bluuebunny/crossref_metadata_2025 huggingface dataset:
The Dietary Flavones Apigenin and Luteolin Impair Smooth Muscle Cell Migration and VEGF Expression through Inhibition of PDGFR-β Phosphorylation
Authors: Lamy Sylvie , Bédard Valérie , Labbé David , Sartelet Hervé , Barthomeuf Chantal , Gingras Denis , Béliveau Richard
Published: November 2008

Platelet-derived growth factor (PDGF)–dependent recruitment of mural cells such as pericytes and smooth muscle cells plays a central role in the maturation and stabilization of newly formed vasculature during angiogenesis. In this work, we show that the dietary flavones apigenin and luteolin may interfere with this event through their inhibitory effect on PDGF-dependent phosphorylation of PDGF receptor β (PDGFR-β) in smooth muscle cells. Inhibition of PDGFR-β activity by apigenin and luteolin occurred at low concentrations of the molecules and resulted in the inhibition of extracellular signal–regulated kinase and Akt phosphorylation triggered by PDGF, as well as in a marked reduction of the migratory and invasive properties of these cells. Apigenin and luteolin also strongly inhibit the PDGF-dependent increase in vascular endothelial growth factor (VEGF) mRNA levels and the secretion of VEGF by smooth muscle cells as well as vessel formation in the mouse Matrigel plug assay, suggesting that the inhibitory effects of both molecules on smooth muscle cell function result in impaired angiogenesis. Overall, these results identify apigenin and luteolin as dietary-derived inhibitors of PDGFR-β activity and suggest that this inhibitory effect may contribute to the chemopreventive properties of these molecules.
Heat Shock Protein 90 Inhibitors Suppress Aryl Hydrocarbon Receptor–Mediated Activation ofCYP1A1andCYP1B1Transcription and DNA Adduct Formation
Authors: Hughes Duncan , Guttenplan Joseph B. , Marcus Craig B. , Subbaramaiah Kotha , Dannenberg Andrew J.
Published: November 2008

The aryl hydrocarbon receptor (AhR), a client protein of heat shock protein 90 (HSP90), plays a significant role in polycyclic aromatic hydrocarbon (PAH)–induced carcinogenesis. Tobacco smoke, a source of PAHs, activates the AhR, leading to enhanced transcription of CYP1A1 and CYP1B1, which encode proteins that convert PAHs to genotoxic metabolites. The main objectives of this study were to determine whether HSP90 inhibitors suppress PAH-mediated induction of CYP1A1 and CYP1B1 or block benzo(a)pyrene [B(a)P]–induced formation of DNA adducts. Treatment of cell lines derived from oral leukoplakia (MSK-Leuk1) or esophageal squamous cell carcinoma (KYSE450) with a saline extract of tobacco smoke, B(a)P, or dioxin induced CYP1A1 and CYP1B1 transcription, resulting in enhanced levels of message and protein. Inhibitors of HSP90 [17-allylamino-17-demethoxygeldanamycin (17-AAG); celastrol] suppressed these inductive effects of PAHs. Treatment with 17-AAG and celastrol also caused a rapid and marked decrease in amounts of AhR protein without modulating levels of HSP90. The formation of B(a)P-induced DNA adducts in MSK-Leuk1 cells was inhibited by 17-AAG, celastrol, and α-naphthoflavone, a known AhR antagonist. The reduction in B(a)P-induced DNA adducts was due, at least in part, to reduced metabolic activation of B(a)P. Collectively, these results suggest that 17-AAG and celastrol, inhibitors of HSP90, suppress the activation of AhR-dependent gene expression, leading, in turn, to reduced formation of B(a)P-induced DNA adducts. Inhibitors of HSP90 may have a role in chemoprevention in addition to cancer therapy.
The Field of Tissue Injury in the Lung and Airway
Authors: Steiling Katrina , Ryan John , Brody Jerome S. , Spira Avrum
Published: November 2008

The concept of field cancerization was first introduced over 6 decades ago in the setting of oral cancer. Later, field cancerization involving histologic and molecular changes of neoplasms and adjacent tissue began to be characterized in smokers with or without lung cancer. Investigators also described a diffuse, nonneoplastic field of molecular injury throughout the respiratory tract that is attributable to cigarette smoking and susceptibility to smoking-induced lung disease. The potential molecular origins of field cancerization and the field of injury following cigarette smoke exposure in lung and airway epithelia are critical to understanding their potential impact on clinical diagnostics and therapeutics for smoking-induced lung disease.
Successful Endoscopic Management of Bouveret’s Syndrome in a Patient with Cholecystoduodenocolic Fistulae
Authors: Tanwar S. , Mawas A. , Tutton M. , O’Riordan D.
Published: November 2008

