bluuebunny/crossref_metadata_2025 huggingface dataset:
Histopathological risk factors for lymph node metastasis in submucosal invasive colorectal carcinoma of pedunculated or semipedunculated type
Authors: Sohn Dae Kyung , Chang Hee Jin , Park Ji Won , Choi Dong Hyun , Han Kyung Su , Hong Chang Won , Jung Kyung Hae , Kim Dae Yong , Lim Seok-Byung , Choi Hyo Seong , Jeong Seung-Yong
Published: September 2006

Aims:To evaluate the histopathological risk factors for lymph node metastasis in cases of pedunculated or semipedunculated submucosal invasive colorectal carcinoma (SICC).

Methods:A total of 48 patients with non-sessile SICC who underwent systematic lymph node dissection were included. Tumour size, histological grade, angiolymphatic invasion, tumour budding, dedifferentiation, objective submucosal invasion depth from the identified muscularis mucosa, relative invasion depth of the submucosal layer, and depth of stalk invasion were investigated histopathologically.

Results:Lymph node metastasis was observed in seven cases (14.6%). Univariate analysis showed angiolymphatic invasion and tumour budding to be significantly associated with lymph node metastasis. Multivariate analysis showed that tumour budding was the only independent factor associated with lymph node metastasis in cases of non-sessile SICC.

Conclusions:Results indicate that tumour budding is a useful risk factor for predicting lymph node metastasis in cases of pedunculated or semipedunculated SICC.
Finding the Kool Mixx: how Brown & Williamson used music marketing to sell cigarettes
Authors: Hafez Navid , Ling Pamela M
Published: September 2006

Objective:To describe the history of Kool’s music-themed promotions and analyse the role that music played in the promotion of the brand.

Methods:Analysis of previously secret tobacco industry documents, legal documents, and promotional materials.

Results:Brown & Williamson started Kool sponsorship of musical events in 1975 with Kool Jazz concerts. Music was considered to be an effective marketing tool because: (1) music helped consumers make emotional connections with the brand; (2) music concerts were effective for targeted marketing; (3) music tied together an integrated marketing campaign; and (4) music had potential to appeal widely to a young audience. Brown & Williamson’s first music campaigns successfully targeted young African-American male audiences. Subsequent campaigns were less effective, exploring different types of music to achieve a broader young adult appeal.

Conclusions:This case study suggests Brown & Williamson used music most successfully for targeted marketing, but they failed to develop a wider audience using music because their attempts lacked consistency with the Kool brand’s established identity. The 2004 “Kool Mixx” campaign both returned to Brown & Williamson’s historic practice targeting young African-American males, and also exploited a musical genre with much more potential to bring Kool more universal appeal, as hip-hop music is increasingly popular among diverse audiences. Tobacco control efforts led by African-American community activists to oppose these marketing strategies should continue; expanding these coalitions to include the hip-hop community may further increase their effectiveness.
US news media coverage of tobacco control issues
Authors: Long Marilee , Slater Michael D , Lysengen Lindsay
Published: September 2006

Objective:To characterise the relative amount and type of daily newspaper, local and national TV newscast, and national news magazine coverage of tobacco control issues in the United States in 2002 and 2003.

Design:Content analysis of daily newspapers, news magazines, and TV newscasts.

Subjects:Items about tobacco in daily newspapers, local and national TV newscasts, and three national news magazines in a nationally representative sample of 56 days of news stratified by day of week and season of the year, from 2002 and 2003.

Main outcome measures:Story theme, tobacco topics, sources, story prominence, story valence (orientation), and story type.

Results:Tobacco coverage was modest over the two-year period as estimated in our sample. Only 21 TV stories, 17 news magazine stories, and 335 daily newspaper stories were found during the two-year sampling period. Noteworthy results for the newspaper data set include the following: (1) government topics predominated coverage; (2) government action and negative health effects topics tended not to occur together in stories; (3) tobacco stories were fairly prominently placed in newspapers; (4) opinion news items tended to favour tobacco control policies, while news and feature stories were evenly split between positive and negative stories; and (5) tobacco coverage in the southeast, which is the country’s major tobacco producing region, did not differ from the rest of the country.

Conclusion:Results suggest mixed support in news coverage for tobacco control efforts in the United States. The modest amount of news coverage of tobacco is troubling, particularly because so few news stories were found on TV, which is a more important news source for Americans than newspapers. When tobacco was covered, government themed stories, which often did not include mentions of negative health effects, were typical, suggesting that media coverage does not reinforce the reason for tobacco control efforts. However, some results were encouraging. For example, when newspapers did cover tobacco, they accorded the stories relatively high prominence, thus increasing the chance that readers would see tobacco stories when they were published.
Tobacco point-of-purchase promotion: examining tobacco industry documents
Authors: Lavack Anne M , Toth Graham
Published: September 2006

In the face of increasing media restrictions around the world, point-of-purchase promotion (also called point-of-sale merchandising, and frequently abbreviated as POP or POS) is now one of the most important tools that tobacco companies have for promoting tobacco products. Using tobacco industry documents, this paper demonstrates that tobacco companies have used point-of-purchase promotion in response to real or anticipated advertising restrictions. Their goal was to secure dominance in the retail setting, and this was achieved through well-trained sales representatives who offered contracts for promotional incentive programmes to retailers, which included the use of point-of-sale displays and merchandising fixtures. Audit programmes played an important role in ensuring contract enforcement and compliance with a variety of tobacco company incentive programmes. Tobacco companies celebrated their merchandising successes, in recognition of the stiff competition that existed among tobacco companies for valuable retail display space.
Effects of preoperative smoking cessation on the incidence and risk of intraoperative and postoperative complications in adult smokers: a systematic review: Table 1
Authors: Theadom Alice , Cropley Mark
Published: September 2006

Objectives:To establish the effect of preoperative smoking cessation on the risk of postoperative complications, and to identify the effect of the timing of preoperative cessation.

