bluuebunny/crossref_metadata_2025 huggingface dataset:
Stroke work or systolic dP/dtmax to evaluate acute response to cardiac resynchronization therapy: are they interchangeable?
Authors: de Roest Gerjan , Knaapen Paul , Götte Marco , Hendriks Thijs , Allaart Cor , de Cock Carel , van Rossum Albert
Published: June 2009

Background

Cardiac resynchronization therapy (CRT) is characterized by a ~30% non‐response. Invasive haemodynamic measurements are a traditional method to evaluate response to CRT. This study evaluates the correlation between acute changes in dP/dtmax and Stroke Work (SW) during CRT.

Methods

Thirty‐four CRT candidates were haemodynamically evaluated by pressure–volume loop analysis during biventricular pacing.

Results

Mean dP/dtmax and SW at baseline were 854 ± 198 and 5186 ± 2349, and displayed an increase during pacing of 106 ± 117 mmHg/s (13% ± 14%) and 1303 ± 3039 mL/mmHg (30% ± 52%), respectively. No correlation was found between the percentage change in dP/dtmax and SW (R = 0.06, P = ns). When defining response an augmentation of 10% relative to baseline for both parameters, 16 patients demonstrated an ambiguous response.

Conclusion

Although both parameters display an average increase during pacing, the change relative to baseline values of SW and dP/dtmax is not related.
Decreased beta‐adrenergic responsiveness following hypertrophy occurs only in cardiomyocytes that also re‐express beta‐myosin heavy chain
Authors: Pandya Kumar , Porter Kristine , Rockman Howard A. , Smithies Oliver
Published: June 2009

Aims

Cardiac hypertrophy is associated with a reduction in the contractile response to beta‐adrenergic stimulation, and with re‐expression of foetal genes such as beta‐myosin heavy chain (MHC). However, whether these two markers of pathology develop concordantly in the same individual cells or independently in different cells is not known.

Methods and results

To answer this question, we examined the beta‐adrenergic response of individual beta‐MHC expressing and non‐expressing myocytes from hypertrophic hearts, using a previously generated mouse model (YFP/beta‐MHC) in which a yellow fluorescent protein (YFP) is fused to the native beta‐MHC protein allowing easy identification of beta‐MHC expressing cells. Yellow fluorescent protein/beta‐MHC mice were submitted to 4 weeks of transverse aortic constriction (TAC), and the contractile parameters of isolated individual myocytes in response to the beta‐adrenergic agonist isoproterenol were assessed. Our results demonstrate that the decrease in isoproterenol‐induced cell shortening that develops in TAC hearts occurs only in those hypertrophic myocytes that re‐express beta‐MHC. Hypertrophic myocytes that do not express beta‐MHC have contractility indices indistinguishable from non‐TAC controls.

Conclusion

These data show that the reduction of beta‐adrenergic response occurs only in subsets, rather than in all myocytes, and is coincident with re‐expression of beta‐MHC.
‘Une tortue avec des ailes’: Progressing in Flaubert's
Bouvard et Pécuchet
Authors: Rees Kate
Published: June 2009

This article considers Flaubert's relationship to the nineteenth-century belief in progress. It focuses on his last, uncompleted novel,
Bouvard et Pécuchet
(1880). Progress is discussed as a historical force of momentum which can be analysed through the metaphor of the journey. The contention is that Flaubert's writing offers a complex response to the flux of history and is detected in
Bouvard et Pécuchet
through the structural dualism offered by the characters' differences, and through the obstacle-strewn journeys they undertake as they embark on their quest for knowledge. Virgil Nemoianu's study of literature and progress,
A Theory of the Secondary
, offers a model for the dynamic found in Flaubert's work. Nemoianu suggests a movement whereby progress is achieved not necessarily in spite of obstacles but as a result of the impediments to linear progression that they provide. These contradictory energies are found in Flaubert's novel and are examined in relation to two of the numerous expeditions undertaken by Bouvard and Pécuchet: their initial move from Paris to the countryside, and a later trip to Fécamp pursued as part of their research into geology.
Pique-niquer sur le volcan: une pratique culturelle de Winckelmann à Sade
Authors: McCallam David
Published: June 2009

A partir de deux épisodes aux accents infernaux tirés de la vie de Winckelmann et de la prose de Sade, cet article examine une étrange pratique culturelle de la fin du dix-huitième siècle: pique-niquer sur le volcan, en l'occurrence le Vésuve, escale essentielle et spectacle sublime du Grand Tour. Puisant dans des lettres et des récits de voyage des touristes français et anglais, nous interrogeons cette commensalité — le fait de manger ensemble — aux flancs du volcan, interrogation qui révise et précise la signification du terme
pique-nique
au dix-huitième siècle. De plus, nous rapprochons cette vision ‘alimentaire’ du volcan d'un autre phénomène culturel napolitain de l'époque: la cocagne. Ainsi, selon nous, volcan et cocagne constituent les deux pôles symboliques entre lesquels s'exerce le régime (au sens à la fois politique et diététique) du roi de Naples. En conclusion, nous analysons quelques réponses des touristes à l'appétit démesuré du Vésuve, constatant que ces réponses (dont le pique-nique lui-même) s'efforcent avant tout d'y réimposer une certaine mesure — que celle-ci soit scientifique ou esthétique.
Mudimbe's Fetish of the West and Epistemological Utopianism
Authors: Fraiture Pierre-Philippe
Published: June 2009

