bluuebunny/crossref_metadata_2025 huggingface dataset:
Penetration of UV irradiance into the global ocean
Authors: Smyth T. J.
Published: August 2011

A new global ocean‐atmosphere model has been developed to determine the penetration of ultraviolet (UV) radiation through the water column. This is accomplished by combining an atmospheric UV irradiance model, taking into consideration the effects of aerosols, clouds, and the air‐sea interface, with empirical in‐water diffuse attenuation coefficient (Kd(λUV)) relationships. These empirical relationships are derived from simultaneous in situ profiles of visible wavelength inherent optical properties and downwelling UV irradiances. The combined model is applied to global data sets using a look‐up table approach to speed up calculation time. The atmospheric model compared against ∼3000 data points gave a root‐mean‐square error (RMSE) of between 10% and 15% at wavelengths of 305, 325, 340, and 380 nm; the coupled global model compared against 30 independent in‐water irradiance profiles gave a logarithmic RMSE of between 0.15 and 0.35 at these wavelengths. On the global scale the 10% irradiance levels were found to be deepest in the oceanic gyres (∼18, 32, 44, and 70 m at 305, 325, 340 and 380 nm, respectively) and shallowest in the optically complex continental shelf regions. The calculated UV doses were shown to be spectrally and seasonally variable, with the highest values being encountered in the eastern Mediterranean during July, with values of ∼0.5, 4, 7, and 10 kJ m−2 d−1 nm−1 at 305, 325, 340, and 380 nm, respectively.
Airborne surveys of snow depth over Arctic sea ice
Authors: Kwok R. , Panzer B. , Leuschen C. , Pang S. , Markus T. , Holt B. , Gogineni S.
Published: August 2011

During the spring of 2009, an ultrawideband microwave radar was deployed as part of Operation IceBridge to provide the first cross‐basin surveys of snow thickness over Arctic sea ice. In this paper, we analyze data from three ∼2000 km transects to examine detection issues, the limitations of the current instrument, and the regional variability of the retrieved snow depth. Snow depth is the vertical distance between the air‐snow and snow‐ice interfaces detected in the radar echograms. Under ideal conditions, the per echogram uncertainty in snow depth retrieval is ∼4–5 cm. The finite range resolution of the radar (∼5 cm) and the relative amplitude of backscatter from the two interfaces limit the direct retrieval of snow depths much below ∼8 cm. Well‐defined interfaces are observed over only relatively smooth surfaces within the radar footprint of ∼6.5 m. Sampling is thus restricted to undeformed, level ice. In early April, mean snow depths are 28.5 ± 16.6 cm and 41.0 ± 22.2 cm over first‐year and multiyear sea ice (MYI), respectively. Regionally, snow thickness is thinner and quite uniform over the large expanse of seasonal ice in the Beaufort Sea, and gets progressively thicker toward the MYI cover north of Ellesmere Island, Greenland, and the Fram Strait. Snow depth over MYI is comparable to that reported in the climatology by Warren et al. (1999). Ongoing improvements to the radar system and the utility of these snow depth measurements are discussed.
Regulation and feedback of cholesterol metabolism
Authors: Griffiths William , Freeman Tom , Ghazal Peter , Mazein Alexander , Watterson Steven , Gibbs Holly , Hsieh Wayne , Abdullah Mohammed Ba , Blanc Mathieu
Published: August 2011

Cholesterol biosynthesis serves as a central metabolic hub for numerous biological processes in health and disease. An integrative knowledge representation of how the cholesterol pathway is structured and how it interacts with other pathway systems is lacking. Here we provide using Systems Biology Graphical Notation the research synthesis of a process diagram integrating the regulatory and feedback systems for cholesterol synthesis.
Liquid-vapour equilibria viii. The systems acetoke +benzene and acetone +carbon tetrachloride at 45°C
Authors: Brown I , Smith F
Published: August 2011

The liquid-vapour equilibrium data are given for the systems acetone+benzene
and acetone+carbon tetrachloride at 45.00� C . These data are used to calculate the
excess free energy of mixing for these systems.
Transcranial Two-Photon Imaging of the Living Mouse Brain
Authors: Grutzendler Jaime , Yang Guang , Pan Feng , Parkhurst Christopher N. , Gan Wen-Biao
Published: August 2011

INTRODUCTION

This protocol describes imaging of the living mouse brain through a thinned skull using two-photon microscopy. This transcranial two-photon laser-scanning microscope (TPLSM) imaging method allows high-resolution imaging of fluorescently labeled neurons, microglia, astrocytes, and blood vessels, as well as subcellular structures such as dendritic spines and axonal varicosities. The surgical procedure that is required to allow imaging thins the cranium so that it becomes optically transparent. Once learned, the surgery can be performed in ∼30 min, and imaging can follow immediately. The procedure can be repeated multiple times, allowing brain cells and tissues to be studied in the same animals over short or long time intervals, depending on the design of the experiment. Two-photon imaging through a thinned and intact skull avoids side effects caused by skull removal and is a minimally invasive method for studying the living mouse brain under physiological and pathological conditions.
Immunolabeling of Cells Grown Attached to a Substratum or in Suspension with Actin Antibodies
Authors: Spudich Anna
Published: August 2011

