bluuebunny/crossref_metadata_2025 huggingface dataset:
Envisaging a new politics for an ethical future
Authors: Beasley Chris , Bacchi Carol
Published: November 2007

In times like these, a new ethico-political ideal is required to contest the adequacy of dominant understandings of social interaction as matters of choice and rational decision-making and in contesting these understandings encourage us to imagine social alternatives. We wish to make a contribution to this project of expanding the universe of political discourse as a means to invigorating ethico-political debate. A range of existing vocabularies — the languages of trust (and relatedly respect), care and associated concepts, including corporeal generosity — are currently put forward as the means to contest the dominance of neo-liberal premises about `atomistic individualism'. While many of these accounts focus on nation-states, others attend to an emerging global community. Nevertheless, we have some reservations about these languages and their premises. In our view they tend frequently to locate the `problem' in the character of citizens. We also make the case that such languages and their associated political agendas reinstate aspects of social hierarchy that mimic neo-liberal conceptions of autonomous individualism. Central to our critique is the claim that the problematic aspects of these existing languages of (inter)connection are due to an attenuated understanding of embodiment and an inadequate dialogue between the socio-political and embodiment. It is this inadequate dialogue we wish to redress. In this paper we offer a new ethical ideal called `social flesh' to ground an alternative politics for reconfiguring exploitative social relations. As an ethico-political starting point, `social flesh' highlights human embodied interdependence and in the process configures a new, more transformative political vision. It draws attention to shared embodied reliance, mutual reliance, of people across the globe on social space, infrastructure and resources. Insistence upon this shared reliance underpins a profoundly levelling perspective, a radical politics.
Feminist prison activism
Authors: Cee Whitehead Jaye
Published: November 2007

In the following ethnography of the California Coalition of Women Prisoners (CCWP), who exist at the forefront of feminist prison activism, I address canonical feminist debates focused on the relationship between subjectivity, experience, knowledge, and power by closely following an explicit attempt at political reform by and for women. I argue that feminist prison activists' attempts to reform the American prison system reveal why feminist theorists must remain committed to a specific, contextual, and localized analysis of the prospects for political empowerment.
Free Trade and Social Citizenship
Authors: Abrahamson Peter
Published: November 2007

The article takes as its starting point the proliferation of regional free trade agreements, and the question is posed: whether increased economic integration in Central America may `spill over' in enhanced social citizenship rights? The question is triggered by the signing in 2004 of the Central American Free Trade Agreement (CAFTA-DR). The article explores the arguments concerning the development of CAFTA-DR and social citizenship, exemplified by labour rights. The article situates the making of CAFTA-DR in the context of historical attempts to promote regionalism. It reviews the arguments for and against free trade agreements in the USA and Central America and argues that there are tangible effects on social citizenship in particular relating to labour rights that can be credited to the signing of the agreement. The article concludes that CAFTA-DR has generated new possibilities for social citizenship in the region.
Culture Stories:Understanding Cultural urban Branding
Authors: Jensen Ole B.
Published: November 2007

This article argues for a narrative approach to the study of urban branding and planning and presents an analytical framework for understanding narratives and place. The notion of the `representational logics of urban intervention' captures this idea that urban branding interventions are guided by certain representations and embedded in certain norms and values. The analytical framework is applied to a case study of cultural urban branding, the harbour front in Aalborg, Denmark, where a number of flagship architecture projects and cultural institutions are planned. It illustrates the competing stories told by proponents and opponents of the interventions, and also shows how the relation to place in the stories differs radically according to their allegiances. The article aims to throwing light on the complex relationship between story and place.
Collaborative Planning in an Uncollaborative World
Authors: Brand Ralf , Gaffikin Frank
Published: November 2007

The purpose of this article is to expose the concept of collaborative planning to the reality of planning, thereby assessing its efficacy for informing and explaining what planners `really' do and can do. In this systematic appraisal, we begin by disaggregating collaborative planning into four elements that can enlighten such conceptual frameworks: ontology, epistemology, ideology and methodology. These four lenses help delimit and clarify the object of our examination and provide transparent criteria that guide our examination of collaborative planning's strengths and weaknesses. The second part of this article comprises an empirical investigation of planning processes in Northern Ireland, ranging from region-wide to local and from statutory to visionary. Planning efforts in this province make suitable test cases because special care has been invested in participatory deliberation processes to compensate for the democratic deficits in its mainstream political system. Such efforts have sought to ensure a maximally inclusive planning process. And indeed, the consultation process leading to the Regional Development Strategy, for example, has earned plaudits from leading exponents of collaborative planning. The final analysis provides a systematic gauge of collaborative planning in light of our empirical evidence, deploying the four conceptual dimensions introduced in the first part. This exposes a range of problems not only with the concept itself but also regarding its affinity with the uncollaborative world within which it has to operate. The former shed light on those aspects where collaborative planning as a conceptual tool for practitioners needs to be renovated, while the latter highlight inconsistencies in a political framework that struggles to accommodate both global competitiveness and local democratic collaboration.
Caught between cultures
Authors: Ezra Rosalyn
Published: November 2007

