bluuebunny/crossref_metadata_2025 huggingface dataset:
Histopathological reporting of paediatric cutaneous vascular anomalies in relation to proposed multidisciplinary classification system
Authors: Al-Adnani M , Williams S , Rampling D , Ashworth M , Malone M , Sebire N J
Published: June 2006

Background:The terminology applied to vascular anomalies has been variable in previously published literature making interpretation suboptimal. The International Society for the Study of Vascular Anomalies (ISSVA) has proposed a revised classification based on clinical features and histopathological findings. This classification is increasingly being accepted as clinically useful and a platform for future studies.

Aims:To examine the extent to which the ISSVA classification can be practically applied to diagnostic histopathological specimens.

Methods:Cutaneous vascular lesions received in a single paediatric pathology unit during a 2-year period (2004–5) were reviewed, including glucose transporter protein 1 (GLUT1) immunostaining where required, and lesions were reclassified according to the ISSVA classification.

Results:144 specimens were identified. Appropriate full clinical information was provided in only 17% of cases at submission. Infantile haemangiomas comprised 46% of cases, 18% of which were regressive type, initially inaccurately identified as vascular malformations before GLUT1 immunostaining. 30% of lymphatic malformations and all lymphovenous malformations were previously classified as vascular malformations, not otherwise specified.

Conclusions:The ISSVA classification of vascular anomalies provides a useful framework for histopathologists to classify vascular anomalies. However, meaningful and appropriate use of such a system is dependent on the adequacy of clinical information provided and routine use of immunohistochemical markers.
Immunohistochemical and quantitative mRNA assessment of ghrelin expression in gastric and oesophageal adenocarcinoma
Authors: Mottershead Marcus , Karteris Emmanuel , Barclay Jill Y , Suortamo Saira , Newbold Mark , Randeva Harpal , Nwokolo Chuka U
Published: June 2006

Background:Ghrelin is an orexigenic gut peptide produced predominantly by the stomach. Gastric mucosal ghrelin production could be compromised by an infiltrating adenocarcinoma.

Aims:To assess the expression of ghrelin mRNA and peptide in oesophagogastric adenocarcinomas and adjacent non-neoplastic mucosa.

Methods:10 gastric and 22 oesophageal adenocarcinoma archival samples were randomly selected from a database. The presence of ghrelin-positive cells was assessed in cancer and corresponding non-neoplastic mucosa by immunohistochemistry. Quantitative reverse transcriptase polymerase chain reaction (PCR) for ghrelin mRNA was also performed on 24 gastric and 8 oesophageal adenocarcinoma specimens and adjacent non-neoplastic mucosa.

Results:Immunohistochemistry and reverse transcriptase PCR confirm a negligible expression of ghrelin in adenocarcinoma specimens. By contrast, non-neoplastic gastric mucosa was rich in ghrelin-positive cells and ghrelin mRNA. The number (median and range) of ghrelin-positive cells per 2 mm section of non-neoplastic mucosa was 73 (45–215) in the corpus; this was significantly higher than in cardia mucosa (9 (0–64), p<0.001) and antral mucosa (5 (0–14), p<0.001).

Conclusions:Gastric and oesophageal adenocarcinomas have no ghrelin-producing cells. The highest level of ghrelin expression was noted in the non-neoplastic mucosa of the gastric corpus. Disruption of the gastric ghrelin-producing mechanism may occur during oesophagogastric malignancy.
Thrombolysis: past, present, and future
Authors: Gray D
Published: June 2006

Management of myocardial infarction evolved because of understanding of underlying disease processes and clinical trials of “chemical” and “mechanical” clot dissolution that reduced in-hospital mortality. Meta-analysis comparing these treatment strategies marginally favours angioplasty. Current European Society of Cardiology guidelines propose primary angioplasty as the preferred therapeutic option but few units in the UK can offer angioplasty on demand as a designated “heart attack centre”. Thrombolysis will continue as it is widely available and training needs and costs less than angioplasty. Community thrombolysis should be made available for those patients who do not wish for such aggressive intervention or as a prelude to transfer time to a heart attack centre distant from a triage hospital.
Reducing transfer times for coronary angiography in patients with acute coronary syndromes: one solution to a national problem
Authors: Bellenger N G , Wells T , Hitchcock R , Watkins M , Duffet C , Jewell D , Palliser D , Shapland L , Curtis R , Scrase S , Burns R , Curzen N
Published: June 2006

Backgound

Patients with acute coronary syndrome (ACS) are at high risk of further cardiac events and benefit from early intervention, as reflected by international guidelines recommending early transfer to interventional centres. The current average waiting time of up to 21 days contravenes evidence based early intervention, creates geographical inequity of access, wastes bed days, and is unsatisfactory for patients.

Methods

A regional transfer unit (RTU) was created to expatiate access of ACS patients referred from other centres to the revascularisation service. By redesigning the care pathway patients arriving on the RTU undergo angiography within 24 hours, and then leave the RTU the following day, allowing other ACS patients to be treated.

Results

During the first six months of the RTU, the mean waiting time from referral to procedure decreased from 20 (SD 15) days (range 0–51) to 8 (SD 3) days (range 0–21) for 365 patients transferred from a distict general hopsital. Ninety seven per cent of patients underwent angiography within 24 hours, 61% having undergone percutaneous coronary intervention at the same sitting, and 78% were discharged home within 24 hours.