Data sources:The Cochrane Library Database, PsycINFO, EMBASE, Medline, and CINAHL databases were searched, using the terms: “smoking”, “smoking-cessation”, “tobacco-use”, “tobacco-abstinence”, “cigarett$”, “complication$”, “postoperative-complication$”, “preoperative”, “perioperative” and “surg$”. Further articles were obtained from reference lists. The search was limited to articles on adults, written in English and published up to November 2005.

Study selection:Prospective cohort designs exploring the effects of preoperative smoking cessation on postoperative complications were included. Two reviewers independently scanned abstracts of relevant articles to determine eligibility. Lack of agreement was resolved through discussion and consensus. Twelve studies met the inclusion criteria.

Data extraction:Methodological quality was assessed by both reviewers, exploring validation of smoking status, clear definition of the period of smoking cessation, control for confounding variables and length of follow-up.

Data synthesis:Only four of the studies specified the exact period of smoking cessation, with six studies specifying the length of the follow-up period. Five studies revealed a lower risk or incidence of postoperative complications in past smokers than current smokers or reported that there was no significant difference between past smokers and non-smokers.

Conclusions:Longer periods of smoking cessation appear to be more effective in reducing the incidence/risk of postoperative complications; there was no increased risk in postoperative complications from short term cessation. An optimal period of preoperative smoking cessation could not be identified from the available evidence.
Adolescent snus use in Finland in 1981–2003: trend, total sales ban and acquisition
Authors: Huhtala Heini S A , Rainio Susanna U , Rimpelä Arja H
Published: September 2006

Objective:To study changes in adolescent snus use from 1981 to 2003, the effects of the total snus sales ban (1995) and snus acquisition.

Design:Biennial postal surveys in 1981–2003.

Setting and participants:Entire Finland; 12-, 14-, 16-, and 18-year-olds (n  =  73 946; 3105−8390 per year).

Main outcome measures:Snus use (experimental, daily/occasionally), snus acquisition (2001, 2003).

Results:Snus experimentation grew in popularity before the total sales ban in 16- and 18-year-old boys and after the ban in all age and sex groups. A decrease was seen between 2001 and 2003, except for 18-year-old boys. Daily/occasional use mainly followed the same pattern in boys while in girls the daily/occasional use was rare and no significant changes were observed. In 2003, boys experimented with snus more often than girls (12-year-olds 1%v0%, 14-year-olds 9%v4%, 16-year-olds 30%v12%, 18-year-olds 44%v18%). Hardly any girls used snus daily/occasionally, but 1% of 14-year-old boys, 7% of 16-year-olds, and 9% of 18-year-olds did. Of daily/occasional users, 84% acquired snus from friends or acquaintances, 55% from tourist trips to neighbouring countries (Estonia, Sweden), and 7% through sport teams; 24% obtained it from under-the-counter sources. For experimenters, the corresponding figures were 79%, 18%, 0.3%, and 5%.

Conclusions:The total sales ban did not stop snus use; instead, the increase continued after the ban. Friends who travel to neighbouring countries act as go-betweens reselling snus. Snus is used even by the youngest adolescents, thus contributing to the nicotine dependence process.
Smoking in immigrants: do socioeconomic gradients follow the pattern expected from the tobacco epidemic?
Authors: Nierkens Vera , de Vries Hein , Stronks Karien
Published: September 2006

Objectives:Although socioeconomic patterns of smoking across the different stages of the tobacco epidemic have been well researched, less is known about these patterns among immigrant populations. This paper aims to assess the smoking prevalence and its socioeconomic gradients among three immigrant populations.

Methods:Three cross-sectional studies, using structured face-to-face interviews, were conducted in three representative (for socioeconomic status) samples of 385 Turkish, 316 Moroccan, and 1072 Surinamese first-generation immigrants aged 35–60 years in Amsterdam, the Netherlands. Information gathered included information about smoking behaviour, educational level and background characteristics. The associations between educational level and smoking rates were assessed using logistic regression analyses stratified by age and sex, for each ethnic group separately.

Results:The prevalence of smoking differed per group, being highest among Turkish and Surinamese men (63% and 55%, respectively), followed by Moroccan men and Turkish and Surinamese women (30%, 32% and 27%, respectively). Higher smoking rates were found among women with higher educational levels, except for Surinamese women aged 35–44 years. However, among Turkish and Moroccan men aged 35–44 years and Surinamese men, smoking rates were higher in lower socioeconomic groups.

