bluuebunny/crossref_metadata_2025 huggingface dataset:
The investigation of capture/emission mechanism in high-k gate dielectric soft breakdown by gate current random telegraph noise approach
Authors: Chung Steve S. , Chang C. M.
Published: November 2008

In this paper, the trapping/detrapping in high-k gate dielectrics has been analyzed by gate current random telegraph noise (IG) measurement. Gate current is suppressed when traps capture electrons and recovers for empty traps. By statistically extracting capture and emission times, we can understand the trap properties. Besides, the influence will be understood by observing the variation of Gate current fluctuation. Through the analysis of the device after soft-breakdown (SBD), the deterioration of the dielectric will change the capture cross section. Moreover, the traps in the SBD path have been identified as the cause of a huge increase in the gate leakage.
Microwave absorption in percolating metal-insulator composites
Authors: Zimmerman D. T. , Cardellino J. D. , Cravener K. T. , Feather K. R. , Miskovsky N. M. , Weisel G. J.
Published: November 2008

We measure several electromagnetic properties of tungsten-Teflon composites as a function of metal volume concentration. The electric (E) and magnetic (H) loss tangents at 2.45GHz and the dc conductivity each exhibits a percolation transition at a different critical value of the metal volume fraction p. Moreover, the transition behavior depends on the average particle size and size distribution of the metal component. We explain the variation in each case by a schematic model derived from established percolation theory and the distinct response of conducting particles to microwave electric and magnetic fields.
Gigahertz photothermal effect in silicon waveguides
Authors: Pernice W. H. P. , Li Mo , Tang H. X.
Published: November 2008

We present a theoretical and experimental study of the frequency response of the photothermal effect in silicon waveguides. The effect is studied for modulation frequencies up to 3GHz using integrated photonic circuits in Mach–Zehnder and ring oscillator configurations. The thermal behavior of silicon waveguides is described by a diffusive substrate heating model. In the low-frequency regime, the frequency response follows a −log(f) dependence, while a f−1∕2 dependence is found in the high-frequency regime. Close agreement between theory and experiment allows for the accurate extraction of the photothermal absorption coefficient.
Batch or trickle: understanding the multiple spawning strategy of southern calamary, Sepioteuthis australis (Mollusca : Cephalopoda)
Authors: Kuipers Matthew R. , Pecl Gretta T. , Moltschaniwskyj Natalie A.
Published: November 2008

Many cephalopods are ‘multiple spawners’; however, we know little about the timing and dynamics of egg production. This has implications for the allocation of energy to reproduction, lifetime fecundity and subsequent recruitment. The current study aimed to determine if Sepioteuthis australis (Quoy and Gaimard, 1832), which spawns multiple times, produces mature oocytes for deposition in a continuous trickle or in larger discrete batches. Throughout a spawning season, developmental stages were assigned to the ovaries of each female by combining macroscopic and histological analyses of the oocytes. Half of the females (46%) showed a significant peak in oocytes at one of the maturation stages, indicating that females were developing eggs in batches. It was hypothesised that the remaining females were also batch spawning, given that the oviduct weights of the remaining females (54%) were high and the other measured biological characteristics were similar to those of the females showing a peak in oocyte stage. Average batch fecundity declined over the 3-month spawning season, but total egg numbers in the ovary increased, suggesting that females might have deposited small batches more often during December. As reproduction requires large allocations of energy, understanding how females distribute reproductive effort throughout their lives is crucial to understanding the behaviour of populations, individuals and their offspring.
Maternal transfer of xenobiotics and effects on larval striped bass in the San Francisco Estuary
Authors: Ostrach David J. , Low-Marchelli Janine M. , Eder Kai J. , Whiteman Shaleah J. , Zinkl Joe G.
Published: November 2008

Aquatic ecosystems around the world face serious threats from anthropogenic contaminants. Results from 8 years of field and laboratory investigations indicate that sublethal contaminant exposure is occurring in the early life stages of striped bass in the San Francisco Estuary, a population in continual decline since its initial collapse during the 1970s. Biologically significant levels of polychlorinated biphenyls, polybrominated diphenyl ethers, and current-use/legacy pesticides were found in all egg samples from river-collected fish. Developmental changes previously unseen with standard methods were detected with a technique using the principles of unbiased stereology. Abnormal yolk utilization, brain and liver development, and overall growth were observed in larvae from river-collected fish. Histopathological analyses confirmed and identified developmental alterations. Using this methodology enabled us to present a conclusive line of evidence for the maternal transfer of xenobiotics and their adverse effects on larval striped bass in this estuary.
Nonlinearity in bacterial population dynamics: Proposal for experiments for the observation of abrupt transitions in patches
Authors: Kenkre V. M. , Kumar Niraj
Published: November 2008

An explicit proposal for experiments leading to abrupt transitions in spatially extended bacterial populations in a Petri dish is presented on the basis of an exact formula obtained through an analytic theory. The theory provides accurately the transition expressions despite the fact that the actual solutions, which involve strong nonlinearity, are inaccessible to it. The analytic expressions are verified through numerical solutions of the relevant nonlinear equation. The experimental setup suggested uses opaque masks in a Petri dish bathed in ultraviolet radiation [Lin A-L,et al. (2004)Biophys J87:75–80 and Perry N (2005)J R Soc Interface2:379–387], but is based on the interplay of two distances the bacteria must traverse, one of them favorable and the other adverse. As a result of this interplay feature, the experiments proposed introduce highly enhanced reliability in interpretation of observations and in the potential for extraction of system parameters.
Self-organization of tidal deltas
Authors: Fagherazzi Sergio
Published: November 2008