INTRODUCTION

Actin is a major component of all eukaryotic cells and is highly conserved across species. The different isoforms of actin show a very high degree of homology, and almost all actins bind cytochalasins, phallotoxins, and DNase I. Actin is important for maintaining cell shape and for myosin-based movements in cells. In addition, the actin cytoskeleton is involved in localization of other molecules in the cytoplasm and in cellular compartmentalization. Polyclonal and monoclonal antibodies with different specificities are commercially available for labeling actin-containing structures in cells. This article describes a protocol for immunolabeling actin that works well for cells grown in tissue culture as monolayers and for cells grown in suspension cultures that can be attached to polylysine-coated coverslips.
Single-Cell Electroporation of Xenopus Tadpole Tectal Neurons
Authors: Liu Xue Feng , Haas Kurt
Published: August 2011

INTRODUCTION

Single-cell electroporation (SCE) is a versatile technique for delivering electrically charged macromolecules, including DNA, RNA, synthetic oligonucleotides, peptides, dyes, and drugs, to individual cells within intact tissues. Here, we describe methods for SCE of single tectal neurons within the albino Xenopus laevis tadpole for delivery of plasmid DNA-expressing protein fluorophores or fluorescent dye. Individual neurons labeled by this technique can then be imaged in three dimensions (3D) within the intact and living brain using in vivo two-photon microscopy for studies of morphology and growth. The SCE protocol is relatively simple and requires minimal and common laboratory equipment, including a fluorescent stereomicroscope, micropipette puller, and electrical stimulator. Once equipment is set up, learning to label cells with fluorescent dyes is straightforward and usually quickly achieved, because direct visualization with fluorescent microscopy offers immediate feedback of success. The main challenges are positioning the pipette tip in a cell body layer and optimizing pipette tip shape and stimulation parameters. Once fluorescent dye loading has been achieved, transfecting neurons with DNA should follow by using the same pipette tip parameters, but extending the stimulation parameters, because plasmid DNA is larger than dye and requires formation of larger pores. Detectable expression of protein fluorophores from transfected DNA typically takes 6–12 h. SCE for dye loading or DNA transfection of tadpole tectal neurons is highly efficient and can be learned in 1 or 2 d by novice laboratory personnel.
Dissection of First- and Second-Instar Drosophila Larvae for Electrophysiological Recording from Neurons: The Flat (or Fillet) Preparation: Figure 1.
Authors: Marley Richard , Baines Richard A.
Published: August 2011

INTRODUCTION

The fruit fly Drosophila melanogaster has been instrumental in expanding our understanding of early aspects of neural development. The use of this model system has greatly added to our knowledge of neural cell-fate determination, axon guidance, and synapse formation. It has also become possible to access and make electrophysiological recordings directly from neurons in situ in an intact central nervous system (CNS), which has facilitated studies of the development and regulation of neuronal signaling. It is possible to obtain electrophysiological recordings from all stages of Drosophila. Exposure of the intact Drosophila CNS is a prerequisite for such electrophysiological recordings. The dissection procedure described here can be applied to both late-stage embryos (stage 16 onward) and larvae. Because of their size, third-instar larvae are more difficult to flatten using this method and, if recording from this stage, the reader might consider using insect pins for the dissection or isolating the CNS using an alternative method. The dissection should take <10 min if all preparation work has been completed in advance. Owing to the short life span of the dissected larva, it is not recommended that the procedure be stopped or the preparation stored for later use.
Characterization of polygenic resistance to powdery mildew in tomato at cytological, biochemical and gene expression level
Authors: LI CHENGWEI , FAINO LUIGI , DONG LIN , FAN JUNMEI , KISS LEVENTE , DE GIOVANNI CLAUDIO , LEBEDA ALES , SCOTT JOHN , MATSUDA YOSHINORI , TOYODA HIDEYOSHI , LINDHOUT PIM , VISSER RICHARD G. F. , BONNEMA GUUSJE , BAI YULING
Published: August 2011

Extensive research in the area of plant innate immunity has increased considerably our understanding of the molecular mechanisms associated with resistance controlled by a dominant resistance gene. In contrast, little is known about the molecular basis underlying the resistance conferred by quantitative trait loci (QTLs). In this study, using the interaction of tomato (Solanum lycopersicum) with Oidium neolycopersici, we compared the cytological, biochemical and molecular mechanisms involved in both monogenic and polygenic resistances conferred by a dominant gene (Ol‐1) and three QTLs (Ol‐qtls), respectively. Our results showed that the three Ol‐qtls jointly confer a very high level of broad‐spectrum resistance and that the resistance is associated with both the hypersensitive response and papillae formation, with the hypersensitive response being prevalent. Both H2O2 and callose accumulation, which are coupled with Ol‐1‐mediated resistance, are also associated with the resistance conferred by Ol‐qtls. Further, we analysed the pathogen‐induced transcript profiles of near‐isogenic lines carrying the three Ol‐qtls and the Ol‐1 gene. Transcript profiles obtained by cDNA‐amplified fragment length polymorphism analysis showed that, on fungal challenge, about 70% of the transcript‐derived fragments are up‐regulated in both susceptible and resistant genotypes. Most of the sequenced transcript‐derived fragments showed homology to genes with functions in defence responses, suggesting that defence‐responsive genes responsible for basal defence are involved in both monogenic and polygenic resistances conferred by Ol‐1 and Ol‐qtls, respectively. Although about 18% of the identified transcript‐derived fragments are specific for either monogenic or polygenic resistance, their expression patterns need to be further verified by quantitative reverse transcriptase‐polymerase chain reaction.
A potential tool to mitigate the impacts of climate change to the caribbean leatherback sea turtle
Authors: Patino‐Martinez Juan , Marco Adolfo , Quiñones Liliana , Hawkes Lucy
Published: August 2011

