bluuebunny/crossref_metadata_2025 huggingface dataset:
Prophylactic effect of liposomal N-acetylcysteine against LPS-induced liver injuries
Authors: Alipour Misagh , Omri Abdelwahab , Smith Milton G. , Suntres Zacharias E.
Published: November 2007

The aim of this study was to evaluate and compare the effectiveness of N-acetylcysteine (NAC) and liposomally-encapsulated NAC (L-NAC) in ameliorating the hepatotoxic effects of lipopolysaccharide (LPS). LPS, a major cell wall molecule of Gram-negative bacteria and the principal initiator of septic shock, causes liver injury in vivo that is dependent on neutrophils, platelets, and several inflammatory mediators, including tumour necrosis factor-α (TNF-α). Male Sprague-Dawley rats were pretreated intravenously with saline, plain liposomes (dipalmitoylphosphatidylcholine [DPPC]), NAC (25 mg/kg body weight), or L-NAC (25 mg/kg NAC body weight) and 4 h later were challenged intravenously with LPS ( Escherichia coli O111:B4, 1.0 mg/kg body weight); animals were killed 20 h post-LPS challenge. Hepatic cell injury was evaluated by measuring the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in plasma. LPS-induced activation of the inflammatory response was evaluated by measuring the levels of myeloperoxidase activity and chloramine concentration in liver homogenates as well as TNF-α levels in plasma. The hepatic levels of lipid peroxidation products and non-protein thiols (NPSH) were used to assess the extent of involvement of oxidative stress mechanisms. In general, challenge of animals with LPS resulted in hepatic injuries, activation of the inflammatory response, decreases in NPSH levels and increases in the levels of lipid peroxidation products (malondialdehyde and 4-hydroxyalkenals). Pretreatment of animals with NAC or empty liposomes did not have any significant protective effect against LPS-induced hepatotoxicity. On the other hand, pretreatment of animals with an equivalent dose of L-NAC conferred protection against the liver injuries induced following LPS challenge. These data suggest that NAC when delivered as a liposomal formulation is a potentially more effective prophylactic pharmacological agent in alleviating LPS-induced liver injuries.
Review: From therapy to experimental model: a hundred years of endotoxin administration to human subjects
Authors: Bahador Marjan , Cross Alan S.
Published: November 2007

This article is a review of studies in which endotoxin has been administered to human subjects for experimental purposes. Data are presented in tabular form so the reader can better appreciate the objectives of individual studies. Although the original intention was to focus on the adverse events associated with these studies, unexpected serious adverse events rarely have been reported.
Spirituality, Culture and the Politics of Environmentalism in India
Authors: Misra Shalini
Published: November 2007

Three main themes run through this article. The first theme points out the distinct character of environmental activist movements India. Unlike environmental movements in the West, they are firmly tied to issues of social justice and equity, human rights and women's rights, and are for the survival of the large number of very poor who depend on the resources of their immediate environment. Religious symbolism is embedded in these activist movements. The second theme indicates the practice of utilitarian conservationism as opposed to protectionist conservationism by Hindus in their daily life. The role played by Hindu tradition in such cognitions and behaviours is explored. The third and final theme is the investigation of the causes of large–scale environmental degradation in India. It is argued that environmental pollution is largely a consequence of political, economic and administrative set–ups, population pressures, over–stretched infrastructure, corruption, individual and societal norms, and indifference towards the environment. The paper concludes with a perspective on the contribution of a Hindu environmental ethic to addressing sustainable development issues.
An Assessment of Validity in Entrepreneurship Research
Authors: Bouckenooghe Dave , Clercq Dirk De , Willem Annick , Buelens Marc
Published: November 2007

Based on an analysis of empirical articles published in the highest-rated academic journals between 1999 and 2003, we examined the current state of entrepreneurship research in terms of its validity. We collected 275 relevant publications in order to explore the entrepreneurship field with respect to internal validity, external validity, construct validity and statistical conclusion validity. Our aim was to gain insight into the dominant methodological and statistical practices that currently shape the field, shed light on possible gaps and compare these observations with the findings in general management literature. We found that entrepreneurship studies are mainly cross-sectional using surveys or field study as methods, emphasising external validity. Entrepreneurship research could benefit from more triangulation in research strategies, more advanced analytical techniques and methodologies, and from more longitudinal research resulting in higher validity levels. However, a positive trend towards more longitudinal research and triangulation in data sources is already visible.
The Exploration of Natural Gas and its Export Potential in Bangladesh
Authors: Rashid Mohammad Mamunur
Published: November 2007