Tidal deltas are characterized by a dendritic network of distributaries that transport water and sediments to the ocean. Here, I show that the distributaries self-organize to uniformly redistribute the tidal prism across the entire delta system. The 2 opposite mechanisms of channel formation by avulsion and channel abandonment drive the entire delta toward a critical state at which every channel is close to the silting threshold. Under these conditions the delta reaches self-organized criticality, with changes of its planimetric channel distribution occurring across several spatial scales.
Laws of population growth
Authors: Rozenfeld Hernán D. , Rybski Diego , Andrade José S. , Batty Michael , Stanley H. Eugene , Makse Hernán A.
Published: November 2008

An important issue in the study of cities is defining a metropolitan area, because different definitions affect conclusions regarding the statistical distribution of urban activity. A commonly employed method of defining a metropolitan area is the Metropolitan Statistical Areas (MSAs), based on rules attempting to capture the notion of city as a functional economic region, and it is performed by using experience. The construction of MSAs is a time-consuming process and is typically done only for a subset (a few hundreds) of the most highly populated cities. Here, we introduce a method to designate metropolitan areas, denoted “City Clustering Algorithm” (CCA). The CCA is based on spatial distributions of the population at a fine geographic scale, defining a city beyond the scope of its administrative boundaries. We use the CCA to examine Gibrat's law of proportional growth, which postulates that the mean and standard deviation of the growth rate of cities are constant, independent of city size. We find that the mean growth rate of a cluster by utilizing the CCA exhibits deviations from Gibrat's law, and that the standard deviation decreases as a power law with respect to the city size. The CCA allows for the study of the underlying process leading to these deviations, which are shown to arise from the existence of long-range spatial correlations in population growth. These results have sociopolitical implications, for example, for the location of new economic development in cities of varied size.
Alert signals enhance animal communication in “noisy” environments
Authors: Ord Terry J. , Stamps Judy A.
Published: November 2008

Environmental noise that reduces the probability that animals will detect communicative signals poses a special challenge for long-range communication. The application of signal-detection theory to animal communication lead to the prediction that signals directed at distant receivers in noisy environments will begin with conspicuous “alerting” components to attract the attention of receivers, before delivery of the information-rich portion of the signal. Whether animals actually adopt this strategy is not clear, despite suggestions that alerts might exist in a variety of taxa. By using a combination of behavioral observations and experimental manipulations with robotic lizard “playbacks,” we show that free-living territorial
Anolis
lizards add an “alert” to visual displays when communicating to distant receivers in situations of poor visibility, and that these introductory alerts in turn enhance signal detection in adverse signaling conditions. Our results show that
Anolis
lizards are able to evaluate environmental conditions that affect the degradation of long-distance signals and adjust their behavior accordingly. This study demonstrates that free-living animals enhance the efficiency of long-range communication through the modulation of signal design and the facultative addition of an alert. Our findings confirm that alert signals are an important strategy for communicating in “noisy” conditions and suggest a reexamination of the existence of alerts in other animals relying on long-range communication.
Insular hypocretin transmission regulates nicotine reward
Authors: Hollander Jonathan A. , Lu Qun , Cameron Michael D. , Kamenecka Theodore M. , Kenny Paul J.
Published: November 2008

Damage to the insular cortex can profoundly disrupt tobacco addiction in human smokers, reflected in spontaneous cessation of the tobacco habit and persistently decreased urge to smoke. Little is known concerning the neurobiological mechanisms through which the insula may control the maintenance of the tobacco habit. Emerging evidence suggests that hypocretin (orexin) transmission may play an important role in drug reinforcement processes, but its role in the rewarding actions of nicotine, considered the key addictive component of tobacco smoke, remains largely unexplored. Here we show that blockade of hypocretin transmission at hypocretin-1 (Hcrt-1; orexin-1) receptors decreases i.v. nicotine self-administration in rats and the motivation to obtain the drug. Blockade of Hcrt-1 receptors also abolished the stimulatory effects of nicotine on brain reward circuitries, as measured by reversal of nicotine-induced lowering of intracranial self-stimulation thresholds. In addition, we show that hypocretin-containing fibers innervate the insula, Hcrt-1 receptors are located on insular cells, and blockade of Hcrt-1 receptors in the insula but not in the adjacent somatosensory cortex decreases nicotine self-administration. These data demonstrate that insular hypocretin transmission plays a permissive role in the motivational properties of nicotine, and therefore may be a key neurobiological substrate necessary for maintaining tobacco addiction in human smokers.
Molecular organization of Gram-negative peptidoglycan
Authors: Gan Lu , Chen Songye , Jensen Grant J.
Published: November 2008

The stress-bearing component of the bacterial cell wall—a multi-gigadalton bag-like molecule called the sacculus—is synthesized from peptidoglycan. Whereas the chemical composition and the 3-dimensional structure of the peptidoglycan subunit (in at least one conformation) are known, the architecture of the assembled sacculus is not. Four decades' worth of biochemical and electron microscopy experiments have resulted in two leading 3-D peptidoglycan models: “Layered” and “Scaffold”, in which the glycan strands are parallel and perpendicular to the cell surface, respectively. Here we resolved the basic architecture of purified, frozen-hydrated sacculi through electron cryotomography. In the Gram-negative sacculus, a single layer of glycans lie parallel to the cell surface, roughly perpendicular to the long axis of the cell, encircling the cell in a disorganized hoop-like fashion.
A general framework for multiple testing dependence
Authors: Leek Jeffrey T. , Storey John D.
Published: November 2008

