bluuebunny/crossref_metadata_2025 huggingface dataset:
Methodological issues with adaptation of clinical trial design
Authors: James Hung H. M. , Wang Sue‐Jane , O'Neill Robert T.
Published: May 2006

Adaptation of clinical trial design generates many issues that have not been resolved for practical applications, though statistical methodology has advanced greatly. This paper focuses on some methodological issues. In one type of adaptation such as sample size re‐estimation, only the postulated value of a parameter for planning the trial size may be altered. In another type, the originally intended hypothesis for testing may be modified using the internal data accumulated at an interim time of the trial, such as changing the primary endpoint and dropping a treatment arm. For sample size re‐estimation, we make a contrast between an adaptive test weighting the two‐stage test statistics with the statistical information given by the original design and the original sample mean test with a properly corrected critical value. We point out the difficulty in planning a confirmatory trial based on the crude information generated by exploratory trials. In regards to selecting a primary endpoint, we argue that the selection process that allows switching from one endpoint to the other with the internal data of the trial is not very likely to gain a power advantage over the simple process of selecting one from the two endpoints by testing them with an equal split of alpha (Bonferroni adjustment). For dropping a treatment arm, distributing the remaining sample size of the discontinued arm to other treatment arms can substantially improve the statistical power of identifying a superior treatment arm in the design. A common difficult methodological issue is that of how to select an adaptation rule in the trial planning stage. Pre‐specification of the adaptation rule is important for the practicality consideration. Changing the originally intended hypothesis for testing with the internal data generates great concerns to clinical trial researchers. Copyright © 2006 John Wiley & Sons, Ltd.
Application of an adaptive design to a randomized phase II selection trial in gastric cancer: a report of the study design
Authors: Morita Satoshi , Sakamoto Junichi
Published: May 2006

Randomized phase II selection trials seek to provide unbiased comparisons for the selection of the most promising treatment arm for evaluation in a future phase III trial. In this paper, we present an application of an adaptive design to a randomized phase II selection trial comparing three experimental treatments with a control arm in patients with advanced gastric cancer. The trial design continuously monitors multiple patient outcomes to protect future patients from treatments with unacceptably high toxicity and/or unacceptably low efficacy. We use a Bayesian approach to monitor the trial and carry out simulations to investigate operating characteristics of the trial design. The simulation study also evaluates the sensitivity of the design to the prior distribution by considering two alternative priors. Copyright © 2006 John Wiley & Sons, Ltd.
Operational challenges in adaptive design implementation
Authors: Gallo Paul
Published: May 2006

Implementation of adaptive clinical trial designs raises challenges with regard to the processes by which accruing trial data is analyzed, reviewed, and acted upon. In line with current monitoring conventions, it should be viewed that inappropriate knowledge of interim results can raise concerns regarding maintaining trial integrity and interpretability of results. Here we discuss issues related to these processes in adaptive trials, and point out distinctions versus other more familiar monitoring situations. One topic involves the composition of the group of individuals who will have access to interim results in order to recommend adaptations. We discuss operational models for data review by this group; one question addressed is whether in adaptive trials a role in this process for a representative of the study sponsor could at times be warranted, and might be justified if adequate protections are in place. Another issue involves whether adaptations made based upon interim data can convey to observers an amount of information about the results, which could rise to a level of concern. We consider whether different types of adaptations might be more or less problematic with regard to this issue, and recommend steps that might be considered to mitigate this concern. Copyright © 2006 John Wiley & Sons, Ltd.
Bayesian decision procedures for binary and continuous bivariate dose‐escalation studies
Authors: Zhou Yinghui , Whitehead John , Bonvini Elisa , Stevens John W.
Published: May 2006

In this paper, Bayesian decision procedures are developed for dose‐escalation studies based on binary measures of undesirable events and continuous measures of therapeutic benefit. The methods generalize earlier approaches where undesirable events and therapeutic benefit are both binary. A logistic regression model is used to model the binary responses, while a linear regression model is used to model the continuous responses. Prior distributions for the unknown model parameters are suggested. A gain function is discussed and an optional safety constraint is included. Copyright © 2006 John Wiley & Sons, Ltd.
Planning for an adaptive design: a case study in COPD
Authors: Jones B. , Atkinson G. , Ward J. , Tan E. , Kerbusch T.
Published: May 2006

We discuss the practical and clinical considerations encountered when planning a Phase IIa trial in chronic obstructive pulmonary disease (COPD). Various adaptive strategies for reducing the cost of the trial and the statistical implications of these are explored. Use of the EAST software to evaluate the properties of the study designs with one or more interim analyses for futility, efficacy or either is described. We emphasize the rationale for choosing between alternative designs and the relationship between the clinical and statistical considerations. Copyright © 2006 John Wiley & Sons, Ltd.
Characterization of high explosive particles using cluster secondary ion mass spectrometry
Authors: Gillen Greg , Mahoney Christine , Wight Scott , Lareau Richard
Published: May 2006