There is a puzzling uncertainty about the real size of gas reserves in Bangladesh. Different institutions and companies provide widely differing estimates. No authority is able to verify the actual reserves. Nevertheless, most evidence shows that the country has vast natural gas reserves, exceeding the present domestic demand. This raises a question: should Bangladesh export some of its gas? Obviously, the export of natural gas will generate revenues for the country to balance its trade, and for investment in many other sectors. It will enable the government to implement social and cultural reforms and development programmes in primary education, poverty reduction, health and infrastructure. However, exporting natural gas in a developing country like Bangladesh is not an easy matter. The public is divided into two camps: those who are in favour and those who are against it. Following a brief history of Bangladeshi gas exploration, this article looks at its natural gas export potential and geology education associated with natural gas exploration. It discusses gas exploration by several national and international companies, and how they became a conduct for the transfer of technology and innovations. It also looks at the idea and plans for a pipeline to India to carry Bangladeshi gas. Finally, it concludes that there is an urgent for radical reforms in the Bangladeshi gas industry and institutions from exploration to marketing.
Sustainable Planning Education as Intercultural Service Learning
Authors: Zaferatos Nicholas C.
Published: November 2007

This article presents an overview of a community development service learning programme operating in the Greek Ionian Island community of Farsa Village. The philosophical approach of the Kefalonia Program is one of ‘threading the past with the future’. It seeks to combine traditional knowledge with contemporary technologies in order to create a sustainable future for a community that was completely destroyed by an earthquake in 1953. The village provides a case study for collaboration, research and community education for students, teachers, researchers, nonprofit organisations, island governments and, in particular, the local Farsan Village community. As a catalyst, the programme has engaged the local community in an active planning process, which both reawakens the dream of village restoration and provides a common vision for the future.
Food and Higher Education for Sustainable Development
Authors: Clugston Richard , Calder Wynn
Published: November 2007

This article argues that food issues are an appropriate, if not necessary, topic for education for sustainable development (ESD) both in terms of teaching and institutional practice. The first section summarises critical topics for a school or university course on food. The second section cites two examples of university efforts—at the University of California Santa Cruz and the University of New Hampshire—to create more humane and sustainable campus food systems.
Regional Centres of Expertise
Authors: Fadeeva Zinaida , Mochizuki Yoko
Published: November 2007

The concept of Regional Centres of Expertise (RCEs) on Education for Sustainable Development (ESD) has been enthusiastically embraced by a diverse array of actors since it was first introduced by the United Nations University (UNU) in 2004. An RCE is conceived of as a ‘network’ of existing organisations of formal, nonformal and informal education, mobilised to promote ESD at the local-regional level. Derived from experiences of mobilising RCEs around the globe, this article offers a range of strategic concepts to explain and facilitate the transformation of RCEs into value-adding localised networks constituting a global network—an emerging ‘Global Learning Space for Sustainable Development’.
Self-Report Measures of Child and Adolescent Psychopathy as Predictors of Offending in Four Samples of Justice-Involved Youth
Authors: Boccaccini Marcus T. , Epstein Monica , Poythress Norman , Douglas Kevin S. , Campbell Justin , Gardner Gail , Falkenbach Diana
Published: November 2007

The authors examined the relation between self-report psychopathy measures and o ficial records of o fending in four samples of justice-involved youth (total N = 447). Psychopathy measures included the Antisocial Process Screening Device (APSD) and a modified version of the Childhood Psychopathy Scale (mCPS). Measures of o fending included the total number of preadmission arrest charges for three samples (n = 392) and the total number of o fenses in the year following release for two samples (n = 138). Neither measure was a strong correlate of preadmission o fenses. Although mCPS scores were associated with postrelease o fending in one sample, e fects for the APSD were observed only when reo fending was conceptualized as a dichotomous variable, indicating a lack of robustness in this association. The findings suggest caution in the use of self-report measures of psychopathic features for decision making with respect to issues of delinquency risk among justice-involved youth.
Development and Validation of the HIV Medication Readiness Scale
Authors: Balfour Louise , Tasca Giorgio A. , Kowal John , Corace Kimberly , Cooper Curtis L. , Angel Jonathan B. , Garber Gary , MacPherson Paul A. , Cameron D. William
Published: November 2007

Excellent medication adherence (> 95%) is required for optimal HIV treatment success. This study aimed to develop and validate a brief scale to assess psychological readiness for successfully starting and adhering to HIV medications. HIV-positive men and women (N = 142) from an HIV outpatient clinic completed the proposed HIV Medication Readiness Scale (HMRS) prior to starting HIV medications. The 10-item HMRS demonstrated high internal consistency (alpha = .90), test-retest reliability (r = .83), and sensitivity to change following a standardized 4-session psychoeducational intervention designed to increase readiness for successful adherence. Predictive validity was supported by higher readiness scores on the day starting HIV medications, predicting higher treatment adherence at 1-month follow-up. The HMRS is a brief, easy-to-use, clinically relevant tool that can assist in identifying people living with HIV at high risk of nonadherence, who might benefit from tailored readiness counseling prior to initiating HIV medications.
The Performance of Two Pathological Gambling Screens in College Students
Authors: Weinstock Jeremiah , Whelan James P. , Meyers Andrew W. , McCausland Claudia
Published: November 2007