We develop a general framework for performing large-scale significance testing in the presence of arbitrarily strong dependence. We derive a low-dimensional set of random vectors, called a dependence kernel, that fully captures the dependence structure in an observed high-dimensional dataset. This result shows a surprising reversal of the “curse of dimensionality” in the high-dimensional hypothesis testing setting. We show theoretically that conditioning on a dependence kernel is sufficient to render statistical tests independent regardless of the level of dependence in the observed data. This framework for multiple testing dependence has implications in a variety of common multiple testing problems, such as in gene expression studies, brain imaging, and spatial epidemiology.
A geometric approach to problems in birational geometry
Authors: Chi Chen-Yu , Yau Shing-Tung
Published: November 2008

A classical set of birational invariants of a variety are its spaces of pluricanonical forms and some of their canonically defined subspaces. Each of these vector spaces admits a typical metric structure which is also birationally invariant. These vector spaces so metrized will be referred to as the pseudonormed spaces of the original varieties. A fundamental question is the following: Given two mildly singular projective varieties with some of the first variety's pseudonormed spaces being isometric to the corresponding ones of the second variety's, can one construct a birational map between them that induces these isometries? In this work, a positive answer to this question is given for varieties of general type. This can be thought of as a theorem of Torelli type for birational equivalence.
The genome sequence ofBifidobacterium longumsubsp.infantisreveals adaptations for milk utilization within the infant microbiome
Authors: Sela D. A. , Chapman J. , Adeuya A. , Kim J. H. , Chen F. , Whitehead T. R. , Lapidus A. , Rokhsar D. S. , Lebrilla C. B. , German J. B. , Price N. P. , Richardson P. M. , Mills D. A.
Published: November 2008

Following birth, the breast-fed infant gastrointestinal tract is rapidly colonized by a microbial consortium often dominated by bifidobacteria. Accordingly, the complete genome sequence ofBifidobacterium longumsubsp.infantisATCC15697 reflects a competitive nutrient-utilization strategy targeting milk-borne molecules which lack a nutritive value to the neonate. Several chromosomal loci reflect potential adaptation to the infant host including a 43 kbp cluster encoding catabolic genes, extracellular solute binding proteins and permeases predicted to be active on milk oligosaccharides. An examination ofin vivometabolism has detected the hallmarks of milk oligosaccharide utilization via the central fermentative pathway using metabolomic and proteomic approaches. Finally, conservation of gene clusters in multiple isolates corroborates the genomic mechanism underlying milk utilization for this infant-associated phylotype.
Urinary incontinence and quality of life in long‐term gynecological cancer survivors: A population‐based cross‐sectional study
Authors: SKJELDESTAD FINN EGIL , RANNESTAD TORIL
Published: November 2008

Objective. To investigate quality of life (QoL) among women reporting urinary incontinence (UI). Design. Population‐based cross‐sectional study. Setting. Survival status for all women who had primary treatment between 1987 and 1996 at the University Hospital, Trondheim, Norway, was assessed in 2003. Eligible for study participation were recurrence‐free survivors of gynecological cancer and age‐matched women selected from the general population. Methods. Women who had no history of gynecological cancer were selected as age‐matched controls in a 4:1 ratio to survivors in the population census. In 2004, all eligible participants were sent an extensive questionnaire. After one reminder the response rate was 55% (176/319) and 41% (521/1276) for survivors and controls, respectively. UI (total, stress, urge and mixed) was in agreement with definitions of the International Continence Society. QoL was measured by Ferrans and Powers’ Quality of Life Index (QLI). The chi‐squared test for categorical variables, unpaired T‐test for continuous variables and logistic regression were applied. Results. A history of recurrence‐free gynecologic cancer was not associated with reduced QLI. The prevalence of UI was 34.5%. Women with UI had lower scores on total QLI and all domains (health/functioning, psychological/spiritual, socio‐economic, and family domain) compared with continent women. A decreasing score of QLI and its domains were found for increasing severity of UI. After adjustment for other co‐morbidities UI remained an independent significant predictor of QLI below the 25. percentile, but not for QLI below the 10. percentile. Conclusion. UI has a negative impact on QoL. The more severe UI, the more reduced were total and all QLI domains.
Treatment of gestational trophoblastic neoplasia according to the FIGO 2000 staging and scoring system: a 20 years’ experience
Authors: WANG KUNG‐LIAHNG , YANG YUH‐CHENG , WANG TAO‐YEUAN , LAI JERRY CHENG‐YEN , CHEN TZE‐CHIEN , CHANG CHI‐LONG
Published: November 2008