Conclusions

Delivering standards laid out in the National Service Framework, reducing inequalities of care across the region, and facilitating evidence based strategies of care represents a challenging and complex issue. For high risk patients suffering ACS who need early invasive investigation, a coordinated network wide approach together with the creation of an RTU resulted in a 62% reduction in waiting times for no extra resources. Further improvements can be expected through increased capacity of this verified strategy.
Colonic involvement in Stevens-Johnson syndrome
Authors: Powell N , Munro J M , Rowbotham D
Published: June 2006

Severe gastrointestinal tract involvement is a rare manifestation of Stevens-Johnson syndrome (SJS). The case is described of a 17 year old man who developed SJS secondary to phenytoin. In addition to the cutaneous, ocular, and oral mucosal lesions typical of SJS, he also developed persistent, bloody diarrhoea associated with life threatening malnutrition. Serial colonoscopy showed severe and progressive colitis. He was treated with a combination of long term nutritional support, probiotic therapy, and supportive measures. He was eventually discharged from hospital six months after admission when the diarrhoea improved and he began to gain weight.
Investigation and treatment of faecal incontinence
Authors: Maslekar S , Gardiner A , Maklin C , Duthie G S
Published: June 2006

Faecal incontinence is a debilitating condition affecting people of all ages, and significantly impairs quality of life. Proper clinical assessment followed by conservative medical therapy leads to improvement in more than 50% of cases, including patients with severe symptoms. Patients with advanced incontinence or those resistant to initial treatment should be evaluated by anorectal physiology testing to establish the severity and type of incontinence. Several treatment options with promising results exist. Patients with gross sphincter defects should undergo surgical repair. Those who fail to respond to sphincteroplasty and those with no anatomical defects have the option of either sacral nerve stimulation or other advanced procedures. Stoma formation should be reserved for patients who do not respond to any of the above procedures.
Support for and reported compliance with smoke-free restaurants and bars by smokers in four countries: findings from the International Tobacco Control (ITC) Four Country Survey
Authors: Borland R , Yong H-H , Siahpush M , Hyland A , Campbell S , Hastings G , Cummings K M , Fong G T
Published: June 2006

Objective:To explore determinants of support for and reported compliance with smoke-free policies in restaurants and bars across the four countries of the International Tobacco Control (ITC) Four Country Survey.

Design:Separate telephone cross-sectional surveys conducted between October and December 2002 with broadly representative samples of over 2000 adult (⩾ 18 years) cigarette smokers in each of the following four countries: the United States, Canada, the United Kingdom, and Australia.

Outcome measures:Support for smoke-free policies in restaurants and pubs/bars and reported compliance with existing policies.

Results:Reported total bans on indoor smoking in restaurants varied from 62% in Australia to 5% in the UK. Smoking bans in bars were less common, with California in the USA being the only major part of any country with documented bans. Support for bans in both restaurants and bars was related to the existence of bans, beliefs about passive smoking being harmful, lower average cigarette consumption, and older age. Self-reported compliance with a smoking ban was generally high and was associated with greater support for the ban.

Conclusions:Among current cigarette smokers, support for smoking bans was associated with living in a place where the law prohibits smoking. Smokers adjust and both accept and comply with smoke-free laws. Associates of support and compliance are remarkably similar across countries given the notably different levels of smoke-free policies.
Effectiveness of cigarette warning labels in informing smokers about the risks of smoking: findings from the International Tobacco Control (ITC) Four Country Survey
Authors: Hammond D , Fong G T , McNeill A , Borland R , Cummings K M
Published: June 2006

Background:Health warnings on cigarette packages are among the most common means of communicating the health risks of smoking. However, few studies have evaluated the impact of package warnings on consumer knowledge about tobacco risks.

Objective:The aim of the current study was to use nationally representative samples of adult smokers from the United States (USA), the United Kingdom (UK), Canada (CAN), and Australia (AUS) from the International Tobacco Control Four Country Survey (ITC-4) to examine variations in smokers’ knowledge about tobacco risks and the impact of package warnings.

Methods:A telephone survey was conducted with 9058 adult smokers from the following countries: USA (n  =  2138), UK (n  =  2401), CAN (n  =  2214) and AUS (n  =  2305). Respondents were asked to state whether they believed smoking caused heart disease, stroke, impotence, lung cancer in smokers, and lung cancer in non-smokers. Respondents were also asked whether the following chemicals are found in cigarette smoke: cyanide, arsenic and carbon monoxide.

Findings:Smokers in the four countries exhibited significant gaps in their knowledge of the risks of smoking. Smokers who noticed the warnings were significantly more likely to endorse health risks, including lung cancer and heart disease. In each instance where labelling policies differed between countries, smokers living in countries with government mandated warnings reported greater health knowledge. For example, in Canada, where package warnings include information about the risks of impotence, smokers were 2.68 (2.41–2.97) times more likely to agree that smoking causes impotence compared to smokers from the other three countries.

Conclusion:Smokers are not fully informed about the risks of smoking. Warnings that are graphic, larger, and more comprehensive in content are more effective in communicating the health risks of smoking.
Effects of the 2003 advertising/promotion ban in the United Kingdom on awareness of tobacco marketing: findings from the International Tobacco Control (ITC) Four Country Survey
Authors: Harris F , MacKintosh A M , Anderson S , Hastings G , Borland R , Fong G T , Hammond D , Cummings K M
Published: June 2006

Background:In February 2003, a comprehensive ban on tobacco promotion came into effect in the United Kingdom, which prohibited tobacco marketing through print and broadcast media, billboards, the internet, direct mail, product placement, promotions, free gifts, coupons and sponsorships.