The psychometric properties of two pathological gambling (PG) screening instruments, the South Oaks Gambling Screen (SOGS) and the Massachusetts Gambling Screen—DSM-IV subscale (MAGS), were explored in a sample of college students (N = 159). Participants completed the two screening instruments, a diagnostic interview for PG, the Gambling—Timeline Followback (G-TLFB), Gambling Self-E ficacy Questionnaire (GSEQ), and the Hopkins Symptom Checklist (HSCL). Both screening measures were found to have adequate internal consistency and were highly correlated with each other and the diagnostic interview. The screening measures demonstrated convergent and discriminant validity. Using the diagnostic interview as the criterion measure, the SOGS demonstrated better sensitivity in identifying PG college students than the MAGS. The MAGS demonstrated better specificity in identifying non-PG college students than the SOGS. The results of this study suggest that although neither measure is perfect in identifying PG college students, the SOGS is a more appropriate measure for screening purposes.
Acknowledging the informal institutional setting of natural resource management
Authors: Lewins Roger
Published: November 2007

The analysis of natural resource management (NRM) institutions is drawn from two predominant theoretical schools – New Institutional Economics (NIE) and Common Property Resource (CPR) theory. There remains a need to transfer usable messages from the theory to those closely engaged with NRM in the development context. The paper brings together the recent theoretical reappraisal of the ‘institution’ in NRM with research findings from Bangladesh to argue the importance of re-emphasizing a simple distinction between formal and informal institutions. Acknowledging the importance of the informal institutional environment is crucial for improved management and evaluation of NRM initiatives.
When sex work isn't `work'
Authors: Collins Dana
Published: November 2007

This interview-based research explores the lived experiences of gay hosts who `work' in a gentrifying urban tourist district in the City of Manila, the Philippines. My analysis complicates research on sex work by highlighting the changing forms of sexual labor in a transnational and `gay' urban neighborhood, which is shaped by state initiatives on sustainable tourism and international gay travel. In place of treating hospitality as `work', I draw on the concept of emotional labor to understand hospitality as an expression of `gay' and local identities and as a celebration of desire and place. I propose that studies of sexual labor in urban spaces struggling with development must contend with expressions of desire rather than treating sexuality as a commodity exchanged in global tourism.
Anthropology and ecotourism in European wetlands
Authors: Russell Andrew
Published: November 2007

Recent literature, particularly in social anthropology, has focused on `bursting the bubble' of ecotourism, arguing that it has become a meaningless umbrella term for too many practices that are essentially `irresponsible' in their nature. This article proposes that, although scepticism is entirely appropriate, such arguments cannot be allowed to negate the value of ecotourism entirely. Based on research conducted in three European wetlands of marginal economic status in Greece, Lithuania and Romania, this article proposes a typology of models — of ecotourism, sustainable tourism, and responsible tourism — that helps to differentiate `practice' from `good practice'. The research highlights the importance of local people's discourse on ecotourism, which in this case was seen not only as an economic activity but as an aspirational moral virtue concerned with tidiness and maintaining the beauty of nature. Anthropology for ecotourism, which takes local people's views and opinions into account in the search for appropriate forms of tourism development that can transform people's lives and environments for the better, is as important as the anthropology of ecotourism.
Disciplined Bodies at Play: Improvisation in a Federal Prison
Authors: Kanter Jodi
Published: November 2007

The essay demonstrates the value of improvisatory theater work as a tool for empowering individuals and communities who have been subjected to powerful cultural and institutional discipline. Specifically, it describes, evokes, and analyzes a theater workshop led by advanced college theater students at the United States Medical Center for Federal Prisoners for inmates with borderline personality disorder. It explores the ways in which theatrical improvisation, in theory and in practice, supported and strengthened the inmates' treatment program, helping them to act against fear, isolation, and despair. It also tracks the effect of the collaboration on individuals in the college and prison communities, and the impact of the project on the relationship between these radically different social groups.
Mentoring and Love: An Open Letter
Authors: Calafell Bernadette Marie
Published: November 2007

This essay blends autobiographical performance, performative writing (Pollock, 1998), and theory, in letter form following in the tradition of Madison (1999) and Ono (1997), to argue for the examination of mentoring as a critical act that blends theory and practice. It offers mentoring as a site of embodied resistance and "homeplace" for faculty of color and the students of color they mentor that exists outside of the traditional confines of research, teaching, and service. This conception of the mentoring relationship is driven by a politics of love (see hooks, 2001; Oliver, 2001) that asks us to challenge our understandings of power and hierarchies in these relationships and academia in general.
The Face of a Terrorist
Authors: Engle Karen
Published: November 2007

This article takes up one of the questions posed by the U.S. government in the wake of September 11, 2001: What does a terrorist look like? Using Internet images of Osama bin Laden that have been circulating online ever since Bush named him as the prime perpetrator behind 9/11, the author explores the techniques and conventions of identifying an Other, with reference to historical practices within the United States. Significantly, all of the images presented here (and these images represent a small percentage of what can be found online) are hypersexualized and rely on tropes of primitivism and misogyny to signify degeneracy and effeminacy. The author's argument here consists of examining the ways in which racialist discourses combine with sexism and fascism in both the official and popular imaginings of the terrorist identity.
SARS News Coverage and Its Determinants in China and the US
Authors: Beaudoin Christopher E.
Published: November 2007

