bluuebunny/crossref_metadata_2025 huggingface dataset:
Snus use and other correlates of smoking cessation in the Swedish Twin Registry
Authors: Furberg H. , Lichtenstein P. , Pedersen N. L. , Bulik C. M. , Lerman C. , Sullivan P. F.
Published: December 2007

Background

We investigated 12 variables and their interactions as correlates of smoking cessation among regular smokers in the population-based Swedish Twin Registry (STR).

Method

Detailed information on tobacco use and personal characteristics were available from 14 715 male and female twins aged 42–64 years who participated in a screening of the population-based STR and reported being regular smokers in their lifetime. A two-stage analytic design was used to examine correlates of smoking cessation. The sample was split at random and significant main effects and interactions identified in the testing set were examined in the validation set. Hazard ratios (HRs) and 95% confidence intervals (CIs) describe the association between correlates and smoking cessation.

Results

Twelve main effects were significantly associated with smoking cessation in the testing set; eight were confirmed in the validation set. Of the nine interactions identified in the testing set, none remained significant when evaluated in the validation set after Bonferroni correction. HRs were highest for Swedish oral smokeless tobacco (snus) use (HR 2.70, 95% CI 2.30–3.20), >11 years of education (HR 1.57, 95% CI 1.43–1.73) and being married or cohabitating (HR 1.51, 95% CI 1.39–1.63). Although not statistically significant after Bonferroni correction, snus use also appeared important in the context of interactions, where lower nicotine dependence score, higher socio-economic status (SES) and greater body size were associated with smoking cessation only among participants who never used snus.

Conclusions

Snus use was the strongest independent correlate of smoking cessation. Further studies should investigate the mechanism of this association.
Associations between ethnicity and self-reported hallucinations in a population sample of young adults in The Netherlands
Authors: Vanheusden K. , Mulder C. L. , van der Ende J. , Selten J.-P. , van Lenthe F. J. , Verhulst F. C. , Mackenbach J. P.
Published: December 2007

Background

Psychotic disorders are more common in people from ethnic minorities. If psychosis exists as a continuous phenotype, ethnic disparities in psychotic disorder will be accompanied by similar ethnic disparities in the rate of psychotic symptoms. This study examined ethnic disparities in self-reported hallucinations in a population sample of young adults.

Method

A cross-sectional population survey (n=2258) was carried out in the south-west Netherlands. Seven ethnic groups were delineated: Dutch natives, Turks, Moroccans, Surinamese/Antilleans, Indonesians, other non-Western immigrants (mostly from Africa or Asia) and Western immigrants (mostly from Western Europe). Self-reported auditory and visual hallucinations were assessed with the Adult Self-Report (ASR). Indicators of social adversity included social difficulties and a significant drop in financial resources.

Results

Compared to Dutch natives, Turkish females [odds ratio (OR) 13.48, 95% confidence interval (CI) 5.97–30.42], Moroccan males (OR 8.36, 95% CI 3.29–21.22), Surinamese/Antilleans (OR 2.19, 95% CI 1.05–4.58), Indonesians (OR 4.15, 95% CI 1.69–10.19) and other non-Western immigrants (OR 3.57, 95% CI 1.62–7.85) were more likely to report hallucinations, whereas Western immigrants, Turkish males and Moroccan females did not differ from their Dutch counterparts. When adjusting for social adversity, the ORs for self-reported hallucinations among the non-Western immigrant groups showed considerable reductions of 28% to 52%.

Conclusions

In a general population sample, several non-Western immigrant groups reported hallucinations more often than Dutch natives, which is consistent with the higher incidence of psychotic disorders in most of these groups. The associations between ethnicity and hallucinations diminished after adjustment for social adversity, which supports the view that adverse social experiences contribute to the higher rate of psychosis among migrants.
Foreign language standards and the contexts of communication
Authors: Phillips June K.
Published: December 2007

Once upon a time, there were four skills. But what did it mean to be a listener? A speaker? A reader? A writer? Skills in a vacuum are useful neither for describing how well one uses language nor for how to teach it effectively. As the Standards were developed, the task force made an effort to look at related disciplines and to investigate how their methods might inform the teaching of second languages. As the discipline of communication was studied, the role of context became evident. For example, the speaker as rhetorician was quite distinct from the speaker in interpersonal or small group communication. The rules that governed those behaviors and the way students were taught to speak in these two situations differed considerably. What are the ramifications for how we look at communication in foreign languages? The answer is ‘The Framework of Communicative Modes’.
Articulating a foreign language sequence through content: A look at the culture standards
Authors: Byrnes Heidi
Published: December 2007

Curricular articulation and the integration of cultural knowledge with language development over extended sequences are among the most persistent challenges for contemporary language teaching and learning. The paper examines the nature of those challenges in light of theories of language and culture while using as the site of investigation the culture standards that have been developed within the framework of theStandards for Foreign Language Learning, a key document for L2 education in the United States, particularly at the K-12 level. Taking four perspectives, it suggests ways in which simultaneous content and language teaching might be tackled through a genre-based way of constructing extended curricula and by using genre-based tasks for informing pedagogical decisions. In this fashion, learners might be able to progress toward a competent cultural literacy that is language-based.
Standards of English and politics of inclusion
Authors: Holliday Adrian
Published: December 2007