The use of secondary ion mass spectrometry (SIMS) for the detection and spatially resolved analysis of individual high explosive particles is described. A C carbon cluster primary ion beam was used in a commercial SIMS instrument to analyze samples of high explosives dispersed as particles on silicon substrates. In comparison with monatomic primary ion bombardment, the carbon cluster primary ion beam was found to greatly enhance characteristic secondary ion signals from the explosive compounds while causing minimal beam‐induced degradation. The resistance of these compounds to degradation under ion bombardment allows explosive particles to be analyzed under high primary ion dose bombardment (dynamic SIMS) conditions, facilitating the rapid acquisition of spatially resolved molecular information. The use of cluster SIMS combined with computer control of the sample stage position allows for the automated identification and counting of explosive particle distributions on silicon surfaces. This will be useful for characterizing the efficiency of transfer of particulates in trace explosive detection portal collectors and/or swipes utilized for ion mobility spectrometry applications. Published in 2006 by John Wiley & Sons, Ltd.
The fragmentation pathways of protonated Amiton in the gas phase: towards the structural characterisation of organophosphorus chemical warfare agents by electrospray ionisation tandem mass spectrometry
Authors: Ellis‐Steinborner Simon , Ramachandran Aravind , Blanksby Stephen J.
Published: May 2006

Amiton (O,O‐diethyl‐S‐[2‐(diethylamino)ethyl] phosphorothiolate), otherwise known as VG, is listed in schedule 2 of the Chemical Weapons Convention (CWC) and has a structure closely related to VX (O‐ethyl‐S‐(2‐diisopropylamino)ethylmethylphosphonothiolate). Fragmentation of protonated VG in the gas phase was performed using electrospray ionisation ion trap mass spectrometry (ESI‐ITMS) and revealed several characteristic product ions. Quantum chemical calculations provide the most probable structures for these ions as well as the likely unimolecular mechanisms by which they are formed. The decomposition pathways predicted by computation are consistent with deuterium‐labeling studies. The combination of experimental and theoretical data suggests that the fragmentation pathways of VG and analogous organophosphorus nerve agents, such as VX and Russian VX, are predictable and thus ESI tandem mass spectrometry is a powerful tool for the verification of unknown compounds listed in the CWC. Copyright © 2006 Commonwealth of Australia. Published by John Wiley & Sons, Ltd.
Density functional theory meets statistical physics: from the atomistic to the mesoscopic properties of alloys
Authors: Müller Stefan
Published: May 2006

Today, calculations based on density functional theory (DFT) allow us to study a number of metal alloy properties, as e.g. formation enthalpies, or electronic and elastic properties of intermetallic compounds. However, such so‐called (ab initio) calculations can only be applied as long as the alloy structure requires only small unit cells for the crystallographic description. This limitation can be overcome by combining DFT calculations with the so‐called Cluster Expansion (CE) methods and Monte‐Carlo (MC) simulations. The concept will be applied to study two characteristic type of interfaces, namely, the boundary between solid solution and precipitate as well as the alloy's surface. Copyright © 2006 John Wiley & Sons, Ltd.
XPS and ToF‐SIMS characterization of a Finemet surface: effect of cooling
Authors: Chenakin S. P. , Vasylyev M. A. , Kruse N. , Tolstogouzov A. B.
Published: May 2006

The surface composition of amorphous Finemet, Fe73Si15.8B7.2Cu1Nb3, was studied by X‐ray photoelectron spectroscopy (XPS) and time‐of‐flight secondary ion mass spectrometry (ToF‐SIMS). The as‐received sample in the original state and after Ar+ sputter‐cleaning was analyzed at room temperature as well as after cooling to − 155 °C. In the cooled state, the surface oxide layer composed of oxides of the alloy constituents was found to become enriched with elemental iron and depleted of elemental silicon, boron, oxygen and carbon as compared to the state at room temperature. Interaction of residual water vapor and hydrogen with the complex oxide layer occurring at low temperatures is believed to be responsible for the enhanced formation of surface hydroxides of the alloy constituents. The processes resulting in the observed redistribution of the elements on the surface of Finemet at low temperatures are discussed. Copyright © 2006 John Wiley & Sons, Ltd.
Seasonal patterns of fine root demography in a cool‐temperate deciduous forest in central Japan
Authors: Satomura Takami , Hashimoto Yasushi , Koizumi Hiroshi , Nakane Kaneyuki , Horikoshi Takao
Published: May 2006

In forest ecosystems, fine roots have a considerable role in carbon cycling. To investigate the seasonal pattern of fine root demography, we observed the fine root production and decomposition processes using a minirhizotron system in a Betula‐dominated forest with understory evergreen dwarf bamboo. The length density of fine roots decreased with increasing soil depth. The seasonal patterns of each fine root demographic parameter (length density of visible roots, rates of stand‐total fine root production and decomposition) were almost the same at different soil depths. The peak seasons of the fine root demographic parameters were observed in the order: stand‐total fine root production rate (late summer) > length density of the visible roots (early autumn) > stand‐total fine root decomposition rate (autumn, and a second small peak in spring). The fine root production rate was high in the latter part of the plant growing season. Fine root production peaked in late summer and remained high until the end of the tree defoliation season. The higher stand‐total fine root production rate in autumn suggests the effect of understory evergreen bamboo on the stand‐total fine root demography. The stand‐total fine root decomposition rate was high in late autumn. In the snow‐cover period, the rates of both fine root production and decomposition were low. The fine root demographic parameters appeared to show seasonal patterns. The fine root production rate had a clearer seasonality than the fine root decomposition rate. The seasonal pattern of stand‐total fine root production rate could be explained by both overstory and understory above‐ground productivities.
The effects of predation risk and current velocity stress on growth, condition and swimming energetics of Japanese minnow (Pseudorasbora parva)
Authors: Sunardi  , Asaeda Takashi , Manatunge Jagath , Fujino Takeshi
Published: May 2006