This article investigates the factors Israeli parents gave as paramount reasons for enrolling their children in a private international school in Israel. A survey and personal interviews were administered to parents designated as host country nationals by school admissions records. Findings revealed that while an English-language education was looked upon as an added benefit for their children's future success in a global context, it was not a main concern. Parents viewed the discord between their own cultural values and those taught at local schools as a significant factor pushing them away from public-sector education, as well as a curriculum perceived as weak, inadequate teacher preparation, poor administrative responses to violence, insufficient classroom discipline and an unwillingness of teachers in public schools to attend to students' individual needs.
How well-prepared do international school teachers believe themselves to be for teaching in culturally diverse classrooms?
Authors: Deveney Barbara
Published: November 2007

This article draws on an investigation into the extent to which teachers in one international school in Thailand had been trained for teaching in culturally diverse classrooms. It focuses on these teachers' initial and subsequent training, and probes how culturally responsive these teachers believed themselves to be. The article also considers how teachers can become more effective in culturally diverse classrooms and offers suggestions as to what international schools can do to improve teachers' knowledge of teaching a multicultural student body. Specific mention is made of Thai culture due to the author's parallel research into the impact of Thai culture on learning.
Analysis of the hybrid proline-rich protein families from seven plant species suggests rapid diversification of their sequences and expression patterns
Authors: Dvořáková Lenka , Cvrčková Fatima , Fischer Lukáš
Published: November 2007

Background

Plant hybrid proline-rich proteins (HyPRPs) are putative cell wall proteins consisting, usually, of a repetitive proline-rich (PR) N-terminal domain and a conserved eight-cysteine motif (8 CM) C-terminal domain. Understanding the evolutionary dynamics of HyPRPs might provide not only insight into their so far elusive function, but also a model for other large protein families in plants.

Results

We have performed a phylogenetic analysis of HyPRPs from seven plant species, including representatives of gymnosperms and both monocot and dicot angiosperms. Every species studied possesses a large family of 14–52 HyPRPs. Angiosperm HyPRPs exhibit signs of recent major diversification involving, at least in Arabidopsis and rice, several independent tandem gene multiplications. A distinct subfamily of relatively well-conserved C-type HyPRPs, often with long hydrophobic PR domains, has been identified. In most of gymnosperm (pine) HyPRPs, diversity appears within the C-type group while angiosperms have only a few of well-conserved C-type representatives. Atypical (glycine-rich or extremely short) N-terminal domains apparently evolved independently in multiple lineages of the HyPRP family, possibly via inversion or loss of sequences encoding proline-rich domains. Expression profiles of potato and Arabidopsis HyPRP genes exhibit instances of both overlapping and complementary organ distribution. The diversified non-C-type HyPRP genes from recently amplified chromosomal clusters in Arabidopsis often share their specialized expression profiles. C-type genes have broader expression patterns in both species (potato and Arabidopsis), although orthologous genes exhibit some differences.

Conclusion

HyPRPs represent a dynamically evolving protein family apparently unique to seed plants. We suggest that ancestral HyPRPs with long proline-rich domains produced the current diversity through ongoing gene duplications accompanied by shortening, modification or loss of the proline-rich domains. Most of the diversity in gymnosperms and angiosperms originates from different branches of the HyPRP family. Rapid sequence diversification is consistent with only limited requirements for structure conservation and, together with high variability of gene expression patterns, limits the interpretation of any functional study focused on a single HyPRP gene or a couple of HYPRP genes in single plant species.
Genome-wide analysis of growth phase-dependent translational and transcriptional regulation in halophilic archaea
Authors: Lange Christian , Zaigler Alexander , Hammelmann Mathias , Twellmeyer Jens , Raddatz Günter , Schuster Stephan C , Oesterhelt Dieter , Soppa Jörg
Published: November 2007

Background

Differential expression of genes can be regulated on many different levels. Most global studies of gene regulation concentrate on transcript level regulation, and very few global analyses of differential translational efficiencies exist. The studies have revealed that in Saccharomyces cerevisiae, Arabidopsis thaliana, and human cell lines translational regulation plays a significant role. Additional species have not been investigated yet. Particularly, until now no global study of translational control with any prokaryotic species was available.

Results

A global analysis of translational control was performed with two haloarchaeal model species, Halobacterium salinarum and Haloferax volcanii. To identify differentially regulated genes, exponentially growing and stationary phase cells were compared.

More than 20% of H. salinarum transcripts are translated with non-average efficiencies. By far the largest group is comprised of genes that are translated with above-average efficiency specifically in exponential phase, including genes for many ribosomal proteins, RNA polymerase subunits, enzymes, and chemotaxis proteins. Translation of 1% of all genes is specifically repressed in either of the two growth phases. For comparison, DNA microarrays were also used to identify differential transcriptional regulation in H. salinarum, and 17% of all genes were found to have non-average transcript levels in exponential versus stationary phase.

In H. volcanii, 12% of all genes are translated with non-average efficiencies. The overlap with H. salinarum is negligible. In contrast to H. salinarum, 4.6% of genes have non-average translational efficiency in both growth phases, and thus they might be regulated by other stimuli than growth phase.