/ This study investigates the prevalence of news frames in SARS news coverage from the Xinhua News Agency and the Associated Press (AP), as well as whether the frames were predicted by news environment and the SARS timeline. Factor analysis supported four frame dimensions: attribution of responsibility, human interest, economic consequences and severity. Frame prevalence was considered in terms of, first, the story as the unit of analysis and, second, word count as the unit of analysis. For both types of measurement, attribution of responsibility and severity frames were more common in AP. For economic consequences, story frame prevalence was higher in AP, while word frame prevalence was higher in Xinhua. For both types of measurement, economic consequences decreased over time, while attribution of responsibility and severity increased. Attribution of responsibility and human interest frames increased more over time in AP, while the severity frame increased more over time in Xinhua.
Analyzing International Radio Stations
Authors: Clark Andrew M. , Werder Olaf
Published: November 2007

/ For many years, international radio broadcasting has been used by nations around the world as a foreign policy tool. As the world political system changed following the end of the Cold War, so the importance of international radio broadcasting to some nations has changed. Although there has been some scholarly work devoted to international radio broadcasting, such work has focused mainly on the station and has neglected the system in which the station operates. This article uses systems theory and organizational communication principles to develop a framework for analyzing how and why nations are using international radio broadcasting.
Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders
Authors: Hexner Elizabeth O. , Serdikoff Cynthia , Jan Mahfuza , Swider Cezary R. , Robinson Candy , Yang Shi , Angeles Thelma , Emerson Stephen G. , Carroll Martin , Ruggeri Bruce , Dobrzanski Pawel
Published: November 2007

Recent studies have demonstrated that patients with myeloproliferative disorders (MPDs) frequently have acquired activating mutations in the JAK2 tyrosine kinase. A multikinase screen determined that lestaurtinib (formerly known as CEP-701) inhibits wild type JAK2 kinase activity with a concentration that inhibits response by 50% (IC50) of 1 nM in vitro. We hypothesized that lestaurtinib would inhibit mutant JAK2 kinase activity and suppress the growth of cells from patients with MPDs. We found that lestaurtinib inhibits the growth of HEL92.1.7 cells, which are dependent on mutant JAK2 activity for growth in vitro and in xenograft models. Erythroid cells expanded from primary CD34+ cells from patients with MPDs were inhibited by lestaurtinib at concentrations of 100 nM or more in 15 of 18 subjects, with concomitant inhibition of phosphorylation of STAT5 and other downstream effectors of JAK2. By contrast, growth of erythroid cells derived from 3 healthy controls was not significantly inhibited. These results demonstrate that lestaurtinib, in clinically achievable concentrations, inhibits proliferation and JAK2/STAT5 signaling in cells from patients with MPDs, and therefore holds promise as a therapeutic agent for patients with these disorders.
Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders
Authors: Pietra Daniela , Li Sai , Brisci Angela , Passamonti Francesco , Rumi Elisa , Theocharides Alexandre , Ferrari Maurizio , Gisslinger Heinz , Kralovics Robert , Cremonesi Laura , Skoda Radek , Cazzola Mario
Published: November 2007

We searched for JAK2 exon 12 mutations in patients with JAK2 (V617F)-negative myeloproliferative disorders. Seventeen patients with polycythemia vera (PV), including 15 sporadic cases and 2 familial cases, carried deletions or duplications of exon 12 in circulating granulocytes but not in T lymphocytes. Two of the 8 mutations detected were novel, and the most frequent ones were N542-E543del and E543-D544del. Most patients with PV carrying an exon 12 mutation had isolated erythrocytosis at clinical onset, unlike patients with JAK2 (V617F)-positive PV, most of whom had also elevations in white blood cell and/or platelet counts. Both patients with familial PV carrying an exon 12 mutation had an affected sibling with JAK2 (V617F)-positive PV. Thus, several somatic mutations of JAK2 exon 12 can be found in a myeloproliferative disorder that is mainly characterized by erythrocytosis. Moreover, a genetic predisposition to acquisition of different JAK2 mutations is inherited in families with myeloproliferative disorders.
Subcellular localisation of Medicago truncatula9/13-hydroperoxide lyase reveals a new localisation pattern and activation mechanism for CYP74C enzymes
Authors: De Domenico Stefania , Tsesmetzis Nicolas , Di Sansebastiano Gian Pietro , Hughes Richard K , Casey Rod , Santino Angelo
Published: November 2007

Background

Hydroperoxide lyase (HPL) is a key enzyme in plant oxylipin metabolism that catalyses the cleavage of polyunsaturated fatty acid hydroperoxides produced by the action of lipoxygenase (LOX) to volatile aldehydes and oxo acids. The synthesis of these volatile aldehydes is rapidly induced in plant tissues upon mechanical wounding and insect or pathogen attack. Together with their direct defence role towards different pathogens, these compounds are believed to play an important role in signalling within and between plants, and in the molecular cross-talk between plants and other organisms surrounding them. We have recently described the targeting of a seed 9-HPL to microsomes and putative lipid bodies and were interested to compare the localisation patterns of both a 13-HPL and a 9/13-HPL from Medicago truncatula, which were known to be expressed in leaves and roots, respectively.