This article will provide a close reading of Mudimbe's early collections of essays
L'Autre Face du royaume
(1973) and
L'Odeur du père
(1982). In the English-language exegesis of Mudimbe's writings, these two key texts have been unduly neglected in favour of
The Invention of Africa
(1988), an essay which, from a chronological point of view, coincided more conveniently with the advent of the postcolonial ‘turn’. I will however contend that these two collections offer a rare combination of revolutionary idealism and early postcolonial methodology. I will also argue that Mudimbe's erudite exploration of Western knowledge on sub-Saharan Africa in these two books, albeit somewhat fetishizing in relation to the ‘West’ and its purported oneness, offers more than a meta-philosophical exercise and assessment of Africa's intellectual dependency. Mudimbe's engagement with Foucault's archaeology is a strategy to advocate an epistemological and hence political revolution which reaffirms Mudimbe's filiation with anticolonialist utopianism and Sartre's philosophy of subjectivity.
Extracting fish and water velocity from Doppler profiler data
Authors: Zedel Len , Cyr-Racine Francis-Yan
Published: June 2009

Zedel, L., and Cyr-Racine, F-Y. 2009. Extracting fish and water velocity from Doppler profiler data. – ICES Journal of Marine Science, 66: 1846–1852. Doppler current profilers are optimized for measuring water velocities, but have the demonstrated capability to measure fish swimming speeds. This is possible when fish form schools that are large enough for all multiple Doppler sonar beams to sample the fish speeds at the same time. In situations where fish are not present in at least three acoustic beams, it is impossible to extract fish velocity with the data-processing algorithms normally used to extract water velocity. We present an alternative method of analysing Doppler sonar data that treats data from individual acoustic beams independently, so that velocities can be extracted when fish appear intermittently in the sonar beams. The method determines the variance for each velocity estimate so that data averaging can be adjusted to achieve the desired accuracy. The algorithm is applied to extract both water and fish velocities from Doppler profiler observations of overwintering Atlantic cod (Gadus morhua) in Smith Sound, Newfoundland. Currents in this enclosed coastal area are slow (∼10 cm s−1), and the fish appear to move passively with the water much of the time. However, there are times when the fish have velocities different from those of the water, and profiles averaged over 20 d show clear differences in fish and water velocities.
Oscillating reproductive strategies of herring in the western Atlantic in response to changing environmental conditions
Authors: Melvin Gary D. , Stephenson Robert L. , Power Michael J.
Published: June 2009

Melvin, G. D., Stephenson, R. L., and Power, M. J. 2009. Oscillating reproductive strategies of herring in the western Atlantic in response to changing environmental conditions. – ICES Journal of Marine Science, 66: 1784–1792. Herring are broadly distributed in the western Atlantic, but reproductive activity is restricted to the central portion, from Cape Cod to northern Newfoundland. Spawning extends from early spring to late autumn. Two spawning types are recognized: spring spawners and autumn spawners. At the southern extreme, spawning occurs almost exclusively in autumn, whereas in the north, spring spawners prevail. Mid-range, both strategies are common, with spawning occurring throughout the entire season. We postulate that the temporal intra-stock dominance of spawning type is an adaptive reproductive strategy to changing environmental conditions. A conceptual model is presented to describe how reproductive success can oscillate between spawning strategies. In most years, environmental conditions appear to favour one type or the other, although strong year classes can co-occur when conditions are right. The recent change in environmental conditions, characterized by a general warming trend, favours autumn spawners and is consistent with our model. At the distributional extremes, stocks are restricted to a single spawning strategy, and broad-scale environmental changes can introduce large interannual variability and limit the reproductive and recovery potential of a stock. The dependence of a stock on a single spawning season may result in longer times to recover to target levels.
Dispersal and settlement of sea scallop larvae spawned in the fishery closed areas on Georges Bank
Authors: Tian Rucheng C. , Chen Changsheng , Stokesbury Kevin D. E. , Rothschild Brian J. , Cowles Geoffrey W. , Xu Qichun , Hu Song , Harris Bradley P. , Marino Michael C.
Published: June 2009

Tian, R. C., Chen, C., Stokesbury, K. D. E., Rothschild, B. J., Cowles, G. W., Xu, Q., Hu, S., Harris, B. P., and Marino II, M. C. 2009. Dispersal and settlement of sea scallop larvae spawned in the fishery closed areas on Georges Bank. – ICES Journal of Marine Science, 66: 2155–2164. Three fishery closed areas in the Georges Bank (GB) region were implemented in 1994 to protect depleted groundfish stocks for population replenishment. However, the drift and ultimate destination of larvae spawned in the closed areas have not been analysed specifically within the framework of ocean currents. To assess the efficiency of the closed areas as population replenishment sources, we conducted a simulation-based analysis on the dispersal and settlement of sea scallop larvae spawned in the closed areas from 1995 to 2005 using circulation fields computed by the Finite-Volume Coastal Ocean Model, scallop survey data, and a population dynamics model. Closed area I located in the Great Southern Channel (GSC) had a persistently high rate of larval retention (86% on average). For closed area II located on eastern GB, a considerable quantity of larvae was dispersed out of the domain. For the Nantucket Lightship Closed Area located on Nantucket Shoals, larvae consistently drifted away from the region during the 11 years simulated. Our simulation revealed three high-retention regions that are the most suitable for closed-area selection and rotational fishery management in terms of larval supply to the GB–GSC region.
Epigenetics of human T cells during the G0→G1 transition
Authors: Smith Alexander E. , Chronis Constantinos , Christodoulakis Manolis , Orr Stephen J. , Lea Nicholas C. , Twine Natalie A. , Bhinge Akshay , Mufti Ghulam J. , Thomas N. Shaun B.
Published: June 2009