Standards of English for English language teacher education need to consider political as well as linguistic factors. Any definition of such standards on the basis of speakerhood would immediately fall into the trap of native-speakerist discrimination, which is intensified by unspoken associations with ‘ethnicity’. Who can be recognized as ‘native speaker’ or ‘near-native speaker’ is not simply a matter of language. Any definition of English standards must therefore acknowledge an alternative established belief that all users of English can claim ownership of the language. This factor is, however, complicated by the recent suggestions that there can be a non-aligned, international English lingua franca, themselves being perceived as Centre-driven. Standards must therefore be convincingly de-Centred, and must allow those who consider themselves Periphery to take Centre-stage. They must be cosmopolitan, non-centred, professional, earned, prestigious and cultured.
Research on foreign language teaching in Poland 2000–2006
Authors: Siek-Piskozub Teresa , Wach Aleksandra , Raulinajtys Anna
Published: December 2007

This is an overview of research on foreign language (FL) teaching published by Polish researchers in the years of 2000–2006. We begin with an outline of the history and the current sociopolitical situation of FL teaching in Poland, which prepares the ground for further discussion. Next, we focus on studies concerned with the evaluation of the recent teaching methodology. The analysis of bilingual programmes and multilingual competence is discussed in ‘Bilingual education and multilingualism’, the process of learning different aspects of language competence is explored in ‘FL learning and second language acquisition’, and cultural issues under a separate heading, ‘Cultural awareness’. In ‘The language learner’, we review studies investigating learner variables which have an important impact on language learning. With new educational directives from the Ministry of Education, emphasising the need for a more reliable assessment, new concepts and studies evaluating them are discussed in ‘Testing and evaluation’. The availability of computers has produced studies assessing various uses of computers in fostering language learning, presented in ‘Application of new technologies’. Finally, in ‘Teacher education’, we report on studies related to FL teacher development.
A Guideline to Establish DGPS Reference Station Requirements
Authors: Kee Changdon , Park Byungwoon , Kim Jeonghan , Cleveland Allen , Parsons Michael , Wolfe David
Published: December 2007

After Selective Availability (SA) was turned off, the rate of change with time of the DGPS common errors (atmospheric delay, satellite orbit and clock error) became quite slow. This inevitably leads to a requirement to modify various configurations of DGPS correction message broadcasting, and reference station (RS) managers need to examine the characteristics of GPS measurement errors with SA-off. GPS error sources are temporally and spatially decorrelated, so the DGPS user position accuracy is varied by the baud-rate of the RS, the distance between the user and the station, and the noise statistics of the receiver. We identify the minimum and maximum size of correction data, interval time, the coverage range and the baud-rate that are required to maintain the existing DGPS service. Moreover, the compatibility and accuracy can be assessed to meet the users' requirements without measurements being needed. The results in this paper are used in the study and testing for the redesign of United States Coast Guard (USCG) RS. We hope that our study will be a great help in determining the flexible factors of both the RS and the user.
Integration of INS and Un-Differenced GPS Measurements for Precise Position and Attitude Determination
Authors: Zhang Yufeng , Gao Yang
Published: December 2007

The integration of GPS and INS observations has been extensively investigated in recent years. Current systems are commonly based on the integration of INS data and the double differenced GPS measurements from two GPS receivers in which one is used as a reference receiver set up at a precisely surveyed control point and another is as the rover receiver whose position is to be determined. The requirement of a base receiver is to eliminate the significant GPS measurement errors related to GPS satellites, signal transmission and GPS receivers by double differencing measurements from the two receivers. With the advent of precise satellite orbit and clock products, the un-differenced GPS measurements from a single GPS receiver can be applied to output accurate position solutions at centimetre level using a positioning technology known as precise point positioning (PPP). This then opens an opportunity for the integration of un-differenced GPS measurements with INS for precise position and attitude determination. In this paper, a tightly coupled un-differenced GPS/INS system will be developed and described. The mathematical models for both INS and un-differenced GPS measurements will be introduced. The methods for mitigating GPS measurement errors will also be presented. A field test has been conducted and the results indicate that the integration of un-differenced GPS and INS observations can provide position and velocity solutions comparable with current double difference GPS/INS integration systems.
When Technology Leads Us Astray: A Broadened View of Human Error
Authors: Schager Bengt
Published: December 2007

This paper discusses human error from two perspectives: errors made by operators on the one hand and errors made by designers and manufacturers of technological aids on the other. The question of operators' reliance on technological aids is discussed, as well as the concept of “overreliance” in connection with technologically aided presentation of navigational information. The accident investigation report following the grounding of the M/V Royal Majesty in 1995 is taken as an example. In that and many reports, designers and technology were not investigated as carefully as the operators on site. In that report, total responsibility for the accident was attributed to the mariners, while unreliable, incorrectly designed or incorrectly mounted technological aids, as well as the constructors, manufacturers and technical expertise behind it, were not investigated. This biased praxis when investigating human error is questioned and another investigative approach is suggested, in which operators and technology are treated equally and where the people behind the technologies can also be scrutinised. Such an approach would have a great beneficial impact on safety at sea.
Airborne Doppler Radar Development by the Decca Company
Authors: Gray Trevor , Blanchard Walter
Published: December 2007