It is now well understood that climate change has the potential to dramatically affect biodiversity, with effects on spatio‐temporal distribution patterns, trophic relationships and survivorship. In the marine turtles, sex is determined by incubation temperature, such that warming temperatures could lead to a higher production of female hatchlings. By measuring nest temperature, and using a model to relate the incubation temperature to sex ratio, we estimate that Caribbean Colombian leatherback sea turtles currently produce approximately 92% female hatchlings. We modelled the relationship between incubation, sand and air temperature, and under all future climate change scenarios (0.4–6.0 °C warming over the next 100 years), complete feminization could occur, as soon as the next decade. However, male producing refugia exist in the periphery of smaller nests (0.7 °C cooler at the bottom than at the centre), within beaches (0.3 °C cooler in the vegetation line and inter‐tidal zone) and between beaches (0.4 °C higher on dark beaches), and these natural refugia could be assigned preferential conservation status. However, there exists a need to develop strategies that may ameliorate deleterious effects of climate‐induced temperature changes in the future. We experimentally shaded clutches using screening material, and found that it was effective in reducing nest temperature, producing a higher proportion of male hatchlings, without compromising the fitness or hatching success. Artificial shade in hatcheries is a very useful and simple tool in years or periods of high environmental temperatures. Nevertheless, this is only an emergency response to the severe impacts that will eventually have to be reversed if we are to guarantee the stability of the populations.
Important variations in the content of care pathway documents for total knee arthroplasty may lead to quality and patient safety problems
Authors: Segal Olivier , Bellemans Johan , Van Gerven Eva , Deneckere Svin , Panella Massimiliano , Sermeus Walter , Vanhaecht Kris
Published: August 2011

Aim  Reducing variations by standardizing the key interventions in clinical processes is an effective tool to minimize the probability of medical errors. Thus, we determined whether variations exist in the key interventions included in care pathway documents (CPDs) of different organizations and in the timing of these interventions during the care process.

Methods  We invited members of the Belgian Dutch Clinical Pathway Network to send their CPDs for external review. We analysed 19 CPDs for total knee arthroplasty. International guidelines were consulted for definition of key interventions. Documentation of these interventions in the pathway documents was checked.

Results  From the 19 CPDs analysed, we retrieved 18 key interventions. Nine of these key interventions appeared in at least 80% of the care pathways. Only two key interventions appeared in all pathway documents. Nine out of 12 interventions that appeared in at least 80% of the pathway documents showed a variation of 1 day in the timing of care from the median timing.

Conclusion  We conclude that important variation exists in the included interventions and in their timing. The results of this study suggest that, before use in daily patient care, CPDs should be reviewed by peers and checked to ensure that all evidence‐based key interventions are included and properly planned. Only in this way can pathways documents be used interprofessionally during the entire perioperative period in the search for optimal quality and patient safety.
The experience of young people with depression: a qualitative study
Authors: MCCANN T. V. , LUBMAN D. I. , CLARK E.
Published: August 2011

Accessible summary

Young people struggle to come to terms with depression.

They may withdraw from friends, fearful of stigma and to preserve friendships in the longer term, but withdrawing from friends can have paradoxical consequences.

They may respond in self‐protective, harmful and sometimes life‐threatening ways to their depression.

People who develop depression experience a maelstrom of emotions as they struggle to understand what is happening to them. While the experience has been comparatively well documented in older adults, much less is known about the depression experience and responses of young people. In this study, we aimed to explore the experience of young people diagnosed with depression. Twenty‐six young people were recruited from a youth mental health service. A qualitative interpretative design was used, incorporating semi‐structured, audio‐recorded interviews. Results provided four overlapping themes, reflecting the young people's difficulties in coming to terms with, and responding in self‐protective, harmful and at times life‐threatening ways to their depression: (1) struggling to make sense of their situation; (2) spiralling down; (3) withdrawing; and (4) contemplating self‐harm or suicide. Study conclusions are that young people faced considerable difficulties coming to terms with, and responding to, depression. Improving young people's understanding of depression and its treatment, reducing community stigma and providing accessible and youth‐focused services remain important targets for intervention. It is also important to improve mental health literacy in the community to increase awareness of depression and how mental health professionals, including nurses, respond effectively to the young person.
RepC protein of the octopine‐type Ti plasmid binds to the probable origin of replication within repC and functions only in cis
Authors: Pinto Uelinton M. , Flores‐Mireles Ana L. , Costa Esther D. , Winans Stephen C.
Published: August 2011

Vegetative replication and partitioning of many plasmids and some chromosomes of alphaproteobacteria are directed by their repABC operons. RepA and RepB proteins direct the partitioning of replicons to daughter cells, while RepC proteins are replication initiators, although they do not resemble any characterized replication initiation protein. Here we show that the replication origin of an Agrobacterium tumefaciens Ti plasmid resides fully within its repC gene. Purified RepC bound to a site within repC with moderate affinity, high specificity and with twofold cooperativity. The binding site was localized to an AT‐rich region that contains a large number of GANTC sites, which have been implicated in replication regulation in related organisms. A fragment of RepC containing residues 26–158 was sufficient to bind DNA, although with limited sequence specificity. This portion of RepC is predicted to have structural homology to members of the MarR family of transcription factors. Overexpression of RepC in A. tumefaciens caused large increases in copy number in cis but did not change the copy number of plasmids containing the same oriV sequence in trans, confirming other observations that RepC functions only in cis.
Echinococcus granulosus glycoconjugates induce peritoneal B cell differentiation into antibody‐secreting cells and cytokine production
Authors: MOURGLIA‐ETTLIN G. , AMEZCUA‐VESELY M. C. , FRAGA R. , BAZ A. , MERINO M. C. , GRUPPI A. , DEMATTEIS S.
Published: August 2011