We investigated functional epigenetic changes that occur in primary human T lymphocytes during entry into the cell cycle and mapped these at the single-nucleosome level by ChIP-chip on tiling arrays for chromosomes 1 and 6. We show that nucleosome loss and flanking active histone marks define active transcriptional start sites (TSSs). Moreover, these signatures are already set at many inducible genes in quiescent cells prior to cell stimulation. In contrast, there is a dearth of the inactive histone mark H3K9me3 at the TSS, and under-representation of H3K9me2 and H3K9me3 defines the body of active genes. At the DNA level, cytosine methylation (meC) is enriched for nucleosomes that remain at the TSS, whereas in general there is a dearth of meC at TSSs. Furthermore, a drop in meC also marks 3′ transcription termination, and a peak of meC occurs at stop codons. This mimics the 3′ nucleosomal distribution in yeast, which we show does not occur in human T cells.
Deterministic protein inference for shotgun proteomics data provides new insights into Arabidopsis pollen development and function
Authors: Grobei Monica A. , Qeli Ermir , Brunner Erich , Rehrauer Hubert , Zhang Runxuan , Roschitzki Bernd , Basler Konrad , Ahrens Christian H. , Grossniklaus Ueli
Published: June 2009

Pollen, the male gametophyte of flowering plants, represents an ideal biological system to study developmental processes, such as cell polarity, tip growth, and morphogenesis. Upon hydration, the metabolically quiescent pollen rapidly switches to an active state, exhibiting extremely fast growth. This rapid switch requires relevant proteins to be stored in the mature pollen, where they have to retain functionality in a desiccated environment. Using a shotgun proteomics approach, we unambiguously identified ∼3500 proteins in Arabidopsis pollen, including 537 proteins that were not identified in genetic or transcriptomic studies. To generate this comprehensive reference data set, which extends the previously reported pollen proteome by a factor of 13, we developed a novel deterministic peptide classification scheme for protein inference. This generally applicable approach considers the gene model–protein sequence–protein accession relationships. It allowed us to classify and eliminate ambiguities inherently associated with any shotgun proteomics data set, to report a conservative list of protein identifications, and to seamlessly integrate data from previous transcriptomics studies. Manual validation of proteins unambiguously identified by a single, information-rich peptide enabled us to significantly reduce the false discovery rate, while keeping valuable identifications of shorter and lower abundant proteins. Bioinformatic analyses revealed a higher stability of pollen proteins compared to those of other tissues and implied a protein family of previously unknown function in vesicle trafficking. Interestingly, the pollen proteome is most similar to that of seeds, indicating physiological similarities between these developmentally distinct tissues.
Learning-induced enhancement of feedback inhibitory synaptic transmission
Authors: Brosh Inbar , Barkai Edi
Published: June 2009

Olfactory-discrimination learning results with a series of intrinsic and excitatory synaptic modifications in piriform cortex pyramidal neurons. Here we show that such learning results with long-lasting enhancement of inhibitory synaptic transmission onto proximal dendrites of these pyramidal neurons. Such enhancement is mediated by a strong hyperpolarizing shift in the reversal potential of fast inhibitory postsynaptic potentials (fIPSPs). Moreover, paired-pulse depression of these IPSPs, indicating enhanced GABA release, is also apparent after learning. We suggest that learning is accompanied by long-lasting enhancement of synaptic inhibition onto excitatory neurons, thus compensating for the increase of excitation in these neurons.
Randomized trial of botulinum toxin injections into the salivary glands to reduce drooling in children with neurological disorders
Authors: Reid S M , Johnstone B R , Westbury C , Rawicki B , Reddihough D S
Published: June 2009

The primary aim of this randomized, controlled trial was to assess the effectiveness of botulinum toxin A (BoNT‐A) injections into the submandibular and parotid glands on drooling in children with cerebral palsy (CP) and other neurological disorders. Secondary aims were to ascertain the duration of any such effect and the timing of maximal response. Of the 48 participants (27 males, 21 females; mean age 11y 4mo [SD 3y 3mo], range 6‐18y), 31 had a diagnosis of CP and 15 had a primary intellectual disability; 27 children were non‐ambulant. Twenty‐four children randomized to the treatment group received 25 units of BoNT‐A into each parotid and submandibular gland. Those randomized to the control group received no treatment. The degree and impact of drooling was assessed by carers using the Drooling Impact Scale questionnaire at baseline and at monthly intervals up to 6 months postinjection/baseline, and again at 1 year. Maximal response was at 1 month at which time there was a highly significant difference in the mean scores between the groups. This difference remained statistically significant at 6 months. Four children failed to respond to the injections, four had mediocre results, and 16 had good results. While the use of BoNT‐A can help to manage drooling in many children with neurological disorders, further research is needed to fully understand the range of responses.
Adrenomedullin treatment reduces intestinal inflammation and maintains epithelial barrier function in mice administered dextran sulphate sodium
Authors: Ashizuka Shinya , Inagaki‐Ohara Kyoko , Kuwasako Kenji , Kato Johji , Inatsu Haruhiko , Kitamura Kazuo
Published: June 2009