Conclusions:The prevalence figures and educational associations suggest that the socioeconomic gradient changes in earlier stages of the epidemic in immigrant populations than in the Western host populations, particularly in men. This provides indications to suggest that smoking prevention measures in male immigrant groups need to be tailored to lower socioeconomic groups in particular throughout the tobacco epidemic, and to higher socioeconomic groups among women.
Smokers and non-smokers talk about regulatory options in tobacco control
Authors: Carter Stacy M , Chapman Simon
Published: September 2006

Objective:Community members are occasionally polled about tobacco control policies, but are rarely given opportunities to elaborate on their views. We examined laypeople’s conversations to understand how 11 regulatory options were supported or opposed in interactions.

Design:Qualitative design; purposive quota sampling; data collection via focus groups.

Setting:Three locations in Sydney, Australia.

Participants:63 smokers and 75 non-smokers, men and women, from three age groups (18–24, 35–44, 55–64 years), recruited primarily via telephone.

Measurements:Semi-structured question route; data managed in NVivo; responses compared between groups.

Results:Laypeople rejected some regulatory proposals and certain arguments about taxation and the cost of cessation treatments. Protecting children and hypothecating tobacco excise for health education and care were highly acceptable. Plain packaging, banning retail displays and youth smoking prevention received qualified support. Bans on political donations from tobacco corporations were popular in principle but considered logistically fraught. Smokers asked for better cessation assistance and were curious about cigarette ingredients. Justice was an important evaluative principle. Support was often conditional and unresolved arguments frequent. We present both sides of these conflicts and the ways in which policies were legitimised or de-legitimised in conversation.

Conclusions:Simple measures of agreement used in polls may obscure the complexity of community responses to tobacco policy. Support was frequently present but contested; some arguments that seem self-evident to advocates were not so to participants. The detailed understanding of laypeople’s responses provided through qualitative methods may help frame proposals and arguments to meet concerns about justice, effectiveness and feasibility.
Observed smoking in cars: a method and differences by socioeconomic area: Table 1
Authors: Martin Josh , George Robert , Andrews Kirsty , Barr Peter , Bicknell Derryn , Insull Elizabeth , Knox Carl , Liu Jessie , Naqshband Mumraiz , Romeril Kate , Wong Donny , Thomson George , Wilson Nick
Published: September 2006

Objectives:To establish a reproducible method to estimate he point prevalence of smoking and second-hand smoke (SHS) exposure in cars, and to compare this prevalence between two areas of contrasting socioeconomic status.

Method:A method involving two teams of observers was developed and evaluated. It involved observing 16 055 cars in Wellington, New Zealand. Two of the observation sites represented a high and a low area of deprivation (based on a neighbourhood deprivation index) and three were in the central city.

Results:A 4.1% point prevalence of smoking in cars was observed (95% confidence interval (CI) 3.8% to 4.4%). There was a higher prevalence of smoking in cars in the high deprivation area relative to the other sites, and particularly compared to the low deprivation area (rate ratio relative to the latter 3.2, 95% CI 2.6 to 4.0). Of cars with smoking, 23.7% had other occupants being exposed to SHS. Cars with smoking and other occupants were significantly more likely to have a window open (especially if the smoker was not the driver). The observation method developed was practical, and inter-observer agreement was high (κ value for the “smoking seen in car” category 0.95).

Conclusions:Observational studies can be an effective way of investigating smoking in cars. The data from this survey suggest that smoking in cars occurs at a higher rate in relatively deprived populations and hence may contribute to health inequalities. Fortunately, there are a number of policy options for reducing SHS exposure in cars including mass media campaigns and laws for smoke-free cars.
Tobacco imagery on New Zealand television 2002–2004: Table 1
Authors: McGee Rob , Ketchel Juanita
Published: September 2006

Considerable emphasis has been placed on the importance of tobacco imagery in the movies as one of the “drivers” of smoking among young people. Findings are presented from a content analysis of 98 hours of prime-time programming on New Zealand television 2004, identifying 152 scenes with tobacco imagery, and selected characteristics of those scenes. About one in four programmes contained tobacco imagery, most of which might be regarded as “neutral or positive”. This amounted to about two scenes containing such imagery for every hour of programming. A comparison with our earlier content analysis of programming in 2002 indicated little change in the level of tobacco imagery. The effect of this imagery in contributing to young viewers taking up smoking, and sustaining the addiction among those already smoking, deserves more research attention.
The consequences of the unregulated cigarette
Authors: Gray Nigel
Published: September 2006

This article considers changes in cigarette design in relation to the concept of “dose”, drawing attention to the observation that there is not one smoking related epidemic of lung cancer, but at least two. Squamous carcinoma is declining in parallel with smoking prevalence while adenocarcinoma is increasing in the face of declining smoking prevalence. It is concluded that the adenocarcinoma epidemic is unnecessary and is due substantially to cigarette design changes, including increases in tobacco specific nitrosamines, manipulation of droplet size and ventilated filters. The need for regulation of smoke constituents is emphasised.
SUSTAINABILITY INTEGRATION AND ASSESSMENT
Authors: MORRISON-SAUNDERS ANGUS , THERIVEL RIKI
Published: September 2006