Helminth parasite infections are associated with predominant Th2‐type cytokine responses, and parasite glycoconjugates have been recognized as partially responsible for such immune bias. It has been proved that Echinococcus granulosus evokes a Th2‐type cytokine pattern characterized by a high production of IL‐4, IL‐5, IL‐6 and IL‐10, and no or mild IFN‐γ levels in animal models and in patients with cystic echinococcosis, respectively. Here, we show that E4+ (a glycoconjugate‐enriched fraction from E. granulosus protoscolex) stimulated the secretion of a high concentration of IL‐6, followed by IL‐10 and TNF‐α by normal peritoneal B cells. We determined that E4+ bound to the surface of peritoneal B cells and induced their activation and, also, triggered the differentiation of peritoneal B cells into IgM‐, IgG2b‐ and IgG3‐secreting cells in a T‐independent way. Interestingly, the IgM released by E4+‐stimulated peritoneal B cells from normal mice recognized protoscolex antigens. Results showed that, after the encounter with antigens from E. granulosus protoscolex, peritonealB cells are a source of Th2‐type cytokines and polyclonal antibodies, some of which recognize parasite antigens, suggesting that peritoneal B cells can condition the outcome of the infection.
Genetic diversity of Philaenus spumarius and P. tesselatus (Hemiptera, Aphrophoridae): implications for evolution and taxonomy
Authors: MARYAŃSKA‐NADACHOWSKA ANNA , KAJTOCH ŁUKASZ , LACHOWSKA DOROTA
Published: August 2011

The meadow spittlebugs Philaenus spumarius and P. tesselatus are closely related taxa with uncertain taxonomic position in the light of previous morphological, ecological, cytological and molecular research. Despite morphological homogeneity of P. spumarius (with the exception of high colour and pattern polymorphism) across its wide Holarctic range, it is possible that additional taxa (species or subspecies) exist. Philaenus spumarius is a potentially important pest in parts of its range where it was introduced. We used DNA markers to describe the genetic diversity of P. spumarius and P. tesselatus and to verify the taxonomic status of P. tesselatus and remote populations of the former species. The mitochondrial (cytochrome B) data showed that there are two main groups encompassing a northeastern (Asia and north‐central Europe) and a southwestern (Mediterranean area and western Europe, including North American specimens) clade. According to the elongation factor‐1α gene, there are three main clades: northeastern (Eurasiatic clade, E1), southeastern (east Mediterranean – Caucasus clade, E2) and southwestern (Iberian clade, E3). These two or three mitochondrial and nuclear clades could be considered as separate taxonomic units. On the other hand, all studied individuals of both species possessed the same internal transcribed spacer 2 haplotype. American specimens most probably originated from some western European populations. All studied specimens of P. tesselatus belong to the southwestern clade and western Mediterranean cluster. Therefore, together with cytological data, its species status is doubtful. To definitively solve the taxonomic status of P. tesselatus and populations of P. spumarius, further research using more samples and more genetic markers are needed.
An Al‐inducible MATE gene is involved in external detoxification of Al in rice
Authors: Yokosho Kengo , Yamaji Naoki , Ma Jian Feng
Published: August 2011

A number of plant species, including rice, secretes citrate from roots in response to Al stress. Here we characterized the functions of a gene, OsFRDL4 (Os01g0919100) that belongs to the multidrug and toxic compound extrusion (MATE) family in rice (Oryza sativa). Heterologous expression in Xenopus oocyte showed that the OsFRDL4 protein was able to transport citrate and was activated by Al. The expression level of the OsFRDL4 gene in roots was very low in the absence of Al, but was greatly enhanced by Al after short exposure. Furthermore, the OsFRDL4 expression was regulated by ART1, a C2H2‐type zinc finger transcription factor for Al tolerance. Transient expression of OsFRDL4 in onion epidermal cells showed that it localized to the plasma membrane. Immunostaining showed that OsFRDL4 was localized in all cells in the root tip. These expression patterns and cell specificity of localization of OsFRDL4 are different from other MATE members identified previously. Knockout of OsFRDL4 resulted in decreased Al tolerance and decreased citrate secretion compared with the wild‐type rice, but did not affect citrate concentration in the xylem sap. Furthermore, there is a positive correlation between OsFRDL4 expression level and the amount of citrate secretion in rice cultivars that are differing in Al tolerance. Taken together, our results show that OsFRDL4 is an Al‐induced citrate transporter localized at the plasma membrane of rice root cells and is one of the components of high Al tolerance in rice.
The fitness of drug‐resistant malaria parasites in a rodent model: multiplicity of infection
Authors: HUIJBEN S. , SIM D. G. , NELSON W. A. , READ A. F.
Published: August 2011