Objective:To investigate the impact of the UK’s comprehensive ban on tobacco promotion on adult smokers’ awareness of tobacco marketing in the UK relative to Canada, the United States and Australia.

Design:A total of 6762 adult smokers participated in two waves of a random digit dialled telephone survey across the four countries. Wave 1 was conducted before the UK ban (October–December 2002) and Wave 2 was conducted after the UK ban (May–September 2003).

Key measures:Awareness of a range of forms of tobacco marketing.

Results:Levels of tobacco promotion awareness declined significantly among smokers in the UK after implementation of the advertising ban. Declines in awareness were greater in those channels regulated by the new law and change in awareness of tobacco promotions was much greater in the UK than the other three countries not affected by the ban. At least in the short term, there was no evidence that the law resulted in greater exposure to tobacco promotions in the few media channels not covered by the law. Notwithstanding the apparent success of the UK advertising ban and the controls in other countries, 9–22% of smokers in the four countries still reported noticing things that promoted smoking “often or very often” at Wave 2.

Conclusions:The UK policy to ban tobacco advertising and promotion has significantly reduced exposure to pro-tobacco marketing influences. These findings support the effectiveness of comprehensive bans on advertising and promotion, as included in the Framework Convention on Tobacco Control.
Prevalence and attributes of roll-your-own smokers in the International Tobacco Control (ITC) Four Country Survey
Authors: Young D , Borland R , Hammond D , Cummings K M , Devlin E , Yong H-H , O’Connnor R J
Published: June 2006

Background:Roll-your-own (RYO) cigarettes are often substantially less expensive than factory made (FM) cigarettes, and appear to be increasing in popularity—perhaps because smokers seek out less expensive options to maintain their nicotine addiction. There is surprisingly little research available on the actual prevalence of RYO cigarette usage, and even less on the attributes of those who smoke RYO cigarettes.

Objectives:This study has two objectives: (1) to compare the prevalence of RYO versus FM cigarette usage among adult smokers in Australia, Canada, the United Kingdom, and the United States; and (2) to compare the attributes of exclusive FM smokers, exclusive RYO smokers, and those who report “mixed” RYO and FM use.

Design:The data were collected from the International Tobacco Control (ITC) Four Country Survey (ITC-4), a random digit dialed telephone survey of representative samples of over 9046 adult smokers from the following four countries: Australia (n  =  2301), Canada (n  =  2,206), the UK (n  =  2400), and the USA (n  =  2,139), surveyed between October and December 2002, and on 6075 smokers followed-up, on average, seven months later.

Results:The prevalence of RYO cigarette usage varied widely across the four countries, with a low of 6.7% in the USA, to 28.4% in the UK. Exclusive use of RYO cigarettes was more common in the UK than in the other three countries. The use of RYO cigarettes was associated with having a lower annual income, male sex, younger average age, higher level of nicotine addiction, a stronger belief that RYO tobacco is less harmful compared to other forms of tobacco, and a more positive perception of tobacco use. Prevalence of RYO use was relatively stable within each of the four countries between the baseline and follow-up survey. RYO use was unrelated to quitting activity at follow-up, although mixed RYO users who had made a quit attempt were more likely to relapse than either exclusive FM or exclusive RYO smokers.

Conclusions:Patterns of RYO use vary considerably across Australia, Canada, the USA, and the UK. RYO smokers are a heterogeneous group; however, the factors associated with RYO use appear to be the same across the four countries studied.
Individual-level predictors of cessation behaviours among participants in the International Tobacco Control (ITC) Four Country Survey
Authors: Hyland A , Borland R , Li Q , Yong H-H , McNeill A , Fong G T , O’Connor R J , Cummings K M
Published: June 2006

Background:The International Tobacco Control (ITC) Four Country Survey (ITC-4) is a prospective cohort study designed to evaluate the psychosocial and behavioural impact of national-level tobacco control policies enacted in the Australia, Canada, the UK, and the USA. Wave 1 of ITC-4 survey was conducted between October 2002 and December 2002. Wave 2 survey was conducted between May 2003 and August 2003.

Objective:To test for individual-level predictors of smoking cessation behaviours (that is, quit attempts and smoking cessation) among cigarette smokers in the ITC Four Country Study measured between Wave 1 and Wave 2. This set of predictors will serve as the base for evaluating the added effect of tobacco control policies and other factors.

Methods:Respondents included in this study are 6682 adult current smokers in the Wave 1 main survey who completed the Wave 2 follow-up (1665 were in Canada, 1329 were in the USA, 1837 were in the UK and 1851 were in Australia).

Results:Factors predictive of making a quit attempt included intention to quit, making a quit attempt in the previous year, longer duration of past quit attempts, less nicotine dependence, more negative attitudes about smoking, and younger age. Lower levels of nicotine dependence were the main factor that predicted future cessation among those that made a quit attempt.