Objective. To reassess the efficacy of the Federation of Gynecology and Obstetrics (FIGO) 2000 staging and risk factor scoring system in comparison to the original World Health Organization (WHO) prognostic scoring system (1983) in a single‐institute setting. Design. Retrospective review of the medical records of 89 patients with gestational trophoblastic neoplasia. Setting. Mackay Memorial Hospital, Taipei, a regional referral center for northern Taiwan, over a 20‐year period. Methods. All selected patients were classified retrospectively by the original WHO prognostic scoring system (1983) and the FIGO 2000 system. Main outcome measure. Efficacy as the correlation of risk categorization by percentage of patients between the original WHO scoring system (1983) and the FIGO 2000 system. Results. The correlation was 97%. Only two patients were classified as middle risk group in the original WHO system (1983), but as high‐risk group by the FIGO 2000 system. Conclusion. There was good correlation between the original WHO (1983) and FIGO 2000 systems. Treatment outcomes by FIGO 2000 system were somewhat better than by the original WHO classification.
Impact of allelic dropout on evidential value of forensic DNA profiles using RMNE
Authors: Van Nieuwerburgh F. , Goetghebeur E. , Vandewoestyne M. , Deforce D.
Published: November 2008

Motivation: Two methods are commonly used to report on evidence carried by forensic DNA profiles: the ‘Random Man Not Excluded’ (RMNE) approach and the likelihood ratio (LR) approach. It is often claimed a major advantage of the LR method that dropout can be assessed probabilistically.

Results: In this article, a new RMNE measure is proposed that like-wise accounts for allelic dropout in an observed forensic DNA profile. We discuss the necessary calculations, underline their simplicity and provide a tool for performing the calculations.

Availability: An Excel file with preprogrammed calculations of RMNE probabilities for DNA profiles up to 16 loci and with a maximum of two dropouts is available at: http://www.labfbt.UGent.be/RMNE.php

Contact:  dieter.deforce@ugent.be
French Connections: The International Propagation of Trademarks in the Nineteenth Century
Authors: Duguid Paul
Published: November 2008

The history of modern brands depends to a significant degree on the history of trademark law, but there are reasons to doubt how comprehensive standard versions of the latter history are. Business, economic, and even legal historians tend to accentuate the importance of the Anglo-Saxon common-law tradition and assume that the continental, civil law tradition followed in its wake. Yet the historical sequence of events suggests that almost exactly the opposite is true. Not only did the French have robust trademark law long before Great Britain and the United States, but the latter two countries only adopted trademark law after signing trademark clauses in diplomatic treaties with France. Drawing on newspaper accounts, public debates, specialist and general newspapers, as well as court cases and diplomatic negotiations, this paper argues that, to a certain degree, Anglo-Saxon trademark law was international before it was national. The evidence suggests that some of the easy verities on which arguments about modern brands, the “second industrial revolution,” and institutional economics are based may be more complex than is generally assumed.
Hemodynamic Assessment Using Apical Suction versus Pericardial Retraction in Beating Heart Surgery
Authors: Gummert Jan F. , Raumanns Joerg , Opfermann Ulrich T. , Bossert Torsten , Ender Joerg , Rastan Ardawan , Falk Volkmar , Walther Thomas , Mohr Friedrich W.
Published: November 2008

Objective

Aim of this study was to evaluate the perioperative hemodynamic function using an apical suction device (Xpose = XS) versus standard pericardial retraction sutures (PS) during off-pump myocardial revascularization.

Methods

Twenty-seven consecutive patients (four female) with three-vessel disease receiving off-pump myocardial revascularization were prospectively evaluated. Mean age was 70 ± 8 years and mean ejection fraction was 55 ± 18%. Pulscontour continuous cardiac output, Swan Ganz catheter, and transesophageal echo measurements were performed. All patients received left internal mammary artery (LIMA)-left anterior descending grafting first. The XS or PS technique for marginal or right coronary artery branch exposure was used and after hemodynamic recovery the same measurements were performed using the other technique, thus each patient served as an intraindividual control. Finally, the anastomosis was performed in the respective territory.

Results

All procedures were completed as off-pump coronary artery bypass without perioperative complications. The mean confidence interval (L/min/m2)/mean arterial pressure (mm Hg) was 2.8 ± 0.5/87 ± 11 after opening the pericardium and 2.4 ± 0.4/75 ± 12 during left anterior descending exposure. During lateral wall exposure, it was 1.8 ± 0.6/67 ± 12 using XS and 1.9 ± 0.6/68 ± 12 using PS (P = ns). During inferior wall exposure, it was 2.1 ± 0.4/69 ± 12 using XS and 1.9 ± 0.4/68 ± 13 using PS (P = ns). No significant differences were seen comparing other parameters (cardiac output (CO), heart rate (HR), intrathoracic blood volume index) as well.

Conclusions

The lateral and inferior coronary arteries can be safely exposed on the beating heart with PS or XS technique. In individual patients, either XS or PS exposure yielded a better preservation of cardiac index and blood pressure compared with baseline.
Diabetic Retinopathy: Two Faces of the Same Coin
Authors: Muñoz Silvia , Sanz Silvia , Planas Núria
Published: November 2008

We report two contrasting cases of diabetic retinopathy to illustrate vascular and retinal abnormalities in this condition. In the first case, mild diabetic retinopathy is diagnosed in an asymptomatic patient with diabetes mellitus of recent onset. The second patient has severe diabetic retinopathy, causing vision loss as a consequence of poor metabolic control.
Nonsurgical Management of the Neurogenic Bladder in Children
Authors: Kryger John
Published: November 2008