The broadening out of environmental assessment to also consider social and economic dimensions poses some unique challenges, not the least of which is understanding exactly what such a process might entail. This paper outlines the spectrum of possibilities and explores the issue of when and how environmental, social and economic considerations can be integrated in sustainability assessment. The integration issue is also relevant to the practice of strategic environmental assessments (SEA). A new way of conceptualising these types of assessment is put forward based on: (i) what is being assessed — the "question" that is being asked; and (ii) what approach is being used — the type of assessment selected from the spectrum of possibilities. The latter ranges from impact minimisation for each of the three sustainability pillars through to sustainability considered as an integrated concept. The combination of the question and assessment approach determines the level, extent and timing of integration of environmental, social and economic considerations that can be achieved. Additional thought needs to be given to who is performing the integration role as well as the nature of a particular proposal or its setting. This approach to thinking about SEA and sustainability assessment is illustrated with examples from Australia and the United Kingdom.
A PRINCIPLE-BASED APPROACH FOR THE EVALUATION OF SUSTAINABLE DEVELOPMENT
Authors: HERMANS FRANS , KNIPPENBERG LUUK
Published: September 2006

In order for sustainability assessments to realise their full potential, there is a need for criteria against which sustainable development might be evaluated. In this article, we employ a principle-based theoretical approach to develop a framework of sustainable development criteria. From an analysis of the different views of the concept of sustainable development, we arrive at two main principles that might guide assessments for sustainable development: resilience and justice. These two principles are explored using the John Rawls's justice theory, and the ideas of C.S. Holling in relation to resilience. We also consider the value to the framework of the concept of efficiency. Finally, the paper concludes with a proposal for the application of this framework within sustainability assessment processes based upon Participatory Integrated Assessment.
The effects of inspiratory intrathoracic pressure production on the cardiovascular response to submaximal exercise in health and chronic heart failure
Authors: Miller Jordan D. , Smith Curtis A. , Hemauer Sarah J. , Dempsey Jerome A.
Published: September 2006

We sought to determine whether the normal inspiratory intrathoracic pressures (PITP) produced during exercise contribute to the blunted cardiac output and locomotor limb blood flow responses observed in chronic heart failure (CHF). Five chronically instrumented dogs exercised on a treadmill at 2.5 mile/h at 5% grade while healthy or after the induction of tachycardia-induced CHF. We observed several key differences in the cardiovascular responses to changes in the inspiratory PITP excursion between health and CHF; namely, 1) removing ∼70% of the normally produced inspiratory PITP excursion during exercise (with 15 cmH2O inspiratory positive pressure ventilation) significantly reduced stroke volume (SV) in healthy animals by 5 ± 2% ( P < 0.05) but significantly increased SV and cardiac output (QTOT) in animals with CHF by 5 ± 1% ( P < 0.05); 2) doubling the magnitude of the inspiratory PITP excursion had no effect on SV or QTOT in healthy animals but significantly reduced steady-state QTOT and SV in animals with CHF by −4 ± 3% and −10 ± 3%, respectively; 3) removing the majority of the normally produced inspiratory PITP excursion had no effect on blood flow distribution in healthy animals but increased hindlimb blood flow (9 ± 3%, P < 0.05) out of proportion to the increases in QTOT; and 4) the only similarity between healthy and CHF animals was that increasing the inspiratory PITP excursion significantly reduced steady-state locomotor limb blood flow by 5 ± 2% and 6 ± 3%, respectively ( P < 0.05 for both). We conclude that 1) the normally produced inspiratory PITP excursions are required for a maximal SV response to submaximal exercise in healthy animals but detrimental to the SV and QTOT responses to submaximal exercise in CHF, 2) the respiratory muscle ergoreflex tonically restrains locomotor limb blood flow during submaximal exercise in CHF, and 3) excessive inspiratory muscle work further compromises cardiac function and blood flow distribution in both health and CHF.
Pharmacogenetics and anti-arrhythmic drug therapy: a theoretical investigation
Authors: Clancy Colleen E. , Zhu Zheng I. , Rudy Yoram
Published: September 2006

Pharmacological management of cardiac arrhythmias has been a long and widely sought goal. One of the difficulties in treating arrhythmia stems, in part, from incomplete understanding of the mechanisms of drug block and how intrinsic properties of channel gating affect drug access, binding affinity, and unblock. In the last decade, a plethora of genetic information has revealed that genetics may play a critical role in determining arrhythmia susceptibility and in efficacy of pharmacological therapy. In this context, we present a theoretical approach for investigating effects of drug-channel interaction. We use as an example open-channel or inactivated-channel block by the local anesthetics mexiletine and lidocaine, respectively, of normal and ΔKPQ mutant Na+ channels associated with the long-QT syndrome type 3. Results show how kinetic properties of channel gating, which are affected by mutations, are important determinants of drug efficacy. Investigations of Na+ channel blockade are conducted at multiple scales (single channel and macroscopic current) and, importantly, during the cardiac action potential (AP). Our findings suggest that channel mean open time is a primary determinant of open state blocker efficacy. Channels that remain in the open state longer, such as the ΔKPQ mutant channels in the abnormal burst mode, are blocked preferentially by low mexiletine concentrations. AP simulations confirm that a low dose of mexiletine can remove early afterdepolarizations and restore normal repolarization without affecting the AP upstroke. The simulations also suggest that inactivation state block by lidocaine is less effective in restoring normal repolarization and adversely suppresses peak Na+ current.
Therapeutic angiogenesis by ex vivo expanded erythroid progenitor cells
Authors: Sasaki Shuji , Inoguchi Toyoshi , Muta Koichiro , Abe Yasunobu , Zhang Min , Hiasa Kenichi , Egashira Kensuke , Sonoda Noriyuki , Kobayashi Kunihisa , Takayanagi Ryoichi , Nawata Hajime
Published: September 2006