Bouveret’s syndrome, first described in 1896 by Léon Bouveret, is rare, limited to approximately 200 published case reports to date [Ariche et al.: Scand J Gastroenterol 2000;35:781–783]. It is a subgroup of gallstone ileus in which a cholecystoduodenal fistula allows the passage of a gallstone that obstructs the duodenum, causing gastric outlet obstruction. This case is unique as it describes Bouveret’s syndrome in a patient with combined cholecystoduodenocolic fistulae. Gastric outlet obstruction was successfully managed endoscopically with lithotripsy. Both fistulae were subsequently managed conservatively without any complications.
Indwelling Bowel Management System as a Cause of Life-Threatening Rectal Bleeding
Authors: Bright Elizabeth , Fishwick Guy , Berry David , Thomas Michael
Published: November 2008

A 79-year-old male was transferred to the intensive care unit for postoperative respiratory support. An indwelling bowel management system was inserted for containment of noninfective diarrhoea. Following only 11 days of continual use the patient developed life-threatening rectal bleeding. Preoperative normal rectal mucosa and anatomy were documented. There was no evidence of postoperative coagulopathy. Mesenteric angiography identified bleeding from a branch of the superior rectal artery. Rectal mucosa pressure necrosis secondary to the indwelling Flexi-Seal® Fecal Management System was diagnosed. The patient required an 11-unit transfusion of packed red cells. Following intraarterial coil embolization of the superior rectal artery the bleeding abated. Indwelling bowel management systems are commonly used in immobile and critically ill patients with diarrhoea or faecal incontinence. This is the first report of this important complication in the literature.
Fatal Bile Duct Necrosis: A Rare Complication of Transcatheter Arterial Chemoembolization in a Patient with Endocrine Hepatic Metastasis
Authors: Pelletier Anne-Laure , Hammel Pascal , Zappa Magali , Bedossa Pierre , Rebours Vinciane , Hentic Olivia , Maire Frédérique , Levy Philippe , Ruszniewski Philippe
Published: November 2008

We report the first case of fatal bile duct necrosis following transcatheter arterial chemoembolization (TACE) in a 58-year-old woman. The patient underwent two TACEs to treat hepatic metastases from an ileal endocrine tumor. Persistent cholestasis occurred after the second procedure, leading to the diagnosis of bile duct necrosis confirmed by liver biopsy. The patient died of liver failure with encephalopathy six months after the second TACE. Even though this complication is very rare, physicians should consider this diagnosis in patients who develop chronic, marked cholestasis following a TACE procedure.
A Rare Case of Peritoneal Sarcoidosis in a 36-Year-Old Construction Worker
Authors: Chubineh Saman , Katona Kyle
Published: November 2008

A 36-year-old man was admitted for persistent abdominal pain and weight loss. He had had significant exposure to asbestos, as he had been active in cleanup after the World Trade Center attack. A CT scan of his abdomen was initially read as peritoneal carcinomatosis without evidence of ascites. Infectious etiology was subsequently ruled out and diagnostic laparoscopy was performed for tissue diagnosis revealing noncaseating granulomas consistent with peritoneal sarcoidosis. Of note, he had an elevated CA-125 level on admission, which is unique in males with peritoneal sarcoidosis.
Autonomic Nervous Function and Arrhythmias in Patients with Acute Viral Myocarditis during a 6-Month Follow-Up Period
Authors: Gao Xiuren , Peng Longyun , Zeng Qunying , Wu Zhong-Kai
Published: November 2008

Objective: It was our aim to study the outcome of autonomic nervous function (ANF), heart rate variability (HRV) and arrhythmias in patients with acute viral myocarditis in a 6-month follow-up period after the diagnosis. Methods: ANF was measured in patients with acute viral myocarditis 1, 3 and 6 months after the disease was diagnosed. HRV and arrhythmias were monitored by 24-hour electrocardiogram during the follow-up examination. Results: Ninety-six patients with acute viral myocarditis were enrolled in this study; 58% showed abnormal ANF tests, and the incidence was reduced to 17% after 6 months (p < 0.01). Time and frequency domain analyses of HRV were significantly reduced in the early stage of the disease and recovered after 6 months (p < 0.05). The incidence of arrhythmias in patients with abnormal ANF was significantly higher than in patients with normal ANF (p < 0.05). The incidence of arrhythmias in patients with abnormal ANF at 6 months was significantly lower than that at the first month (p < 0.05). Conclusions: There is a significant impairment of ANF and a higher incidence of arrhythmias in the early stage of acute myocarditis. ANF and HRV abnormalities are significantly improved, and the incidence of arrhythmia is significantly reduced after 6 months in patients with acute myocarditis.
Differential Analgesic Effects of a Mu-Opioid Peptide, [Dmt1]DALDA, and Morphine
Authors: Shimoyama Megumi , Szeto Hazel H. , Schiller Peter W. , Tagaito Yugo , Tokairin Hideyuki , Eun Chong moon , Shimoyama Naohito
Published: November 2008