Conclusion:Intention to quit and other cognitive variables were associated with quit attempts, but not cessation. Behavioural variables related to task difficulty, including measures of dependence, predicted both making attempts and their success. Predictors of making quit attempts and cessation were similar for each of the four countries, but there were some differences in predictors of success.
The conceptual framework of the International Tobacco Control (ITC) Policy Evaluation Project
Authors: Fong G T , Cummings K M , Borland R , Hastings G , Hyland A , Giovino G A , Hammond D , Thompson M E
Published: June 2006

This paper describes the conceptual model that underlies the International Tobacco Control Policy Evaluation Project (ITC Project), whose mission is to measure the psychosocial and behavioural impact of key policies of the Framework Convention on Tobacco Control (FCTC) among adult smokers, and in some countries, among adult non-smokers and among youth. The evaluation framework utilises multiple country controls, a longitudinal design, and a pre-specified, theory-driven conceptual model to test hypotheses about the anticipated effects of specific policies. The ITC Project consists of parallel prospective cohort surveys of representative samples of adult smokers currently in nine countries (inhabited by over 45% of the world’s smokers), with other countries being added in the future. Collectively, the ITC Surveys constitute the first-ever international cohort study of tobacco use. The conceptual model of the ITC Project draws on the psychosocial and health communication literature and assumes that tobacco control policies influence tobacco related behaviours through a causal chain of psychological events, with some variables more closely related to the policy itself (policy-specific variables) and other variables that are more downstream from the policy, which have been identified by health behaviour and social psychological theories as being important causal precursors of behaviour (psychosocial mediators). We discuss the objectives of the ITC Project and its potential for building the evidence base for the FCTC.
Building the evidence base for effective tobacco control policies: the International Tobacco Control Policy Evaluation Project (the ITC Project): Table 1
Authors: Fong G T , Cummings K M , Shopland D R
Published: June 2006

The Framework Convention on Tobacco Control (FCTC) is a seminal event in tobacco control and in global health. Scientific evidence guided the creation of the FCTC, and as the treaty moves into its implementation phase, scientific evidence can be used to guide the formulation of evidence-based tobacco control policies. The International Tobacco Control Policy Evaluation Project (ITC Project) is a transdisciplinary international collaboration of tobacco control researchers who have created research studies to evaluate and understand the psychosocial and behavioural impact of FCTC policies as they are implemented in participating ITC countries, which together are inhabited by over 45% of the world’s smokers. This introduction to the ITC Project supplement ofTobacco Controlpresents a brief outline of the ITC Project, including a summary of key findings to date. The overall conceptual model and methodology of the ITC Project—involving representative national cohort surveys created from a common conceptual model, with common methods and measures across countries—may hold promise as a useful paradigm in efforts to evaluate and understand the impact of population-based interventions in other important domains of health, such as obesity.
Inner shell electron-energy loss spectroscopy of some heterocyclic molecules
Authors: Newbury D C , Ishii I , Hitchcock A P
Published: June 2006

The carbon K-shell spectra of gaseous furan, pyrrole, tetrahydrofuran, pyrrolidine, tetrahydropyran, and piperidine have been recorded by electron energy loss spectroscopy (ISEELS) under electric dipole scattering conditions (2.5 keV impact, small angle.) The spectra are dominated by transitions to unoccupied valence states of π and σ symmetry. Features attributed to transitions to π*(CH2) levels are consistently observed below the ionization threshold in the spectra of the saturated species. the positions of continuum features are generally in agreement with a previously documented correlation with bond lengths. Additional weak continuum features are observed in the smaller saturated heterocyclic species which are ascribed to delocalized σ* states.
AN ANALYSIS OF THE REGIOSELECTIVITY IN HETERO DIELS–ALDER REACTIONS USING DFT-BASED REACTIVITY INDEXES
Authors: CHEMOURI H. , MEKELLECHE S. M.
Published: June 2006

The regioselectivity of hetero Diels–Alder reactions (HDA) of 2-azabutadiene with aldehydes has been elucidated by means of Gazquez–Mendez rules, which are based on the calculation of local softnesses of the four terminal atoms involved in cyclization. The theoretical results obtained with the B3LYP/6-31G(d) method confirm the regioselectivities observed experimentally for all substituents ( R = H , CH 3, CN ) present in the aldehyde reactant. The regioselectivities of these HDA reactions have been confirmed by the calculation of the activation barriers corresponding to the two cyclization modes, and also by the application of the Houk rule and the maximum hardness principle.
Max Weber's Contribution to the Economic Sociology of Law
Authors: Swedberg Richard
Published: June 2006

▪ Abstract  During recent years, a few scholars have advocated that more attention be paid to the intersection of law, economics, and sociology—what may be called the economic sociology of law. This review suggests that a theoretical foundation for such a field of study, or parts of such a foundation, may be found in the work of Max Weber. It also provides an introduction to those parts of Weber's work that are relevant in this context. Weber especially emphasizes the role that law plays in raising the probability that actions will take place, in the economy and elsewhere, and that this probability has to be established while taking the motives of the actors into account. The main contribution of the legal system to modern capitalism, Weber also argues, is to make economic life more calculable. This review also discusses which factors account for the increasing rationalization of law, including economic factors.
DnaA: Controlling the Initiation of Bacterial DNA Replication and More
Authors: Kaguni Jon M.
Published: June 2006

Escherichia coli is a model system to study the mechanism of DNA replication and its regulation during the cell cycle. One regulatory pathway ensures that initiation of DNA replication from the chromosomal origin, oriC, is synchronous and occurs at the proper time in the bacterial cell cycle. A major player in this pathway is SeqA protein and involves its ability to bind preferentially to oriC when it is hemi-methylated. The second pathway modulates DnaA activity by stimulating the hydrolysis of ATP bound to DnaA protein. The regulatory inactivation of DnaA function involves an interaction with Hda protein and the beta dimer, which functions as a sliding clamp for the replicase, DNA polymerase III holoenzyme. The datA locus represents a third mechanism, which appears to influence the availability of DnaA protein in supporting rifampicin-resistant initiations.
Surface Proteins of Gram-Positive Bacteria and How They Get There
Authors: Scott June R. , Barnett Timothy C.
Published: June 2006