Recent reports have demonstrated that erythroid progenitor cells contain and secrete various angiogenic cytokines. Here, the impact of erythroid colony-forming cell (ECFC) implantation on therapeutic angiogenesis was investigated in murine models of hindlimb ischemia. During the in vitro differentiation, vascular endothelial growth factor (VEGF) secretion by ECFCs was observed from day 3 (burst-forming unit erythroid cells) to day 10 (erythroblasts). ECFCs from day 5 to day 7 (colony-forming unit erythroid cells) showed the highest VEGF productivity, and day 6 ECFCs were used for the experiments. ECFCs contained larger amounts of VEGF and fibroblast growth factor-2 (FGF-2) than peripheral blood mononuclear cells (PBMNCs). In tubule formation assays with human umbilical vein endothelial cells, ECFCs stimulated 1.5-fold more capillary growth than PBMNCs, and this effect was suppressed by antibodies against VEGF and FGF-2. Using an immunodeficient hindlimb ischemia model and laser-Doppler imaging, we evaluated the limb salvage rate and blood perfusion after intramuscular implantation of ECFCs. ECFC implantation increased both the salvage rate (38% vs. 0%, P < 0.05) and the blood perfusion (82.8% vs. 65.6%, P < 0.01). In addition, ECFCs implantation also significantly increased capillaries with recruitment of vascular smooth muscle cells and the capillary density was 1.6-fold higher than in the control group. Continuous production of human VEGF from ECFCs in the skeletal muscle was confirmed at least 7 days after the implantation. Implantation of ECFCs promoted angiogenesis in ischemic limbs by supplying angiogenic cytokines (VEGF and FGF-2), suggesting a possible novel strategy for therapeutic angiogenesis.
Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells
Authors: Prunier Fabrice , Pfister Otmar , Hadri Lahouria , Liang Lifan , del Monte Federica , Liao Ronglih , Hajjar Roger J.
Published: September 2006

We examined the cardiac effects of chronic erythropoietin (EPO) therapy initiated 7 days after myocardial infarction (MI) in rats. A single high dose of EPO has been shown to reduce infarct size by preventing apoptosis when injected immediately after myocardial ischemia. The proangiogenic potential of EPO has also been reported, but the effects of chronic treatment with standard doses after MI are unknown. In this study, rats underwent coronary occlusion followed by reperfusion or a sham procedure. Infarcted rats were assigned to one of three treatment groups: 1) 0.75 μg/kg darbepoetin (MI+darb 0.75, n = 12); 2) 1.5 μg/kg darbepoetin (MI+darb 1.5, n = 12); 3) vehicle (MI+PBS, n = 16), once a week from day 7 postsurgery. Sham rats received the vehicle alone ( n = 10). After 8 wk of treatment, the animals underwent echocardiography, left ventricular pressure-volume measurements, and peripheral blood endothelial progenitor cell (EPC) counting. MI size and capillary density in the border zone and the area at risk (AAR) were measured postmortem. The AAR was similar in the three MI groups. Compared with MI+PBS, the MI+darb 1.5 group showed a reduction in the MI-to-AAR ratio (20.8% vs. 38.7%; P < 0.05), as well as significantly reduced left ventricle dilatation and improved cardiac function. This reduction in post-MI remodeling was accompanied by increased capillary density ( P < 0.05) and by a higher number of EPC ( P < 0.05). Both darbepoetin doses increased the hematocrit, whereas MI+darb 0.75 did not increase EPC numbers or capillary density and had no functional effect. We found that chronic EPO treatment reduces MI size and improves cardiac function only at a dose that induces EPC mobilization in blood and that increases capillary density in the infarct border zone.
Effects of pacemaker currents on creation and modulation of human ventricular pacemaker: theoretical study with application to biological pacemaker engineering
Authors: Kurata Yasutaka , Matsuda Hiroyuki , Hisatome Ichiro , Shibamoto Toshishige
Published: September 2006

A cardiac biological pacemaker (BP) has been created by suppression of the inward rectifier K+ current ( IK1) or overexpression of the hyperpolarization-activated current ( Ih). We theoretically investigated the effects of incorporating Ih, T-type Ca2+ current ( ICa,T), sustained inward current ( Ist), and/or low-voltage-activated L-type Ca2+ channel current ( ICa,LD) on 1) creation of BP cells, 2) robustness of BP activity to electrotonic loads of nonpacemaking (NP) cells, and 3) BP cell ability to drive NP cells. We used a single-cell model for human ventricular myocytes (HVMs) and also coupled-cell models composed of BP and NP cells. Bifurcation structures of the model cells were explored during changes in conductance of the currents and gap junction. Incorporating the pacemaker currents did not yield BP activity in HVM with normal IK1 but increased the critical IK1 conductance for BP activity to emerge. Expressing Ih appeared to be most helpful in facilitating creation of BP cells via IK1 suppression. In the coupled-cell model, Ist significantly enlarged the gap conductance ( GC) region where stable BP cell pacemaking and NP cell driving occur, reducing the number of BP cells required for robust pacemaking and driving. In contrast, Ih enlarged the GC region of pacemaking and driving only when IK1 of the NP cell was relatively low. ICa,T or ICa,LD exerted effects similar to those of Ist but caused shrinkage or irregularity of BP oscillations. These findings suggest that expressing Ist most effectively improves the structural stability of BPs to electrotonic loads and the BP ability to drive the ventricle.
H2O2 increases production of constrictor prostaglandins in smooth muscle leading to enhanced arteriolar tone in Type 2 diabetic mice
Authors: Erdei Nóra , Bagi Zsolt , Édes István , Kaley Gabor , Koller Akos
Published: September 2006