Aims: H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA), a highly selective μ-opioid peptide, is potently analgesic after systemic and intrathecal administration but is less potent given intracerebroventricularly. This study was performed to further characterize the analgesic effects of [Dmt1]DALDA. Methods:We compared the effects of [Dmt1]DALDA and morphine after systemic administration in two different acute pain tests, the tail flick test and the paw withdrawal test, and examined how antagonizing the spinal opioid actions would affect their analgesic effects. Results: [Dmt1]DALDA was markedly more potent in the tail flick test than in the hot plate test, while the potencies of morphine were similar in the two tests. Intrathecal naloxone completely blocked the effect of systemic [Dmt1]DALDA in the tail flick test, while it only partially blocked the effect of morphine. At higher doses that produced analgesia in the hot plate test, the effect of [Dmt1]DALDA in this test was only partially blocked by naloxone. Conclusion:Systemic [Dmt1]DALDA has a unique analgesic property clearly different from that of morphine and it has a propensity to produce spinal analgesia.
Prenatal Diagnosis of Thanatophoric Dysplasia by 3-D Helical Computed Tomography and Genetic Analysis
Authors: Tsutsumi Seiji , Sawai Hideaki , Nishimura Gen , Hayasaka Kiyoshi , Kurachi Hirohisa
Published: November 2008

Objective: We report the first case of thanatophoric dysplasia (TD) successfully diagnosed in utero by a combination of 2-D ultrasound, computed tomography (CT) 3-D imaging and genetic analysis at 26 weeks’ gestation. Methods: Prenatal sonographic examinations performed at 23 weeks’ gestation revealed micromelic shortening of the limbs, reduced thoracic cavity and a presence of cloverleaf skull deformity. Based on these findings, a lethal form of skeletal dysplasia was suspected and a helical CT imaging with 3-D reconstruction depicted skeletal abnormalities which suggested TD. The prenatal diagnosis was affirmed on amniotic fluid cells by DNA mutation analysis of the fibroblast growth factor receptor 3 gene. Results: A missense mutation (tyrosine 373 to cysteine) was detected, and was diagnosed as TD type I. Conclusion: Helical CT imaging with 3-D reconstruction and molecular testing are useful adjuncts to 2-D ultrasonography in the diagnosis of lethal skeletal dysplasias, allowing for appropriate perinatal support including genetic counseling.
Politics and Identity in Maltese Theatre: Adaptation or Innovation?
Authors: Cremona Vicki Ann
Published: November 2008

The period from the 1960s to the 1990s was one of great political change in Malta. Up until its independence in 1964, Malta had been under foreign domination, and this new political direction meant change in the way the Maltese saw and governed themselves. Theatre during this period expressed this emerging new identity. Looking at theatre and political protest during this period reveals that in contrast to the more politically engaged post-independence theatre, recent Maltese theatre is relatively unchanging, perhaps due to a more general decline in political involvement.
Collective Improvisation: The Practice and Vision of Ingemar Lindh
Authors: Camilleri Frank
Published: November 2008

Ingemar Lindh's research on the principles of collective improvisation and performance conceived as process announce an important development in the 20th-century tradition of the actor's work. After early studies with Étienne Decroux and working collaborations with Jerzy Grotowski, Eugenio Barba, and Yves Lebreton, Lindh founded the first laboratory theatre in Sweden in 1971, the Institutet för Scenkonst. His practice of collective improvisation is viewed in light of postdramatic concerns such as its resistance to fixed scores, directorial montage, and choreography as an organizing principle.
Introduction Bias, Prenegotiation and Leverage in Mediation
Authors: Zartman William
Published: November 2008

Although analysts have long held that bias disqualifies a mediator, more recent analysis, pioneered by Saadia Touval, shows that bias can be quite helpful to mediation under the assumption that the mediator delivers the agreement of the party toward which it is biased. Of course, the mediator is still expected to be trustworthy in dealing with the parties and reliable in communications. Prenegotiation and diagnosis, probably the least analyzed early stages of negotiation, are shown to be crucial to a successful negotiation and the necessary preconditions to an efficient and effective process. Leverage, the term for “power” in negotiation, is a scarce resource and takes the form of effective persuasion rather than material inducements and punishments; it depends above all on the need of the conflicting parties for an agreement, which in turn depends on the attractiveness of their alternatives or security points (BATNAs).
Cyprus's Accession Negotiations to the European Union: Conditional Carrots, Good Faith, and Miscalculations
Authors: Ramming Saskia
Published: November 2008

The European Union did not push forcefully for an intercommunal settlement that would reunite Cyprus as a prerequisite for EU accession. As a result, it gave away the carrot without tying it to an important condition. Several explanations are drawn from an analysis of processual and structural factors in the negotiation context.
A Private Matter? Evolving Approaches to the Freedom to Manifest Religious Convictions in the Workplace
Authors: Hambler Andrew
Published: November 2008