Hyperactivation and hyperpermeability of the intestinal epithelium is a hallmark of IBD. AM has been shown to reduce the severity of colitis in the acetic acid and TNBS‐induced colitis model, however the mechanism of the therapeutic effect of AM against the colitis has not been clarified. Here, we show that the protective capability of AM is associated with suppression of inflammation and maintenance of the intestinal epithelial barrier function. In the DSS‐induced colitis model, intra‐rectal AM‐treated mice showed a reduction in loss of body weight and severity of colitis. AM‐treatment suppressed phosphorylation of STAT1 and STAT3 in the colonic epithelium, and altered the cytokine balance in the intestinal T cells, with lower levels of IFN‐γ and TNF‐α but higher levels of TGF‐β. Expression of the epithelial intercellular junctions such as tight and adherence junctions were sustained in the AM‐treated mice. In contrast, the epithelial junctions were down‐regulated in the control mice, leading to loss of epithelial barrier integrity and enhanced permeability. Collectively, these data indicate a broad spectrum of AM‐induced effects with respect to protection against DSS‐induced colitis, and suggest a potential therapeutic value of this treatment for IBD.
Identification of PAK4 as a putative target gene for amplification within 19q13.12‐q13.2 in oral squamous‐cell carcinoma
Authors: Begum Asma , Imoto Issei , Kozaki Ken‐ichi , Tsuda Hitoshi , Suzuki Emina , Amagasa Teruo , Inazawa Johji
Published: June 2009

Amplification of chromosomal DNA is thought to be one of the mechanisms activating cancer‐related genes in tumors. To identify the most likely target for amplification in the region 19q13.12‐q13.2, detected previously in SKN‐3 cells by a genome‐wide screening of DNA copy‐number aberrations in a panel of oral squamous‐cell carcinoma (OSCC) cell lines, we determined the extent of the amplicon, analyzed a panel of cell lines for the expression of candidate genes within the amplicon, and then evaluated growth‐suppressive effects by knocking down genes of interest. Reported information about the function and/or expression of each gene, remarkable overexpression in SKN‐3 cells and relatively frequent overexpression in additional OSCC lines compared with an immortalized normal oral epithelial cell line, and expression level–dependent proliferation‐promoting activity led us to conclude that the p21‐activated kinase 4 (PAK4) gene was the most likely target. An immunohistochemical analysis of primary tumors from 105 cases of head and neck SCC including 50 cases of OSCC demonstrated the overexpression of PAK4 to be significantly associated with a poorer prognosis. These findings reveal that the PAK4 overexpression through amplification or other mechanisms promotes the proliferation and/or survival of OSCC cells, and that PAK4 might be a good diagnostic and/or therapeutic target. (Cancer Sci 2009; 100: 1908–1916)
Inhibitory effects of epigallocatechin‐3 gallate, a polyphenol in green tea, on tumor‐associated endothelial cells and endothelial progenitor cells
Authors: Ohga Noritaka , Hida Kyoko , Hida Yasuhiro , Muraki Chikara , Tsuchiya Kunihiko , Matsuda Kohei , Ohiro Yoichi , Totsuka Yasunori , Shindoh Masanobu
Published: June 2009

The polyphenol epigallocatechin‐3 gallate (EGCG) in green tea suppresses tumor growth by direct action on tumor cells and by inhibition of angiogenesis, but it is not known whether it specifically inhibits tumor angiogenesis. We examined the anti‐angiogenic effect of EGCG on tumor‐associated endothelial cells (TEC), endothelial progenitor cells (EPC), and normal endothelial cells (NEC). EGCG suppressed the migration of TEC and EPC but not NEC. EGCG also inhibited the phosphorylation of Akt in TEC but not in NEC. Furthermore, vascular endothelial growth factor‐induced mobilization of EPC into circulation was inhibited by EGCG. MMP‐9 in the bone marrow plasma plays key roles in EPC mobilization into circulation. We observed that expression of MMP‐9 mRNA was downregulated by EGCG in mouse bone marrow stromal cells. In an in vivo model, EGCG suppressed growth of melanoma and reduced microvessel density. Our study showed that EGCG has selective anti‐angiogenic effects on TEC and EPC. It is suggested that EGCG could be a promising angiogenesis inhibitor for cancer therapy. (Cancer Sci 2009; 100: 1963–1970)
Phase I clinical study of a peptide vaccination for hepatitis C virus‐infected patients with different human leukocyte antigen‐class I‐A alleles
Authors: Yutani Shigeru , Komatsu Nobukazu , Shichijo Shigeki , Yoshida Kazumi , Takedatsu Hiroko , Itou Minoru , Kuromatu Ryoko , Ide Tatsuya , Tanaka Masatoshi , Sata Michio , Yamada Akira , Itoh Kyogo
Published: June 2009

Hepatitis C virus (HCV) infection has a high risk of liver cirrhosis and hepatocellular carcinoma at later stages. We recently identified a peptide derived from the HCV core protein capable of inducing both cellular and humoral responses to nearly all HCV‐positive patients in Japan with different human leukocyte antigen (HLA)‐class I‐A alleles. To assess the safety and immune responses to this novel peptide, we conducted a phase I dose‐escalation study of the vaccination for 26 HCV‐positive patients who were either non‐responders to the interferon‐based therapy (n = 23) or refused it (n = 3). The regimen was well tolerated, with no severe vaccine‐related toxicity. Twenty‐five and 22 patients completed the first and second cycle vaccination (6 and 12 vaccine injections), respectively. After a series of six vaccine injections, peptide‐specific CTL activity was augmented in peripheral blood mononuclear cells from 15 of 25 patient samples, with an expected optimal dose of 1 mg peptide. After 12 vaccine injections, peptide‐specific IgG production was augmented in plasma from the majority of patients (15 of 22 patients) tested, but not in a dose‐dependent fashion. There were two HCV RNA responders with >1 log declines. Among patients whose pre‐vaccination levels of alanine aminotransferase and alpha feto‐protein exceeded the normal ranges, a <30% decrease was found in 7 of 24 and three of six patients, respectively. Because of its tolerability and higher rate of immune boosting, this protocol is recommended for a phase II study to investigate its clinical efficacy. (Cancer Sci 2009; 100: 1935–1942)
Prostaglandin E2, Wnt, and BMP in gastric tumor mouse models
Authors: Oshima Hiroko , Oguma Keisuke , Du Yu‐Chen , Oshima Masanobu
Published: June 2009