This paper is intended as an historical document describing the entry and success of the Decca Radar Company into the production of Doppler-based navigation units. It is based on an original personal paper written in about 1970 by Trevor Gray, then Head of Doppler Department, Decca Radar, updated and edited with additions by Walter Blanchard (past President of the RIN) assisted by Trevor Gray in May 2007. The paper first covers the basic theory and principles of Doppler radar systems, continues through the setting up of the Decca Doppler Department in the mid-1950s and the production of the first transistor-based Doppler system. Success led to the development of both civil and military Doppler systems culminating in the Decca Doppler 70 Series which was fitted to some 30 types of aircraft and helicopters, worldwide.
Who are the Navigators?
Authors: Last David
Published: December 2007

The 2007 Annual General Meeting of the Royal Institute of Navigation was particularly significant; not only did it celebrate the 60th anniversary of the founding, but also celebrated the granting of the Royal Charter of Incorporation to the Institute by Her Majesty Queen Elizabeth II. Our President, Professor David Last, marked the occasion with his Presidential Address which is recorded here.
TILL DEATH DO US PART
Authors: Diel Lori Boornazian
Published: December 2007

Though infrequent, the inclusion of marriage statements in Aztec histories reveals the political nature of matrimony for elite Nahua rulers in Late Postclassic-period central Mexico. The rules governing these elite marriages were so standardized that unconventional marriages particularly stand out as strong political declarations. This article focuses on four case studies—two marriages that violated already established political alliances and two marriages in which aggressions were taken out against the royal wives. These case studies reveal shifting alliances and political maneuvering that are not as clearly evident when looking strictly at Conquest history. Ultimately, these marriages illuminate increasing political tensions within the Aztec empire. Moreover, they reveal the potential, though largely hidden, role of noblewomen in Aztec politics. Clearly, the political stakes in these unconventional marriages were high; in the four cases studies presented here, each ends with the death of one of the spouses.
DROUGHT AND THE MAYA COLLAPSE
Authors: Gill Richardson B. , Mayewski Paul A. , Nyberg Johan , Haug Gerald H. , Peterson Larry C.
Published: December 2007

Between a.d. 760 and 930, millions of Maya disappeared from the Earth. We examine changes in the physical environment in which the Maya lived. The ice-core evidence from Greenland indicates that around the time of the Maya Collapse, a minimum in solar insolation and a low in solar activity occurred, accompanied by severe cold and dryness over Greenland, indicating hemispheric climatic conditions propitious for drought in the Maya Lowlands. In the northeastern Caribbean, sea-surface salinity (SSS) was lowered. The most severe drought of the past 7,000 years devastated the Yucatan Peninsula. Large Maya cities collapsed in four phases of abandonment spaced about fifty years apart around a.d. 760, 810, 860, and 910. A new core taken from Lake Chichancanab in Quintana Roo shows three peak episodes of brutal drought within a 150- to 200-year drought. A marine core from the Cariaco Basin off Venezuela precisely dates four severe drought episodes to 760, 810, 860, and 910, coincident with the four phases of abandonment of cities. The long-term drought appears to have lasted from 760 to 930 in the Cariaco Basin. The climatic changes were the most drastic the Maya had faced in the preceding 1,500 years and the most severe of the preceding 7,000 years.
Vertical dust mixing and the interannual variations in the Mars thermosphere
Authors: Bell Jared M. , Bougher Stephen W. , Murphy James R.
Published: December 2007

Mars winter polar warming is a phenomenon of the lower thermosphere temperatures and densities that is well documented by in situ accelerometer data taken during spacecraft aerobraking maneuvers. Previous work by Bougher et al. (2006) simulates two specific time periods, corresponding to existing aerobraking data sets, and confirms the existence of winter polar warming structures in the Martian upper atmosphere, using the coupled Mars General Circulation Model–Mars Thermosphere General Circulation Model (MGCM‐MTGCM). The present work investigates the underlying mechanisms that drive winter polar warming in three major studies: (1) a systematic analysis of vertical dust mixing in the lower atmosphere and its impact upon the dynamics of the lower thermosphere (100–130 km), (2) an interannual investigation utilizing 3 years of lower atmosphere infrared (IR) dust optical depth data acquired by the Thermal Emission Spectrometer (TES) instrument on board Mars Global Surveyor (MGS), and finally (3) a brief study of the MTGCM's response to variations in upward propagating waves and tides from the lower atmosphere. From the first study, we find that the vertical dust mixing greatly modifies the simulated winter polar warming features in the MTGCM's thermosphere at both solstice seasons. Furthermore, this sensitivity study confirms that an interhemispheric Hadley circulation and the concomitant adiabatic heating rates are the primary causes for these winter polar warming structures. From the second study, we find that as revealed in the lower atmosphere by Liu et al. (2003), the polar lower thermosphere exhibits a high degree of variability at LS = 270, with reduced yet significant variability at LS = 090. Finally, the third numerical experiment indicates, as was found in the lower atmosphere by Wilson (1997), that upward propagating waves and tides allow meridional flows to access the thermosphere's winter polar latitudes. This last investigation also indicates that the Hadley circulation responsible for thermospheric winter polar warming originates in the lower atmosphere and extends high into the upper atmosphere. In summary, these new efforts establish a baseline numerical study upon which more comprehensive model‐to‐data comparisons may be conducted for the Martian thermosphere.
Upscaling river biomass using dimensional analysis and hydrogeomorphic scaling
Authors: Barnes Elizabeth A. , Power Mary E. , Foufoula‐Georgiou Efi , Hondzo Miki , Dietrich William E.
Published: December 2007