Our previous study showed that arteriolar tone is enhanced in Type 2 diabetes mellitus (T2-DM) due to an increased level of constrictor prostaglandins. We hypothesized that, in mice with T2-DM, hydrogen peroxide (H2O2) is involved in the increased synthesis of constrictor prostaglandins, hence enhanced basal tone in skeletal muscle arterioles. Isolated, pressurized gracilis muscle arterioles (∼100 μm in diameter) of mice with T2-DM (C57BL/KsJ- db−/ db−) exhibited greater basal tone to increases in intraluminal pressure (20–120 mmHg) than that of control vessels (at 80 mmHg, control: 25 ± 5%; db/ db: 34 ± 4%, P < 0.05), which was reduced back to control level by catalase ( db/ db: 24 ± 4%). Correspondingly, in carotid arteries of db/ db mice, the level of dichlorofluorescein-detectable and catalase-sensitive H2O2 was significantly greater. In control arterioles, exogenous H2O2 (0.1–100 μmol/l) elicited dilations (maximum, 58 ± 10%), whereas in arterioles of db/ db mice H2O2 caused constrictions (−28 ± 8%), which were converted to dilations (maximum, 16 ± 5%) by the thromboxane A2/prostaglandin H2 (TP) receptor antagonist SQ-29548. In addition, arteriolar constrictions in response to the TP receptor agonist U-46619 were not different between the two groups of vessels. Endothelium denudation did not significantly affect basal tone and H2O2-induced arteriolar responses in either control or db/ db mice. Also, in arterioles of db/ db mice, but not in controls, 3-nitrotyrosine staining was detected in the endothelial layer of vessels. Thus we propose that, in mice with T2-DM, arteriolar production of H2O2 is enhanced, which leads to increased synthesis of the constrictor prostaglandins thromboxane A2/prostaglandin H2 in the smooth muscle cells, which enhance basal arteriolar tone. These alterations may contribute to disturbed regulation of skeletal muscle blood flow in Type 2 diabetes mellitus.
Salt loading produces severe renal hemodynamic dysfunction independent of arterial pressure in spontaneously hypertensive rats
Authors: Matavelli Luis C. , Zhou Xiaoyan , Varagic Jasmina , Susic Dinko , Frohlich Edward D.
Published: September 2006

We have previously shown that salt excess has adverse cardiac effects in spontaneously hypertensive rats (SHR), independent of its increased arterial pressure; however, the renal effects have not been reported. In the present study we evaluated the role of three levels of salt loading in SHR on renal function, systemic and renal hemodynamics, and glomerular dynamics. At 8 wk of age, rats were given a 4% ( n = 11), 6% ( n = 9), or 8% ( n = 11) salt-load diet for the ensuing 8 wk; control rats ( n = 11) received standard chow (0.6% NaCl). Rats had weekly 24-h proteinuria and albuminuria quantified. At the end of salt loading, all rats had systemic and renal hemodynamics measured; glomerular dynamics were specially studied by renal micropuncture in the control, 4% and 6% salt-loaded rats. Proteinuria and albuminuria progressively increased by the second week of salt loading in the 6% and 8% salt-loaded rats. Mean arterial pressure increased minimally, and glomerular filtration rate decreased in all salt-loaded rats. The 6% and 8% salt-loaded rats demonstrated decreased renal plasma flow and increased renal vascular resistance and serum creatinine concentration. Furthermore, 4% and 6% salt-loaded rats had diminished single-nephron plasma flow and increased afferent and efferent arteriolar resistances; glomerular hydrostatic pressure also increased in the 6% salt-loaded rats. In conclusion, dietary salt loading as low as 4% dramatically deteriorated renal function, renal hemodynamics, and glomerular dynamics in SHR independent of a minimal further increase in arterial pressure. These findings support the concept of a strong independent causal relationship between salt excess and cardiovascular and renal injury.
Vascular endothelium-derived factors and arterial stiffness in strength- and endurance-trained men
Authors: Otsuki Takeshi , Maeda Seiji , Iemitsu Motoyuki , Saito Yoko , Tanimura Yuko , Ajisaka Ryuichi , Miyauchi Takashi
Published: September 2006

