictive value of 65%, and negative predictive value of 63%. However, the discriminative power of MELD score was not superior to that of INR alone or of the King's College Hospital criteria.

Conclusion

: MELD score may be useful as a predictor of FHF in patients admitted with acetaminophen toxicity. However, as a predictor of death from FHF, MELD score did not provide more information than the King's College Hospital criteria or INR alone. (Hepatology 2007;45:789–796.)
Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis
Authors: Di Tommaso Luca , Franchi Giada , Park Young Nyun , Fiamengo Barbara , Destro Annarita , Morenghi Emanuela , Montorsi Marco , Torzilli Guido , Tommasini Maurizio , Terracciano Luigi , Tornillo Luigi , Vecchione Raffaella , Roncalli Massimo
Published: February 2007

Hepatocellular nodules in cirrhosis include regenerative (large regenerative, LRN) and dysplastic (low and high grade, LGDN and HGDN) nodules, early and grade 1 HCC (eHCC-G1), and overt HCC. The differential diagnosis may be particularly difficult when lesions such as HGDN and eHCC-G1 are involved. We investigated the diagnostic yield of a panel of 3 putative markers of hepatocellular malignancy such as HSP70, glypican 3 (GPC3), and glutamine synthetase (GS). We selected 52 surgically removed nonmalignant nodules (15 LRNs, 15 LGDNs, 22 HGDNs) and 53 HCCs (10 early, 22 grade 1, and 21 grade 2-3) and immunostained them for HSP70, GPC3, and GS. The sensitivity and specificity of the individual markers for the detection of eHCC-G1 were 59% and 86% for GS, 69% and 91% for GPC3, and 78% and 95% for HSP70. We identified 2 main phenotypes: (1) all negative, seen in 100% LRN and LGDN, 73% HGDN and 3% eHCC-G1; (2) all positive, a feature detected in less than half the eHCC-G1. Using a 3-marker panel, when at least 2 of them, regardless which, were positive, the sensitivity and specificity for the detection of eHCC-G1 were respectively 72% and 100%; the most sensitive combination was HSP70+/GPC3+ (59%) when a 2-marker panel was used.

Conclusion:

The adopted panel of 3 markers is very helpful in distinguishing eHCC-G1 from dysplastic nodules arising in cirrhosis. (Hepatology 2007;45:725–734.)
Sertraline as a first-line treatment for cholestatic pruritus
Authors: Mayo Marlyn J. , Handem Iorna , Saldana Sandra , Jacobe Heidi , Getachew Yonas , Rush John A.
Published: February 2007

Pruritus is frequently the most debilitating symptom of cholestatic liver diseases. Moreover, existing therapies are often ineffective. Recent small, retrospective case series reports suggest that serotonin reuptake inhibitors can improve pruritus. This study was undertaken to establish the dose of sertraline and to evaluate its efficacy for cholestatic pruritus. Twenty one subjects with chronic pruritus due to liver disease (including primary biliary cirrhosis, primary sclerosing cholangitis, chronic hepatitis C, and postnecrotic cirrhosis) initially underwent an open-label, dose escalation to determine the dose with optimal efficacy and tolerability. After a washout period, 12 of the subjects entered a randomized, double-blind, placebo-controlled trial. Participants quantified their pruritus using a 0-10 visual analog scale, and pruritus was assessed for distribution, timing, degree of disability, and physical evidence of scratching. The optimum sertraline dose (75-100 mg/day) was well tolerated. In the controlled portion of the study, itch scores improved in patients taking sertraline, but worsened in patients taking placebo (

P

= 0.009). Changes in itch distribution, duration, direction, and physical evidence of scratching paralleled changes in the visual analog pruritus score.