Conclusion

For the first time in any prokaryotic species it was shown that a significant fraction of genes is under differential translational control. Groups of genes with different regulatory patterns were discovered. However, neither the fractions nor the identity of regulated genes are conserved between H. salinarum and H. volcanii, indicating that prokaryotes as well as eukaryotes use differential translational control for the regulation of gene expression, but that the identity of regulated genes is not conserved.

For 70 H. salinarum genes potentiation of regulation was observed, but for the majority of regulated genes either transcriptional or translational regulation is employed.
Coupled down-regulation of mTOR and telomerase activity during fluorouracil-induced apoptosis of hepatocarcinoma Cells
Authors: Bu Xinxin , Jia Fengqi , Wang Weifeng , Guo Xianling , Wu Mengchao , Wei Lixin
Published: November 2007

Background

Hepatocellular carcinoma (HCC) is the most invasive and frequently diagnosed malignancy and the second leading cause of cancer death in many regions of Asia. The PI3K/Akt/mTOR signal pathway is involved in multiple cellular functions including proliferation, differentiation, tumorigenesis, and apoptosis. Up-regulation of telomerase activity is thought to be a critical step leading to cell transformation.

Methods

This study investigated changes in mTOR pathway and telomerase activity in hepatocarcinoma cell line SMMC-7721 treated with chemotherapeutic agent 5-fluorouracil (5-Fu). We detected apoptosis of hepatocarcinoma cells by TUNEL assay. Telomerase activity, hTERT transcription level and p- p70 S6k was demonstrated by the telomeric repeat amplification protocol and silver staining assay, Dual-Luciferase Reporter Assay and Western blot analysis respectively.

Results

Treating SMMC-7721 cells with 5-Fu leads to apoptosis of the cells, and reduction in telomerase activity, as well as a dramatic reduction in the activated form of p70 S6 kinase, a mTOR substrate. The 5-Fu treatment nearly abolishes transcription of hTERT (the major component of telomerase) mRNA. Treating SMMC-7721 cells with Rapamycin, a specific mTOR inhibitor, significantly reduce hTERT protein level but did not affect hTERT transcription. 5-Fu and rapamycin were synergistic in regards to down-regulation of telomerase activity in hepatocarcinoma cells.

Conclusion

These results suggest that chemotherapeutic agent 5-Fu may down-regulate telomerase activity at both transcriptional level and PI3K/Akt/mTOR pathway-dependent post-transcriptional level to facilitate hepatocellular carcinoma cell apoptosis.
What do District Health Planners in Tanzania think about improving priority setting using 'Accountability for Reasonableness'?
Authors: Mshana Simon , Shemilu Haji , Ndawi Benedict , Momburi Roman , Olsen Oystein Evjen , Byskov Jens , Martin Douglas K
Published: November 2007

Background

Priority setting in every health system is complex and difficult. In less wealthy countries the dominant approach to priority setting has been Burden of Disease (BOD) and cost-effectiveness analysis (CEA), which is helpful, but insufficient because it focuses on a narrow range of values – need and efficiency – and not the full range of relevant values, including legitimacy and fairness. 'Accountability for reasonableness' is a conceptual framework for legitimate and fair priority setting and is empirically based and ethically justified. It connects priority setting to broader, more fundamental, democratic deliberative processes that have an impact on social justice and equity. Can 'accountability for reasonableness' be helpful for improving priority setting in less wealthy countries?

Methods

In 2005, Tanzanian scholars from the Primary Health Care Institute (PHCI) conducted 6 capacity building workshops with senior health staff, district planners and managers, and representatives of the Tanzanian Ministry of Health to discussion improving priority setting in Tanzania using 'accountability for reasonableness'. The purpose of this paper is to describe this initiative and the participants' views about the approach.

Results

The approach to improving priority setting using 'accountability for reasonableness' was viewed by district decision makers with enthusiastic favour because it was the first framework that directly addressed their priority setting concerns. High level Ministry of Health participants were also very supportive of the approach.

Conclusion

Both Tanzanian district and governmental health planners viewed the 'accountability for reasonableness' approach with enthusiastic favour because it was the first framework that directly addressed their concerns.
The costs of preventing the spread of respiratory infection in family physician offices: a threshold analysis
Authors: Hogg William , Gray David , Huston Patricia , Zhang Wei
Published: November 2007

Background

Influenza poses concerns about epidemic respiratory infection. Interventions designed to prevent the spread of respiratory infection within family physician (FP) offices could potentially have a significant positive influence on the health of Canadians. The main purpose of this paper is to estimate the explicit costs of such an intervention.

Methods

A cost analysis of a respiratory infection control was conducted. The costs were estimated from the perspective of provincial government. In addition, a threshold analysis was conducted to estimate a threshold value of the intervention's effectiveness that could generate potential savings in terms of averted health-care costs by the intervention that exceed the explicit costs. The informational requirements for these implicit costs savings are high, however. Some of these elements, such as the cost of hospitalization in the event of contacting influenza, and the number of patients passing through the physicians' office, were readily available. Other pertinent points of information, such as the proportion of infected people who require hospitalization, could be imported from the existing literature. We take an indirect approach to calculate a threshold value for the most uncertain piece of information, namely thereductionin the probability of the infection spreading as a direct result of the intervention, at which the intervention becomes worthwhile.