The neurogenic bladder can have many serious consequences. However, with proper understanding of the disease spectrum, and with proper awareness of the surveillance and management tools, adverse outcomes can be minimized. The incidence of renal failure is uncommon. With proper medical therapy, one can achieve continence and minimize the risk of symptomatic urinary tract infections. There are a number of nonsurgical strategies described that can help in the management of the neurogenic bladder.
Radical Pancreaticoduodenectomy for Benign Disease
Authors: Kavanagh D. O. , O'Riain C. , Ridgway P. F. , Neary P. , Crotty T. C. , Geoghegan J. G. , Traynor O.
Published: November 2008

Whipple's procedure is the treatment of choice for pancreatic and periampullary malignancies. Preoperative histological confirmation of malignancy is frequently unavailable and some patients will subsequently be found to have benign disease. Here, we review our experience with Whipple's procedure for patients ultimately proven to have benign disease. The medical records of all patients who underwent Whipple's procedure during a 15-year period (1987–2002) were reviewed; 112 patients underwent the procedure for suspected malignancy. In eight cases, the final histology was benign (7.1%). One additional patient was known to have benign disease at resection. The mean age was 50 years (range: 30–75). The major presenting features included jaundice (five), pain (two), gastric outlet obstruction (one), and recurrent gastrointestinal haemorrhage (one). Investigations included ultrasound (eight), computerised tomography (eight), endoscopic retrograde cholangiopancreatography (seven; of these, four patients had a stent inserted and three patients had sampling for cytology), and endoscopic ultrasound (two). The pathological diagnosis included benign biliary stricture (two), chronic pancreatitis (two), choledochal cyst (one), inflammatory pseudotumour (one), cystic duodenal wall dysplasia (one), duodenal angiodysplasia (one), and granular cell neoplasm (one). There was no operative mortality. Morbidity included intra-abdominal collection (one), anastomotic leak (one), liver abscess (one), and myocardial infarction (one). All patients remain alive and well at mean follow-up of 41 months. Despite recent advances in diagnostic imaging, 8% of the patients undergoing Whipple's procedure had benign disease. A range of unusual pathological entities can mimic malignancy. Accurate preoperative histological diagnosis may have allowed a less radical operation to be performed. Endoscopic ultrasound–guided fine needle aspirate (EUS-FNA) may reduce the need for Whipple's operation in benign pancreaticobiliary disease in the future.
Immunostaining of Lgr5, an Intestinal Stem Cell Marker, in Normal and Premalignant Human Gastrointestinal Tissue
Authors: Becker Laren , Huang Qin , Mashimo Hiroshi
Published: November 2008

Lgr5 has recently been identified as a murine marker of intestinal stem cells. Its expression has not been well characterized in human gastrointestinal tissues, but has been reported in certain cancers. With the increasing appreciation for the role of cancer stem cells or tumor-initiating cells in certain tumors, we sought to explore the expression of Lgr5 in normal and premalignant human gastrointestinal tissues. Using standard immunostaining, we compared expression of Lgr5 in normal colon and small intestine vs. small intestinal and colonic adenomas and Barrett's esophagus. In the normal tissue, Lgr5 was expressed in the expected stem cell niche, at the base of crypts, as seen in mice. However, in premalignant lesions, Lgr5+cells were not restricted to the crypt base. Additionally, their overall numbers were increased. In colonic adenomas, Lgr5+cells were commonly found clustered at the luminal surface and rarely at the crypt base. Finally, we compared immunostaining of Lgr5 with that of CD133, a previously characterized marker for tumor-initiating cells in colon cancer, and found that they identified distinct subpopulations of cells that were in close proximity, but did not costain. Our findings suggest that (1) Lgr5 is a potential marker of intestinal stem cells in humans and (2) loss of restriction to the stem cell niche is an early event in the premalignant transformation of stem cells and may play a role in carcinogenesis.
Comparison of Three Different Chemotherapy Regimens Containing Epirubicin in Hormone-Refractory Prostate Cancer Patients
Authors: Ersoy Hamit , Yigitbası Orhan , Sagnak Levent , Topaloglu Hikmet , Kiper Ahmet
Published: November 2008

We compared three different chemotherapy regimens containing epirubicin in hormonerefractory prostate cancer (HRPC) patients. Sixty-nine patients with HRPC were randomized into three groups. The first group (22 patients) received 30 mg/m2/week i.v. epirubicin for 8 weeks. The second group (24 patients) received 30 mg/m2/week i.v. epirubicin for 8 weeks followed by monthly maintenance therapy for 4–6 months. The third group (23 patients) received oral estramustine phosphate (EMP) at a dose of 840 mg/day together with weekly and monthly maintenance epirubicin. The response rates, mean survival times, and toxicity were determined. Within the first 3 months, pain and performance scores were improved by at least one degree in all the groups. One patient in group two and three patients in group three had complete response. Partial response rates were 23% in group 1, 25% in group 2, and 17% in group 3. Stable disease rates were 41% in group 1, 33% in group 2, and 26% in group 3. The progression rates within the first 3 months were 36% in group 1, 38% in group 2, and 44% in group 3. None of the patients developed complications that were significant enough to terminate the treatment. Two patients in group 3 died of cardiotoxicity. The mean survival times were 10.1, 15.8, and 16.1 months in groups 1, 2, and 3, respectively. It was determined that weekly and maintenance epirubicin treatment protocol, and estramustine treatment protocol in addition to this treatment, was only meaningfully more effective against weekly epirubicin treatment in the statistical sense (0.01 < p < 0.05). However, due to the complications of EMP, which influence the quality of life, we believe that this was usable only when measures were adopted against these effects.
EnsemblCompara GeneTrees: Complete, duplication-aware phylogenetic trees in vertebrates
Authors: Vilella Albert J. , Severin Jessica , Ureta-Vidal Abel , Heng Li , Durbin Richard , Birney Ewan
Published: November 2008