Surface proteins are critical in determining the identifying characteristics of individual bacteria and their interaction with the environment. Because the structure of the cell surface is the major characteristic that distinguishes gram-positive from gram-negative bacteria, the processes used to transport and attach these proteins show significant differences between these bacterial classes. This review is intended to highlight these differences and to focus attention on areas that are ripe for further investigation.
The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock
Authors: Raman Kathleen G. , Sappington Penny L. , Yang Runkuan , Levy Ryan M. , Prince Jose M. , Liu Shiguang , Watkins Simon K. , Schmidt Ann Marie , Billiar Timothy R. , Fink Mitchell P.
Published: June 2006

The receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of numerous conditions associated with excessive inflammation. To determine whether RAGE-dependent signaling is important in the development of intestinal barrier dysfunction after hemorrhagic shock and resuscitation (HS/R), C57Bl/6, rage−/−, or congenic rage+/+ mice were subjected to HS/R (mean arterial pressure of 25 mmHg for 3 h) or a sham procedure. Twenty-four hours later, bacterial translocation to mesenteric lymph nodes and ileal mucosal permeability to FITC-labeled dextran were assessed. Additionally, samples of ileum were obtained for immunofluorescence microscopy, and plasma was collected for measuring IL-6 and IL-10 levels. HS/R in C57Bl/6 mice was associated with increased bacterial translocation, ileal mucosal hyperpermeability, and high circulating levels of IL-6. All of these effects were prevented when C57Bl/6 mice were treated with recombinant human soluble RAGE (sRAGE; the extracellular ligand-binding domain of RAGE). HS/R induced bacterial translocation, ileal mucosal hyperpermeability, and high plasma IL-6 levels in rage+/+ but not rage−/− mice. Circulating IL-10 levels were higher in rage−/− compared with rage+/+ mice. These results suggest that activation of RAGE-dependent signaling is a key factor leading to gut mucosal barrier dysfunction after HS/R.
P2Y1receptors mediate inhibitory purinergic neuromuscular transmission in the human colon
Authors: Gallego Diana , Hernández Pilar , Clavé Pere , Jiménez Marcel
Published: June 2006

Indirect evidence suggests that ATP is a neurotransmitter involved in inhibitory pathways in the neuromuscular junction in the gastrointestinal tract. The aim of this study was to characterize purinergic inhibitory neuromuscular transmission in the human colon. Tissue was obtained from colon resections for neoplasm. Muscle bath, microelectrode experiments, and immunohistochemical techniques were performed. 2′-deoxy- N6-methyl adenosine 3′,5′-diphosphate tetraammonium salt (MRS 2179) was used as a selective inhibitor of P2Y1receptors. We found that 1) ATP (1 mM) and adenosine 5′-β-2-thiodiphosphate (ADPβS) (10 μM), a preferential P2Y agonist, inhibited spontaneous motility and caused smooth muscle hyperpolarization (about −12 mV); 2) MRS 2179 (10 μM) and apamin (1 μM) significantly reduced these effects; 3) both the fast component of the inhibitory junction potential (IJP) and the nonnitrergic relaxation induced by electrical field stimulation were dose dependently inhibited (IC50∼1 μM) by MRS 2179; 4) ADPβS reduced the IJP probably by a desensitization mechanism; 5) apamin (1 μM) reduced the fast component of the IJP (by 30–40%) and the inhibitory effect induced by electrical field stimulation; and 6) P2Y1receptors were localized in smooth muscle cells as well as in enteric neurons. These results show that ATP or a related purine is released by enteric inhibitory motoneurons, causing a fast hyperpolarization and smooth muscle relaxation. The high sensitivity of MRS 2179 has revealed, for the first time in the human gastrointestinal tract, that a P2Y1receptor present in smooth muscle probably mediates this mechanism through a pathway that partially involves apamin-sensitive calcium-activated potassium channels. P2Y1receptors can be an important pharmacological target to modulate smooth muscle excitability.
Selective inhibition of p38α MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury
Authors: Li Zhihe , Ma Jing Ying , Kerr Irene , Chakravarty Sarvajit , Dugar Sundeep , Schreiner George , Protter Andrew A.
Published: June 2006

p38 MAPK is activated during heart diseases that might associate with myocardial damage and deterioration of cardiac function. In a rat model of myocardial injury, we have investigated cardioprotective effects of the inhibition of p38 MAPK using a novel, orally available p38α MAPK inhibitor. Rats were treated with Nω-nitro-l-arginine methyl ester (l-NAME, 40 mg·kg−1·day−1) in drinking water plus 1% salt for 14 days and ANG II (0.5 mg·kg−1·day−1) for 3 days. A selective p38α MAPK inhibitor, SD-282 (60 mg/kg), was administrated orally, twice a day for 4 days, starting 1 day before ANG II administration. The cardioprotective effects of p38α MAPK inhibition were evaluated by improvement of cardiac function, reduction of inflammatory cell infiltration, and cardiomyocyte apoptosis. SD-282 significantly improved cardiac function indicated by increasing stroke volume, cardiac output, ejection fraction, and stroke work and significantly decreasing arterial elastance. SD-282 also significantly reduced macrophage infiltration as judged by reduction of a specific marker, ED-1-positive staining cells ( P < 0.05) in the myocardium. Furthermore, cardiomyocyte apoptosis as indicated by caspase-3 immunohistochemical staining was abolished by SD-282, and this effect may contribute to the reduction of myocardial damage evaluated by imaging analysis ( P < 0.05 in both cases). Data suggest that p38α MAPK may play a critical role in the pathogenesis of cardiac dysfunction. Inhibition of p38α MAPK may be used as a novel cardioprotective strategy in attenuation of inflammatory response and deterioration of cardiac function that occurs in acute cardiovascular disease such as myocardial infarction.
Adenosine receptors located in the NTS contribute to renal sympathoinhibition during hypotensive phase of severe hemorrhage in anesthetized rats
Authors: Scislo Tadeusz J. , O'Leary Donal S.
Published: June 2006