Malaria infections normally consist of more than one clonally replicating lineage. Within‐host interactions between sensitive and resistant parasites can have profound effects on the evolution of drug resistance. Here, using thePlasmodium chabaudimouse malaria model, we ask whether the costs and benefits of resistance are affected by the number of co‐infecting strains competing with a resistant clone. We found strong competitive suppression of resistant parasites in untreated infections and marked competitive release following treatment. The magnitude of competitive suppression depended on competitor identity. However, there was no overall effect of the diversity of susceptible parasites on the extent of competitive suppression or release. If these findings generalize, then transmission intensity will impact on resistance evolution because of its effect on the frequency of mixed infections, not because of its effect on the distribution of clones per host. This would greatly simplify the computational problems of adequately capturing within‐host ecology in models of drug resistance evolution in malaria.
Chromosomal regions associated with dollar spot resistance in colonial bentgrass
Authors: Rotter David , Merewitz Emily , Huang Bingru , Belanger Faith C.
Published: August 2011

With 1 figure and 4 tables

Interspecific hybridization between colonial bentgrass and creeping bentgrasses may be a useful approach for introducing resistance to Sclerotinia homoeocarpa, the causal agent of dollar spot disease, into creeping bentgrass. An interspecific backcross population of 271 genotypes was evaluated for dollar spot in a 2‐year field study, and 11% of the genotypes were resistant to dollar spot. In the subset of the backcross population used for genetic linkage mapping, some resistant plants were identified, but no quantitative trait locus (QTL) was detected. A model of qualitative 3‐gene recessive epistasis for dollar spot resistance in colonial bentgrass was proposed, and the limitations of QTL analysis to detect genomic regions conferring multigenic qualitative traits were examined. In the simulations, monogenic traits and 2‐gene recessive epistatic traits were readily detectable by QTL analysis, whereas for 3‐gene recessive epistasis, a QTL was not detectable. As an alternative to QTL analysis, screening of resistant plants from the backcross population for genomic regions held in common suggests that linkage groups 2A1 and 3A1 are possibly genomic locations of dollar spot resistance in colonial bentgrass.
Protective role of uncoupling protein‐2 against dextran sodium sulfate‐induced colitis
Authors: Zhang Hongjie , Kuai Xiao‐yi , Yu Pengli , Lin Lin , Shi Ruihua
Published: August 2011

Background and Aims:  Uncoupling protein‐2 (UCP‐2) is a negative regulator of reactive oxygen species (ROS) production. We investigated the effect of UCP‐2 on disease progression in a murine dextran sodium sulfate (DSS)‐induced colitis model, and the expression and distribution of tight junction (TJ) proteins, such as occludin, zonula‐1 (ZO‐1), claudin‐4, and junctional adhesion molecule‐1 (JAM‐1).

Methods:  Male UCP‐2−/− mice and wild‐type littermates were divided into four groups: groups I and II, which comprised each type of mouse, were administered 2.5% DSS dissolved in drinking water to create a colitis model. The control groups (groups III and IV, which comprised each type of mouse) were given normal drinking water. Disease progression was evaluated according to colon length and the disease activity index. The distribution of TJ proteins was detected by immunohistochemical analysis.

Results:  Compared with wild‐type littermates, UCP‐2−/− mice treated with DSS developed more severe diarrhea, body weight loss (P < 0.01), significantly short colon length, and more inflammatory cell infiltration into the mucosa and submucosa. The level of malondialdehyde in colonic mucosa increased in UCP‐2−/− mice treated with DSS compared with the wild‐type littermates (P < 0.001). The distribution of the ZO‐1 and JAM‐1 proteins was significantly decreased in the colonic mucosa of UCP‐2−/− mice compared with the wild‐type littermates, whereas occludin and claudin‐4 distribution were not different between the UCP‐2−/− mice and wild‐type littermates.

Conclusions:  UCP‐2 might reduce intestinal inflammatory response through the negative regulation of ROS, and affects the expression and distribution of TJ proteins.
Ribavirin downmodulates inducible costimulator on CD4+ T cells and their interleukin‐10 secretion to assist in hepatitis C virus clearance
Authors: Atsukawa Masanori , Nakatsuka Katsuhisa , Kobayashi Tamaki , Shimizu Masumi , Tamura Hideto , Harimoto Hirotomo , Takahashi Hidemi , Sakamoto Choitsu
Published: August 2011

Background and Aim:  The immunological mechanism by which ribavirin (RBV) polarizes the T‐helper (Th) 1/2 balance toward Th1 predominancy is not fully understood. We therefore examined whether RBV affects costimulatory signaling, which is known to be essential for regulating the Th1/2 balance.

Methods:  The expression of costimulatory molecules and their ligands, and levels of various cytokines, released from CD4+ T cells obtained from healthy individuals or patients with chronic hepatitis C virus (HCV) infection were analyzed.

Results:  In CD4+ T cells, RBV selectively downmodulates the expression of inducible costimulator (ICOS), a ligand for B7–H2 on dendritic cells, which mainly differentiates Th0 into Th2 cells. Moreover, the levels of interleukin‐10 (IL‐10) released from RBV‐stimulated CD4+ T cells also decreased, indicating that the downmodulation of ICOS induced by RBV might be correlated with the decrease in IL‐10 released from Th cells, leading to the inhibition of Th2 activity. An analysis of the association between ICOS kinetics and hepatitis C virus (HCV) elimination in hepatitis C patients receiving combined pegylated interferon and RBV indicated that HCV elimination tended to occur more frequently in patients showing ICOS downmodulation with RBV treatment. A decrease in IL‐10 production by CD4+ T cells was also observed in association with ICOS downregulation in patients who succeeded in HCV elimination.