Results

The 5-week intervention costs amounted to a total of $52,810.71, or $131,094.73 prorated according to the length of the flu season, or $512,729.30 prorated for the entire calendar year. The variable costs that were incurred for this 5-week project amounted to approximately $923.16 per participating medical practice. The (fixed) training costs per practice were equivalent to $73.27 for the 5-week intervention, or $28.14 for 13-week flu season, or $7.05 for an entire one-year period.

Conclusion

Based on our conservative estimates for the direct cost savings, there are indications that the outreach facilitation intervention program would be cost effective if it can achieve a reduction in the probability of infection on the order of 0.83 (0.77, 1.05) percentage points. A facilitation intervention initiative tailored to the environment and needs of the family medical practice and walk-in clinics is of promise for improving respiratory infection control in the physicians' offices.
Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children
Authors: Armah Henry B , Wilson Nana O , Sarfo Bismark Y , Powell Michael D , Bond Vincent C , Anderson Winston , Adjei Andrew A , Gyasi Richard K , Tettey Yao , Wiredu Edwin K , Tongren Jon Eric , Udhayakumar Venkatachalam , Stiles Jonathan K
Published: November 2007

Background

Plasmodium falciparumcan cause a diffuse encephalopathy known as cerebral malaria (CM), a major contributor to malaria associated mortality. Despite treatment, mortality due to CM can be as high as 30% while 10% of survivors of the disease may experience short- and long-term neurological complications. The pathogenesis of CM and other forms of severe malaria is multi-factorial and appear to involve cytokine and chemokine homeostasis, inflammation and vascular injury/repair. Identification of prognostic markers that can predict CM severity will enable development of better intervention.

Methods

Postmortem serum and cerebrospinal fluid (CSF) samples were obtained within 2–4 hours of death in Ghanaian children dying of CM, severe malarial anemia (SMA), and non-malarial (NM) causes. Serum and CSF levels of 36 different biomarkers (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGF basic protein, CRP, G-CSF, GM-CSF, IFN-γ, TNF-α, IP-10, MCP-1 (MCAF), MIP-1α, MIP-1β, RANTES, SDF-1α, CXCL11 (I-TAC), Fas-ligand [Fas-L], soluble Fas [sFas], sTNF-R1 (p55), sTNF-R2 (p75), MMP-9, TGF-β1, PDGF bb and VEGF) were measured and the results compared between the 3 groups.

Results

After Bonferroni adjustment for other biomarkers, IP-10 was the only serum biomarker independently associated with CM mortality when compared to SMA and NM deaths. Eight CSF biomarkers (IL-1ra, IL-8, IP-10, PDGFbb, MIP-1β, Fas-L, sTNF-R1, and sTNF-R2) were significantly elevated in CM mortality group when compared to SMA and NM deaths. Additionally, CSF IP-10/PDGFbb median ratio was statistically significantly higher in the CM group compared to SMA and NM groups.

Conclusion

The parasite-induced local cerebral dysregulation in the production of IP-10, 1L-8, MIP-1β, PDGFbb, IL-1ra, Fas-L, sTNF-R1, and sTNF-R2 may be involved in CM neuropathology, and their immunoassay may have potential utility in predicting mortality in CM.
Efficacy of eleven antimicrobials against a gregarine parasite (Apicomplexa: Protozoa)
Authors: Johny Shajahan , Merisko Amber , Whitman Douglas W
Published: November 2007

Background

The Apicomplexa are a diverse group of obligate protozoan parasites infesting a wide range of invertebrate and vertebrate hosts including humans. These parasites are notoriously difficult to control and many species continue to evolve resistance to commercial antibiotics. In this study, we sought to find an effective chemotherapeutic treatment against arthropod gregarines (Apicomplexa), and to identify candidate compounds for testing against other groups of protozoan parasites.

Methods

We tested eleven commercial antibiotics against a gregarine parasite of Romalea microptera grasshoppers. Infected insects were fed daily, lettuce containing known amounts of specific antibiotics. On Days 15 or 20, we measured the number of gregarines remaining in the digestive tract of each grasshopper.

Results

Treatment with metronidazole and griseofulvin in host insects significantly reduced gregarine counts, whereas, gregarine counts of insects fed, albendazole, ampicillin, chloramphenicol, fumagillin, quinine, streptomycin, sulfadimethoxine, thiabendazole or tetracycline, were not significantly different from the controls. However, albendazole produced a strong, but non-significant reduction in gregarine count, and streptomycin exhibited a non-significant antagonistic trend.