Stimulation of nucleus of the solitary tract (NTS) A2a-adenosine receptors elicits cardiovascular responses quite similar to those observed with rapid, severe hemorrhage, including bradycardia, hypotension, and inhibition of renal but activation of preganglionic adrenal sympathetic nerve activity (RSNA and pre-ASNA, respectively). Because adenosine levels in the central nervous system increase during severe hemorrhage, we investigated to what extent these responses to hemorrhage may be due to activation of NTS adenosine receptors. In urethane- and α-chloralose-anesthetized male Sprague-Dawley rats, rapid hemorrhage was performed before and after bilateral nonselective or selective blockade of NTS adenosine-receptor subtypes [A1- and A2a-adenosine-receptor antagonist 8-( p-sulfophenyl)theophylline (1 nmol/100 nl) and A2a-receptor antagonist ZM-241385 (40 pmol/100 nl)]. The nonselective blockade reversed the response in RSNA (−21.0 ± 9.6 Δ% vs. +7.3 ± 5.7 Δ%) (where Δ% is averaged percent change from baseline) and attenuated the average heart rate response (change of −14.8 ± 4.8 vs. −4.4 ± 3.4 beats/min). The selective blockade attenuated the RSNA response (−30.4 ± 5.2 Δ% vs. −11.1 ± 7.7 Δ%) and tended to attenuate heart rate response (change of −27.5 ± 5.3 vs. −15.8 ± 8.2 beats/min). Microinjection of vehicle (100 nl) had no significant effect on the responses. The hemorrhage-induced increases in pre-ASNA remained unchanged with either adenosine-receptor antagonist. We conclude that adenosine operating in the NTS via A2aand possibly A1receptors may contribute to posthemorrhagic sympathoinhibition of RSNA but not to the sympathoactivation of pre-ASNA. The differential effects of NTS adenosine receptors on RSNA vs. pre-ASNA responses to hemorrhage supports the hypothesis that these receptors are differentially located/expressed on NTS neurons/synaptic terminals controlling different sympathetic outputs.
H2O2-induced redox-sensitive coronary vasodilation is mediated by 4-aminopyridine-sensitive K+channels
Authors: Rogers Paul A. , Dick Gregory M. , Knudson Jarrod D. , Focardi Marta , Bratz Ian N. , Swafford Albert N. , Saitoh Shu-ichi , Tune Johnathan D. , Chilian William M.
Published: June 2006

Hydrogen peroxide (H2O2) is a proposed endothelium-derived hyperpolarizing factor and metabolic vasodilator of the coronary circulation, but its mechanisms of action on vascular smooth muscle remain unclear. Voltage-dependent K+(KV) channels sensitive to 4-aminopyridine (4-AP) contain redox-sensitive thiol groups and may mediate coronary vasodilation to H2O2. This hypothesis was tested by studying the effect of H2O2on coronary blood flow, isometric tension of arteries, and arteriolar diameter in the presence of K+channel antagonists. Infusing H2O2into the left anterior descending artery of anesthetized dogs increased coronary blood flow in a dose-dependent manner. H2O2relaxed left circumflex rings contracted with 1 μM U46619, a thromboxane A2mimetic, and dilated coronary arterioles pressurized to 60 cmH2O. Denuding the endothelium of coronary arteries and arterioles did not affect the ability of H2O2to cause vasodilation, suggesting a direct smooth muscle mechanism. Arterial and arteriolar relaxation by H2O2was reversed by 1 mM dithiothreitol, a thiol reductant. H2O2-induced relaxation was abolished in rings contracted with 60 mM K+and by 10 mM tetraethylammonium, a nonselective inhibitor of K+channels, and 3 mM 4-AP. Dilation of arterioles by H2O2was antagonized by 0.3 mM 4-AP but not 100 nM iberiotoxin, an inhibitor of Ca2+-activated K+channels. H2O2-induced increases in coronary blood flow were abolished by 3 mM 4-AP. Our data indicate H2O2increases coronary blood flow by acting directly on vascular smooth muscle. Furthermore, we suggest 4-AP-sensitive K+channels, or regulating proteins, serve as redox-sensitive elements controlling coronary blood flow.
Effects of sequential biventricular pacing during acute right ventricular pressure overload
Authors: Quinn T. Alexander , Berberian George , Cabreriza Santos E. , Maskin Lauren J. , Weinberg Alan D. , Holmes Jeffrey W. , Spotnitz Henry M.
Published: June 2006