Conclusion:

Sertraline seems to be an effective, well-tolerated treatment for pruritus due to chronic liver disease. These results suggest that serotonergic pathways are important in the perception of itch. (Hepatology 2007;45:666–674.)
Immunosuppression reactivates viral replication long after resolution of woodchuck hepatitis virus infection
Authors: Menne Stephan , Cote Paul J. , Butler Scott D. , Toshkov Ilia A. , Gerin John L. , Tennant Bud C.
Published: February 2007

Resolution of hepatitis B virus (HBV) infection is characterized by coordinated humoral and cellular immune responses. Immunity is durable over decades, protecting the host from reinfection and potential activation of residual HBV. Woodchucks infected at birth with woodchuck hepatitis virus (WHV) cleared viremia and developed antibodies to surface antigen (anti-WHs). Woodchucks became seronegative for anti-WHs 3-6 years later, but in some, WHV DNA was detected in serum, liver, and/or peripheral blood mononuclear cells (PBMCs). Those with WHV DNA had increased

in vitro

cellular immune responses to viral antigens, CD4 and CD8 markers, and Th1-type cytokines, suggesting active WHV-specific T lymphocytes. Immunosuppression for 12 weeks using cyclosporine A in such woodchucks resulted in transient reactivation of WHV replication. Serum of 1 woodchuck that became positive for WHV DNA during immunosuppression was inoculated into WHV-susceptible woodchucks, and a productive infection was demonstrated. The results indicate that after infection durable cellular immunity to WHV is essential for the long-term control of viral replication and is probably maintained by continuous priming from residual virus.

Conclusion:

These experimental observations demonstrate the potential of immunosuppression to reactivate HBV after resolution of infection. (Hepatology 2007;45:614–622.)
Revelation of simple and complex liver acini after portal transplantation of pancreatic islets or thyroid follicles in rats
Authors: Dombrowski Frank , Evert Matthias
Published: February 2007

The microarchitecture of the liver is still not completely understood although various concepts of structural liver organization have been proposed. Among them, Rappaport's liver acinus stands out as one of the most accepted models. The correctness of this model, however, has also been doubted, and its applicability is hampered by the fact that the outlines of the liver acinus are disguised and nobody was ever able to give visual evidence by “unmasking” a simple liver acinus from the surrounding liver tissue. After intraportal transplantation of pancreatic islets or thyroid follicles into diabetic or thyroidectomized rats, respectively, the transplants engraft in small portal tracts and morphologically alter the downstream liver tissue due to excessive hormone secretion. Using a combined approach of perfusion fixation, stereomicroscopy, and light microscopy, we demonstrate in this study that these foci of altered liver tissue represent simple and complex liver acini, exactly as described by Rappaport. We present stereomicroscopical and histological examples of all important cut levels of altered simple and complex liver acini, including their topographical relation to the supplying and draining vessels and to the “central vein” liver lobule. Moreover, by computer-aided reconstruction of serial semi-thin sections, we were able to present the first 3-dimensional images of simple and complex liver acini.

Conclusion:

Our results prove the correctness of Rappaport's acinus model and confirm the simple liver acinus as the principal microcirculatory unit of the liver. (Hepatology 2007;45:705–715.)
Combined GM-CSF and IL-12 gene therapy synergistically suppresses the growth of orthotopic liver tumors
Authors: Chang Chun-Jung , Chen Yi-Hsiang , Huang Kai-Wen , Cheng Hao-Wei , Chan Suit-Fong , Tai Kuo-Feng , Hwang Lih-Hwa
Published: February 2007

Immunotherapy is often effective only for small tumor burdens and, in many cases, is restricted to subcutaneous tumors. Here, we investigated the antitumor effects of combination therapy with GM-CSF and IL-12 on orthotopic liver tumors with intermediate or large tumor volumes, or on chemically-induced multifocal liver tumors in animals. Adenoviruses encoding GM-CSF or IL-12 were injected intratumorally to animals bearing transplanted tumors, or injected via intrahepatic artery in animals with primary multifocal liver tumors induced by diethylnitrosamine. Our results demonstrated that IL-12, but not GM-CSF, monotherapy displayed significant therapeutic effects, whereas combination therapy with both cytokines displayed synergistic antitumor effects not only on transplanted tumor models with intermediate or large tumor loads, but also on carcinogen-induced multifocal liver tumors. Effector cell analyses, revealed by