The development of gastric cancer is closely associated with Helicobacter pylori (H. pylori) infection. The expression of cylooxigenase‐2 (COX‐2), a rate‐limiting enzyme for prostaglandin biosynthesis, is induced in H. pylori‐associated chronic gastritis, which thus results in the induction of proinflammatory prostaglandin, PGE2. The COX‐2/PGE2 pathway plays a key role in gastric tumorigenesis. On the other hand, several oncogenic pathways have been shown to trigger gastric tumorigenesis. The activation of Wnt/β‐catenin signaling is found in 30–50% of gastric cancers, thus suggesting that Wnt signaling plays a causal role in gastric cancer development. Mutations in the bone morphogenetic protein (BMP) signaling pathway are responsible for the subset of juvenile polyposis syndrome (JPS) that develops hamartomas in the gastrointestinal tract. BMP suppression appears to contribute to gastric cancer development because gastric cancer risk is increased in JPS. Wnt signaling is important for the maintenance of gastrointestinal stem cells, while BMP promotes epithelial cell differentiation. Accordingly, it is possible that both Wnt activation and BMP suppression can cause gastric tumorigenesis through enhancement of the undifferentiated status of epithelial cells. Recent mouse model studies have indicated that induction of the PGE2 pathway is required for the development of both gastric adenocarcinoma and hamartoma in the Wnt‐activated and BMP‐suppressed gastric mucosa, respectively. This article reviews the involvement of the PGE2, Wnt, and BMP pathways in the development of gastric cancer, and gastric phenotypes that are found in transgenic mouse models of PGE2 induction, Wnt activation, BMP suppression, or a combination of these pathways. (Cancer Sci 2009; 100: 1779–1785)
Cellular characterization of the peritumoral edema zone in malignant brain tumors
Authors: Engelhorn Tobias , Savaskan Nic E. , Schwarz Marc A. , Kreutzer Jürgen , Meyer Eric P. , Hahnen Eric , Ganslandt Oliver , Dörfler Arnd , Nimsky Christopher , Buchfelder Michael , Eyüpoglu Ilker Y.
Published: June 2009

Brain edema is a hallmark of human malignant brain tumors and contributes to the clinical course and outcome of brain tumor patients. The so‐called perifocal edema or brain swelling imposes in T2‐weighted MR scans as high intensity areas surrounding the bulk tumor mass. The mechanisms of this increased fluid attraction and the cellular composition of the microenvironment are only partially understood. In this study, we focus on imaging perifocal edema in orthotopically implanted gliomas in rodents and correlate perifocal edema with immunohistochemical markers. We identified that areas of perifocal edema not only include the tumor invasion zone, but also are associated with increased glial fibrillary acidic protein (GFAP) and aquaporin‐4 expression surrounding the bulk tumor mass. Moreover, a high number of activated microglial cells expressing CD11b and macrophage migration inhibitory factor (MIF) accumulate at the tumor border. Thus, the area of perifocal edema is mainly dominated by reactive changes of vital brain tissue. These data corroborate that perifocal edema identified in T2‐weighted MR scans are characterized with alterations in glial cell distribution and marker expression forming an inflammatory tumor microenvironment. (Cancer Sci 2009; 100: 1856–1862)
Efficacy of methotrexate in Crohn’s disease and ulcerative colitis patients unresponsive or intolerant to azathioprine /mercaptopurine
Authors: WAHED M. , LOUIS‐AUGUSTE J. R. , BAXTER L. M. , LIMDI J. K. , MCCARTNEY S. A. , LINDSAY J. O. , BLOOM S. L.
Published: June 2009

Background  Despite the wide use of azathioprine/mercaptopurine (AZA/MP) therapy in the management of both Crohn’s disease (CD) and ulcerative colitis (UC), approximately 20% of patients cannot tolerate the drugs and 30% do not respond.

Aim  To examine the efficacy and safety profile of methotrexate (MTX) in patients with CD or UC who are either intolerant or non‐responsive to AZA/MP.

Methods  A total of 131 patients with IBD treated with MTX were identified. Retrospective data were obtained by case note review. Clinical response (defined as steroid withdrawal, normalization of previously raised CRP or physician’s clinical assessment of improvement) was assessed at 6 months.

Results  Clinical response in Crohn’s disease occurred in 18 of 29 patients (62%) refractory to AZA/MP and 42 of 70 patients (60%) intolerant to AZA/MP, with no difference between the groups (P = 1.0). In UC, clinical response was seen in 7 of 9 (78%) patients refractory to AZA/MP and 15 of 23 (65%) intolerant to thiopurines. MTX was well tolerated in a majority of individuals.

Conclusions  Methotrexate appears effective in both CD and UC patients who fail to respond to or are intolerant to AZA/MP therapy.
Irritable bowel syndrome is strongly associated with generalized anxiety disorder: a community study
Authors: LEE S. , WU J. , MA Y. L. , TSANG A. , GUO W.‐J. , SUNG J.
Published: June 2009

Background  No previous study has examined the comorbidity of Irritable Bowel Syndrome (IBS) and Generalized Anxiety Disorder (GAD) in a general population using standardized diagnostic methods.

Aim  To examine the prevalence, comorbidity and risk correlates of IBS and GAD in a general population.