A Japanese minnow, Pseudorasbora parva, was exposed simultaneously to multiple dangers in experimental tanks. The study aimed to quantify to what extent the risk of predation coinciding with an adverse environmental factor, high flow velocity, affects prey in terms of growth and energy expenditure. In this experiment, two measures of growth (i.e., body weight and length), condition, feeding, swimming cost and behavioral responses were analyzed. The results showed that in such an environment, prey showed lowered growth and were in a poorer condition. As the prey shifted to the shallow area with high flow velocity, the prey consumed a lower ration and incurred multiple costs for swimming locomotion that might reduce the allocation of energy to biomass and energy storage. Reduction in activity might decrease the cost of locomotion, but it did not have a considerable effect on overall swimming energy expenditure. In stream ecosystems, the high swimming energy expenditure appears to magnify the effects of predation risk by causing lowered growth and a poorer condition and, hence, fitness. The present study shows that high flow velocity is one of the environmental factors that determine the energetic responses of a potential prey to the presence of predators.
An exploratory study of the relationship of family support and coping with adjustment: Implications for college students with a chronic illness
Authors: Wodka Ericka L. , Barakat Lamia P.
Published: May 2006

To examine the role of family support and coping in the adjustment of adolescents with chronic illness (CI) transitioning into college, college freshmen and sophomores (Nchronic illness=32, Nprimarily negative life event=53, Nprimarily positive life event=16) were administered standard measures. CI group reported more anxiety and a trend towards more depression than the primarily positive life events group (PLE). Coping strategy (active and passive) was positively associated with anxiety in CI group, whereas, family support was negatively associated with depression and anxiety in the primarily negative life events group (NLE), and passive coping was positively associated with depression in PLE. Development of adaptive coping should be the focus of programs aimed at supporting students with CI as they transition to college.
Predicting change over time in career planning and career exploration for high school students
Authors: Creed Peter A , Patton Wendy , Prideaux Lee‐Ann
Published: May 2006

This study assessed 166 high school students in Grade 8 and again in Grade 10. Four models were tested: (a) whether the T1 predictor variables (career knowledge, indecision, decision‐making selfefficacy, self‐esteem, demographics) predicted the outcome variable (career planning/exploration) at T1; (b) whether the T1 predictor variables predicted the outcome variable at T2; (c) whether the T1 predictor variables predicted change in the outcome variable from T1−T2; and (d) whether changes in the predictor variables from T1−T2 predicted change in the outcome variable from T1−T2. Strong associations (R2=34%) were identified for the T1 analysis (confidence, ability and paid work experience were positively associated with career planning/exploration). T1 variables were less useful predictors of career planning/exploration at T2 (R2=9%; having more confidence at T1 was associated with more career planning/exploration at T2) and change in career planning/exploration from T1−T2 (R2=11%; less confidence and no work experience were associated with change in career planning/exploration from T1−T2). When testing effect of changes in predictor variables predicting changes in outcome variable (R2=22%), three important predictors, indecision, work experience and confidence, were identified. Overall, results indicated important roles for self‐efficacy and early work experiences in current and future career planning/exploration of high school students.
Mechano‐chemical signaling in F9 cells
Authors: Klemm Anna H. , Suchodolski Klaudiusz , Goldmann Wolfgang H.
Published: May 2006

We investigated the molecular mechanism by which cells recognize and respond to physical forces in their local environment. Using a model system, to study wild type mouse F9 embryonic carcinoma cells, we examined how these cells sense mechanical stresses and translate them into biochemical responses through their cell surface receptor integrin and via the focal adhesion complex (FAC). Based on studies that show that many signal transducing molecules are immobilized on the cytoskeleton at the site of integrin binding within the focal adhesion complex, we found a time‐dependent increase of focal adhesion kinase (pp125FAK) phosphorylation possibly due to protein kinase C (PKC) activation as well as protein kinase A (PKA) activity increase upon cell adhesion/spreading. These studies provide some insight into intracellular mechano‐chemical signaling.
Familial occurrence of isolated non‐compaction cardiomyopathy
Authors: Lorsheyd Anouk , Cramer Maarten‐Jan M. , Velthuis Birgitta K. , Vonken Evert‐Jan P. , van der Smagt Jasper , van Tintelen Peter , Hauer Richard N.W.
Published: May 2006

Background and aims

Isolated left ventricular non‐compaction cardiomyopathy (LVNC) may have an autosomal dominant or X‐linked recessive inheritance. We focus on the familial occurrence of LVNC after misdiagnosing this disorder in symptomatic patients in two families. After identification of the index patient we studied the families more intensively in order to unmask affected family members.