Conclusion

Our results confirm that gregarine infections are difficult to control and suggest the possibility that streptomycin might aggravate gregarine infection. In addition, the insect system described here, provides a simple, inexpensive, and effective method for screening antibiotics.
The correlation between clinical, nuclear and histologic findings in a patient with Von Recklinghausen's disease
Authors: Brinkman Justus-Martijn , Bron Johannes L , Wuisman Paul I J M , van Diest Paul J , Comans Emile F I , Molthoff Carla F M
Published: November 2007

Background

Malignant peripheral nerve sheath tumours (MPNST) are known to develop in patients with Neurofibromatosis type I (NF1) resulting in a decreased overall survival. The association between NF1 and the development of such MPNST has been investigated in detail. The biological behaviour however of multiple disseminated neurofibromas in patients with NF1 and the risk factors for malignant transformation remain unknown. Clinical signs are unreliable and additional imaging techniques are therefore required. Of such, positron emission tomography using [18F]-2-fluoro-2-deoxy-D-glucose (18FDG PET) is used to detect malignant changes in neurofibromas.

Case presentation

A case is presented of a patient suffering from NF1 with clinical signs of malignant change and accumulation of18FDG in multiple neurofibromas. Histopathological examination of 20 lesions however, did not reveal any malignant features. There was no statistically significant relation between18FDG accumulation and malignant change, but rather with pain, size and growth.

Conclusion

This case adds to the knowledge of the diverse biological behaviour of neurofibromas in patients with NF1
A three-year longitudinal evaluation of the forearm bone density of users of etonogestrel- and levonorgestrel-releasing contraceptive implants
Authors: Monteiro-Dantas Cecilia , Espejo-Arce Ximena , Lui-Filho Jeffrey F , Fernandes Arlete M , Monteiro Ilza , Bahamondes Luis
Published: November 2007

Background

The aim of this study was to evaluate bone mineral density (BMD) at baseline and at 18 and 36 months of use of etonogestrel (ENG)-and levonorgestrel (LNG)-releasing contraceptive implants. This is a continuation of a previous study in which BMD was evaluated at baseline and at 18 months of use.

Methods

A total of 111 women, 19–43 years of age, wererandomly allocated to use one of the two implants. At 36 months of follow-up, only 36 and 39 women were still using the ENG- and LNG-releasing implants, respectively. BMD was evaluated at the distal and at the ultra-distal radius of the non-dominant forearm using dual-energy X-ray absorptiometry.

Results

There was no difference in the BMD of users of either implant at 18 and at 36 months. BMD was significantly lower at 18 and at 36 months at the distal radius in both groups of users compared to pre-insertion values; however, no difference was found at the ultra-distal radius.

Conclusion

Women 19–43 years of age using either one of these two contraceptive implants for 36 months had lower BMD values at the distal radius compared to pre-insertion values; however, no difference was found at the ultra-distal radius.
Recurrent laryngeal nerve palsy due to impacted dental plate in the thoracic oesophagus: case report
Authors: Sutcliffe Robert P , Rohatgi Ashish , Forshaw Matthew J , Mason Robert C
Published: November 2007

Background

Retained oesophageal foreign bodies must be urgently removed to prevent potentially serious complications. Recurrent laryngeal nerve palsy is rare and has not been reported in association with a foreign body in the thoracic oesophagus.

Case presentation

We present a case of a dental plate in the thoracic oesophagus that caused high dysphagia. Delayed diagnosis led to a recurrent laryngeal nerve palsy, which persisted despite successful surgical removal of the foreign body.

Conclusion

Oesophagoscopy is essential to fully assess patients with persistent symptoms after foreign body ingestion, irrespective of the level of dysphagia. Recurrent laryngeal nerve palsy may indicate impending perforation and should prompt urgent evaluation and treatment.
Tissue interactions in the developing chick diencephalon
Authors: Guinazu Maria Flavia , Chambers David , Lumsden Andrew , Kiecker Clemens
Published: November 2007

Background

The developing vertebrate brain is patterned first by global signalling gradients that define crude anteroposterior and dorsoventral coordinates, and subsequently by local signalling centres (organisers) that refine cell fate assignment within pre-patterned regions. The interface between the prethalamus and the thalamus, the zona limitans intrathalamica (ZLI), is one such local signalling centre that is essential for the establishment of these major diencephalic subdivisions by secreting the signalling factor Sonic hedgehog. Various models for ZLI formation have been proposed, but a thorough understanding of how this important local organiser is established is lacking.

Results

Here, we describe tissue explant experiments in chick embryos aimed at characterising the roles of different forebrain areas in ZLI formation. We found that: the ZLI becomes specified unexpectedly early; flanking regions are required for its characteristic morphogenesis; ZLI induction can occur independently from ventral tissues; interaction between any prechordal and epichordal neuroepithelial tissue anterior to the midbrain-hindbrain boundary is able to generate a ZLI; and signals from the dorsal diencephalon antagonise ZLI formation. We further show that a localised source of retinoic acid in the dorsal diencephalon is a likely candidate to mediate this inhibitory signal.

Conclusion

Our results are consistent with a model where planar, rather than vertical, signals position the ZLI at early stages of neural development and they implicate retinoic acid as a novel molecular cue that determines its dorsoventral extent.
Receptor downregulation and desensitization enhance the information processing ability of signalling receptors
Authors: Shankaran Harish , Wiley H Steven , Resat Haluk
Published: November 2007

Background

In addition to initiating signaling events, the activation of cell surface receptors also triggers regulatory processes that restrict the duration of signaling. Acute attenuation of signaling can be accomplished either via ligand-induced internalization of receptors (endocytic downregulation) or via ligand-inducedreceptor desensitization. These phenomena have traditionally been viewed in the context ofadaptationwherein the receptor system enters a refractory state in the presence of sustained ligand stimuli and thereby prevents the cell from over-responding to the ligand. Here we use the epidermal growth factor receptor (EGFR) and G-protein coupled receptors (GPCR) as model systems to respectively examine the effects of downregulation and desensitization on the ability of signaling receptors to decode time-varying ligand stimuli.