The manifestation of religion is protected in the United Kingdom by human rights instruments and also, since 2003, by discrimination law. When religious faith is manifested in the workplace it potentially involves some clash with other rights, particularly an employer's freedom of contract. How far an employer is able to restrict its employees' freedom to manifest religion in pursuit of a 'legitimate aim' is therefore of great interest to employers and 'religious' employees alike. This article explores this issue by first categorising 'manifestation' into three forms and then surveying the jurisprudence relevant to each, considering most recent cases in greater detail. Although it is acknowledged that conclusions must be tentative, given the relatively recent innovation of the discrimination law provisions, evidence considered in this article points towards very little protection for employees to manifest their religious convictions except those aspects of what is referred to here as 'negative manifestation' which are most congruent with the private sphere—the so-called forum internum.
Orographic Precipitation in the Tropics: Experiments in Dominica
Authors: Smith R. B. , Schafer P. , Kirshbaum D. J. , Regina E.
Published: November 2008

The “natural laboratory” of mountainous Dominica (15°N) in the trade wind belt is used to study the physics of tropical orographic precipitation in its purest form, unforced by weather disturbances or by the diurnal cycle of solar heating. A cross-island line of rain gauges and 5-min radar scans from Guadeloupe reveal a large annual precipitation at high elevation (7 m yr−1) and a large orographic enhancement factor (2 to 8) caused primarily by repetitive convective triggering over the windward slope. The triggering is caused by terrain-forced lifting of the conditionally unstable trade wind cloud layer. Ambient humidity fluctuations associated with open-ocean convection may play a key role. The convection transports moisture upward and causes frequent brief showers on the hilltops. The drying ratio of the full air column from precipitation is less than 1% whereas the surface air dries by about 17% from the east coast to the mountain top. On the lee side, a plunging trade wind inversion and reduced instability destroys convective clouds and creates an oceanic rain shadow.
Interannual Variability and Seasonal Evolution of Summer Monsoon Rainfall in South America
Authors: Grimm Alice M. , Zilli Marcia T.
Published: November 2008

The analysis of the interannual variability of the South American monsoon rainfall is carried out separately for austral spring and summer (and for November and January), based on a 40-yr station gauge dataset. Relationships between modes of variability in these seasons show the influence of antecedent conditions in spring (or November) on the evolution of the monsoon rainfall in peak summer (or January). In spring the first mode is dipolelike, with opposite loadings over central-eastern and southeastern South America. It is connected with ENSO. The second mode shows the highest loadings slightly south of the South Atlantic convergence zone. The leading mode of summer also features dipolelike oscillations between central-eastern and southeastern South America, but is not strongly connected with ENSO. The second mode represents the impact of ENSO, and the third is modulated by SST anomalies in the southern tropical Atlantic.

Significant relationships are disclosed between the first dipolelike modes of spring and summer rainfall and thus between the rainfall in spring and summer over central-eastern South America, which includes part of the monsoon core region. These dipolelike modes are associated with a rotational anomaly over southeast Brazil that either conveys moisture flux into central-eastern Brazil (if it is cyclonic) or into southeastern South America (if it is anticyclonic). In spring this anomaly seems to be remotely forced, but after strong rainfall anomalies over central-eastern Brazil in spring, it tends to reverse sign in peak summer, inverting the dipolelike rainfall anomalies. This reversal is hypothesized to be locally forced by surface–atmosphere feedback triggered by the spring anomalies, as weaker teleconnections in summer allow local processes that are stronger in summer to overcome remote forcing. SST and circulation anomalies associated with the first modes in spring and summer, and also the relationship between the first summer mode and surface temperature in spring, are consistent with that hypothesis.
Sensitivity Study of Regional Climate Model Simulations to Large-Scale Nudging Parameters
Authors: Alexandru Adelina , de Elia Ramon , Laprise René , Separovic Leo , Biner Sébastien
Published: November 2008

Previous studies with nested regional climate models (RCMs) have shown that large-scale spectral nudging (SN) seems to be a powerful method to correct RCMs’ weaknesses such as internal variability, intermittent divergence in phase space (IDPS), and simulated climate dependence on domain size and geometry. Despite its initial success, SN is not yet in widespread use because of disagreement regarding the main premises—the unconfirmed advantages of removing freedom from RCMs’ large scales—and lingering doubts regarding its potentially negative side effects. This research addresses the latter issue. Five experiments have been carried out with the Canadian RCM (CRCM) over North America. Each experiment, performed under a given SN configuration, consists of four ensembles of simulations integrated on four different domain sizes for a summer season. In each experiment, the effects of SN on internal variability, time means, extremes, and power spectra are discussed. As anticipated from previous investigations, the present study confirms that internal variability, as well as simulated-climate dependence on domain size, decreases with increased SN strength. Our results further indicate a noticeable reduction of precipitation extremes as well as low-level vorticity amplitude in almost all length scales, as a side effect of SN; these effects are mostly perceived when SN is the most intense. Overall results indicate that the use of a weak to mild SN may constitute a reasonable compromise between the risk of decoupling of the RCM internal solution from the lateral boundary conditions (when using large domains without SN) and an excessive control of the large scales (with strong SN).
Description and Verification of the NOAA Smoke Forecasting System: The 2007 Fire Season
Authors: Rolph Glenn D. , Draxler Roland R. , Stein Ariel F. , Taylor Albion , Ruminski Mark G. , Kondragunta Shobha , Zeng Jian , Huang Ho-Chun , Manikin Geoffrey , McQueen Jeffery T. , Davidson Paula M.
Published: November 2008