Methods  A random community‐based telephone survey was conducted. The questionnaire covered symptoms of IBS, GAD, core depressive symptoms, help‐seeking behaviour and functional impairment on the Sheehan Disability Scale.

Results  A total of 2005 participants completed the interview. The current prevalence of IBS was 5.4% and the 12‐month prevalence of GAD was 4%. GAD was five times more common among IBS respondents than non‐IBS respondents (OR: 5.84, P < 0.001), whereas IBS was 4.7 times more common among GAD respondents than among non‐GAD respondents (OR: 6.32, P < 0.001). Core depressive symptoms (OR: 6.25, P < 0.01) and education level (OR: 5.918, P = 0.021) were risk correlates of GAD among IBS respondents. Comorbid respondents were more impaired than respondents having either disorder alone, but were not more likely to seek professional help than IBS‐only respondents.

Conclusion  Irritable Bowel Syndrome and GAD comorbidity was common and added to impairment in the community. The strong association between psychiatric morbidity and IBS observed in referral centres was not a consequence of increased help‐seeking behaviour.
Systematic review: secondary prevention with band ligation, pharmacotherapy or combination therapy after bleeding from oesophageal varices
Authors: CHEUNG J. , ZEMAN M. , Van ZANTEN S. V. , TANDON P.
Published: June 2009

Background  Variable methods are available for secondary prevention after oesophageal variceal bleeding (EVB).

Aim  To compare band ligation (BL), pharmacotherapy (PT) and BL+PT for EVB secondary prevention.

Methods  A systematic search of databases, references and meeting abstracts was conducted for randomized trials of BL, PT or BL+PT. The outcomes were mortality, rebleeding and adverse events. A random‐effects model was used for meta‐analyses.

Results  Twelve trials were included (6 BL vs. PT, 4 BL+PT vs. BL, 2 BL+PT vs. PT). All trials used beta‐blockers ± isosorbide mononitrate (ISMN) as PT. Mortality was not significantly different among trials. Rebleeding was not significantly different for BL vs. PT (RR 1.00, 95% CI 0.73–1.37). BL reduced rebleeding compared with PT for trials with mean beta‐blocker dose <80 mg/day (RR 0.67, 95% CI 0.49–0.91). There were nonsignificant differences in rebleeding for BL+PT vs. BL (RR 0.57, 95% CI 0.31–1.08) and BL+PT vs. PT (RR 0.76, 95% CI 0.56–1.03). There was no difference in adverse events between BL vs. PT, but was higher with BL+PT vs. BL.

Conclusion  Band ligation and PT alone are comparable for secondary prevention of rebleeding after EVB. Further trials with adequate PT dosing are required to determine the efficacy of combination BL+PT therapy.
Transmitochondrial embryonic stem cells containing pathogenic mtDNA mutations are compromised in neuronal differentiation
Authors: Kirby D. M.  , Rennie K. J.  , Smulders‐Srinivasan T. K.  , Acin‐Perez R.  , Whittington M.  , Enriquez J.‐A.  , Trevelyan A. J.  , Turnbull D. M.  , Lightowlers R. N. 
Published: June 2009

Objectives:  Defects of the mitochondrial genome (mtDNA) cause a series of rare, mainly neurological disorders. In addition, they have been implicated in more common forms of movement disorders, dementia and the ageing process. In order to try to model neuronal dysfunction associated with mitochondrial disease, we have attempted to establish a series of transmitochondrial mouse embryonic stem cells harbouring pathogenic mtDNA mutations.

Materials and methods:  Transmitochondrial embryonic stem cell cybrids were generated by fusion of cytoplasts carrying a variety of mtDNA mutations, into embryonic stem cells that had been pretreated with rhodamine 6G, to prevent transmission of endogenous mtDNA. Cybrids were differentiated into neurons and assessed for efficiency of differentiation and electrophysiological function.

Results:  Neuronal differentiation could occur, as indicated by expression of neuronal markers. Differentiation was impaired in embryonic stem cells carrying mtDNA mutations that caused severe biochemical deficiency. Electrophysiological tests showed evidence of synaptic activity in differentiated neurons carrying non‐pathogenic mtDNA mutations or in those that caused a mild defect of respiratory activity. Again, however, neurons carrying mtDNA mutations that resulted in severe biochemical deficiency had marked reduction in post‐synaptic events.

Conclusions:  Differentiated neurons carrying severely pathogenic mtDNA defects can provide a useful model for understanding how such mutations can cause neuronal dysfunction.
Service user participation in diverse child protection contexts: principles for practice
Authors: Healy Karen , Darlington Yvonne
Published: June 2009

Promoting the participation of children and parents in child protection practice is one of the most complex and sensitive areas of social work practice. Increasingly, child protection legislation and policy in many parts of the world enshrines ideals of service user participation. Yet, with the exception of extensive discussion about family group conferencing, the principles and methods for achieving participatory practices in child protection work remain underdeveloped. We use the term ‘child protection’ to refer to a broad spectrum of child and family welfare services aimed at prevention of (or intervention to address) child abuse and neglect. This spectrum of services includes intensive family support, family support, domestic violence, statutory child protection and child and family advocacy services. In this paper, we present findings from the first phase of a 3‐year study into participatory practice in child protection. In this paper, we present findings from a qualitative analysis of interviews with 28 child protection practitioners across five domains of child protection work. Our analysis reveals three core principles of participatory practice underpinning these practitioners' accounts as well as contextual differences among them. We conclude with a discussion of the educational implications of our findings.
Coagulation activation in autoimmune bullous diseases
Authors: Marzano A V , Tedeschi A , Spinelli D , Fanoni D , Crosti C , Cugno M
Published: June 2009