Results

To study the subcellular localisation of plant 9/13-HPLs, a set of YFP-tagged chimeric constructs were prepared using two M. truncatula HPL cDNAs and the localisation of the corresponding chimeras were verified by confocal microscopy in tobacco protoplasts and leaves. Results reported here indicated a distribution of M.truncatula 9/13-HPL (HPLF) between cytosol and lipid droplets (LD) whereas, as expected, M.truncatula 13-HPL (HPLE) was targeted to plastids. Notably, such endocellular localisation has not yet been reported previously for any 9/13-HPL. To verify a possible physiological significance of such association, purified recombinant HPLF was used in activation experiments with purified seed lipid bodies. Our results showed that lipid bodies can fully activate HPLF.

Conclusion

We provide evidence for the first CYP74C enzyme, to be targeted to cytosol and LD. We also showed by sedimentation and kinetic analyses that the association with LD or lipid bodies can result in the protein conformational changes required for full activation of the enzyme. This activation mechanism, which supports previous in vitro work with synthetic detergent micelle, fits well with a mechanism for regulating the rate of release of volatile aldehydes that is observed soon after wounding or tissue disruption.
What are the benefits of cognitive enhancers for Alzheimer's Disease: use of Population Impact Measures
Authors: Gammanpila Udaya P , Burns Alistair , Heller Richard F , Purandare Nitin
Published: November 2007

Background

The study aims to quantify the population impact of prescribing cholinesterase inhibitors to slow the cognitive decline in Alzheimer's disease (AD), and to compare with the benefit of treating hypertension to prevent the onset of AD.

Methods

Literature review to ascertain the prevalence of AD, benefits of interventions, analysis of local and national surveys to measure the current use of interventions in the relevant population and application of the relevant findings to calculate Population Impact Measures. The Number of Events Prevented in a Population (NEPP) by the intervention over a defined time period is calculated for a UK urban population in one Local Authority (population size 217,000).

Results

Treatment of all eligible patients with mild to moderate AD with Cholinesterase Inhibitors would prevent cognitive deterioration (measured by ADAS – cog scale) in 123.6 (95% Confidence Intervals (CI) 82.3, 169.1), 16.4 (95% CI 2.1, 31.2) would show a mild improvement (4 points or more on the ADAS – cog scale) and 2.6 (95% CI 0.2, 5.8) would show an improvement of 7 points or more over a period of 6 months. This would require the treatment of 406 patients with Cholinesterase Inhibitors.

Increasing from the current treatment rate of 46% of eligible patients to 'best practice' level would prevent cognitive deterioration in 66.8 (95% CI 44.0, 92.6), 8.99 (95% CI 1.2, 16.8) and 1.4 (95% CI 0.11, 3.2) would improve by 4 and 7 points respectively on the ADAS – cog scale over 6 months. This would require the treatment of an extra 187 patients with Cholinesterase Inhibitors beyond current practice, at an additional annual direct drug cost of £187,000.

Improving the treatment of hypertension from current practice by 20% could prevent 8.2 (95% CI 2.3, 16.8) incident cases of AD in the next year. This would require the treatment of an extra 2711 patients with antihypertensive drugs.

Conclusion

Population Impact Measures are a new method to allow a demonstration of the magnitude of the benefit for the whole population following interventions. The use of drugs to slow cognitive decline, or to prevent AD by treating hypertension, can thus be assessed in a prioritisation exercise in competition with alternative use of resources.
Sentinel surveillance for travellers' diarrhoea in primary care
Authors: Northey Gemma , Evans Meirion R , Sarvotham Tinnu S , Thomas Daniel R , Howard Tony J
Published: November 2007

Background

Travellers' diarrhoea is the most common health problem among international travellers and much of the burden falls on general practitioners. We assessed whether sentinel surveillance based in primary care could be used to monitor changes in the epidemiology of travellers' diarrhoea.

Methods

A sentinel surveillance scheme of 30 volunteer general practices distributed throughout Wales provides weekly reports of consultations for eight infectious diseases to the national Communicable Disease Surveillance Centre. Travellers' diarrhoea was introduced as a new reportable infection in July 2002.

Results

Between 1 July 2002 and 31 March 2005 there were 90 reports of travellers' diarrhoea. The mean annual consultation rate was 15.2 per 100,000 population (95% confidence interval: 12.2–18.7), with the highest rates in summer, in people aged 15–24 years, and in travellers to Southern Europe. A higher proportion of travellers than expected had visited destinations outside Europe and North America when compared to the proportion of all United Kingdom travellers visiting these destinations (38% vs. 11%; Chi2 = 53.3, p < 0.0001).