We propose a methodology for upscaling biomass in a river using a combination of dimensional analysis and hydro‐geomorphologic scaling laws. We first demonstrate the use of dimensional analysis for determining local scaling relationships between Nostoc biomass and hydrologic and geomorphic variables. We then combine these relationships with hydraulic geometry and streamflow scaling in order to upscale biomass from point to reach‐averaged quantities. The methodology is demonstrated through an illustrative example using an 18 year dataset of seasonal monitoring of biomass of a stream cyanobacterium (Nostoc parmeloides) in a northern California river.
Spatial and temporal characteristics of the decadal abrupt changes of global atmosphere‐ocean system in the 1970s
Authors: Xiao Dong , Li Jianping
Published: December 2007

Using NOAA extended reconstruction SST (ERSST.v2) and NCEP/NCAR reanalysis, a movingttest technique is employed to detect the decadal abrupt change years (DACYs) in the time series of several atmosphere‐ocean variables. The decadal abrupt changes (DACs) existed widely in the ocean‐atmosphere system in 1973–1978. In the ocean, the decreased DACs (DDACs, the variable decreases after the DACY) occurred in the North and South Pacific and the increased DACs (IDACs, the variable increases after the DACY) mainly took place in the eastern Pacific, southern South Pacific and South Indian Ocean. In the atmosphere, the IDACs happened over the Eastern Hemispheric tropics and subtropics in the low troposphere and over the global tropics and subtropics in the middle and upper troposphere and stratosphere. The higher pressure levels, the larger the DAC regions and the later the DACYs generally. The initial oceanic DACs in the 1970s cannot be explained by the DACs of wind stress, which happened 2 years (a) later than the original oceanic DACs. In addition, the tropical influence through atmosphere and ocean cannot explain the initial DDACs of SST and atmosphere of the North Pacific, which occurred about 2 a in advance of tropical warming. The DDACs in the 1970s of the North Pacific cannot interpret that of other oceanic regions, because they were not the initial oceanic DACs in the 1970s. These findings suggest that the DACs in the 1970s may initially originate from the ocean and a coupled atmosphere‐ocean decadal interaction mechanism existed in the winter of the North Pacific.
Sulfur species behavior in soil organic matter during decomposition
Authors: Schroth Andrew W. , Bostick Benjamin C. , Graham Margaret , Kaste James M. , Mitchell Myron J. , Friedland Andrew J.
Published: December 2007

Soil organic matter (SOM) is a primary reservoir of terrestrial sulfur (S), but its role in the global S cycle remains poorly understood. We examine S speciation by X‐ray absorption near‐edge structure (XANES) spectroscopy to describe S species behavior during SOM decomposition. Sulfur species in SOM were best represented by organic sulfide, sulfoxide, sulfonate, and sulfate. The highest fraction of S in litter was organic sulfide, but as decomposition progressed, relative fractions of sulfonate and sulfate generally increased. Over 6‐month laboratory incubations, organic sulfide was most reactive, suggesting that a fraction of this species was associated with a highly labile pool of SOM. During humification, relative concentrations of sulfoxide consistently decreased, demonstrating the importance of sulfoxide as a reactive S phase in soil. Sulfonate fractional abundance increased during humification irrespective of litter type, illustrating its relative stability in soils. The proportion of S species did not differ systematically by litter type, but organic sulfide became less abundant in conifer SOM during decomposition, while sulfate fractional abundance increased. Conversely, deciduous SOM exhibited lesser or nonexistent shifts in organic sulfide and sulfate fractions during decomposition, possibly suggesting that S reactivity in deciduous litter is coupled to rapid C mineralization and independent of S speciation. All trends were consistent in soils across study sites. We conclude that S reactivity is related to speciation in SOM, particularly in conifer forests, and S species fractions in SOM change during decomposition. Our data highlight the importance of intermediate valence species (sulfoxide and sulfonate) in the pedochemical cycling of organic bound S.
Comparing effects of oligotrophication and upstream hydropower dams on plankton and productivity in perialpine lakes
Authors: Finger David , Schmid Martin , Wüest Alfred
Published: December 2007

In recent decades, many perialpine lakes have been affected by oligotrophication due to efficient sewage treatment and by altered water turbidity due to upstream hydropower operations. Such simultaneous environmental changes often lead to public debate on the actual causes of observed productivity reductions. We evaluate the effects of those two changes by a combined approach of modeling and data interpretation for a case study on Lake Brienz (Switzerland), a typical oligotrophic perialpine lake, located downstream of several hydropower reservoirs. A physical k‐ɛ scheme and a biogeochemical advection‐diffusion‐reaction model were implemented and applied for several hypothetical scenarios with different nutrient loads and different particle input dynamics. The simulation results are compared to long‐term biotic data collected from 1999 to 2004. The analysis shows that enhanced nutrient supply increases the nutritious value of algae, stimulating zooplankton growth, while phytoplankton growth is limited by stronger top‐down control. Annually integrated productivity is only slightly influenced by altered turbidity, as phosphorous limitation prevails. Simulations indicate that the spring production peak is delayed because of increased turbidity in winter caused by upstream hydropower operation. As a consequence, the entire nutrient cycle is seasonally delayed, creating an additional stress for zooplankton and fish in the downstream lake.
The cardiac persistent sodium current: an appealing therapeutic target?
Authors: Saint D A
Published: December 2007