Temporary sequential biventricular pacing (BiVP) is a promising treatment for postoperative cardiac dysfunction, but the mechanism for improvement in right ventricular (RV) dysfunction is not understood. In the present study, cardiac output (CO) was optimized by sequential BiVP in six anesthetized, open-chest pigs during control and acute RV pressure overload (RVPO). Ventricular contractility was assessed by the maximum rate of increase of ventricular pressure (dP/d tmax). Mechanical interventricular synchrony was measured by the area of the normalized RV-left ventricular (LV) pressure diagram ( APP). Positive APP indicates RV pressure preceding LV pressure, whereas zero indicates complete synchrony. In the control state, CO was maximized with nearly simultaneous stimulation of the RV and LV, which increased RV ( P = 0.006) and LV dP/d tmax ( P = 0.002). During RVPO, CO was maximized with RV-first pacing, which increased RV dP/d tmax ( P = 0.007), but did not affect LV dP/d tmax, and decreased the left-to-right, end-diastolic pressure gradient ( P = 0.023). Percent increase of RV dP/d tmax was greater than LV dP/d tmax ( P = 0.014). There were no increases in end-diastolic pressure to account for increases in dP/d tmax. In control and RVPO, RV dP/dtmax was linearly related to APP ( r = 0.779, P < 0.001). The relation of CO to APP was curvilinear, with a peak in CO with positive APP in the control state ( P = 0.004) and with APP approaching zero during RVPO ( P = 0.001). These observations imply that, in our model, BiVP optimization improves CO by augmenting RV contractility. This is mediated by changes in mechanical interventricular synchrony. Afterload increases during RVPO exaggerate this effect, making CO critically dependent on simultaneous pressure generation in the RV and LV, with support of RV contractility by transmission of LV pressure across the interventricular septum.
NO and prostanoids blunt endothelin-mediated coronary vasoconstrictor influence in exercising swine
Authors: Merkus Daphne , Sorop Oana , Houweling Birgit , Boomsma Frans , van den Meiracker Anton H. , Duncker Dirk J.
Published: June 2006

Withdrawal of the endothelin (ET)-mediated vasoconstrictor influence contributes to metabolic coronary vasodilation during exercise. Because production of nitric oxide (NO) and prostanoids increases with increasing shear stress and because NO and prostanoids are able to modify the release of ET, we hypothesized that the withdrawal of ET-mediated coronary vasoconstriction during exercise is mediated through NO and/or prostanoids. To test this hypothesis, 19 chronically instrumented swine were studied at rest and while running on a treadmill up to 85–90% of maximal heart rate. Blockade of ETA/ETBreceptors with tezosentan resulted in an increase in coronary venous O2levels (i.e., in coronary vasodilation) at rest, which waned at increasing levels of exercise intensity. Inhibition of either NO synthase [ Nω-nitro-l-arginine (l-NNA)] or cyclooxygenase (indomethacin) did not affect the response to tezosentan under resting conditions but unmasked a vasodilator response to tezosentan during exercise. The vasodilator response to tezosentan during exercise increased progressively after combined administration of l-NNA and indomethacin. These findings suggest that NO and prostanoids act synergistically to inhibit the vasoconstrictor influence of ET on the coronary circulation during exercise, thereby facilitating the exercise-induced vasodilation of coronary resistance vessels.
Impact of osmotic compression on sarcomere structure and myofilament calcium sensitivity of isolated rat myocardium
Authors: Farman Gerrie P. , Walker John S. , de Tombe Pieter P. , Irving Thomas C.
Published: June 2006

Changes in interfilament lattice spacing have been proposed as the mechanism underlying myofilament length-dependent activation. Much of the evidence to support this theory has come from experiments in which high-molecular-weight compounds, such as dextran, were used to osmotically shrink the myofilament lattice. However, whether interfilament spacing directly affects myofilament calcium sensitivity (EC50) has not been established. In this study, skinned isolated rat myocardium was osmotically compressed over a wide range (Dextran T500; 0–6%), and EC50 was correlated to both interfilament spacing and I1,1/ I1,0 intensity ratio. The latter two parameters were determined by X-ray diffraction in a separate group of skinned muscles. Osmotic compression induced a marked reduction in myofilament lattice spacing, concomitant with increases in both EC50 and I1,1/ I1,0 intensity ratio. However, interfilament spacing was not well correlated with EC50 ( r2 = 0.78). A much better and deterministic relationship was observed between EC50 and the I1,1/ I1,0 intensity ratio ( r2 = 0.99), albeit with a marked discontinuity at low levels of dextran compression; that is, a small amount of external osmotic compression (0.38 kPa, corresponding to 1% Dextran T500) produced a stepwise increase in the I1,1/ I1,0 ratio concomitant with a stepwise decrease in EC50. These parameters then remained stable over a wide range of further applied osmotic compression (up to 6% dextran). These findings provide support for a “switch-like” activation mechanism within the cardiac sarcomere that is highly sensitive to changes in external osmotic pressure.
Ultrafine carbon particles induce apoptosis and proliferation in rat lung epithelial cells via specific signaling pathways both using EGF-R
Authors: Sydlik Ulrich , Bierhals Katrin , Soufi Maria , Abel Josef , Schins Roel P. F. , Unfried Klaus
Published: June 2006