Conclusion

Sentinel surveillance has the potential to monitor secular trends in travellers' diarrhoea and to help characterise population groups or travel destinations associated with higher risk.
S100A7 (Psoriasin), highly expressed in Ductal Carcinoma In Situ(DCIS), is regulated by IFN-gamma in mammary epithelial cells
Authors: Petersson Stina , Bylander Anna , Yhr Maria , Enerbäck Charlotta
Published: November 2007

Background

The aim of the present work was to explore signal transduction pathways used in the regulation of S100A7 (psoriasin). Members of the S100 gene family participate in many important cellular functions. Psoriasin, S100A8 (calgranulin A) and S100A9 (calgranulin B) are expressed in ductal carcinoma in situ (DCIS), as well as in the hyperproliferative skin disease, psoriasis. In the latter condition, a disturbance in the STAT pathway has recently been reported. This pathway is implicated in the regulation of IFN-gamma, widely recognized as a key cytokine in psoriasis. IFN-gamma also exerts anti-tumor action in a number of tumor cell types, including breast cancer. We therefore examined the effect of IFN-gamma and STAT-signaling on the psoriasin expression.

Methods

We established a TAC2 mouse mammary epithelial cell line with tetracycline-inducible psoriasin expression (Tet-Off). Viability in cell culture was estimated using MTS assay. Protein and gene expression were evaluated by Western blotting and quantitative real-time PCR. Statistical analyses were assessed using a one-tailed, paired t-test.

Results

We report the downregulation of psoriasin by IFN-gamma in the MDA-MB-468 breast cancer cell line, as well as the downregulation of psoriasin induced by anoikis in cell lines derived from different epithelial tissues. In contrast, IFN-gamma had no suppressive effect on calgranulin A or calgranulin B. IFN-gamma is an important activator of the STAT1 pathway and we confirmed an active signaling pathway in the cell lines that responded to IFN-gamma treatment. In contrast, in the SUM190 breast carcinoma cell line, IFN-gamma did not suppress the expression of endogenous psoriasin. Moreover, a reduced phosphorylation of the STAT1 protein was observed. We showed that IFN-gamma treatment and the inhibition of the transcription factor NFkappaB had a synergistic effect on psoriasin levels. Finally, in TAC2 cells with tetracycline-induced psoriasin expression, we observed the increased viability of psoriasin-expressing cells after IFN-gamma treatment.

Conclusion

Our data support the possibility that psoriasin expression is transcriptionally suppressed by IFN-gamma and that this effect is likely to be mediated by the activation of the STAT1 signaling pathway. The increased viability of psoriasin-expressing cells after IFN-gamma exposure suggests that psoriasin expression leads to the development of an apoptosis-resistant phenotype.
Methodological considerations for a randomised controlled trial of podiatry care in rheumatoid arthritis: lessons from an exploratory trial
Authors: Turner Deborah E , Helliwell Philip S , Woodburn James
Published: November 2007

Background

Whilst evidence exists to support the use of single treatments such as orthoses and footwear, the effectiveness of podiatry-led care as a complex intervention for patients with rheumatoid arthritis (RA) related foot problems is unknown. The aim of this study was to undertake an exploratory randomised controlled parallel arm clinical trial (RheumAFooT) to inform the design and implementation of a definitive trial and to understand the potential benefits of this care.

Methods

Patients with a definite diagnosis of RA, stable drug management 3 months prior to entry, and a current history of foot problems (pain, deformity, stiffness, skin or nail lesions, or footwear problems) were recruited from a hospital outpatient rheumatology clinic and randomised to receive 12 months of podiatry treatment or no care. The primary outcome was change in foot health status using the impairment/footwear (LFISIF) and activity limitation/participation restriction (LFISAP) subscales of the Leeds Foot Impact Scale. Disease Activity Score (DAS), Health Assessment Questionnaire (HAQ) score and walking speed (m/s) were also recorded.

Results

Of the 80 patients identified, 64 patients were eligible to participate in the pilot and 34 were recruited. 16 patients were randomised to receive podiatry led foot care and 18 received no care. Against a backdrop of stable disease (DAS and HAQ scores), there was a statistically significant between group difference in the change in foot health status for foot impairment (LFISIF) but not activity/participation (LFISAP) or function (walking speed) over 12 months. In the podiatry arm, 1 patient declined treatment following randomisation (did not want additional hospital visits) and 3 self-withdrew (lost to follow-up). Patients received an average of 3 consultations for assessment and treatment comprising routine care for skin and nail lesions (n = 3), foot orthoses (n = 9), footwear referral to the orthotist (n = 5), and ultrasound guided intra-articular steroid injection (n = 1).

Conclusion

In this exploratory trial patients were difficult to recruit (stable drug management and co-morbid disease) and retain (lack of benefit/additional treatment burden) but overall the intervention was safe (no adverse reactions). Twelve months of podiatry care maintained but did not improve foot health status. These observations are important for the design and implementation of a definitive randomised controlled trial.