An overview of the National Oceanic and Atmospheric Administration’s (NOAA) current operational Smoke Forecasting System (SFS) is presented. This system is intended as guidance to air quality forecasters and the public for fine particulate matter (≤2.5 μm) emitted from large wildfires and agricultural burning, which can elevate particulate concentrations to unhealthful levels. The SFS uses National Environmental Satellite, Data, and Information Service (NESDIS) Hazard Mapping System (HMS), which is based on satellite imagery, to establish the locations and extents of the fires. The particulate matter emission rate is computed using the emission processing portion of the U.S. Forest Service’s BlueSky Framework, which includes a fuel-type database, as well as consumption and emissions models. The Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLIT) model is used to calculate the transport, dispersion, and deposition of the emitted particulate matter. The model evaluation is carried out by comparing predicted smoke levels with actual smoke detected from satellites by the HMS and the Geostationary Operational Environmental Satellite (GOES) Aerosol/Smoke Product. This overlap is expressed as the figure of merit in space (FMS), the intersection over the union of the observed and calculated smoke plumes. Results are presented for the 2007 fire season (September 2006–November 2007). While the highest FMS scores for individual events approach 60%, average values for the 1 and 5 μg m−3 contours for the analysis period were 8.3% and 11.6%, respectively. FMS scores for the forecast period were lower by about 25% due, in part, to the inability to forecast new fires. The HMS plumes tend to be smaller than the corresponding predictions during the winter months, suggesting that excessive emissions predicted for the smaller fires resulted in an overprediction in the smoke area.
Socio-Political Contexts, Identity Formation, and Regulatory Compliance
Authors: Lee Eungkyoon
Published: November 2008

This article attempts to fill the gaps in traditional compliance theories and argues that the actor's identity formulated by socio-political contexts influences the propensity to move toward or away from compliance. Although regulated entities are sometimes instrumentally rational or norms oriented, they also base their behavioral choices on situated judgments in ways that are more varied and changing than existing compliance theories have suggested. The comparative case studies presented here focus on how the socio-political relations of actors are manifested in identities of self and others in interaction and, in turn, translate into compliance choice making.
Stability of Physical Activity across the Lifespan
Authors: Friedman Howard S. , Martin Leslie R. , Tucker Joan S. , Criqui Michael H. , Kern Margaret L. , Reynolds Chandra A.
Published: November 2008

Physical activity is associated with various health-relevant psychosocial and physiological processes, but activity stability across extended time periods is inadequately understood. This lifespan longitudinal cohort study examined activity levels of 723 males and 554 females. Associations across time were computed and structural equation modeling compared a one factor model and a simplex model. Results showed activity levels are somewhat stable from childhood through middle and late adulthood. Further, a simplex model provided a better fit than a one factor model. Successful models and interventions to improve health will likely require a more nuanced, pattern-sensitive understanding of physical activity across time.
Project IMPACT
Authors: Cholewa Scott , Irwin Jennifer D.
Published: November 2008

The effectiveness of a buddy system, record-keeping device, or both for increasing university students' physical activity (PA) was assessed. Pre- and post-measures of PA, self-efficacy, and body mass index were taken. PA increased significantly in the record-keeping and combination arms of the study, p < .05. Significant increases in barriers efficacy occurred for all participants, p < .05. No significant changes in task efficacy or BMI occurred. Project IMPACT is an effective PA intervention requiring wider-spread implementation and evaluation.
Global Trade and Mental Health
Authors: Corrigall Joanne , Plagerson Sophie , Lund Crick , Myers Johnathan
Published: November 2008

The consequences of the unprecedented growth of global trade on development and population health are significantly influenced by global trade policies that have delivered millions from poverty, but have constrained the ability of governments to regulate their economies and protect health. While the effects of global trade policy on health have been documented, mental health considerations have been very limited. This analysis explores the impact of global trade policy on a number of socio-structural determinants of mental health including poverty, social inequality, food security, mental health systems, alcohol consumption, access to pharmaceuticals and occupational health. The evidence reviewed makes a strong argument that global trade is likely to have a significant impact on mental health. However, the mental health outcomes of global trade will be influenced by a host of contextual factors and will therefore be heterogeneous. Preliminary recommendations for discussion are considered.
A Juvenile Justice Approach Built on Human Rights Principles
Authors: Hammarberg Thomas
Published: November 2008