Methods and results

LVNC was defined as an end‐systolic non‐compacted subendocardial layer of the left ventricular wall of at least twice the thickness of the subepicardial compacted layer (2D echocardiogram and MRI). This was studied in 13 patients in 2 families (A and B). LVNC was found in 3 out of 11 patients in family A. The grandmother was asymptomatic. Her daughter suffered from recurrent syncope and heart failure. Her daughter received a cardiac transplant because of progressive heart failure at the age of 14 years. In family B, LVNC was found in 2 patients, a father and his son and presumed in a brother and a sister of the father who died suddenly at the age of 17 and 21 years, respectively.

Conclusions

In all symptomatic patients, proven LVNC was previously misdiagnosed as hypertrophic or dilated cardiomyopathy. Misdiagnosis may lead to insufficient treatment and will misdirect targeted molecular genetic analysis. LVNC was identified in seven patients in two families. Family screening may unmask affected family members for primary prevention including anti‐coagulation and ICD‐therapy.
Spontaneous hormonal variations in male cats following gonadectomy
Authors: Martin Lucile JM , Siliart Brigitte , Dumon Henri JW , Nguyen Patrick
Published: May 2006

The increased prevalence of obesity after neutering in cats is problematic in veterinary practice. Although many factors seem to be involved, the role of prolactin (PRL) and insulin-like growth factor-I (IGF-I), both implicated in adipose tissue development and glucose intolerance, should be considered. Seven male cats were castrated when 11 months old. Body weight was then recorded for 56 weeks and PRL, IGF-I and leptin assayed for 44 weeks. Body weight increased steadily but only significantly after 36 weeks. It stabilised after 44 weeks, and the cats then gained about 20% of their initial body weight. IGF-I increased rapidly and was significantly higher by week 3. PRL and leptin increased with initial peaks during the eighth and eleventh weeks, respectively. This study confirms that castration rapidly modifies the hormonal balance, partly explaining the body weight increase, and that hormonal changes precede this body weight increase. Hyperleptinaemia is apparently a consequence of excess weight.
Correlations between dialogue acts and learning in spoken tutoring dialogues
Authors: LITMAN DIANE , FORBES-RILEY KATE
Published: May 2006

We examine correlations between dialogue behaviors and learning in tutoring, using two corpora of spoken tutoring dialogues: a human-human corpus and a human-computer corpus. To formalize the notion of dialogue behavior, we manually annotate our data using a tagset of student and tutor dialogue acts relative to the tutoring domain. A unigram analysis of our annotated data shows that student learning correlates both with the tutor's dialogue acts and with the student's dialogue acts. A bigram analysis shows that student learning also correlates with joint patterns of tutor and student dialogue acts. In particular, our human-computer results show that the presence of student utterances that display reasoning (whether correct or incorrect), as well as the presence of reasoning questions asked by the computer tutor, both positively correlate with learning. Our human-human results show that student introductions of a new concept into the dialogue positively correlates with learning, but student attempts at deeper reasoning (particularly when incorrect), and the human tutor's attempts to direct the dialogue, both negatively correlate with learning. These results suggest that while the use of dialogue act n-grams is a promising method for examining correlations between dialogue behavior and learning, specific findings can differ in human versus computer tutoring, with the latter better motivating adaptive strategies for implementation.
A computer-aided environment for generating multiple-choice test items
Authors: MITKOV RUSLAN , AN HA LE , KARAMANIS NIKIFOROS
Published: May 2006

This paper describes a novel computer-aided procedure for generating multiple-choice test items from electronic documents. In addition to employing various Natural Language Processing techniques, including shallow parsing, automatic term extraction, sentence transformation and computing of semantic distance, the system makes use of language resources such as corpora and ontologies. It identifies important concepts in the text and generates questions about these concepts as well as multiple-choice distractors, offering the user the option to post-edit the test items by means of a user-friendly interface. In assisting test developers to produce items in a fast and expedient manner without compromising quality, the tool saves both time and production costs.
Identifying off-topic student essays without topic-specific training data
Authors: HIGGINS D. , BURSTEIN J. , ATTALI Y.
Published: May 2006

Educational assessment applications, as well as other natural-language interfaces, need some mechanism for validating user responses. If the input provided to the system is infelicitous or uncooperative, the proper response may be to simply reject it, to route it to a bin for special processing, or to ask the user to modify the input. If problematic user input is instead handled as if it were the system's normal input, this may degrade users' confidence in the software, or suggest ways in which they might try to “game” the system. Our specific task in this domain is the identification of student essays which are “off-topic”, or not written to the test question topic. Identification of off-topic essays is of great importance for the commercial essay evaluation system CriterionSM. The previous methods used for this task required 200–300 human scored essays for training purposes. However, there are situations in which no essays are available for training, such as when users (teachers) wish to spontaneously write a new topic for their students. For these kinds of cases, we need a system that works reliably without training data. This paper describes an algorithm that detects when a student's essay is off-topic without requiring a set of topic-specific essays for training. This new system is comparable in performance to previous models which require topic-specific essays for training, and provides more detailed information about the way in which an essay diverges from the requested essay topic.
Detecting errors in English article usage by non-native speakers
Authors: HAN NA-RAE , CHODOROW MARTIN , LEACOCK CLAUDIA
Published: May 2006