The sodium current in the heart is not a single current with a mono‐exponential decay but rather a mixture of currents with different kinetics. It is not clear whether these arise from distinct populations of channels, or from modulation of a single population. A very slowly inactivating component, [INa(P)] INa(P)is usually about 1% of the size of the peak transient current [INa(T)], but is enhanced by hypoxia. It contributes to Na+loading and cellular damage in ischaemia and re‐perfusion, and perhaps to ischaemic arrhythmias. Class I antiarrhythmic agents such as flecainide, lidocaine and mexiletine generally block INA(P)more potently than block of INa(T)and have been used clinically to treat LQT3 syndrome, which arises because mutations in SCN5A produce defective inactivation of the cardiac sodium channel. The same approach may be useful in some pathological situations, such as ischaemic arrhythmias or diastolic dysfunction, and newer agents are being developed with this goal. For example, ranolazine blocks INa(P)about 10 times more potently than INa(T)and has shown promise in the treatment of angina. Alternatively, the combination of INa(P)block with K+channel block may provide protection from the induction of Torsades de Pointe when these agents are used to treat atrial arrhythmias (eg Vernakalant). In all of these scenarios, an understanding of the role of INa(P)in cardiac pathophysiology, the mechanisms by which it may affect cardiac electrophysiology and the potential side effects of blocking INa(P)in the heart and elsewhere will become increasingly important.

British Journal of Pharmacology(2008)153, 1133–1142; doi:10.1038/sj.bjp.0707492; published online 10 December 2007
Inhibition of late sodium current to reduce electrical and mechanical dysfunction of ischaemic myocardium
Authors: Shryock J C , Belardinelli L
Published: December 2007

This commentary on the review by DA Saint in the current issue of the British Journal of Pharmacology focuses on the pathological role of late INa in the heart, the evidence supporting inhibition of late INa as a therapeutic target in ischaemic heart disease, and the therapeutic applications and challenges for development of new late INa inhibitors. Recent reports from a large clinical outcome trial (MERLIN) of ranolazine, a drug known to inhibit late INa, indicated that it was safe and reduced recurrent ischaemia and arrhythmic activity. In combination with other results indicating that inhibition of late INa reduces ischaemia, myocardial Ca2+ overload, and electrical and mechanical dysfunction when late INa is increased, the new clinical trial results suggest that reduction of cardiac late INa is safe and therapeutically beneficial.

British Journal of Pharmacology (2008) 153, 1128–1132; doi:10.1038/sj.bjp.0707522; published online 10 December 2007
Cannabinoid receptors and the regulation of bone mass
Authors: Bab I , Zimmer A
Published: December 2007

A functional endocannabinoid system is present in several mammalian organs and tissues. Recently, endocannabinoids and their receptors have been reported in the skeleton. Osteoblasts, the bone forming cells, and osteoclasts, the bone resorbing cells, produce the endocannabinoids anandamide and 2‐arachidonoylglycerol and express CB2 cannabinoid receptors. Although CB2 has been implicated in pathological processes in the central nervous system and peripheral tissues, the skeleton appears as the main system physiologically regulated by CB2. CB2‐deficient mice show a markedly accelerated age‐related bone loss and theCNR2gene (encoding CB2) in women is associated with low bone mineral density. The activation of CB2 attenuates ovariectomy‐induced bone loss in mice by restraining bone resorption and enhancing bone formation. Hence synthetic CB2 ligands, which are stable and orally available, provide a basis for developing novel anti‐osteoporotic therapies. Activation of CB1 in sympathetic nerve terminals in bone inhibits norepinephrine release, thus balancing the tonic sympathetic restrain of bone formation. Low levels of CB1 were also reported in osteoclasts. CB1‐null mice display a skeletal phenotype that is dependent on the mouse strain, gender and specific mutation of the CB1 encoding gene,CNR1.

British Journal of Pharmacology(2008)153, 182–188; doi:10.1038/sj.bjp.0707593; published online 10 December 2007
Role of the NO/cGMP/KATP pathway in the protective effects of sildenafil against ethanol‐induced gastric damage in rats
Authors: Medeiros J V R , Gadelha G G , Lima S J , Garcia J A , Soares P M G , Santos A A , Brito G A C , Ribeiro R A , Souza M H L P
Published: December 2007

Background and purpose:

Sildenafil is a selective inhibitor of cGMP‐specific phosphodiesterase. Sildenafil, acting via NO‐dependent mechanisms, prevents indomethacin‐induced gastropathy. Activation of ATP‐sensitive potassium channels (KATP) is involved in gastric defence. Our objective was to evaluate the role of the NO/cGMP/KATP pathway in the protective effects of sildenafil against ethanol‐induced gastric damage.