This article by the Council of Europe Commissioner for Human Rights explains the importance of ensuring that juvenile justice approaches incorporate compliance with children's rights standards in the United Nations and the Council of Europe. It explains the importance of a high age of criminal responsibility, the incorporation into juvenile justice systems of education, reintegration and rehabilitation, and the need to ensure that detention is a last resort. The importance of ensuring that children receive a prompt and a fair trial is also highlighted. The article concludes with reference to measures being adopted by the Council of Europe to secure the rights of children in conflict with the law.
The Empirical Implications of Electoral College Reform
Authors: Goux Darshan J. , Hopkins David A.
Published: November 2008

The events of 2000 inspired renewed debate in America over the manner in which presidents are chosen, with many critics of the existing system favoring the alternative of direct popular election. These advocates of reform often argue that the strategic environment shaped by the electoral college distorts the democratic process by encouraging candidates to focus on a few politically competitive states while virtually ignoring the majority of the nation. Using empirical evidence, we evaluate the claim that the electoral college is antidemocratic due to its effect on campaign strategy. Furthermore, we consider the possible alternative strategies adopted by candidates under a hypothetical national popular presidential election. We conclude that many of the consequences of electoral college reform, unacknowledged by its proponents, would not necessarily make presidential elections substantially more democratic, and we call for additional empirical research on a topic that has heretofore been dominated by theoretical debate and speculation.
Pre-eclampsia: the pivotal role of the placenta in its pathophysiology and markers for early detection
Authors: Hawfield Amret , Freedman Barry I.
Published: November 2008

Pre-eclampsia is the second leading cause of maternal morbidity and mortality in the United States. Infants born to affected mothers face a five-fold increase in death rate [Lain and Roberts 2002; National Heart Lung and Blood Institute 2001]. Although pre-eclampsia has been recognized by physicians for millennia, relatively little is known about its pathogenesis or prevention. Predicting its development is often extremely difficult, perhaps leading the Greeks to use the name 'eklampsis' meaning lightening. Recent studies provide novel insights into the role of the placenta in the development of pre-eclampsia and demonstrate novel markers to assist in predicting the onset of disease and potential therapeutic targets. Following an introduction which highlights the classification of hypertensive disorders of pregnancy and defines incidence and adverse outcomes of pre-eclampsia, this manuscript will discuss the role of the placenta in the pathophysiology of pre-eclampsia and recent markers that may predict its onset.
Review: Therapeutic advances and future prospects in immune-mediated inflammatory myopathies
Authors: Dalakas Marinos C.
Published: November 2008

The inflammatory myopathies include three distinct entities: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). A T-cell-mediated cytotoxic process in PM and IBM and a complement-mediated microangiopathy in DM are the hallmarks of the underlying autoimmune processes. The most consistent therapeutic problem remains the distinction of PM from the difficult-to-treat mimics such as s-IBM, necrotizing myopathies and inflammatory dystrophies. This review provides a step-by-step approach to the treatment of inflammatory myopathies, highlights the common pitfalls and mistakes in therapy, and identifies the emerging new therapies. In uncontrolled studies, PM and DM respond to prednisone to some degree and for some period of time, while a combination with one immunosuppressive drug (azathioprine, cyclosporine, mycophenolate, methotrexate) offers additional benefit or steroid-sparing effect. In contrast, IBM is resistant to most of these therapies, most of the time. Controlled studies have shown that IVIg is effective and safe for the treatment of DM, where is used as a second, and at times first, line therapy. IVIg seems to be also effective in the majority of patients with PM based on uncontrolled series, but it offers transient help to a small number of patients with IBM especially those with dysphagia. Bona fide patients with PM and DM who become resistant to the aforementioned therapies, may respond to rituximab, tacrolimus or rarely to an tumor necrosis factor alpha inhibitor. For IBM patients, experience with alemtuzumab, a T-cell-depleting monoclonal antibody, is encouraging.
Review: Future perspectives for brain pharmacotherapies: implications of drug transport processes at the blood—brain barrier
Authors: Hermann Dirk M.
Published: November 2008

Years ago, ischemic stroke was regarded as a model disease for the development of neuroprotective therapies by the pharmacological industry. Results were disappointing. There are still no treatments available allowing the rescue of brain tissue once a stroke has occurred. Study failure is not only a problem in the stroke field. In other neurodegenerative conditions and in non-degenerative brain disorders, progress in drug development was also rather scarce until recently. An important factor in drug failure is the blood—brain barrier, which expresses active transporters that eliminate drugs from the brain. These transporters exhibit strong variations between different animals, which make it difficult to predict brain concentrations of drugs over species barriers. This paper claims that more detailed knowledge about:

(1) the biology of blood—brain barrier transporters; (2) their regulation in brain disease,