We have developed a comprehensive gene orientated phylogenetic resource, EnsemblCompara GeneTrees, based on a computational pipeline to handle clustering, multiple alignment, and tree generation, including the handling of large gene families. We developed two novel non-sequence-based metrics of gene tree correctness and benchmarked a number of tree methods. The TreeBeST method from TreeFam shows the best performance in our hands. We also compared this phylogenetic approach to clustering approaches for ortholog prediction, showing a large increase in coverage using the phylogenetic approach. All data are made available in a number of formats and will be kept up to date with the Ensembl project.
Fast and flexible simulation of DNA sequence data
Authors: Chen Gary K. , Marjoram Paul , Wall Jeffrey D.
Published: November 2008

Simulation of genomic sequences under the coalescent with recombination has conventionally been impractical for regions beyond tens of megabases. This work presents an algorithm, implemented as the program MaCS (Markovian Coalescent Simulator), that can efficiently simulate haplotypes under any arbitrary model of population history. We present several metrics comparing the performance of MaCS with other available simulation programs. Practical usage of MaCS is demonstrated through a comparison of measures of linkage disequilibrium between generated program output and real genotype data from populations considered to be structured.
Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor‐β receptor inhibitor on extravasation of nanoparticles from neovasculature
Authors: Kano Mitsunobu R. , Komuta Yukari , Iwata Caname , Oka Masako , Shirai Yo‐taro , Morishita Yasuyuki , Ouchi Yasuyoshi , Kataoka Kazunori , Miyazono Kohei
Published: November 2008

There are a number of kinase inhibitors that regulate components of the neovasculature. We previously reported the use of transforming growth factor (TGF)‐β inhibitor on neovasculature in stroma‐rich tumor models to increase the intratumoral distribution of nanoparticles. Here, we compared the effects of two other kinase inhibitors, imatinib and sorafenib, with TGF‐β inhibitor (LY364947) on extravasation of a modeled nanoparticle, 2 MDa dextran. We first used a mouse model of neoangiogenesis, the Matrigel plug assay, to compare neovasculature formed inside of and around Matrigel plugs (intraplug and periplug regions, respectively). Intraplug vasculature was more strongly pericyte covered, whereas periplug vasculature was less covered. In this model, TGF‐β inhibitor exhibited the most potent effect on intraplug vasculature in increasing the extravasation of dextran, whereas sorafenib had the strongest effect on periplug vasculature. Although imatinib and TGF‐β inhibitor each reduced pericyte coverage, imatinib also reduced the density of endothelium, resulting in a decrease in overall delivery of nanoparticles. These findings were confirmed in two tumor models, the CT26 colon cancer model and the BxPC3 pancreatic cancer model. The vasculature phenotype in the CT26 model resembled that in the periplug region, whereas the latter resembled that in the intraplug region. Consistent with this, sorafenib most potently enhanced the accumulation of nanoparticles in the CT26 model, whereas TGF‐β inhibitor did in the BxPC3 model. In conclusion, the appropriate strategy for optimization of tumor vasculature for nanoparticles may differ depending on tumor type, and in particular on the degree of pericyte coverage around the vasculature. (Cancer Sci 2009; 100: 173–180)
Histological and immunophenotypic changes in 59 cases of B‐cell non‐Hodgkin's lymphoma after rituximab therapy
Authors: Maeshima Akiko Miyagi , Taniguchi Hirokazu , Nomoto Junko , Maruyama Dai , Kim Sung‐Won , Watanabe Takashi , Kobayashi Yukio , Tobinai Kensei , Matsuno Yoshihiro
Published: November 2008

Rituximab is a chimeric monoclonal antibody that recognizes the CD20 antigen. It has been used to treat B‐cell non‐Hodgkin lymphoma (B‐NHL), but recently rituximab resistance has been a cause for concern. We examined histological and immunohistochemical changes in 59 patients with B‐NHL after rituximab therapy. The patients comprised 32 men and 27 women with a median age of 59 years. Pre‐rituximab specimens comprised 34 follicular lymphomas (FL), 11 diffuse large B‐cell lymphomas (DLBCL), 10 mantle cell lymphomas, two marginal zone B‐cell lymphomas (MZBCL), and two chronic lymphocytic leukemias (CLL). CD20 expression in lymphoma cells was evaluated by immunohistochemistry or flow cytometry. Post‐rituximab materials were taken a median of 6 months (4 days to 59 months) after rituximab therapy. Sixteen cases (27%) showed loss of CD20 expression with four histological patterns: pattern 1, no remarkable histological change (FL, 5; DLBCL, 3; and CLL, 2); pattern 2, proliferation of plasmacytoid cells (FL, 2; DLBCL, 1; and MZBCL, 1); pattern 3, transformation to classical Hodgkin's lymphoma (FL, 1); and pattern 4, transformation to anaplastic large cell lymphoma‐like undifferentiated lymphoma (FL, 1). Loss of CD20 was unrelated to the interval of biopsies, treatment regimen, clinical response, and frequency of rituximab administration. Loss of CD20 within 1 month of rituximab therapy (3/14, 21%) and regain of CD20 (2/7, 29%) were not frequent. CD20‐positive relapse with transformation occurred most frequently in cases of early relapse. In conclusion, B‐NHL showed various histological and immunophenotypic changes after rituximab therapy, including not only CD20 loss but also proliferation of plasmacytoid cells or transformation to special subtypes of lymphoma. (Cancer Sci 2009; 100: 54–61)
Targeting the ubiquitin‐proteasome system for cancer therapy
Authors: Yang Yili , Kitagaki Jirouta , Wang Honghe , Hou De‐Xing , Perantoni Alan O.
Published: November 2008