One of the most difficult challenges faced by non-native speakers of English is mastering the system of English articles. We trained a maximum entropy classifier to select among a/an, the, or zero article for noun phrases (NPs), based on a set of features extracted from the local context of each. When the classifier was trained on 6 million NPs, its performance on published text was about 83% correct. We then used the classifier to detect article errors in the TOEFL essays of native speakers of Chinese, Japanese, and Russian. These writers made such errors in about one out of every eight NPs, or almost once in every three sentences. The classifier's agreement with human annotators was 85% (kappa = 0.48) when it selected among a/an, the, or zero article. Agreement was 89% (kappa = 0.56) when it made a binary (yes/no) decision about whether the NP should have an article. Even with these levels of overall agreement, precision and recall in error detection were only 0.52 and 0.80, respectively. However, when the classifier was allowed to skip cases where its confidence was low, precision rose to 0.90, with 0.40 recall. Additional improvements in performance may require features that reflect general knowledge to handle phenomena such as indirect prior reference. In August 2005, the classifier was deployed as a component of Educational Testing Service's Criterion$^{SM}$ Online Writing Evaluation Service.
Evaluating State-of-the-Art Treebank-style Parsers for Coh-Metrix and Other Learning Technology Environments
Authors: HEMPELMANN CHRISTIAN F. , RUS VASILE , GRAESSER ARTHUR C. , MCNAMARA DANIELLE S.
Published: May 2006

This paper evaluates four of the most commonly used, freely available, state-of-the-art parsers on a standard benchmark as well as with respect to a set of data relevant for measuring text cohesion, as one example of a learning technology application that requires fast and accurate syntactic parsing. We outline advantages and disadvantages of existing technologies and make recommendations. Our performance report uses traditional measures based on a gold standard as well as novel dimensions for parsing evaluation. To our knowledge, this is the first attempt to evaluate parsers across genres and grade levels for the implementation in learning technology using both gold standard and directed evaluation methods.
Steep REE patterns and enriched Pb isotopes in southern Central American arc magmas: Evidence for forearc subduction erosion?
Authors: Goss A. R. , Kay S. M.
Published: May 2006

The appearance of adakitic magmas with steep rare earth element (REE) patterns in southern Costa Rica and Panama at ∼4 Ma coincides with the collision of the Cocos Ridge and the inception of slab shallowing along the margin. Distinctly higher 206Pb/204Pb and 208Pb/204Pb ratios in these adakitic lavas than in older Miocene lavas suggest that components enriched in radiogenic Pb also entered the mantle magma source at ∼4 Ma. Published Pb‐isotopic data for Central American arc lavas show that a similar radiogenic component is not present in lavas farther north and that maxima in post‐Miocene 206Pb/204Pb and 208Pb/204Pb ratios occur in central Costa Rica and western Panama. Cretaceous and early Tertiary ophiolites in the forearc, whose origins have been linked to the Galápagos hot spot, show a similar spatial pattern in Pb isotopic ratios. The incorporation of ophiolitic forearc crust into the mantle wedge by forearc subduction erosion can explain the along‐arc spatial and temporal pattern of Pb‐isotopic ratios in southern Central American arc lavas. Partial melting of crust removed from the base of the forearc and subjected to high‐pressure metamorphism in the subduction channel provides an explanation for the steep adakitic REE patterns in some Costa Rican and Panamanian arc lavas.
Seasonality of westward‐propagating disturbances over Southeast and south Asia originated from typhoons
Authors: Fudeyasu H. , Iizuka S. , Matsuura T.
Published: May 2006

We investigate the seasonal changes in the westward‐propagating disturbances (WDs) in Southeast and South Asia originated from typhoons over the western North Pacific. WDs tend to move over the northern part of the Indochina Peninsula and South Asia in summer, while over the southern part of the Indochina Peninsula and the Bay of Bengal in fall. Although the number of landfall on the Indochina Peninsula is the largest in fall, the active season for WD with a more west‐oriented track is identified in late summer. The seasonality is related to large‐scale atmospheric conditions. The easterly region throughout the latitude band 15°–25°N at 700 hPa during the active phases of intraseasonal variation in monsoon trough and the large‐scale trough in lower troposphere over the Bay of Bengal are favorable conditions for taking the more west‐oriented track of WD in late summer. Such conditions are found neither earlier summer nor fall.
How do winter thundercloud systems generate sprite‐inducing lightning in the Hokuriku area of Japan?
Authors: Suzuki Tomoyuki , Hayakawa Masashi , Matsudo Yu , Michimoto Koichiro
Published: May 2006

Lightning and thundercloud systems leading to the generation of sprites were examined on the basis of analyses on the interrelation among radar reflectivity, lightning, and static electric field during the winter of 2004/2005 in the Hokuriku area of Japan. Eleven cases from the observed fifteen sprite events exhibit similar characteristics, so we present a typical case study of the thundercloud system. The analysis results are summarized as follows: (1) The sprite‐inducing +CG was triggered by a cloud flash produced by an active cell. (2) The sprite‐inducing +CG removed large positive charge from the stratiform region of another thunderstorm cell by the long linear lightning channel. (3) The origin of sprite‐inducing large positive charge appears to be located in the stratiform region.
Three‐dimensional seismic velocity structure around the focal area of the 1978 Miyagi‐Oki earthquake
Authors: Yamamoto Yojiro , Hino Ryota , Nishino Minoru , Yamada Tomoaki , Kanazawa Toshihiko , Hashimoto Tetsuo , Aoki Gen
Published: May 2006