Results

Using a mathematical model, we show that downregulation and desensitization mechanisms can lead to tight and efficient input-output coupling thereby ensuring synchronous processing of ligand inputs. Frequency response analysis indicates that upstream elements of the EGFR and GPCR networks behave like low-pass filters with the system being able to faithfully transduce inputs below a critical frequency. Receptor downregulation and desensitization increase the filter bandwidth thereby enabling the receptor systems to decode inputs in a wider frequency range. Further, system-theoretic analysis reveals that the receptor systems are analogous to classical mechanical over-damped systems. This analogy enables us to metaphorically describe downregulation and desensitization as phenomena that make the systems more resilient in responding to ligand perturbations thereby improving the stability of the system resting state.

Conclusion

Our findings suggest that in addition to serving as mechanisms for adaptation, receptor downregulation and desensitization can play a critical role in temporal information processing. Furthermore, engineering metaphors such as the ones described here could prove to be invaluable in understanding the design principles of biological systems.
A fatal case of recurrent amiodarone-induced thyrotoxicosis after percutaneous tracheotomy: a case report
Authors: Papaioannou Vasilios , Terzi Irene , Dragoumanis Christos , Konstantonis Dimitrios , Theodorou Vassiliki , Pneumatikos Ioannis
Published: November 2007

Background

Amiodarone is a widely used antiarrythmic drug, which may produce secondary effects on the thyroid. In 14–18% of amiodarone-treated patients, there is overt thyroid dysfunction, usually in the form of amiodarone-induced thyrotoxicosis, which can be difficult to manage with standard medical treatment.

Case presentation

Presented is the case of a 65-year-old man, under chronic treatment of atrial fibrillation with amiodarone, who was admitted to the Intensive Care Unit with acute cardio-respiratory failure and fever. He was recently hospitalized with respiratory distress, attributed to amiodarone-induced pulmonary fibrosis. Clinical and laboratory investigation revealed thyrotoxicosis due to amiodarone treatment. He was begun on thionamide, prednisone and beta-blockers. After a short term improvement of his clinical status the patient underwent percutaneous tracheotomy due to weaning failure from mechanical ventilation, which led to the development of recurrent thyrotoxicosis, unresponsive to medical treatment. Finally, the patient developed multiple organ failure and died, seven days later.

Conclusion

We suggest that percutaneous tracheotomy could precipitate a thyrotoxic crisis, particularly in non-euthyroid patients suffering from concurrent severe illness and should be performed only in parallel with emergency thyroid surgery, when indicated.
Signal transducer and activator of transcription 5b: a new target of breast tumor kinase/protein tyrosine kinase 6
Authors: Weaver Amanda M , Silva Corinne M
Published: November 2007

Introduction

Signal transducers and activators of transcription (STATs) are mediators of cytokine and growth factor signaling. In recent years, STAT5b has emerged as a key regulator of tumorigenesis. STAT5b phosphorylation and activation is mediated by several kinases known to be overexpressed in breast cancer, such as epidermal growth factor receptor, HER2, and c-Src. Breast tumor kinase (Brk), also known as protein tyrosine kinase 6, is a nonreceptor tyrosine kinase expressed in more than 60% of breast cancers. Only a few substrates of the Brk tyrosine kinase have been identified, the most recent being STAT3. In the present article we investigate the potential role of Brk in the phosphorylation and activation STAT5b.

Methods

To determine whether Brk can phosphorylate STAT5b, transient transfection and in vitro kinase assays were performed. Luciferase reporter assays were used to measure Brk-induced STAT5b transcriptional activity. siRNA technology was utilized to investigate the biological significance of Brk-induced activation of STAT5b in breast cancer cell models.

Results

Phosphospecific antibodies, mutational analysis, and in vitro kinase assays demonstrated that Brk specifically mediated STAT5b phosphorylation at the activating tyrosine, Y699. Transient transfection of Brk into the Brk-negative BT-549 breast cancer cell line enhanced STAT5b transcriptional activity, as measured by a STAT5-specific luciferase reporter. Furthermore, overexpression of kinase active c-Src enhanced Brk-induced STAT5b transcriptional activity. In Brk-positive breast cancer cell lines BT-20 and SKBr3, knockdown of Brk protein or of STAT5b protein using siRNA methodology resulted in a decrease in DNA synthesis. Knockdown of Brk and STAT5b together did not further decrease DNA synthesis compared with each alone, suggesting that Brk and STAT5b converge on the same pathway, ultimately leading to cellular proliferation.