Experimental approach:

Rats were treated with L‐NAME (1 or 3 mg kg−1, i.p.) or with L‐arginine (200 mg kg−1, i.p.) +L‐NAME (3 mg kg−1, i.p.), the guanylate cyclase inhibitor, ODQ (10 mg kg−1, i.p.), glibenclamide (0.1, 0.3, 1 or 3 mg kg−1, i.p.) or with glibenclamide (1 mg kg−1, i.p.) + diazoxide (3 mg kg−1, i.p.). After thirty minutes, the rats received sildenafil (1 mg kg−1, by gavage), followed by intragastric instillation of absolute ethanol (4 ml kg−1) to induce gastric damage. One hour later, gastric damage (haemorrhagic or ulcerative lesions) was measured with a planimetry programme. Samples of stomach were also taken for histopathological assessment and for assays of tissue glutathione and haemoglobin.

Key results:

Sildenafil significantly reduced ethanol‐induced gastric damage in rats. L‐NAME alone, without L‐arginine, significantly reversed the protection afforded by sildenafil. Inhibition of guanylate cyclase by ODQ completely abolished the gastric protective effect of sildenafil against ethanol‐induced gastric damage. Glibenclamide alone reversed sildenafil's gastric protective effect. However, glibenclamide plus diazoxide did not alter the effects of sildenafil.

Conclusions:

Sildenafil had a protective effect against ethanol‐induced gastric damage through the activation of the NO/cGMP/KATP pathway.

British Journal of Pharmacology (2008) 153, 721–727; doi:10.1038/sj.bjp.0707605; published online 10 December 2007
Rifampicin exacerbates isoniazid‐induced toxicity in human but not in rat hepatocytes in tissue‐like cultures
Authors: Shen C , Meng Q , Zhang G , Hu W
Published: December 2007

Background and purpose:

Rifampicin has been extensively reported to exacerbate the hepatotoxicity of isoniazid in patients with tuberculosis. However, this was controversially claimed by previous reports using rat models. This study evaluated the effect of rifampicin on isoniazid‐induced hepatocyte toxicity by using human and rat hepatocytes in tissue‐like culture.

Experimental approach:

Hepatocytes in tissue‐like gel entrapment were used to examine isoniazid toxicity, as shown by cell viability, intracellular glutathione content and albumin secretion. For demonstration of the differential effects of rifampicin on human and rat hepatocytes, induction by rifampicin of cytochromeP450 (CYP) 2E1, a major enzyme associated with isoniazid hepatotoxicity, was detected by 4‐nitrocatechol formation and RT‐PCR analysis.

Key results:

Rifampicin (12 μM) enhanced isoniazid‐induced toxicity in human hepatocytes but not in rat hepatocytes. Enhanced CYP 2E1 enzymic activity and mRNA expression were similarly detected in human hepatocytes but not in rat hepatocytes. Both rat and human hepatocytes in gel entrapment were more sensitive to isoniazid treatment compared with the corresponding hepatocytes in a monolayer culture.

Conclusions and implications:

The difference in induction of CYP 2E1 by rifampicin between rat and human hepatocytes accounted for the difference in exacerbation of isoniazid hepatocyte toxicity by rifampicin, with more significant toxicity in gel entrapment than in monolayer cultures. Thus, human hepatocytes in tissue‐like cultures (gel entrapment) could be an effective model for hepatotoxicity researchin vitro, closer to thein vivosituation.

British Journal of Pharmacology(2008)153, 784–791; doi:10.1038/sj.bjp.0707611; published online 10 December 2007
α1‐Adrenoceptor antagonists prevent paracetamol‐induced hepatotoxicity in mice
Authors: Randle L E , Sathish J G , Kitteringham N R , Macdonald I , Williams D P , Park B K
Published: December 2007

Background and purpose:

Paracetamol, a major cause of acute liver failure (ALF) represents a significant clinical problem. Adrenoceptor stimulation or antagonism can modulate chemical‐induced hepatotoxicity. We investigated the role of endogenous catecholamines and α1‐adrenoceptors in the development of paracetamol‐ induced hepatotoxicity.

Experimental approach:

Paracetamol (3.5 mmol kg−1) was administered to male CD‐1 mice, with and without α1‐adrenoceptor antagonists (prazosin, doxazosin, terazosin and tamsulosin; 35.7 μmol kg−1). Serum transaminases and hepatic glutathione (GSH) levels were assessed as markers of hepatic damage. Paracetamol bioactivation was assessed by covalent binding, hepatic and urinary conjugate formation and uridine glucuronosyltransferase activity. Plasma catecholamines levels and hepatic congestion were also analysed.

Key results:

Plasma catecholamine levels were significantly elevated 5 h post paracetamol administration. Prazosin prevented hepatotoxicity when administered 1 h before a toxic paracetamol insult and importantly, when administered up to 1 h post paracetamol injection. Prazosin had no effect on paracetamol‐induced depletion of hepatic GSH, paracetamol bioactivation or paracetamol‐induced transcription of defence genes. Paracetamol toxicity is associated with marked accumulation of erythrocytes within hepatic sinusoids and prazosin completely prevented this accumulation.

Conclusion and implications:

Paracetamol‐induced hepatocellular damage is associated with increased circulating catecholamines. α1‐Adrenoceptor antagonists conferred complete protection from paracetamol ‐induced hepatotoxicity. Protection was associated with absence of hepatic erythrocyte accumulation. Increased catecholamine levels may contribute to the pathophysiology of paracetamol‐induced hepatotoxicity by compromising hepatic perfusion. Protection against paracetamol toxicity by α1antagonists in mice has implications for therapeutic management of patients presenting with paracetamol overdose and ALF.