Trial Registration

ISRCTN: 01982076
Adeno-associated viral vectors engineered for macrolide-adjustable transgene expression In mammalian cells and mice
Authors: Fluri David A , Baba Marie Daoud-El , Fussenegger Martin
Published: November 2007

Background

Adjustable gene expression is crucial in a number of applications such as de- or transdifferentiation of cell phenotypes, tissue engineering, various production processes as well as gene-therapy initiatives. Viral vectors, based on the Adeno-Associated Virus (AAV) type 2, have emerged as one of the most promising types of vectors for therapeutic applications due to excellent transduction efficiencies of a broad variety of dividing and mitotically inert cell types and due to their unique safety features.

Results

We designed recombinant adeno-associated virus (rAAV) vectors for the regulated expression of transgenes in different configurations. We integrated the macrolide-responsive E.REX systems (EON and EOFF) into rAAV backbones and investigated the delivery and expression of intracellular as well as secreted transgenes for binary set-ups and for self- and auto-regulated one-vector configurations. Extensive quantitative analysis of an array of vectors revealed a high level of adjustability as well as tight transgene regulation with low levels of leaky expression, both crucial for therapeutical applications. We tested the performance of the different vectors in selected biotechnologically and therapeutically relevant cell types (CHO-K1, HT-1080, NHDF, MCF-7). Moreover, we investigated key characteristics of the systems, such as reversibility and adjustability to the regulating agent, to determine promising candidates for in vivo studies. To validate the functionality of delivery and regulation we performed in vivo studies by injecting particles, coding for compact self-regulated expression units, into mice and adjusting transgene expression.

Conclusion

Capitalizing on established safety features and a track record of high transduction efficiencies of mammalian cells, adeno- associated virus type 2 were successfully engineered to provide new powerful tools for macrolide-adjustable transgene expression in mammalian cells as well as in mice.
Effectiveness and costs of implementation strategies to reduce acid suppressive drug prescriptions: a systematic review
Authors: Smeets Hugo M , Hoes Arno W , de Wit Niek J
Published: November 2007

Background

Evaluation of evidence for the effectiveness of implementation strategies aimed at reducing prescriptions for the use of acid suppressive drugs (ASD).

Methods

A systematic review of intervention studies with a design according to research quality criteria and outcomes related to the effect of reduction of ASD medication retrieved from Medline, Embase and the Cochrane Library. Outcome measures were the strategy of intervention, quality of methodology and results of treatment to differences of ASD prescriptions and costs.

Results

The intervention varied from a single passive method to multiple active interactions with GPs. Reports of study quality had shortcomings on subjects of data-analysis. Not all outcomes were calculated but if so rction of prescriptions varied from 8% up to 40% and the cost effectiveness was in some cases negative and in others positive. Few studies demonstrated good effects from the interventions to reduce ASD.

Conclusion

Poor quality of some studies is limiting the evidence for effective interventions. Also it is difficult to compare cost-effectiveness between studies. However, RCT studies demonstrate that active interventions are required to reduce ASD volume. Larger multi-intervention studies are necessary to evaluate the most successful intervention instruments.
Older adults' perspectives on key domains of childhood social and economic experiences and opportunities: a first step to creating a multidimensional measure
Authors: Yen Irene H , Stewart Anita L , Scherzer Teresa , Pérez-Stable Eliseo J
Published: November 2007

Objectives

Although research has found that childhood socioeconomic status (SES) is associated with physical and mental health in mid- and later life, most of these studies used conventional, single dimension SES measures for the childhood period such as household income or educational attainment of parents. Life course and health disparities research would benefit from identification and measurement of a variety of childhood social and economic experiences and opportunities that might affect health in later life.

Design

This study utilized qualitative research methods to identify key dimensions of childhood experiences related to SES. We conducted in-depth interviews with 25 adults age 55 to 80 years from diverse economic and ethnic backgrounds. Topics included home, neighborhood, school, and work experiences during early childhood and adolescence. Interviews were audio-taped and transcripts were coded to identify thematic domains.

Results

We identified eight thematic domains, many of which had clear subdomains: home and family circumstances, neighborhood, work and money, potential for advancement through schooling, school quality and content, discrimination, influence and support of adults, and leisure activities. These domains highlight individual characteristics and experiences and also economic and educational opportunities.

Conclusion

These domains of childhood social and economic circumstances add breadth and depth to conventional conceptualization of childhood SES. When the domains are translated into a measurement tool, it will allow for the possibility of classifying people along multiple dimensions, such as from a low economic circumstance with high levels of adult support.
Calibrating E-values for MS2 database search methods
Authors: Alves Gelio , Ogurtsov Aleksey Y , Wu Wells W , Wang Guanghui , Shen Rong-Fong , Yu Yi-Kuo
Published: November 2007

Background

The key to mass-spectrometry-based proteomics is peptide identification, which relies on software analysis of tandem mass spectra. Although each search engine has its strength, combining the strengths of various search engines is not yet realizable largely due to the lack of a unified statistical framework that is applicable to any method.