Conclusion

Our studies demonstrate that Brk phosphorylates STAT5b on Y699, leading to increased STAT5b transcriptional activity. Furthermore, analysis of DNA synthesis suggests that STAT5b and Brk are converging upon the same proproliferative signaling pathway in breast cancer cells. We propose that Brk, like other tyrosine kinases, signals downstream to STAT5b to mediate proliferation of breast cancer cells. These results further establish STAT5b as well as Brk as potential targets for breast cancer therapy.
GeneChip analysis of human embryonic stem cell differentiation into hemangioblasts: an in silicodissection of mixed phenotypes
Authors: Lu Shi-Jiang , Hipp Jennifer A , Feng Qiang , Hipp Jason D , Lanza Robert , Atala Anthony
Published: November 2007

Background

Microarrays are being used to understand human embryonic stem cell (hESC) differentiation. Most differentiation protocols use a multi-stage approach that induces commitment along a particular lineage. Therefore, each stage represents a more mature and less heterogeneous phenotype. Thus, characterizing the heterogeneous progenitor populations upon differentiation are of increasing importance. Here we describe a novel method of data analysis using a recently developed differentiation protocol involving the formation of functional hemangioblasts from hESCs. Blast cells are multipotent and can differentiate into multiple lineages of hematopoeitic cells (erythroid, granulocyte and macrophage), endothelial and smooth muscle cells.

Results

Large-scale transcriptional analysis was performed at distinct time points of hESC differentiation (undifferentiated hESCs, embryoid bodies, and blast cells, the last of which generates both hematopoietic and endothelial progenies). Identifying genes enriched in blast cells relative to hESCs revealed a genetic signature indicative of erythroblasts, suggesting that erythroblasts are the predominant cell type in the blast cell population. Because of the heterogeneity of blast cells, numerous comparisons were made to publicly available data sets in silico, some of which blast cells are capable of differentiating into, to assess and characterize the blast cell population. Biologically relevant comparisons masked particular genetic signatures within the heterogeneous population and identified genetic signatures indicating the presence of endothelia, cardiomyocytes, and hematopoietic lineages in the blast cell population.

Conclusion

The significance of this microarray study is in its ability to assess and identify cellular populations within a heterogeneous population through biologically relevant in silico comparisons of publicly available data sets. In conclusion, multiple in silico comparisons were necessary to characterize tissue-specific genetic signatures within a heterogeneous hemangioblast population.
Combined treatment of CpG-oligodeoxynucleotide with Nutlin-3 induces strong immune stimulation coupled to cytotoxicity in B-chronic lymphocytic leukemic (B-CLL) cells
Authors: Secchiero Paola , Melloni Elisabetta , Tiribelli Mario , Gonelli Arianna , Zauli Giorgio
Published: November 2007

We have investigated the effect of combined treatment with CpG-oligodeoxynucleotide (CpG-ODN) plus Nutlin-3, a small molecule inhibitor of the murine double minute 2/p53 interaction, on the immune activation, cell cycle progression, and apoptosis of peripheral blood B chronic lymphocytic leukemia (B-CLL) cells. CpG-ODN induced a robust up-regulation of immune activation markers (CD54, CD69, CD80, CD86, MHC-II) in Zap70high and Zap70low B-CLL samples. Although cotreatment of B-CLL cells with CpG-ODN + Nutlin-3 did not interfere with such immune activation, CpG-ODN potentiated the Nutlin-3-mediated induction of the death receptors CD95 and TRAIL receptor 2. Importantly, treatment with CpG-ODN did not interfere with the ability of Nutlin-3 to inhibit cell cycle progression and to induce apoptosis. Thus, a therapeutic regimen including CpG-ODN plus Nutlin-3 might have the advantage to preserve the immune activation of B-CLL cells while restraining the prosurvival/proliferative potential of CpG-ODN treatment.
IL-17 receptor signaling influences virus-induced corneal inflammation
Authors: Molesworth-Kenyon Sara J , Yin Rong , Oakes John E , Lausch Robert N
Published: November 2007

IL-17 has been associated with selected inflammatory and autoimmune diseases. We characterized the expression of this proinflammatory cytokine following HSV-1 corneal infection and investigated whether IL-17R signaling modulated the host response to the viral pathogen at early time-points postinfection. IL-17 was elevated in the murine cornea 24 h after high-dose virus infection and subsequently persisted at low levels during the first week. Immunofluorescent studies showed that the IL-17R was expressed by cultured mouse corneal fibroblasts. Exposure of corneal cells to IL-17 led to production of IL-6 and MIP-2 in vitro and in vivo, indicating that the IL-17R was functional. Mice lacking IL-17R displayed significantly reduced neutrophil infiltration and corneal opacity. However, this effect was transient, as corneal pathology and neutrophil influx resembled that of wild-type (WT) hosts 4 days postinfection. HSV-1 growth and clearance in IL-17R−/− hosts were similar to that of the WT controls. Infection of IFN-γ gene knockout mice was associated with elevated IL-17 levels and accelerated corneal opacity, suggesting that IFN-γ negatively regulated IL-17 expression. Collectively, our results establish that IL-17 is rapidly produced in the cornea after HSV-1 infection and is regulated at least in part by IFN-γ. The absence of IL-17 signaling results in a transient decrease in the expression of proinflammatory mediators, neutrophil migration, and corneal pathology, but control of virus growth in the cornea and trigeminal ganglia is not compromised. Thus, IL-17 actively influences early virus-induced corneal inflammation.
Cardiovascular Adverse Events During Adjuvant Endocrine Therapy for Early Breast Cancer Using Letrozole or Tamoxifen: Safety Analysis of BIG 1-98 Trial
Authors: Mouridsen Henning , Keshaviah Aparna , Coates Alan S. , Rabaglio Manuela , Castiglione-Gertsch Monica , Sun Zhuoxin , Thürlimann Beat , Mauriac Louis , Forbes John F. , Paridaens Robert , Gelber Richard D. , Colleoni Marco , Smith Ian , Price Karen N. , Goldhirsch Aron
Published: November 2007