Arterial stiffness is higher in strength-trained humans and lower in endurance-trained humans. However, the mechanisms underlying these different adaptations are unclear. Vascular endothelium-derived factors, such as endothelin-1 (ET-1) and nitric oxide (NO), play an important role in the regulation of vascular tonus. We hypothesized that endogenous ET-1 and NO participate in the adaptation of arterial stiffness in different types of exercise training. The purpose of this study was to investigate plasma ET-1 and NO concentrations and arterial stiffness in strength- and endurance-trained men. Young strength-trained athletes (SA; n = 11), endurance-trained athletes (EA; n = 12), and sedentary control men (C; n = 12) participated in this study. Maximal handgrip strength in SA and maximal oxygen uptake in EA were markedly greater than in C. Aortic pulse-wave velocity, which is an established index of arterial stiffness, was higher in SA and lower in EA than in C. Additionally, we measured systemic arterial compliance (SAC) using carotid artery applanation tonometry and Doppler echocardiography, because arterial stiffness is a primary determinant of the compliance. SAC was lower in SA and higher in EA compared with that in C. Plasma ET-1 concentrations were higher in SA compared with C and EA. We did not find significant differences in plasma NO concentrations (measured as the stable end product of NO, i.e., nitrite/nitrate). The relationships of plasma ET-1 concentrations to aortic pulse-wave velocity and SAC were linear. These results suggest that differences in endogenous ET-1 may partly participate in the mechanism underlying different adaptations of arterial stiffness in strength- and endurance-trained men.
Smooth muscle cell-specific transcription is regulated by nuclear localization of the myocardin-related transcription factors
Authors: Hinson Jeremiah S. , Medlin Matthew D. , Lockman Kashelle , Taylor Joan M. , Mack Christopher P.
Published: September 2006

On the basis of our previous studies on RhoA signaling in smooth muscle cells (SMC), we hypothesized that RhoA-mediated nuclear translocalization of the myocardin-related transcription factors (MRTFs) was important for regulating SMC phenotype. MRTF-A protein and MRTF-B message were detected in aortic SMC and in many adult mouse organs that contain a large SMC component. Both MRTFs upregulated SMC-specific promoter activity as well as endogenous SM22α expression in multipotential 10T1/2 cells, although to a lesser extent than myocardin. We used enhanced green fluorescent protein (EGFP) fusion proteins to demonstrate that the myocardin factors have dramatically different localization patterns and that the stimulation of SMC-specific transcription by certain RhoA-dependent agonists was likely mediated by increased nuclear translocation of the MRTFs. Importantly, a dominant-negative form of MRTF-A (ΔB1/B2) that traps endogenous MRTFs in the cytoplasm inhibited the SM α-actin, SM22α, and SM myosin heavy chain promoters in SMC and attenuated the effects of sphingosine 1-phosphate and transforming growth factor (TGF)-β on SMC-specific transcription. Our data confirmed the importance of the NH2-terminal RPEL domains for regulating MRTF localization, but our analysis of MRTF-A/myocardin chimeras and myocardin RPEL2 mutations indicated that the myocardin B1/B2 region can override this signal. Gel shift assays demonstrated that myocardin factor activity correlated well with ternary complex formation at the SM α-actin CArGs and that MRTF-serum response factor interactions were partially dependent on CArG sequence. Taken together, our results indicate that the MRTFs regulate SMC-specific gene expression in at least some SMC subtypes and that regulation of MRTF nuclear localization may be important for the effects of selected agonists on SMC phenotype.
Differential responsiveness of RVLM sympathetic premotor neurons to hypoxia in rabbits
Authors: Koganezawa Tadachika , Terui Naohito
Published: September 2006

To determine whether differential sympathetic nerve responses to hypoxia are explained by opposing effects of hypoxia upon sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM), the cardiac sympathetic nerve and the renal sympathetic nerve were recorded in anesthetized and vagotomized rabbits. Renal sympathetic nerve was activated by the injection of sodium cyanide solution close to the bifurcation of the common carotid artery and/or by inhalation of hypoxic gas (3% oxygen-97% nitrogen). On the other hand, cardiac sympathetic nerve was inhibited by these stimuli. Barosensitive (inhibited by the stimulation of baroreceptor afferents) reticulospinal (antidromically activated by the stimulation of the spinal cord) neurons in the RVLM were divided into three groups according to their responses to hypoxic stimulation: neurons (Type I, n = 25), the activity of which was inhibited by the injection of sodium cyanide solution close to the bifurcation of the common carotid artery and/or by inhalation of hypoxic gas, neurons (Type II, n = 99), the activity of which was facilitated by the same stimulation, and neurons (Type III, n = 11), the activity of which was not changed. These data indicated that the differential responses of cardiac and renal sympathetic nerves might be due to opposing effects of hypoxia on individual RVLM neurons.
Role of endogenous TGF-β in glucocorticoid-induced lung type II cell differentiation
Authors: McDevitt Theresa M. , Gonzales Linda W. , Savani Rashmin C. , Ballard Philip L.
Published: September 2006

In the fetal lung, endogenous transforming growth factor (TGF)-β inhibits early morphogenesis and blocks hormone-induced type II cell differentiation. We hypothesized that endogenous TGF-β inhibits type II cell differentiation and that the stimulatory effects of glucocorticoids result in part from suppression of TGF-β. Epithelial cells were isolated from human fetal lung and cultured under defined conditions with and without dexamethasone plus cAMP to promote type II cell differentiation. Control cells produced TGF-β, which was activated in part by αVβ6-integrin. Treatment with dexamethasone, but not cAMP, reduced TGF-β1 and -β2 transcripts and TGF-β bioactivity in culture medium. To examine the effects of decreased TGF-β in the absence of glucocorticoid, cells were treated with antibodies to TGF-β and its receptors. By real-time RT-PCR, antibody blockade of TGF-β reduced serpine1, a TGF-β-inducible gene, and increased gene expression for sftpa, sftpb, sftpc, and titf1, mimicking the response to hormone treatment. By microarray analysis, 29 additional genes were induced by both TGF-β antibody and hormone treatment, and 20 other genes were repressed by both treatments. For some genes, the fold response was comparable for antibody and hormone treatment. We conclude that endogenous TGF-β suppresses expression of surfactant proteins and selected other type II cell genes in fetal lung, in part secondary to increased expression of titf1, and we propose that the mechanism of glucocorticoid-induced type II cell differentiation includes antagonism of TGF-β gene suppression. Surfactant production during fetal development is likely influenced by relative levels of TGF-β and glucocorticoids.
Dissociation of Crk-associated substrate from the vimentin network is regulated by p21-activated kinase on ACh activation of airway smooth muscle
Authors: Wang Ruping , Li Qing-Fen , Anfinogenova Yana , Tang Dale D.
Published: September 2006