Conclusions:  The downmodulation of ICOS in correlation with a reduction in IL‐10 produced by CD4+ T cells is possibly the immunological mechanism of action of RBV, which polarizes the Th1/2 balance toward a Th1 cytokine profile, thus contributing to the elimination of cells chronically infected with HCV.
Colorectal cancer mouse models: Integrating inflammation and the stroma
Authors: Ernst Matthias , Ramsay Robert G
Published: August 2011

Sequences of molecular events that initiate and advance the progression of human colorectal cancer (CRC) are becoming clearer. Accepting that these events, once they are in place, accumulate over time, rapid disease progression might be expected. Yet CRC usually develops slowly over decades. Emerging insights suggest that the tumor cell microenvironment encompassing fibroblasts and endothelial and immune cells dictate when, whether, and how malignancies progress. Signaling pathways that affect the microenvironment and the inflammatory response seem to play a central role in CRC. Indeed, some of these pathways directly regulate the stem/progenitor cell niche at the base of the crypt; it now appears that the survival and growth of neoplastic cells often relies upon their subverted engagement of these pathways. Spurned on by the use of gene manipulation technologies in the mouse, dissecting and recapitulating these complex molecular interactions between the tumor and its microenvironment in the gastrointestinal (GI) tract is a reality. In parallel, our ability to isolate and grow GI stem cells in vitro enables us, for the first time, to complement reductionist in vitro findings with complex in vivo observations. Surprisingly, data suggest that the large number of signaling pathways underpinning the reciprocal interaction between the neoplastic epithelium and its microenvironment converge on a small number of common transcription factors. Here, we review the separate and interactive roles of NFκB, Stat3, and Myb, transcription factors commonly overexpressed or excessively activated in CRC. They confer molecular links between inflammation, stroma, the stem cell niche, and neoplastic cell growth.
Current status on the diagnosis and management of pancreatic cysts in the Asia–Pacific region: Role of endoscopic ultrasound
Authors: Lim Lee Guan , Itoi Takao , Lim Wee Chian , Mesenas Steven Joseph , Seo Dong Wan , Tan Jonard , Wang Hsiu Po , Akaraviputh Thawatchai , Lakhtakia Sandeep , Omar Salem , Rantachu Thawee , Sachitanandan Sharmila , Yasuda Kenjiro , Varadarajulu Shyam , Wong Jennie , Dhir Vinay , Ho Khek Yu ,   the Asian Consortium of EUS
Published: August 2011

Endoscopic ultrasound (EUS) and EUS‐guided fine‐needle aspiration (EUS‐FNA) play increasingly prominent roles in the diagnosis and management of pancreatic cysts. The Asian Consortium of Endoscopic Ultrasound was recently formed to conduct collaborative research in this area. This is a review of literature on true pancreatic cysts. Due to the lack of systematic studies, there are no robust data on the true incidence of pancreatic cystic lesions in Asia and any change in over the recent decades. Certain EUS morphological features have been used to predict particular types of pancreatic cysts. Pancreatic cyst fluid viscosity, cytology, pancreatic enzymes, and tumor markers, in particular carcinoembryonic antigen, can aid in the diagnosis of pancreatic cysts. Hemorrhage and infection are the most common complications of EUS‐FNA of pancreatic cysts. Pancreatic cysts can either be observed or resected depending on the benign or malignant nature, or malignant potential of the lesions. Guidelines from an international consensus did not require positive cytological findings to be present in their recommendation for resection, which included all mucinous cystic neoplasms, all main‐duct intraductal papillary mucinous neoplasms (IPMN), all mixed IPMN, symptomatic side‐branch IPMN, and side‐branch IPMN larger than 3 cm. In patients with poor surgical risks, EUS‐guided cyst ablation of mucinous pancreatic cysts is an alternative. As long‐term prospective data on pancreatic cysts are still not available in Asia, management strategies are largely based on risk stratification by surgical risk and malignant potential. Gene expression profiling of pancreatic cyst fluid and confocal laser endomicroscopic examination of pancreatic cysts are novel techniques currently being studied.
Differential prognostic impact of renal insufficiency on patients with hepatocellular carcinoma: A propensity score analysis and staging strategy
Authors: Hsu Chia‐Yang , Hsia Cheng‐Yuan , Huang Yi‐Hsiang , Su Chien‐Wei , Lin Han‐Chieh , Chiou Yi‐You , Lee Rheun‐Chuan , Lee Fa‐Yauh , Huo Teh‐Ia , Lee Shou‐Dong
Published: August 2011

Background and Aim:  Renal insufficiency (RI) can coexist in patients with hepatocellular carcinoma (HCC). This study analyzed the prognostic impact of RI on patients with HCC and determined the optimal staging strategy for these patients.

Methods:  RI was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2. A total of 502 and 1701 HCC patients with and without RI, respectively, were enrolled. One‐to‐one matched patient cohorts according to treatments were built by using the propensity model. The prognostic ability of the Cancer of the Liver Italian Program, Barcelona Clinic Liver Cancer, Japan Integrated Scoring, and Taipei Integrated Scoring (TIS) systems in HCC patients with RI was compared by using the Akaike information criterion (AIC).