(3) the affinity of transporters to candidate drugs; and (4) the accumulation of drugs in brain tissue is needed for the overall success of clinical trials to be improved. An alternative strategy could be the use of disease-modifying treatments that do not have to enter the brain to exert their function. As such, restorative and anti-inflammatory strategies acting at the blood—brain interface might gain therapeutic potential in the future.
Review: Escalating immunotherapy of multiple sclerosis
Authors: Rieckmann Peter , Traboulsee Anthony , Devonshire Virginia , Oger Joel
Published: November 2008

Basic disease-modifying treatment for relapsing forms of active multiple sclerosis (MS) is now available in many countries with high prevalence rates, for this chronic inflammatory disease of the central nervous system. Several lines of evidence support early immunomodulatory treatment with either recombinant interferon-beta or glatiramer acetate, and positive results from phase III trials encourage start of treatment even in patients with clinically isolated syndromes (CIS). However, currently available drugs for basic therapy are only partially effective and patients may still encounter relapses or disease progression. As treatment-refractory, clinically active MS can quickly lead to irreversible neurological disability there is an urgent need for effective escalating strategies. Patients with suboptimal treatment response to basic therapy have been treated with combination therapies, cytotoxic drugs (such as mitoxantrone and cyclophosphamide) or autologous hematopoietic stem cell transplantation. Recently, the monoclonal antibody, natalizumab, was added to this armamentarium. None of these strategies have been vigorously evaluated in large randomized, controlled phase III trials with patients who failed basic therapy. Therefore, the decision to escalate immunotherapy is still based on limited evidence. This article will review potential candidates for intensified immunosuppression and call for innovative study designs to better evaluate escalating immunotherapy in MS.
Review: Recombinant human erythropoietin: novel strategies for neuroprotective/neuroregenerative treatment of multiple sclerosis
Authors: Bartels Claudia , Späte Kira , Krampe Henning , Ehrenreich Hannelore
Published: November 2008

Treatment of multiple sclerosis (MS) is still unsatisfactory and essentially non-existing for the progressive course of the disease. Recombinant human erythropoietin (EPO) may be a promising neuroprotective/neuroregenerative treatment of MS. In the nervous system, EPO acts anti-apoptotic, antioxidative, anti-inflammatory, neurotrophic and plasticity-modulating. Beneficial effects have been shown in animal models of various neurological and psychiatric diseases, including different models of experimental autoimmune encephalomyelitis. EPO is also effective in human brain disease, as shown in double-blind placebo-controlled clinical studies on ischemic stroke and chronic schizophrenia. An exploratory study on chronic progressive MS yielded lasting improvement in motor and cognitive performance upon high-dose long-term EPO treatment.
Both alleles of PSF1 are required for maintenance of pool size of immature hematopoietic cells and acute bone marrow regeneration
Authors: Ueno Masaya , Itoh Machiko , Sugihara Kazushi , Asano Masahide , Takakura Nobuyuki
Published: November 2008

Hematopoietic stem cells (HSCs) have a very low rate of cell division in the steady state; however, under conditions of hematopoietic stress, these cells can begin to proliferate at high rates, differentiate into mature hematopoietic cells, and rapidly reconstitute ablated bone marrow (BM). Previously, we isolated a novel evolutionarily conserved DNA replication factor, PSF1 (partner of SLD5-1), from an HSC-specific cDNA library. In the steady state, PSF1 is expressed predominantly in CD34+KSL (c-kit+/Sca-1+/Lineage−) cells and progenitors, whereas high levels of PSF1 expression are induced in KSL cells after BM ablation. In 1-year-old PSF1+/− mice, the pool size of stem cells and progenitors is decreased. Whereas young PSF1+/− mutant mice develop normally, are fertile, and have no obvious differences in hematopoiesis in the steady state compared with wild-type mice, intravenous injection of 5-fluorouracil (5-FU) is lethal in PSF1+/− mice, resulting from a delay in induction of HSC proliferation during ablated BM reconstitution. Overexpression studies revealed that PSF1 regulates molecular stability of other GINS components, including SLD5, PSF2, and PSF3. Our data indicate that PSF1 is required for acute proliferation of HSCs in the BM of mice.
Abnormal megakaryocyte morphology and proplatelet formation in mice with megakaryocyte-restricted MYH9 inactivation
Authors: Eckly Anita , Strassel Catherine , Freund Monique , Cazenave Jean-Pierre , Lanza François , Gachet Christian , Léon Catherine
Published: November 2008