We performed a 3D seismic tomography around the rupture area of the 1978 Miyagi‐Oki earthquake (M 7.4) using both onshore and offshore seismic station data. In our results, the subducting oceanic crust and the mantle wedge of the overriding plate were imaged as the landward dipping low P‐wave velocity (∼7.0 km/s) layer and the high velocity (∼8.0 km/s) layer above it, respectively. Most of the earthquakes were relocated along the plate boundary, including the mainshock and the aftershocks of 16 August 2005 Miyagi‐Oki earthquake (M 7.2). The relationship between spatial extents of the rupture areas of the 1978 and 2005 earthquakes and the velocity variation in the mantle wedge suggests that the heterogeneity of the upper plate delimits the extent of the rupture area of large (M > 7) interplate earthquakes.
Thermohaline circulation in the deep South China Sea basin inferred from oxygen distributions
Authors: Li Li , Qu Tangdong
Published: May 2006

On the basis of the historical oxygen data available, distributions of dissolved oxygen were analyzed in detail to investigate the thermohaline circulation in the South China Sea (SCS). The analyses confirmed the existence of a layer of minimal oxygen content at intermediate depths of the basin, which shows a low‐oxygen (<1.6 mL L−1) core in the southern basin with water “ages” shorter than 100 years after entering the SCS and which appears isolated from its counterpart of the western Philippine Sea. North to the core along the northern slope, there is a band of oxygen‐rich water in both upper and intermediate layers. Above 700 m the band can be attributed to the intrusion of high‐oxygen water through the Luzon Strait, while vertical flux appears to be responsible between 700 and 1500 m. The oxygen distribution provides additional evidence for a sandwiched vertical structure in transports through the Luzon Strait, with outflows in the intermediate layer and inflows above and below. While the abyssal water of the SCS is being replenished by the deep inflows, an abrupt change of water properties was observed in both upper and intermediate layers across the Luzon Strait, suggesting possible domination of local vertical mixing over horizontal spreading of inflows in the northern SCS. A four‐cell conceptual model was proposed for the thermohaline circulation, which consists of a three‐layer, cross‐basin exchange cell in the Luzon Strait, an active ventilation cell in the upper and intermediate layers along the northern slope, an abyssal replenishment cell in the deep, and a cyclonic recirculation cell in the interior basin.
Sources, size distribution, and downwind grounding of aerosols from Mount Etna
Authors: Allen A. G. , Mather T. A. , McGonigle A. J. S. , Aiuppa A. , Delmelle P. , Davison B. , Bobrowski N. , Oppenheimer C. , Pyle D. M. , Inguaggiato S.
Published: May 2006

The number concentrations and size distributions of aerosol particles >0.3 μm diameter were measured at the summit of Mount Etna and up to 10 km downwind from the degassing vents during July and August 2004. Aerosol number concentrations reached in excess of 9 × 106 L−1 at summit vents, compared to 4–8 × 104 L−1 in background air. Number concentrations of intermediate size particles were higher in emissions from the Northeast crater compared to other summit crater vents, and chemical composition measurements showed that Northeast crater aerosols contained a higher mineral cation content compared to those from Voragine or Bocca Nuova, attributed to Strombolian or gas puffing activity within the vent. Downwind from the summit the airborne plume was located using zenith sky ultraviolet spectroscopy. Simultaneous measurements indicated a coincidence of elevated ground level aerosol concentrations with overhead SO2, demonstrating rapid downward mixing of the plume onto the lower flanks of the volcano under certain meteorological conditions. At downwind sites the ground level particle number concentrations were elevated in all size fractions, notably in the 2.0–7.5 μm size range. These findings are relevant for assessing human health hazard and suggest that aerosol size distribution measurements may aid volcanic risk management.
Volatile organic compounds composition of merged and aged forest fire plumes from Alaska and western Canada
Authors: de Gouw J. A. , Warneke C. , Stohl A. , Wollny A. G. , Brock C. A. , Cooper O. R. , Holloway J. S. , Trainer M. , Fehsenfeld F. C. , Atlas E. L. , Donnelly S. G. , Stroud V. , Lueb A.
Published: May 2006

The NOAA WP‐3 aircraft intercepted aged forest fire plumes from Alaska and western Canada during several flights of the NEAQS‐ITCT 2k4 mission in 2004. Measurements of acetonitrile (CH3CN) indicated that the air masses had been influenced by biomass burning. The locations of the plume intercepts were well described using emissions estimates and calculations with the transport model FLEXPART. The best description of the data was generally obtained when FLEXPART injected the forest fire emissions to high altitudes in the model. The observed plumes were generally drier than the surrounding air masses at the same altitude, suggesting that the fire plumes had been processed by clouds and that moisture had been removed by precipitation. Different degrees of photochemical processing of the plumes were determined from the measurements of aromatic VOCs. The removal of aromatic VOCs was slow considering the transport times estimated from the FLEXPART model. This suggests that the average OH levels were low during the transport, which may be explained by the low humidity and high concentrations of carbon monoxide and other pollutants. In contrast with previous work, no strong secondary production of acetone, methanol and acetic acid is inferred from the measurements. A clear case of removal of submicron particle volume and acetic acid due to precipitation scavenging was observed.
Detection of multiple H3receptor affinity states utilizing [3H]A‐349821, a novel, selective, non‐imidazole histamine H3receptor inverse agonist radioligand
Authors: Witte David G , Yao Betty Bei , Miller Thomas R , Carr Tracy L , Cassar Steven , Sharma Rahul , Faghih Ramin , Surber Bruce W , Esbenshade Timothy A , Hancock Arthur A , Krueger Kathleen M
Published: May 2006