Apoptosis and proliferation are important causes of adverse health effects induced by inhaled ultrafine particles. The molecular mechanisms of particle cell interactions mediating these end points are therefore a major topic of current particle toxicology and molecular preventive medicine. Initial studies revealed that ultrafine particles induce apoptosis and proliferation in parallel in rat lung epithelial cells, dependent on time and dosage. With these end points, two antagonistic reactions seem to be induced by the same extracellular stimulus. It was therefore investigated whether proliferation is induced directly by the particles or as a compensation of particle-caused cell death. Experimental conditions excluding compensatory proliferation demonstrated that both end points are induced independently by specific signaling pathways. Events eliciting signaling cascades leading to apoptosis and proliferation were studied with specific inhibitors of membrane receptors. Epidermal growth factor receptor (EGF-R) kinase activity was identified as essential for apoptosis as well as for proliferation. As ultrafine particle-induced proliferation alone was dependent on the activation of β1-integrins, these membrane receptors are suggested to mediate the specificity of EGF-R signaling concerning the decision as to whether apoptosis or proliferation is triggered. Accordingly, MAP kinase signaling downstream of EGF-R showed comparable specificity with regard to receptor-dependent induction of apoptosis and proliferation. As key mediators of signaling cascades, the activation of extracellular signal-regulated kinases 1 and 2 proved to be specific for proliferation in a β1-integrin-dependent manner, whereas phosphorylation of c-Jun NH2-terminal kinases 1 and 2 was correlated with the induction of apoptosis.
Effects of corticosteroid-induced apoptosis on airway epithelial wound closure in vitro
Authors: Dorscheid Delbert R. , Patchell Benjamin J. , Estrada Oscar , Marroquin Bertha , Tse Roberta , White Steven R.
Published: June 2006

Damage to the airway epithelium is common in asthma. Corticosteroids induce apoptosis in and suppress proliferation of airway epithelial cells in culture. Whether apoptosis contributes to impaired epithelial cell repair after injury is not known. We examined whether corticosteroids would impair epithelial cell migration in an in vitro model of wound closure. Wounds (∼0.5–1.3 mm2) were created in cultured 1HAEo−human airway epithelial cell monolayers, after which cells were treated with up to 10 μM dexamethasone or budesonide for 24 h. Cultured cells were pretreated for 24 or 48 h with dexamethasone to observe the effect of long-term exposure on wound closure. After 12 h, the remaining wound area in monolayers pretreated for 48 h with 10 μM dexamethasone was 43 ± 18% vs. 10 ± 8% for untreated control monolayers. The addition of either corticosteroid immediately after injury did not slow closure significantly. After 12 h the remaining wound area in monolayers treated with 10 μM budesonide was 39 ± 4% vs. 43 ± 3% for untreated control monolayers. The proportion of apoptotic epithelial cells as measured by terminal deoxynucleotidyltransferase-mediated dUTP biotin nick end labeling both at and away from the wound edge was higher in monolayers treated with budesonide compared with controls. However, wound closure in the apoptosis-resistant 1HAEo−.Bcl-2+cell line was not different after dexamethasone treatment. We demonstrate that corticosteroid treatment before mechanical wounding impairs airway epithelial cell migration. The addition of corticosteroids after injury does not slow migration, despite their ability to induce apoptosis in these cells.
Shepherds at Umma in the Third Dynasty of Ur: Interlocutors with a World beyond the Scribal Field of Ordered Vision
Authors: Adams Robert
Published: June 2006

The Third Dynasty of Ur was a highly bureaucratized, late 3rd millennium B.C.E. empire centering in southern Mesopotamia. Its state superstructure, known almost exclusively from many tens of thousands of looted cuneiform tablets, has long been studied. However, these sources deal only indirectly or not at all with the impacts of imperial rule on the great mass of the subject population. Drawing upon an earlier prosopographic study of animal husbandry for the single province and city of Umma, this article focuses on shepherds, the lowest level of the administration, as a means of penetrating that wall of silence. As interlocutors, needing to face and be credible in both directions, they become the basis for a more inclusive view of the nature of the Ur III state. Largely indifferent to the condition of its subjects and to the complex realities of the economic tasks imposed on them by heavy taxes and arduous corvée labor, the administrative elite emerges as not only repressive, but more narrowly extractive rather than broadly managerial in its intent and operations. The overriding focus in pursuit of which it was highly successful (although for less than a century), appears to have been the flow of resources that would enhance its own hegemony and well-being. La Troisième Dynastie d'Ur était un empire hautement bureaucratisé de la seconde moitié du 3^e millénaire avant l'ère chrétien, centré sur la Mésopotamie du sud. Sa superstructure étatique, connue presque exclusivement grâce à des dizaines de milliers de tablettes cunéiformes pillés, a été longuement étudiée. Toutefois, ces sources ne portent pratiquement sur l'impact qu'avait l'autorité impériale sur la population assujettie. Puisant dans une étude prosopographique antérieure sur l'élevage dans la seule province et ville d'Umma, cet article concerne les bergers, personnages situés au niveau le plus bas de l'administration, dont l'étude doit permettre de percer ce mur de silence. En tant qu'interlocuteurs crédibles tournés à la fois vers le bas comme vers le haut, ils peuvent fournir les bases d'une image plus globale de l'état d'Ur III. Il ressort l'image d'une élite administrative plus ou moins indifférente aux conditions des sujets et aux réalités complexes des taches économiques qui leur sont imposés par des impôts importants et des corvées pénibles ; elle était non seulement répressive mais animée par des intentions et des opérations plus extractives que managerielles. L'essentiel du fonctionnement étatique, poursuivi avec beaucoup de succès (bien que pendant moins d'un siècle), semble avoir été d'assurer un flux de ressources à même d'augmenter sa propre hégémonie et bien-être.