Purpose

Previous analyses of adjuvant studies of aromatase inhibitors versus tamoxifen, including the Breast International Group (BIG) 1-98 study, have suggested a small numerical excess of cardiac adverse events (AEs) on aromatase inhibitors, a reduction in the incidence of hypercholesterolemia on tamoxifen, and significantly higher incidence of thromboembolic AEs on tamoxifen. The purpose of the present study is to provide detailed updated information on these AEs in BIG 1-98.

Patients and Methods

Eight thousand twenty-eight postmenopausal women with receptor-positive early breast cancer were randomly assigned (double-blind) between March 1998 and May 2003 to receive 5 years of adjuvant endocrine therapy with letrozole, tamoxifen, or a sequence of these agents. Seven thousand nine hundred sixty-three patients who actually received therapy are included in this safety analysis, which focuses on cardiovascular events. AE recording ceased 30 days after therapy completion (or after switch on the sequential arms).

Results

Baseline comorbidities were balanced. At a median follow-up time of 30.1 months, we observed similar overall incidence of cardiac AEs (letrozole, 4.8%; tamoxifen, 4.7%), more grade 3 to 5 cardiac AEs on letrozole (letrozole, 2.4%; tamoxifen, 1.4%; P = .001)—an excess only partially attributable to prior hypercholesterolemia—and more overall (tamoxifen, 3.9%; letrozole, 1.7%; P < .001) and grade 3 to 5 thromboembolic AEs on tamoxifen (tamoxifen, 2.3%; letrozole, 0.9%; P < .001). There was no significant difference between tamoxifen and letrozole in incidence of hypertension or cerebrovascular events.

Conclusion

The present safety analysis, limited to cardiovascular AEs in BIG 1-98, documents a low overall incidence of cardiovascular AEs, which differed between treatment arms.
Executive Federalism and Medicaid Demonstration Waivers: Implications for Policy and Democratic Process
Authors: Thompson Frank J. , Burke Courtney
Published: November 2007

Executive federalism emphasizes collaboration between the executive branches at the national and state levels to transform grant programs through the implementation process. In this regard, Medicaid demonstration waivers loomed large during the presidencies of Bill Clinton and George W. Bush. This article documents and compares the volume and substance of section 1115 Medicaid waiver activity under the two presidencies. From the perspective of policy performance, Medicaid demonstration waivers provide modest support for the view that states serve as laboratories for policy learning in the health care arena. More broadly, the waivers have not yielded a major solution to the problem of the uninsured and are unlikely to do so. At the same time, they have not (as some have suggested) been a subterranean force for the erosion of Medicaid. To the contrary, these waivers have often enhanced health services for low-income people; above all, they have helped preserve Medicaid as an entitlement by undercutting support for those seeking to convert the program into a block grant. From the perspective of the democratic process, we find that Congress has been a more significant player in shaping waivers than the executive federalism model suggests. While the decision processes surrounding Medicaid waivers often fall short of democratic standards with respect to transparency and opportunities for public input, they still compare favorably to certain alternatives.
Optimum grouping in a modified genetic algorithm for discrete-time, non-linear system identification
Authors: Jamaluddin H , Samad M F Abd , Ahmad R , Yaacob M. S.
Published: November 2007

The genetic algorithm approach is widely recognized as an effective and flexible optimization method for system identification. The flexibility of a genetic algorithm allows various strategies to be applied to it. One of the strategies applied is the modified genetic algorithm which relies on, among other things, the separation of the population into groups where each group undergoes mutual recombination operations. The strategy has been shown to be better than the simple genetic algorithm and conventional statistical method, but it contains inadequate justification of how the separation is made. The usage of objective function values for separation of groups does not carry much flexibility and is not suitable since different time-dependent data have different levels of equilibrium and thus different ranges of objective function values. This paper investigates the optimum grouping of chromosomes by fixed group ratios, enabling more efficient identification of dynamic systems using a NARX (Non-linear AutoRegressive with eXogenous input) model. Several simulated systems and real-world timedependent data are used in the investigation. Comparisons based on widely used optimization performance indicators along with outcomes from other research are used. The issue of model parsimony is also addressed, and the model is validated using correlation tests. The study reveals that, when recombination and mutation are used for different groups, equal composition of both groups produces a better result in terms of accuracy, parsimony, speed, and consistency.