A‐349821 is a selective histamine H3receptor antagonist/inverse agonist. Herein, binding of the novel non‐imidazole H3receptor radioligand [3H]A‐349821 to membranes expressing native or recombinant H3receptors from rat or human sources was characterized and compared with the binding of the agonist [3H]N‐α‐methylhistamine ([3H]NαMH).

[3H]A‐349821 bound with high affinity and specificity to an apparent single class of saturable sites and recognized human H3receptors with 10‐fold higher affinity compared to rat H3receptors. [3H]A‐349821 detected larger populations of receptors compared to [3H]NαMH.

Displacement of [3H]A‐349821 binding by H3receptor antagonists/inverse agonists was monophasic, suggesting recognition of a single binding site, while that of H3receptor agonists was biphasic, suggesting recognition of both high‐ and low‐affinity H3receptor sites.

pKivalues of high‐affinity binding sites for H3receptor competitors utilizing [3H]A‐349821 were highly correlated with pKivalues obtained with [3H]NαMH, consistent with labelling of H3receptors by [3H]A‐349821.

Unlike assays utilizing [3H]NαMH, addition of GDP had no effect on saturation parameters measured with [3H]A‐349821, while displacement of [3H]A‐349821 binding by the H3receptor agonist histamine was sensitive to GDP.

In conclusion, [3H]A‐349821 labels interconvertible high‐ and low‐affinity states of the H3receptor, and displays improved selectivity over imidazole‐containing H3receptor antagonist radioligands. [3H]A‐349821 competition studies showed significant differences in the proportions and potencies of high‐ and low‐affinity sites across species, providing new information about the fundamental pharmacological nature of H3receptors.

British Journal of Pharmacology(2006)148, 657–670. doi:10.1038/sj.bjp.0706752
Insensitivity of cardiac delayed‐rectifier IKr to tyrosine phosphorylation inhibitors and stimulators
Authors: Missan Sergey , Zhabyeyev Pavel , Linsdell Paul , McDonald Terence F
Published: May 2006

The rapidly activating delayed‐rectifying K+ current (IKr) in heart cells is an important determinant of repolarisation, and decreases in its density are implicated in acquired and inherited long QT syndromes. The objective of the present study on IKr in guinea‐pig ventricular myocytes was to evaluate whether the current is acutely regulated by tyrosine phosphorylation.

Myocytes configured for ruptured‐patch or perforated‐patch voltage‐clamp were depolarised with 200‐ms steps to 0 mV for measurement of IKr tail amplitude on repolarisations to −40 mV.

IKr in both ruptured‐patch and perforated‐patch myocytes was only moderately (14–20%) decreased by 100 μM concentrations of protein tyrosine kinase (PTK) inhibitors tyrphostin A23, tyrphostin A25, and genistein. However, similar‐sized decreases were induced by PTK‐inactive analogues tyrphostin A1 and daidzein, suggesting that they were unrelated to inhibition of PTK.

Ruptured‐patch and perforated‐patch myocytes were also treated with promoters of tyrosine phosphorylation, including phosphotyrosyl phosphatase (PTP) inhibitor orthovanadate, exogenous c‐Src PTK, and four receptor PTK activators (insulin, insulin‐like growth factor‐1, epidermal growth factor, and basic fibroblast growth factor). None of these treatments had a significant effect on the amplitude of IKr.

We conclude that Kr channels in guinea‐pig ventricular myocytes are unlikely to be regulated by PTK and PTP.

British Journal of Pharmacology (2006) 148, 724–731. doi:10.1038/sj.bjp.0706776
Peptides modified by myristoylation activate eNOS in endothelial cells through Akt phosphorylation
Authors: Krotova Karina , Hu Hanbo , Xia Shen‐Ling , Belayev Leonid , Patel Jawaharlal M , Block Edward R , Zharikov Sergey
Published: May 2006

Myristoylated pseudosubstrate of PKCζ(mPS) – a synthetic myristoylated peptide with a sequence (13 amino acids) mimicking the endogenous PKCζpseudosubstrate region – is considered a selective cell‐permeable inhibitor of PKCζ. We present strong evidence that in endothelial cells the action of mPS is not limited to inhibition of PKC activity and that myristoylation of certain peptides can activate eNOS (endothelial nitric oxide synthase) through Akt phosphorylation.

mPS at micromolar concentrations (1–10 μM) induced profound phosphorylation of eNOS, Akt, ERK 1/2, and p38 MAPK in cultured pulmonary artery endothelial cells (PAEC). The same changes were observed after treatment of PAEC with a myristoylated scrambled version of mPS (mScr), whereas a cell‐permeable version of PKCζpseudosubstrate fused to the HIV‐TAT membrane‐translocating peptide did not induce analogous changes, suggesting that myristoylation confers new properties on the peptides consisting of activation of different signaling pathways in endothelial cells.