in vivo

cell subset depletion, flow cytometry analysis, and immunohistochemical staining of tumor infiltrates, indicated that NK cells were the prominent antitumor effectors for the IL-12–mediated antitumor activity, whereas CD8+ T cells, NKT cells, and macrophages were more important than NK cells in the combination therapy–mediated antitumor effects. Both IL-12 monotherapy and combination therapy could induce various types of effectors and high levels of IFN-γ; however, the latter induced much higher levels than the former, which may explain why combination therapy is superior to IL-12 monotherapy.

Conclusion:

Combination therapy with GM-CSF and IL-12 represents a promising immunotherapy strategy for treating orthotopic, widespread liver tumors. (Hepatology 2007;45:746–754.)
Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of interferon-γ1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis
Authors: Pockros Paul J. , Jeffers Lennox , Afdhal Nezam , Goodman Zachary D. , Nelson David , Gish Robert G. , Reddy Rajender K. , Reindollar Robert , Rodriguez-Torres Maribel , Sullivan Sarah , Blatt Lawrence M. , Faris-Young Sima
Published: February 2007

Interferon-γ1b (IFN-γ1b) is a pleiotropic cytokine that displays antifibrotic, antiviral, and antiproliferative activity. A total of 502 patients with compensated liver disease and an Ishak fibrosis score of 4-6 were randomized in a double-blind, placebo-controlled study, and 488 of these patients received subcutaneous injections of IFN-γ1b 100 μg (group 1, n = 169), IFN-γ1b 200 μg (group 2, n = 157), or placebo (group 3, n = 162) 3 times a week for 48 weeks. Most patients (83.6%) had cirrhosis at baseline (Ishak score = 5 or 6). Posttreatment liver biopsies were assessed in a blinded fashion for a reduction of 1 or more Ishak points (primary endpoint). Four hundred twenty patients with pretreatment and posttreatment liver biopsies were evaluable and showed no improvement in Ishak score between the 3 treatment groups (12.1%, 12.4%, and 16% of patients in groups 1, 2, and 3, respectively;

P

> 0.05). Analysis of IFN-γ–inducible biomarkers revealed that interferon-inducible T cell–alpha chemoattractant (ITAC), an IFN-γ–inducible CXCR3 chemokine was an independent predictor of stable or improving Ishak score. IFN-γ1b was well tolerated. There were similar numbers of deaths in all 3 arms (5, 5, and 4, respectively), and most were related to complications of cirrhosis.

Conclusion:

IFN-γ1b therapy was not able to reverse fibrosis in patients with advanced liver disease for 1 year. Subgroups of patients with elevated ITAC levels and perhaps less advanced disease may be considered for future studies with IFN-γ1b. (Hepatology 2007;45:569–578.)
The model for end-stage liver disease (MELD)
Authors: Kamath Patrick S. , Kim Ray W.
Published: February 2007

The Model for End-stage Liver Disease (MELD) was initially created to predict survival in patients with complications of portal hypertension undergoing elective placement of transjugular intrahepatic portosystemic shunts. The MELD which uses only objective variables was validated subsequently as an accurate predictor of survival among different populations of patients with advanced liver disease. The major use of the MELD score has been in allocation of organs for liver transplantation. However, the MELD score has also been shown to predict survival in patients with cirrhosis who have infections, variceal bleeding, as well as in patients with fulminant hepatic failure and alcoholic hepatitis. MELD may be used in selection of patients for surgery other than liver transplantation and in determining optimal treatment for patients with hepatocellular carcinoma who are not candidates for liver transplantation. Despite the many advantages of the MELD score, there are approximately 15%-20% of patients whose survival cannot be accurately predicted by the MELD score. It is possible that the addition of variables that are better determinants of liver and renal function may improve the predictive accuracy of the model. Efforts at further refinement and validation of the MELD score will continue. (Hepatology 2007;45:797–805.)