The intermediate filament protein vimentin has been shown to be required for smooth muscle contraction. The adapter protein p130 Crk-associated substrate (CAS) participates in the signaling processes that regulate force development in smooth muscle. However, the interaction of vimentin filaments with CAS has not been well elucidated. In the present study, ACh stimulation of tracheal smooth muscle strips increased the ratio of soluble to insoluble vimentin (an index of vimentin disassembly) in association with force development. ACh activation also induced vimentin phosphorylation at Ser56as assessed by immunoblot analysis. More importantly, CAS was found in the cytoskeletal vimentin fraction, and the amount of CAS in cytoskeletal vimentin was reduced in smooth muscle strips on contractile stimulation. CAS redistributed from the myoplasm to the periphery during ACh activation of smooth muscle cells. The ACh-elicited decrease in CAS distribution in cytoskeletal vimentin was attenuated by the downregulation of p21-activated kinase (PAK) 1 with antisense oligodeoxynucleotides. Vimentin phosphorylation at this residue, the ratio of soluble to insoluble vimentin, and active force in smooth muscle strips induced by ACh were also reduced in PAK-depleted tissues. These results suggest that PAK may regulate CAS release from the vimentin intermediate filaments by mediating vimentin phosphorylation at Ser56and the transition of cytoskeletal vimentin to soluble vimentin. The PAK-mediated dissociation of CAS from the vimentin network may participate in the cellular processes that affect active force development during ACh activation of tracheal smooth muscle tissues.
Acinar origin of CFTR-dependent airway submucosal gland fluid secretion
Authors: Wu Jin V. , Krouse Mauri E. , Wine Jeffrey J.
Published: September 2006

Cystic fibrosis (CF) airway disease arises from defective innate defenses, especially defective mucus clearance of microorganisms. Airway submucosal glands secrete most airway mucus, and CF airway glands do not secrete in response to VIP or forskolin. CFTR, the protein that is defective in CF, is expressed in glands, but immunocytochemistry finds the highest expression of CFTR in either the ciliated ducts or in the acini, depending on the antibodies used. CFTR is absolutely required for forskolin-mediated gland secretion; we used this finding to localize the origin of forskolin-stimulated, CFTR-dependent gland fluid secretion. We tested the hypothesis that secretion to forskolin might originate from the gland duct rather than or in addition to the acini. We ligated gland ducts at various points, stimulated the glands with forskolin, and monitored the regions of the glands that swelled. The results supported an acinar rather than ductal origin of secretion. We tracked particles in the mucus using Nomarski time-lapse imaging; particles originated in the acini and traveled toward the duct orifice. Estimated bulk flow accelerated in the acini and mucus tubules, consistent with fluid secretion in those regions, but was constant in the unbranched duct, consistent with a lack of fluid secretion or absorption by the ductal epithelium. We conclude that CFTR-dependent gland fluid secretion originates in the serous acini. The failure to observe either secretion or absorption from the CFTR and epithelial Na+channel (ENaC)-rich ciliated ducts is unexplained, but may indicate that this epithelium alters the composition rather than the volume of gland mucus.
Type 2 immune response associated with silicosis is not instrumental in the development of the disease
Authors: Misson Pierre , Brombacher Frank , Delos Monique , Lison Dominique , Huaux Francois
Published: September 2006

It has been proposed that the development of lung fibrosis is associated with a T helper type 2 response, mainly characterized by IL-4 and IL-13 production. We investigated the potential role of type 2 immune polarization in the silicotic process and examined the pulmonary response to silica particles in mice genetically deficient for IL-4. We found that IL-4−/−mice were not protected against the development of silicosis, suggesting that IL-4 is not essential for the development of this fibrotic disease. By evaluating the intensity of silica-induced lung fibrosis in mice deficient for IL-4 receptor α (IL-4Rα), we showed that the establishment of pulmonary fibrosis was independent of both IL-4 and IL-13. Strong impairment of the type 2 immune response (IgG1) in the lungs of IL-4−/−and IL-4Rα−/−mice did not affect the development of the disease. Measurement of IL-13α2 receptor expression and IgG2a, IL-12p70, and IFN-γ levels in silica-treated IL-4−/−and IL-4Rα−/−animals showed that the development of silicosis was not related to an IL-13 signaling pathway or a switch to a type 1 response in deficient animals. Our data clearly indicate that the type 2 immune response associated with silicosis in mice is not required for the development of this inflammatory and fibrotic disease.