The main autoimmune blistering skin disorders are pemphigus vulgaris (PV) and bullous pemphigoid (BP). They differ in the inflammatory infiltrate, which is more intense in BP. Inflammation is known to activate coagulation in several disorders. Local and systemic activation of coagulation was evaluated in BP and PV. We studied 20 BP patients (10 active and 10 remittent), 23 PV patients (13 active and 10 remittent) and 10 healthy subjects. The coagulation markers prothrombin fragment F1+2 and D-dimer were measured by enzyme-immunoassays in plasma. The presence of tissue factor (TF), the main initiator of blood coagulation, was evaluated immunohistochemically in skin specimens from 10 patients with active PV, 10 patients with active BP and 10 controls. Plasma F1+2 and D-dimer levels were significantly high in active BP (P = 0·001), whereas in active PV the levels were normal. During remission, F1+2 and D-dimer plasma levels were normal in both BP and PV. TF immunoreactivity was found in active BP but neither in active PV nor in normal skin. TF reactivity scores were higher in active BP than in controls or active PV (P = 0·0001). No difference in TF scores was found between active PV and controls. BP is associated with coagulation activation, which is lacking in PV. This suggests that BP but not PV patients have an increased thrombotic risk. The observation that thrombotic complications occur more frequently in BP than in PV further supports this view.
Multi-nucleated giant cell formation from human cord blood monocytesin vitro, in comparison with adult peripheral blood monocytes
Authors: Kondo Y , Yasui K , Yashiro M , Tsuge M , Kotani N , Morishima T
Published: June 2009

Multi-nucleated giant cells (MGCs; Langhans-type cell), formed from macrophage fusion, are recognized as a hallmark histological feature in chronic inflammation. However, their precise pathological role is still poorly understood, especially for microorganism pathogens in the neonatal immune system, which are capable of surviving intracellularly in phagocytes. To conduct a partial evaluation of the monocyte function of neonates, we investigated the ability of human cord blood monocytes to form MGCs in vitro by stimulating various cytokines and comparing them with adult peripheral blood monocytes. Monocytes from cord blood and adult peripheral blood were isolated and cultured for 14 days with cytokines known to induce MGC in vitro. The fusion index in experiments with a combination of interleukin (IL)-4 and macrophage colony-stimulating factor (M-CSF) and a combination of IL-4 and granulocyte–macrophage colony-stimulating factor (GM-CSF) was significantly lower in cord blood than in adult blood monocytes (P = 0·0018 and P = 0·0141, respectively). The number of nuclei per MGC was significantly lower in cord blood than in adult blood monocytes in experiments with IL-4 alone, the combination of IL-4 and M-CSF, and the combination of IL-4 and GM-CSF (P < 0·0001). These results suggest the possibility that the susceptibility of newborns to mycobacterium infection is due partly to impaired MGC formation.
Phenotypic characteristics of familial glucocorticoid deficiency (FGD) type 1 and 2
Authors: Chung Teng‐Teng L. L. , Chan Li F. , Metherell Louise A. , Clark Adrian J. L.
Published: June 2009

Context  Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder as a result of mutation in genes encoding either the ACTH receptor [melanocortin 2 receptor (MC2R)] or its accessory protein [melanocortin 2 receptor accessory protein (MRAP)]. The disorder is known as FGD type 1 and 2, respectively.

Objective  The aim of the study was to compare the phenotype/genotype relationships between FGD 1 and 2.

Design and patients  Forty patients with missense MC2R mutations and 22 patients with MRAP mutations were included. Forty‐four of these patients had been referred for genetic screening and 18 were patients published by other authors.

Results  The median age at presentation for FGD type 1 was variable at 2·0 years; range 0·02–16 years, and this was associated with unusually tall stature, mean height SDS + 1·75 ± 1·53 (mean ± SD). In contrast, FGD type 2 presented at a much earlier median age (0·08 years; range at birth to 1·6 years) (P < 0·01) and patients were of normal height SDS + 0·12 ± 1·35 (P < 0·001). No differences in baseline cortisol or ACTH levels were seen between FGD types 1 and 2.

Conclusion  FGD type 2 appears to present earlier. This may reflect the functional significance of the underlying mutations in that all MRAP mutations are nonsense or splice site mutations that result in abolition of a functional protein, whereas most of the MC2R mutations are missense mutations and give rise to proteins with some residual function. Tall stature is associated with mutations in MC2R but not in MRAP. There were no other significant clinical distinctions between the two.
Ribavirin dose reduction raises relapse rate dose‐dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha‐2b plus ribavirin
Authors: Hiramatsu N. , Oze T. , Yakushijin T. , Inoue Y. , Igura T. , Mochizuki K. , Imanaka K. , Kaneko A. , Oshita M. , Hagiwara H. , Mita E. , Nagase T. , Ito T. , Inui Y. , Hijioka T. , Katayama K. , Tamura S. , Yoshihara H. , Imai Y. , Kato M. , Yoshida Y. , Tatsumi T. , Ohkawa K. , Kiso S. , Kanto T. , Kasahara A. , Takehara T. , Hayashi N.
Published: June 2009