British Journal of Pharmacology(2008)153, 820–830; doi:10.1038/sj.bjp.0707620; published online 10 December 2007
Inhibition of matrix metalloproteinases prevents peroxynitrite‐induced contractile dysfunction in the isolated cardiac myocyte
Authors: León H , Baczkó I , Sawicki G , Light P E , Schulz R
Published: December 2007

Background and purpose:

The potent oxidant peroxynitrite (ONOO−) induces mechanical dysfunction in the intact heart in part through activation of matrix metalloproteinase‐2 (MMP‐2). This effect may be independent of the proteolytic actions of MMPs on extracellular matrix proteins. The purpose of this study was to examine the effects of ONOO− on contractile function at the level of the single cardiac myocyte and whether this includes the action of MMPs.

Experimental approach:

Freshly isolated ventricular myocytes from adult rats were superfused with Krebs–Henseleit buffer at 21 °C and paced at 0.5 Hz. Contractility was measured using a video edge‐detector. ONOO− or decomposed ONOO− (vehicle control) were co‐infused over 40 min to evaluate the contraction cease time (CCT). The effects of ONOO− on intracellular [Ca2+] were determined in myocytes loaded with calcium green‐1 AM. MMP‐2 activity was measured by gelatin zymography.

Key results:

ONOO− (30‐600 μM) caused a concentration‐dependent reduction in CCT. Myocytes subjected to 300 μM ONOO− had a shorter CCT than decomposed ONOO− (14.9+1.5 vs 32.2+3.5 min, n=7–8; P<0.05) and showed increased MMP‐2 activity. The MMP inhibitors doxycycline (100 μM) or PD 166793 (2 μM) reduced the decline in CCT induced by 300 μM ONOO−. ONOO− caused shorter calcium transient cease time and significant alterations in intracellular [Ca2+] homoeostasis which were partially prevented by doxycycline.

Conclusions and implications:

This is the first demonstration that inhibition of MMPs protects the cardiac myocyte from ONOO−‐induced contractile failure via an action unrelated to proteolysis of extracellular matrix proteins.

British Journal of Pharmacology (2008) 153, 676–683; doi:10.1038/sj.bjp.0707621; published online 10 December 2007
Bretylium abolishes neurotransmitter release without necessarily abolishing the nerve terminal action potential in sympathetic terminals
Authors: Brain K L , Cunnane T C
Published: December 2007

Background and purpose:

The antidysrhythmic bretylium is useful experimentally because it selectively abolishes neurotransmitter release from sympathetic peripheral nerve terminals. Its mechanism of action seemed settled, but recent results from optical monitoring of single terminals now suggests a new interpretation.

Experimental approach:

Orthograde transport of a dextran‐conjugated Ca2+ indicator to monitor Ca2+ in nerve terminals of mouse isolated vas deferens with a confocal microscope. In some experiments, local neurotransmitter release was detected by monitoring neuroeffector Ca2+ transients (NCTs) in adjacent smooth muscles, a local measure of purinergic transmission. Sympathetic terminals were identified with catecholamine fluorescence (UV excitation) or post‐experiment immunohistochemistry.

Key results:

Bretylium (10 μM) abolished NCTs at 60/61 junctions over the course of 2 h, indicating effective abolition of neurotransmitter release. However, bretylium did not abolish the field stimulus‐induced Ca2+ transient in most nerve terminals, but did increase both action potential delay (by 2±0.4 ms) and absolute refractory period (by 4±2 ms). Immunohistochemistry demonstrated that 85–96% of terminals orthogradely filled with a dextran‐conjugated fluorescent probe contained Neuropeptide Y (NPY). A formaldehyde–glutaraldehyde‐induced catecholamine fluorescence (FAGLU) technique was modified to allow sympathetic terminals to be identified with a Ca2+ indicator present. Most terminals contained catecholamines (based on FAGLU) or secrete ATP (as NCTs in adjacent smooth muscle cells are abolished).

Conclusions and implications:

Bretylium can inhibit neurotransmitter release downstream of Ca2+ influx without abolishing the nerve terminal action potential. Bretylium‐induced increases in the absolute refractory period permit living sympathetic terminals to be identified.

British Journal of Pharmacology (2008) 153, 831–839; doi:10.1038/sj.bjp.0707623; published online 10 December 2007
Negative and positive allosteric modulators of the P2X7receptor
Authors: Michel A D , Chambers L J , Walter D S
Published: December 2007

Background and purpose:

Antagonist effects at the P2X7receptor are complex with many behaving in a non‐competitive manner. In this study, the effects ofN‐[2‐({2‐[(2‐hydroxyethyl)amino]ethyl}amino)‐5‐quinolinyl]‐2‐tricyclo[3.3.1.13,7]dec‐1‐ylacetamide (compound‐17) andN2‐(3,4‐difluorophenyl)‐N1‐[2‐methyl‐5‐(1‐piperazinylmethyl)phenyl]glycinamide dihydrochloride (GW791343) on P2X7receptors were examined and their mechanism of action explored.

Experimental approach:

Antagonist effects were studied by measuring agonist‐stimulated ethidium accumulation in cells expressing human or rat recombinant P2X7receptors and in radioligand binding studies.