Results:  For patients undergoing percutaneous ablation and transarterial chemoembolization (TACE), RI was significantly associated with decreased long‐term survival (P = 0.001 and 0.004, respectively). In patients receiving resection and other treatments, there were no significant survival differences between patients with and without RI. With similar demographics generated in the propensity model, significantly decreased survival was found in patients with RI in the TACE group (P = 0.018), but not in the resection, percutaneous ablation, and other treatment groups. Among HCC patients with RI, the TIS system had the lowest AIC value.

Conclusions:  RI is often present in patients with HCC and predicts a poor outcome in patients undergoing TACE. The survival of HCC patients receiving resection, percutaneous ablation, and other treatments is not affected by RI. The TIS staging system is a more feasible prognostic model for HCC patients with RI.
Is transient elastography valuable for high‐risk esophageal varices prediction in patients with hepatitis‐B‐related cirrhosis?
Authors: Chen Yong Peng , Zhang Qi , Dai Lin , Liang Xie Er , Peng Jie , Hou Jin Lin
Published: August 2011

Background and Aim:  The aim of this study was to evaluate the clinical value of transient elastography (TE) for high‐risk esophageal varices (HREV) prediction in hepatitis‐B‐related cirrhosis patients.

Methods:  A total of 238 patients with hepatitis B cirrhosis were prospectively enrolled. All patients had undergone TE and upper gastrointestinal endoscopy. Diagnostic value was assessed by the area under ROC curve (AUROC), predictive value and likelihood ratio.

Results:  The size of esophageal varices correlated with liver stiffness with Kendall's tau_b 0.236 overall and 0.425 in patients with ALT ≥ 5 × upper limit of normal (ULN). The AUROC of TE predicting HREV was 0.73 (95% confidence interval 0.66–0.80) overall and 0.92 (0.82–1.01) for patients with ALT ≥ 5 × ULN. In patients with ALT ≥ 5 × ULN, cut‐off 36.1 kPa predicted HREV with a 100% negative predictive value (NPV), an indefinite negative likelihood ratio (NLR), a 72.7% positive predictive value (PPV) and a positive likelihood ratio (PLR) of 9.3. The AUROC of HREV‐predicting model, constructed by ultrasonography and TE (USLS), was 0.84 (0.77–0.90) in the training set and 0.85 (0.76–0.94) in the validating set. Cut‐off 3.30 excluded HREV with NPV 0.946 and NLR 0.10, and cut‐off 5.98 determined HREV with PPV 0.870 and PLR 10.24. Using USLS, nearly 50% of patients could avoid endoscopic screening. The model's predictive values were maintained at similar accuracy in the validation set. Differences of AUROC in USLS, liver stiffness/spleen diameter to platelet ratio score and ultrasonic score were not significant.

Conclusions:  TE may predict HREV in patients with ALT ≥ 5 × ULN. Overall, the clinical values of TE and USLS for HREV prediction should be evaluated by further studies.
Literature review in cases with exacerbation of ulcerative colitis induced by treatment with interferon and/or ribavirin
Authors: Watanabe Takuya , Hirono Haruka , Hasegawa Katsuhiko , Soga Kenji , Shibasaki Koichi
Published: August 2011

Ulcerative colitis (UC) is an immune disorder of the gastrointestinal tract which has been reported to be precipitated by interferon (IFN) therapy. We describe the results of a literature review of cases in which the development or exacerbation of UC was coincident with IFN and/or ribavirin (RIB) treatment for chronic hepatitis C. We summarized the studies on the effectiveness of IFN for UC or Crohn's disease, which were primarily carried out in Europe and the USA.

In the nine reported cases of UC exacerbation by IFN therapy in Japan, seven involved IFN‐α, one involved IFN‐α2b plus RIB, and the other involved IFN‐β; thus cases induced by IFN‐α were more common. The period between the initiation of IFN treatment and the development or exacerbation of UC varied widely among the reported cases (from 1 day to 4.5 years). The reports have all assumed a cause‐and‐effect correlation between IFN treatment and UC. However, although combination therapy of IFN and RIB has become widespread in Japan, UC development or exacerbation induced by IFN has not increased concurrently.

Conversely, numerous studies reporting the effectiveness of IFN for treating UC and Crohn's disease have been published in Europe and the USA. One reason for this finding may be the difference in the balance of T helper cell 1 and T helper cell 2 between populations.
Critical appraisal of clinical practice guidelines for diagnosis and treatment of hepatocellular carcinoma
Authors: Schmidt Sebastian , Follmann Markus , Malek Nisar , Manns Michael P. , Greten Tim F.
Published: August 2011

Background and Aim:  Hepatocellular carcinoma (HCC) is the third most common reason for cancer‐related death worldwide. Many countries either lack appropriate clinical practice guidelines for the diagnosis and treatment of HCC or the quality of their guidelines has never been evaluated. The main objective of our work was to identify published HCC guidelines and assess their quality with the Appraisal of Guidelines for Research and Evaluation instrument (AGREE) and their suitability regarding adaptation for future guidelines.

Methods:  We performed a systematic literature search on HCC clinical practice guidelines of MEDLINE, National Guidelines Clearinghouse and the Guidelines International Network. Methodological quality of selected guidelines was assessed by the AGREE instrument, Version 2001.