Results

We have developed a universal scheme for statistical calibration of peptide identifications. The protocol can be used for both de novo approaches as well as database search methods. We demonstrate the protocol using only the database search methods. Among seven methods -SEQUEST (v27 rev12), ProbID (v1.0), InsPecT (v20060505), Mascot (v2.1), X!Tandem (v1.0), OMSSA (v2.0) and RAId_DbS – calibrated, except for X!Tandem and RAId_DbS most methods require a rescaling according to the database size searched. We demonstrate that our calibration protocol indeed produces unified statistics both in terms of average number of false positives and in terms of the probability for a peptide hit to be a true positive. Although both the protocols for calibration and the statistics thus calibrated are universal, the calibration formulas obtained from one laboratory with data collected using either centroid or profile format may not be directly usable by the other laboratories. Thus each laboratory is encouraged to calibrate the search methods it intends to use. We also address the importance of using spectrum-specific statistics and possible improvement on the current calibration protocol. The spectra used for statistical (E-value) calibration are freely available upon request.

Open peer review

Reviewed by Dongxiao Zhu (nominated by Arcady Mushegian), Alexey Nesvizhskii (nominated by King Jordan) and Vineet Bafna. For the full reviews, please go to the Reviewers' comments section.
A procephalic territory in Drosophila exhibiting similarities and dissimilarities compared to the vertebrate midbrain/hindbrain boundary region
Authors: Urbach Rolf
Published: November 2007

Background

In vertebrates, the primordium of the brain is subdivided by the expression of Otx genes (forebrain/anterior midbrain), Hox genes (posterior hindbrain), and the genes Pax2, Pax5 and Pax8 (intervening region). The latter includes the midbrain/hindbrain boundary (MHB), which acts as a key organizer during brain patterning. Recent studies in Drosophila revealed that orthologous sets of genes are expressed in a similar tripartite pattern in the late embryonic brain, which suggested correspondence between the Drosophila deutocerebral/tritocerebral boundary region and the vertebrate MHB. To gain more insight into the evolution of brain regions, and particularly the MHB, I examined the expression of a comprehensive array of MHB-specific gene orthologs in the procephalic neuroectoderm and in individually identified neuroblasts during early embryonic stages 8-11, at which the segmental organization of the brain is most clearly displayed.

Results and conclusion

I show that the early embryonic brain exhibits an anterior Otx/otd domain and a posterior Hox1/lab domain, but that Pax2/5/8 orthologs are not expressed in the neuroectoderm and neuroblasts of the intervening territory. Furthermore, the expression domains of Otx/otd and Gbx/unpg exhibit a small common interface within the anterior deutocerebrum. In contrast to vertebrates, Fgf8-related genes are not expressed posterior to the otd/unpg interface. However, at the otd/unpg interface the early expression of other MHB-specific genes (including btd, wg, en), and of dorsoventral patterning genes, closely resembles the situation at the vertebrate MHB. Altogether, these results suggest the existence of an ancestral territory within the primordium of the deutocerebrum and adjacent protocerebrum, which might be the evolutionary equivalent of the region of the vertebrate MHB. However, lack of expression of Pax2/5/8 and Fgf8-related genes, and significant differences in the expression onset of other key regulators at the otd/unpg interface, imply that genetic interactions crucial for the vertebrate organizer activity are absent in the early embryonic brain of Drosophila.
Left-right olfactory asymmetry results from antagonistic functions of voltage-activated calcium channels and the Raw repeat protein OLRN-1 in C. elegans
Authors: Bauer Huang Sarah L , Saheki Yasunori , VanHoven Miri K , Torayama Ichiro , Ishihara Takeshi , Katsura Isao , van der Linden Alexander , Sengupta Piali , Bargmann Cornelia I
Published: November 2007

Background

The left and right AWC olfactory neurons in Caenorhabditis elegans differ in their functions and in their expression of chemosensory receptor genes; in each animal, one AWC randomly takes on one identity, designated AWCOFF, and the contralateral AWC becomes AWCON. Signaling between AWC neurons induces left-right asymmetry through a gap junction network and a claudin-related protein, which inhibit a calcium-regulated MAP kinase pathway in the neuron that becomes AWCON.

Results

We show here that the asymmetry gene olrn-1 acts downstream of the gap junction and claudin genes to inhibit the calcium-MAP kinase pathway in AWCON. OLRN-1, a protein with potential membrane-association domains, is related to the Drosophila Raw protein, a negative regulator of JNK mitogen-activated protein (MAP) kinase signaling. olrn-1 opposes the action of two voltage-activated calcium channel homologs, unc-2 (CaV2) and egl-19 (CaV1), which act together to stimulate the calcium/calmodulin-dependent kinase CaMKII and the MAP kinase pathway. Calcium channel activity is essential in AWCOFF, and the two AWC neurons coordinate left-right asymmetry using signals from the calcium channels and signals from olrn-1.

Conclusion

olrn-1 and voltage-activated calcium channels are mediators and targets of AWC signaling that act at the transition between a multicellular signaling network and cell-autonomous execution of the decision. We suggest that the asymmetry decision in AWC results from the intercellular coupling of voltage-regulated channels, whose cross-regulation generates distinct calcium signals in the left and right AWC neurons. The interpretation of these signals by the kinase cascade initiates the sustained difference between the two cells.