In addition to mPS and mScr, a number of other myristoylated peptides induced phosphorylation of eNOS suggesting that myristoylation of peptides can activate eNOS by mechanisms unrelated to inhibition of PKC. All active myristoylated peptides contained basic amino acids motif and were longer than six amino acids.

Activation of eNOS by myristoylated peptides was dependent on the PI3K/Akt pathway and the rise of intracellular calcium and was associated with an elevation of cGMP levels in PAEC and with relaxation of precontracted isolated pulmonary artery segments.

Myristoylated peptides can be considered a new class of activators of NO production in endothelial cells and that using mPS as a specific inhibitor of PKCζshould be done with caution, especially in endothelial cells.

British Journal of Pharmacology(2006)148, 732–740. doi:10.1038/sj.bjp.0706777
Modulation of P‐glycoprotein activity by cannabinoid molecules in HK‐2 renal cells
Authors: Nieri Paola , Romiti Nadia , Adinolfi Barbara , Chicca Andrea , Massarelli Ilaria , Chieli Elisabetta
Published: May 2006

Endogenous and synthetic cannabinoid molecules have been investigated as possible MDR‐1/P‐glycoprotein (P‐gp) modulators in HK‐2‐immortalized renal cells, using calcein acetoxymethylester (calcein‐AM) as a P‐gp substrate.

Among the endocannabinoid molecules tested, anandamide (AEA), but not 2‐arachidonoyl‐glycerol (2‐AG) or palmitoyl‐ethanolamide (PEA), increased the intracellular fluorescence emitted by calcein, a metabolic derivative of the P‐gp substrate calcein‐AM, indicative of a reduction in transport capacity.

All the three synthetic cannabimimetics tested, that is, R‐(+)‐methanandamide (R(+)‐MET), AM 251 and CP55,940 significantly increased calcein accumulation in the cytosol.

RT–PCR demonstrated that HK‐2 cells do not express CB1 or CB2 cannabinoid receptors.

R(+)‐MET, AM251 and CP55,940 were also evaluated as modulators of P‐gp expression, by Western blot analysis. Only AM251 weakly enhanced the protein levels (by 1.2‐fold) after a 4‐day‐long incubation with the noncytotoxic drug concentration 2 μM.

The present data provide the first evidence that the endocannabinoid AEA and different synthetic cannabinoids may inhibit the P‐gp activity in vitro via a cannabinoid receptor‐independent mechanism.

British Journal of Pharmacology (2006) 148, 682–687. doi:10.1038/sj.bjp.0706778
Role of reactive oxygen species and gp91phox in endothelial dysfunction of pulmonary arteries induced by chronic hypoxia
Authors: Fresquet Fleur , Pourageaud Fabrice , Leblais Véronique , Brandes Ralf P , Savineau Jean‐Pierre , Marthan Roger , Muller Bernard
Published: May 2006

This study investigates the role of nitric oxide (NO) and reactive oxygen species (ROS) on endothelial function of pulmonary arteries in a mice model of hypoxia‐induced pulmonary hypertension.

In pulmonary arteries from control mice, the NO‐synthase inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME) potentiated contraction to prostaglandin F2α (PGF2α) and completely abolished relaxation to acetylcholine. In extrapulmonary but not intrapulmonary arteries, acetylcholine‐induced relaxation was slightly inhibited by polyethyleneglycol‐superoxide dismutase (PEG‐SOD) or catalase.

In pulmonary arteries from hypoxic mice, ROS levels (evaluated using dihydroethidium staining) were higher than in controls. In these arteries, relaxation to acetylcholine (but not to sodium nitroprusside) was markedly diminished. L‐NAME abolished relaxation to acetylcholine, but failed to potentiate PGF2α‐induced contraction. PEG‐SOD or catalase blunted residual relaxation to acetylcholine in extrapulmonary arteries, but did not modify it in intrapulmonary arteries. Hydrogen peroxide elicited comparable (L‐NAME‐insensitive) relaxations in extra‐ and intrapulmonary arteries from hypoxic mice.

Exposure of gp91phox–/– mice to chronic hypoxia also decreased the relaxant effect of acetylcholine in extrapulmonary arteries. However, in intrapulmonary arteries from hypoxic gp91phox–/– mice, the effect of acetylcholine was similar to that obtained in mice not exposed to hypoxia.

Chronic hypoxia increases ROS levels and impairs endothelial NO‐dependent relaxation in mice pulmonary arteries. Mechanisms underlying hypoxia‐induced endothelial dysfunction differ along pulmonary arterial bed. In extrapulmonary arteries from hypoxic mice, endothelium‐dependent relaxation appears to be mediated by ROS, in a gp91phox‐independent manner. In intrapulmonary arteries, endothelial dysfunction depends on gp91phox, the latter being rather the trigger than the mediator of impaired endothelial NO‐dependent relaxation.

British Journal of Pharmacology (2006) 148, 714–723. doi:10.1038/sj.bjp.0706779