Key results:

Compound‐17 and GW791343 were non‐competitive inhibitors of human P2X7receptors. Receptor protection studies using decavanadate and pyridoxalphosphate‐6‐azophenyl‐2',4′‐disulphonic acid (PPADS) showed that neither compound‐17 nor GW791343 competitively interacted at the ATP binding site and so were probably negative allosteric modulators of the P2X7receptor. GW791343 prevented the slowly reversible blockade of the human P2X7receptor produced by compound‐17 and inhibited [3H]‐compound‐17 binding to the P2X7receptor suggesting they may bind to similar or interacting sites. At rat P2X7receptors, compound‐17 was a negative allosteric modulator but the predominant effect of GW791343 was to increase agonist responses. Antagonist interaction and radioligand binding studies revealed that GW791343 did not interact at the ATP binding site but did interact with the compound‐17 binding site suggesting that GW791343 is a positive allosteric modulator of the rat P2X7receptor.

Conclusions:

Compound‐17 was a negative allosteric modulator of human and rat P2X7receptors. GW791343 was a negative allosteric modulator of the human P2X7receptor but at the rat P2X7receptor its predominant effect was positive allosteric modulation. These compounds should provide valuable tools for mechanistic studies on P2X7receptors.

British Journal of Pharmacology(2008)153, 737–750; doi:10.1038/sj.bjp.0707625; published online 10 December 2007
A Holy Grail of asthma management: toward understanding how long‐acting β2‐adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids
Authors: Giembycz M A , Kaur M , Leigh R , Newton R
Published: December 2007

There is unequivocal evidence that the combination of an inhaled corticosteroid (ICS)—i.e. glucocorticoid—and an inhaled long‐acting β2‐adrenoceptor agonist (LABA) is superior to each component administered as a monotherapy alone in the clinical management of asthma. Moreover, Calverley and colleagues (Lancet 2003, 361: 449–456; N Engl J Med 2007, 356: 775–789) reporting for the ‘TRial of Inhaled STeroids ANd long‐acting β2‐agonists (TRISTAN)’ and ‘TOwards a Revolution in COPD Health (TORCH)’ international study groups also demonstrated the superior efficacy of LABA/ICS combination therapies over ICS alone in the clinical management of chronic obstructive pulmonary disease. This finding has been independently confirmed indicating that the therapeutic benefit of LABA/ICS combination therapies is not restricted to asthma and may be extended to other chronic inflammatory diseases of the airways. Despite the unquestionable benefit of LABA/ICS combination therapies, there is a vast gap in our understanding of how these two drugs given together deliver superior clinical efficacy. In this article, we review the history of LABA/ICS combination therapies and critically evaluate how these two classes of drugs might interact at the biochemical level to suppress pro‐inflammatory responses. Understanding the molecular basis of this fundamental clinical observation is a Holy Grail of current respiratory diseases research as it could permit the rational exploitation of this effect with the development of new ‘optimized’ LABA/ICS combination therapies.

British Journal of Pharmacology (2008) 153, 1090–1104; doi:10.1038/sj.bjp.0707627; published online 10 December 2007
An effective light trapping configuration for thin-film solar cells
Authors: Rim Seung-Bum , Zhao Shanbin , Scully Shawn R. , McGehee Michael D. , Peumans Peter
Published: December 2007

Many thin-film solar cells make a compromise between achieving complete optical absorption using films that are thicker than the optical absorption length and achieving efficient conversion of the absorbed photons into photocurrent which is favored in thinner structures. We evaluate the performance of a V-shaped light trapping configuration that substantially increases the photocurrent generation efficiency for all angles of incidence and that is applicable to a broad class of low-cost thin-film solar cells. We experimentally demonstrate its effectiveness for small molecular weight and polymer organic solar cells. A 52% efficiency enhancement is obtained for a 170-nm-thick polymer cell.
Atomistic simulation of nanoporous layered double hydroxide materials and their properties. II. Adsorption and diffusion
Authors: Kim Nayong , Harale Aadesh , Tsotsis Theodore T. , Sahimi Muhammad
Published: December 2007

Nanoporous layered double hydroxide (LDH) materials have wide applications, ranging from being good adsorbents for gases (particularly CO2) and liquid ions to membranes and catalysts. They also have applications in medicine, environmental remediation, and electrochemistry. Their general chemical composition is [M1−xIIMxIII(OH−)2]x+[Xn∕mm−∙nH2O], where M represents a metallic cation (of valence II or III), and Xn∕mm− is an m-valence inorganic, or heteropolyacid, or organic anion. We study diffusion and adsorption of CO2 in a particular LDH with MII=Mg, MIII=Al, and x≃0.71, using an atomistic model developed based on energy minimization and molecular dynamics simulations, together with a modified form of the consistent-valence force field. The adsorption isotherms and self-diffusivity of CO2 in the material are computed over a range of temperature, using molecular simulations. The computed diffusivities are within one order of magnitude of the measured ones at lower temperatures, while agreeing well with the data at high temperatures. The measured and computed adsorption isotherms agree at low loadings, but differ by about 25% at high loadings. Possible reasons for the differences between the computed properties and the experimental data are discussed, and a model for improving the accuracy of the computed properties is suggested. Also studied are the material’s hydration and swelling properties. As water molecules are added to the pore space, the LDH material swells to some extent, with the hydration energy exhibiting interesting variations with the number of the water molecules added. The implications of the results are discussed.