The ubiquitin‐proteasome system plays a critical role in controlling the level, activity and location of various cellular proteins. Significant progress has been made in investigating the molecular mechanisms of ubiquitination, particularly in understanding the structure of the ubiquitination machinery and identifying ubiquitin protein ligases, the primary specificity‐determining enzymes. Therefore, it is now possible to target specific molecules involved in ubiquitination and proteasomal degradation to regulate many cellular processes such as signal transduction, proliferation and apoptosis. In particular, alterations in ubiquitination are observed in most, if not all, cancer cells. This is manifested by destabilization of tumor suppressors, such as p53, and overexpression of oncogenes such as c‐Myc and c‐Jun. In addition to the development and clinical validation of proteasome inhibitor, bortezomib, in myeloma therapy, recent studies have demonstrated that it is possible to develop inhibitors for specific ubiquitination and deubiquitination enzymes. With the help of structural studies, rational design and chemical synthesis, it is conceivable that we will be able to use ‘druggable’ inhibitors of the ubiquitin system to evaluate their effects in animal tumor models in the not‐so‐distant future. (Cancer Sci 2009; 100: 24–28)
Clinicopathological relevance of UbcH10 in breast cancer
Authors: Fujita Takeo , Ikeda Hirokuni , Kawasaki Kensuke , Taira Naruto , Ogasawara Yutaka , Nakagawara Akira , Doihara Hiroyoshi
Published: November 2008

Abrogated mitotic progression is a common hallmark of cancer. UbcH10, one of the components of the ubiquitin/proteasome pathway, plays a pivotal role in the regulation of mitotic progression. Abnormal UbcH10 activity is reported in certain types of human cancers; its overexpression is occasionally encountered in cancerous tissue compared with adjacent normal tissue. Current studies have suggested the critical role of UbcH10 in the spindle assembly checkpoint and the subsequent accurate separation of sister chromatids, which is orchestrated by a series of molecular interactions governed by the complex and diverse cell cycle machinery. To validate the potential role of UbcH10 in cell proliferation in cancer, we have analyzed the clinicopathological relevance of UbcH10 in progression of breast cancer using a combinatorial approach of human tumor arrays and biochemical analyses. Our results show that the percentage of tested samples which stained positive for UbcH10 in breast cancer tissues is significantly higher compared to the adjacent nonmalignant tissue. Furthermore, results from the clinicopathological analysis have revealed that elevated expression of UbcH10 is associated with higher histological grade tumors. In addition, depletion of UbcH10 by RNA interference in breast cancer cells resulted in decreased cellular proliferation, while overexpression of UbcH10 significantly enhanced cellular growth in breast cancer. Our results suggest a pathological correlation between UbcH10 and cell proliferation in breast cancer. Thus, aberrant UbcH10 activity may induce the dysfunction of proper cell cycle progression and result in the aggressive behavior of tumor cells in patients with breast cancer. (Cancer Sci 2009; 100: 238–248)
Systematic review: the epidemiology of gastro‐oesophageal reflux disease in primary care, using the UK General Practice Research Database
Authors: EL‐SERAG H. , HILL C. , JONES R.
Published: November 2008

Background  Gastro‐oesophageal reflux disease (GERD) is a common diagnosis in primary care; however, there has been no comprehensive review of the epidemiology of GERD in this setting.

Aim  To review systematically articles that used the General Practice Research Database to study the epidemiology of GERD.

Methods  Systematic literature searches.

Results  Seventeen articles fulfilled the inclusion criteria. The incidence of GERD in primary care was 4.5 new diagnoses per 1000 person‐years in 1996 (95% CI: 4.4–4.7). A new diagnosis of GERD was associated with being overweight, obese or an ex‐smoker. Prior diagnoses of ischaemic heart disease, peptic ulcer disease, nonspecific chest pain, nonspecific abdominal pain, chronic obstructive pulmonary disease and asthma were associated with a subsequent new GERD diagnosis. A first diagnosis of GERD was associated with an increased risk of a subsequent diagnosis of oesophageal adenocarcinoma, oesophageal stricture, chronic cough, sinusitis, chest pain, angina, gallbladder disease, irritable bowel syndrome or sleep problems. Mortality may be higher in patients with a GERD diagnosis than in those without in the first year after diagnosis, but not long term.

Conclusion  The General Practice Research Database is an effective way of studying the epidemiology of GERD in a large population‐based primary care setting.
Phylogeography of the brown hare (Lepus europaeus) in Europe: a legacy of south‐eastern Mediterranean refugia?
Authors: Stamatis Costas , Suchentrunk Franz , Moutou Katerina A. , Giacometti Marco , Haerer Gunther , Djan Mihajla , Vapa Ljiljana , Vukovic Marijana , Tvrtković Nikola , Sert Hakan , Alves Paulo C. , Mamuris Zissis
Published: November 2008

Aim  We analysed the population genetics of the brown hare (Lepus europaeus) in order to test the hypothesis that this species migrated into central Europe from a number of late glacial refugia, including some in Asia Minor.