Results:  A total of 286 citations were screened and 32 relevant guidelines were identified. Overall, the guidelines performed well in the clarity and presentation domain with a mean score of 67%, followed by scope and purpose (55%) and rigor of development (50%). In contrast, poor scores were given for the remaining domains: stakeholder involvement (23%), applicability (28%) and editorial independence (31%). According to the AGREE instrument, four guidelines can be strongly recommended, 18 with provisos and alterations while the remaining cannot be recommended for adaptation due to poor methodological quality.

Conclusion:  Although existing HCC guidelines may accurately reflect agreed clinical practice, many guidelines lack proper methodological quality. Future guidelines should place more emphasis on these methodological shortcomings.
Hepatocellular carcinoma and vitamin D: A review
Authors: Chiang Kun‐Chun , Yeh Chun‐Nan , Chen Miin‐Fu , Chen Tai C
Published: August 2011

The non‐classical actions of vitamin D, namely antiproliferation, pro‐differentiation, pro‐apoptosis, anti‐inflammation, and immune regulation, have received great attention during the past decade. Increasing evidence from epidemiological studies showing the inverse association between vitamin D status and incidence of many forms of cancer as well as biochemical studies has suggested that vitamin D deficiency may play a role in the cause and progression of these types of cancer. Recently, vitamin D and its analogs have been deemed as potential regimen to treat a variety of cancers alone or in combination with other drugs. Although, the epidemiologic evidence regarding the association of vitamin D and hepatocellular carcinoma (HCC) is still inconclusive, biochemical evidence clearly indicates that HCC cells are responsive to the inhibitory effect of vitamin D and its analogs. In this review, we discuss the current status of HCC and its treatment, the source, metabolism, functions, and the mechanism of actions of vitamin D, and the biochemical studies of vitamin D analogs and their implications in the prevention and treatment of HCC.
Effect of oral hepatocyte growth factor gene mediated by attenuated salmonella on 2‐, 4‐, 6‐trinitro‐benzene‐sulfonic‐acid‐induced ulcerative colitis in rat
Authors: Ha Xiaoqin , Yin Qiang , Hui Ling , Jia Qinghua , Wang Meiliang , Zhang Junli , Xu Yuebin , Chang Yewei , Yang Xiaopeng
Published: August 2011

Background and Aim:  In order to explore a new therapeutic method, we investigated the effects of exogenously expressed hepatocyte growth factor mediated by attenuated salmonella (TPH) on rats with ulcerative colitis (UC) induced by 2‐, 4‐, 6‐trinitro‐benzene‐sulfonic acid.

Methods:  The UC rats were treated with TPH, attenuated salmonella with a eukaryotic expression vector (TP) or sodium bicarbonate (model control [MC]) every other day. Cluster of differentiation (CD)4+ and CD8+ T cells and immunoglobulins in the blood were analyzed by flow cytometry. The HGF expression was determined by immunohistochemistry. A macroscopic‐scale observation of the colon and a histological assessment were also carried out.

Results:  The CD4+T counts and the CD4+/CD8+ ratio in the TPH group were significantly lower than that in the MC group. The immunoglobulin M and immunoglobulin G1 levels in the TPH group were significantly lower than that in the MC group and TP group. After treatment with TPH, the symptoms of the ulcerative rats were significantly alleviated. The colonic lesion grades in the TPH group were lower than that in the TP group and MC group. Significant improvement occurred after the TPH treatment, as evidenced by alleviated mucosal inflammation. At 7 days post‐treatment, the HGF expression in the colonic tissues that were treated with TPH was stronger than that in the samples treated with TP.

Conclusions:  TPH inhibits the proliferation of T lymphocytes and the antibody production of B lymphocytes. Furthermore, it ameliorates mucosal inflammation and promotes the regeneration of mucosa and the healing of the colonic ulceration.
Blind peritoneal catheter placement with a tenckhoff trocar by nephrologists: A single‐center experience
Authors: KANG SEOK HUI , DO JUN YOUNG , CHO KYU HYANG , PARK JONG WON , YOON KYUNG WOO
Published: August 2011

Aim:  Blind peritoneal dialysis (PD) catheter instrumentation with a Tenckhoff trocar is performed without direct visualization of the peritoneum. This method requires the least equipment, it is safe and it can be performed mainly by nephrologists. We report here on our long‐term experience with this method as performed by nephrologists.

Methods:  We reviewed the medical records at Yeungnam University Hospital in Korea and identified all the patients who had undergone blind PD catheter instrumentation with a Tenckhoff trocar by nephrologists. Four hundred and three patients were enrolled.

Results:  Early complications occurred in 7.7% (four patients with pericatheter bleeding, one patient with pleural leakage, two patients with migration, two patients with omental wrapping, three patients with exit site/tunnel infection and 19 patients with peritonitis). The late mechanical complications included eight cases of hernia, three cases of catheter extrusion, five cases of leakage, four cases of migration and five cases of omental wrapping. Exit site/tunnel infection and peritonitis occurred at a rate of 0.067 and 0.40 episodes/year, respectively. The intervention free survival rate was 84.5% at one year and 63.3% at 5 years. The catheter survival rate was 96.5% at one year and 83.6% at 5 years.

Conclusion:  This study provides evidence that blind PD catheter placement with a Tenckhoff trocar requires the least equipments, and it is easy to perform. Therefore, if the general anesthesia is impossible or equipment, such as fluoroscopy and laparoscopy, were not available, this method may be an alternative choice for PD catheter placement.