Summary.  The impact of ribavirin exposure on virologic relapse remains controversial in combination therapy with pegylated interferon (Peg‐IFN) and ribavirin for patients with chronic hepatitis C (CH‐C) genotype 1. The present study was conducted to investigate this. Nine hundred and eighty‐four patients with CH‐C genotype 1 were enrolled. The drug exposure of each medication was calculated by averaging the dose actually taken. For the 472 patients who were HCV RNA negative at week 24 and week 48, multivariate logistic regression analysis showed that the degree of fibrosis (P = 0.002), the timing of HCV RNA negativiation (P < 0.001) and the mean doses of ribavirin (P < 0.001) were significantly associated with relapse, but those of Peg‐IFN were not. Stepwise reduction of the ribavirin dose was associated with a stepwise increase in relapse rate from 11% to 60%. For patients with complete early virologic response (c‐EVR) defined as HCV RNA negativity at week 12, only 4% relapse was found in patients given ≥12 mg/kg/day of ribavirin and ribavirin exposure affected the relapse even after treatment week 12, while Peg‐IFN could be reduced to 0.6 μg/kg/week after week 12 without the increase of relapse rate. Ribavirin showed dose‐dependent correlation with the relapse. Maintaining as high a ribavirin dose as possible (≥12 mg/kg/day) during the full treatment period can lead to suppression of the relapse in HCV genotype 1 patients responding to Peg‐IFN alpha‐2b plus ribavirin, especially in c‐EVR patients.
Suppression of constitutive SOS expression by recA4162 (I298V) and recA4164 (L126V) requires UvrD and RecX in Escherichia coli K‐12
Authors: Long Jarukit E. , Renzette Nicholas , Sandler Steven J.
Published: June 2009

Sensing DNA damage and initiation of genetic responses to repair DNA damage are critical to cell survival. In Escherichia coli, RecA polymerizes on ssDNA produced by DNA damage creating a RecA–DNA filament that interacts with the LexA repressor inducing the SOS response. RecA filament stability is negatively modulated by RecX and UvrD. recA730 (E38K) and recA4142 (F217Y) constitutively express the SOS response. recA4162 (I298V) and recA4164 (L126V) are intragenic suppressors of the constitutive SOS phenotype of recA730. Herein, it is shown that these suppressors are not allele specific and can suppress SOSC expression of recA730 and recA4142 in cis and in trans. recA4162 and recA4164 single mutants (and the recA730 and recA4142 derivatives) are Rec+, UVR and are able to induce the SOS response after UV treatment like wild‐type. UvrD and RecX are required for the suppression in two (recA730,4164 and recA4142,4162) of the four double mutants tested. To explain the data, one model suggests that recAC alleles promote SOSC expression by mimicking RecA filament structures that induce SOS and the suppressor alleles mimic RecA filament at end of SOS. UvrD and RecX are attracted to these latter structures to help dismantle or destabilize the RecA filament.
Heterogeneity in quorum sensing‐regulated bioluminescence of Vibrio harveyi
Authors: Anetzberger Claudia , Pirch Torsten , Jung Kirsten
Published: June 2009

Quorum sensing (QS) refers to the ability of bacterial populations to read out the local environment for cell density and to collectively activate gene expression. Vibrio harveyi, one of the best characterized model organisms in QS, was used to address the question how single cells behave within a QS‐activated community in a homogeneous environment. Analysis of the QS‐regulated bioluminescence of a wild type strain revealed that even at high cell densities only 69% of the cells of the population produced bioluminescence, 25% remained dark and 6% were dead. Moreover, light intensities greatly varied from cell to cell at high population density. Addition of autoinducer to a bright liquid culture of V. harveyi increased the percentage of luminescent cells up to 98%, suggesting that V. harveyi produces and/or keeps the autoinducers at non‐saturating concentrations. In contrast, all living cells of a constitutive QS‐active mutant (ΔluxO) produced light. We also found that QS affects biofilm formation in V. harveyi. Our data provide first evidence that a heterogeneous population produces more biofilm than a homogeneous one. It is suggested that even a QS‐committed population of V. harveyi takes advantage of heterogeneity, which extends the current view of QS‐regulated uniformity.
The PhyR‐σEcfG signalling cascade is involved in stress response and symbiotic efficiency in Bradyrhizobium japonicum
Authors: Gourion Benjamin , Sulser Sandra , Frunzke Julia , Francez‐Charlot Anne , Stiefel Philipp , Pessi Gabriella , Vorholt Julia A. , Fischer Hans‐Martin
Published: June 2009

PhyR is an unusual type of response regulator consisting of a receiver domain and an extracytoplasmic function (ECF) sigma factor‐like domain. It was recently described as a master regulator of general stress response in Methylobacterium extorquens. Orthologues of this regulator are present in essentially all free‐living Alphaproteobacteria. In most of them, phyR is genetically closely linked to a gene encoding an ECF σ factor. Here, we investigate the role of these two regulators in the soybean symbiont Bradyrhizobium japonicum USDA110. Using deletion mutants and phenotypic assays, we showed that PhyR and the ECF σ factor σEcfG are involved in heat shock and desiccation resistance upon carbon starvation. Both mutants had symbiotic defects on the plant hosts Glycine max (soybean) and Vigna radiata (mungbean). They induced fewer nodules than the wild type and these nodules were smaller, less pigmented, and their specific nitrogenase activity was drastically reduced 2 or 3 weeks after inoculation. Four weeks after infection, soybean nodule development caught up to a large extent whereas most mungbean nodules remained defective even 5 weeks after infection. Remarkably, both mutants triggered aberrant nodules on the different host plants with ectopically emerging roots. Microarray analysis revealed that PhyR and σEcfG control congruent regulons suggesting both regulators are part of the same signalling cascade. This finding was further substantiated by in vitro protein–protein interaction studies which are in line with a partner‐switching mechanism controlling gene regulation triggered by phosphorylation of PhyR. The large number of genes of unknown function present in the PhyR/σEcfG regulon and the conspicuous symbiotic phenotype suggest that these regulators are involved in the Bradyrhizobium–legume interaction via yet undisclosed mechanisms.