Location  Thirty‐three localities in Greece, Bulgaria, Italy, Croatia, Serbia, Poland, Switzerland, Austria, France, Germany, the Netherlands, Spain, the United Kingdom, Turkey and Israel.

Methods  In total, 926 brown hares were analysed for mitochondrial DNA (mtDNA) variation by restriction fragment length polymorphism (RFLP) performed on polymerase chain reaction‐amplified products spanning cytochrome b (cyt b)/control region (CR), cytochrome oxidase I (COI) and 12S–16S rRNA. In addition, sequence analysis of the mtDNA CR‐I region was performed on 69 individuals, and the data were compared with 137 mtDNA CR‐I sequences retrieved from GenBank.

Results  The 112 haplotypes detected were partitioned into five phylogeographically well‐defined major haplogroups, namely the ‘south‐eastern European type haplogroup’ (SEEh), ‘Anatolian/Middle Eastern type haplogroup’ (AMh), ‘European type haplogroup, subgroup A’ (EUh‐A), ‘European type haplogroup, subgroup B’ (EUh‐B) and ‘Intermediate haplogroup’ (INTERh). Sequence data retrieved from GenBank were consistent with the haplogroups determined in this study. In Bulgaria and north‐eastern Greece numerous haplotypes of all five haplogroups were present, forming a large overlap zone.

Main conclusions  The mtDNA results allow us to infer post‐glacial colonization of large parts of Europe from a late glacial/early Holocene source population in the central or south‐central Balkans. The presence of Anatolian/Middle Eastern haplotypes in the large overlap zone in Bulgaria and north‐eastern Greece reveals gene flow from Anatolia to Europe across the late Pleistocene Bosporus land‐bridge. Although various restocking operations could be partly responsible for the presence of unexpected haplotypes in certain areas, we nevertheless trace a strong phylogeographic signal throughout all regions under study. Throughout Europe, mtDNA results indicate that brown hares are not separated into discernable phyletic groups.
Using the Mahalanobis distance statistic with unplanned presence‐only survey data for biogeographical models of species distribution and abundance: a case study of badger setts
Authors: Etherington Thomas R. , Ward Alastair I. , Smith Graham C. , Pietravalle Stéphane , Wilson Gavin J.
Published: November 2008

Aim  Project‐specific data for biogeographical models are often logistically impractical to collect, forcing the use of existing data from a variety of sources. Use of these data is complicated when neither absence nor an estimate of the area sampled is available, as these are requirements of most analytical techniques. We demonstrate the Mahalanobis distance statistic (D2), which is a presence‐only modelling technique and does not require information on species absence or the sampled area. We use badger (Meles meles) setts as the basis for this investigation, as their landscape associations are well understood, and survey data exist against which to compare estimates of sett distribution and abundance.

Location  England and Wales (151,403 km2).

Methods  We used stratified random samples of sett locations, and landscape variables that are known to be important for choice of badger sett location within a geographic information system at a cell resolution of 100 × 100 m. Landscape conditions at two scales were extracted, at and around sett locations, and the D2 was used to classify all cells in England and Wales into a sett suitability model. Comparison of this sett suitability model with known main sett densities allowed estimates of main sett density to be made across England and Wales, with associated uncertainty.

Results  The sett suitability model was shown through iterative sampling and model evaluation using independent data to be stable and accurate. Main sett density estimates were biologically plausible in comparison with previous field‐derived estimates. We estimate 58,000 main setts within England and Wales, with 95% confidence intervals suggesting a value between 31,000 and 93,000.

Main conclusions  The D2, which could be applied to other species and locations, proved useful in our context, where absence data were not available and the sampled area could not be reliably established. We were able to predict sett suitability across a large area and at a fine resolution, and to generate plausible estimates of main sett density. The final model provides valuable information on probable badger sett distribution and abundance, and may contribute to future research on the spatial ecology of badgers in England and Wales.
Spread of an introduced vector‐borne banana virus in Hawaii
Authors: ALMEIDA RODRIGO P.P. , BENNETT GORDON M. , ANHALT MANDY D. , TSAI CHI‐WEI , O’GRADY PATRICK
Published: November 2008

Emerging diseases are increasing in incidence; therefore, understanding how pathogens are introduced into new regions and cause epidemics is of importance for the development of strategies that may hinder their spread. We used molecular data to study how a vector‐borne banana virus, Banana bunchy top virus (BBTV), spread in Hawaii after it was first detected in 1989. Our analyses suggest that BBTV was introduced once into Hawaii, on the island of Oahu. All other islands were infected with isolates originating from Oahu, suggesting that movement of contaminated plant material was the main driving factor responsible for interisland spread of BBTV. The rate of mutation inferred by the phylogenetic analysis (1.4 × 10−4 bp/year) was similar to that obtained in an experimental evolution study under greenhouse conditions (3.9 × 10−4 bp/year). We used these values to estimate the number of infections occurring under field conditions per year. Our results suggest that strict and enforced regulations limiting the movement of banana plant material among Hawaiian islands could have reduced interisland spread of this pathogen.