Mutations in the MYH9 gene encoding nonmuscle myosin IIA lead to macrothrombocytopenia as observed in MYH9-related disorders. We used mice with megakaryocyte-restricted MYH9 inactivation to explore the role of myosin in thrombopoiesis. In situ, bone marrow MYH9Δ megakaryocytes were irregularly shaped, appearing leaky with poorly defined limits. The demarcation membranes were abnormally organized and poorly developed, pointing to an insufficient reservoir for the future formation of platelets. The cytoskeletal-rich peripheral zone was lacking due to the absence of the myosin filament network that normally surrounds the granular zone in wild-type cells. In vitro studies of cultured cells showed that MYH9Δ megakaryocytes were unable to form stress fibers upon adhesion to collagen, suggesting that the leaky shape results from defects in internal tension and anchorage to the extracellular environment. Surprisingly, the proportion of cells extending proplatelets was increased in MYH9Δ megakaryocytes and the proplatelet buds were larger. Overall, this study provides evidence for a role of myosin in different steps of megakaryocyte development through its participation in the maintenance of cell shape, formation and organization of the demarcation membranes and the peripheral zone, anchorage to the extracellular matrix, and proplatelet formation.
Frailty Intervention Trial (FIT)
Authors: Fairhall Nicola , Aggar Christina , Kurrle Susan E , Sherrington Catherine , Lord Stephen , Lockwood Keri , Monaghan Noeline , Cameron Ian D
Published: November 2008

Background

Frailty is a term commonly used to describe the condition of an older person who has chronic health problems, has lost functional abilities and is likely to deteriorate further. However, despite its common use, only a small number of studies have attempted to define the syndrome of frailty and measure its prevalence. The criteria Fried and colleagues used to define the frailty syndrome will be used in this study (i.e. weight loss, fatigue, decreased grip strength, slow gait speed, and low physical activity). Previous studies have shown that clinical outcomes for frail older people can be improved using multi-factorial interventions such as comprehensive geriatric assessment, and single interventions such as exercise programs or nutritional supplementation, but no interventions have been developed to specifically reverse the syndrome of frailty.

We have developed a multidisciplinary intervention that specifically targets frailty as defined by Fried et al. We aim to establish the effects of this intervention on frailty, mobility, hospitalisation and institutionalisation in frail older people.

Methods and Design

A single centre randomised controlled trial comparing a multidisciplinary intervention with usual care. The intervention will target identified characteristics of frailty, functional limitations, nutritional status, falls risk, psychological issues and management of chronic health conditions. Two hundred and thirty people aged 70 and over who meet the Fried definition of frailty will be recruited from clients of the aged care service of a metropolitan hospital. Participants will be followed for a 12-month period.

Discussion

This research is an important step in the examination of specifically targeted frailty interventions. This project will assess whether an intervention specifically targeting frailty can be implemented, and whether it is effective when compared to usual care. If successful, the study will establish a new approach to the treatment of older people at risk of further functional decline and institutionalisation. The strategies to be examined are readily transferable to routine clinical practice and are applicable broadly in the setting of aged care health services.

Trial Registration

Australian New Zealand Clinical Trails Registry: ACTRN12608000250336.
Exposure to ambient concentrations of particulate air pollution does not influence vascular function or inflammatory pathways in young healthy individuals
Authors: Bräuner Elvira V , Møller Peter , Barregard Lars , Dragsted Lars O , Glasius Marianne , Wåhlin Peter , Vinzents Peter , Raaschou-Nielsen Ole , Loft Steffen
Published: November 2008

Background

Particulate air pollution is associated with increased risk of cardiovascular events although the involved mechanisms are poorly understood. The objective of the present study was to investigate the effects of controlled exposure to ambient air fine and ultrafine particles on microvascular function and biomarkers related to inflammation, haemostasis and lipid and protein oxidation.

Methods

Twenty-nine subjects participated in a randomized, two-factor crossover study with or without biking exercise for 180 minutes and with 24 hour exposure to particle rich (number concentrations, NC: 11600 ± 5600 per cm3, mass concentrations: 13.8 ± 7.4 μg/m3 and 10.5 ± 4.8 μg/m3 for PM10-2.5 and PM2.5, respectively) or particle filtered (NC: 555 ± 1053 per cm3) air collected above a busy street. Microvascular function was assessed non-invasively by measuring digital peripheral artery tone following arm ischemia. Biomarkers included haemoglobin, red blood cells, platelet count, coagulation factors, C-reactive protein, fibrinogen, interleukin-6, tumour necrosis factor α, lag time to copper-induced oxidation of plasma lipids and protein oxidation measured as 2-aminoadipic semialdehyde in plasma.

Results

No statistically significant differences were observed on microvascular function or the biomarkers after exposure to particle rich or particle filtered air.

Conclusion

This study indicates that exposure to air pollution particles at outdoor concentrations is not associated with detectable systemic inflammation, lipid or protein oxidation, altered haemostasis or microvascular function in young healthy participants.
Ewing sarcoma of the mandible mimicking an odontogenic abscess – a case report
Authors: Gosau Martin , Baumhoer Daniel , Ihrler Stefan , Kleinheinz Johannes , Driemel Oliver
Published: November 2008

Ewing sarcoma (ES) of the mandible is rare and can be mistaken for inflammation of dental origin. We present a 24-year old male patient which underwent radical tumour surgery and primary reconstruction with a microvascular osteoseptocutaneous free fibular flap as well as postoperative adjuvant chemotherapy. Incomplete osseous tumour resection required a second intervention. This case report recapitulates the clinical and histopathological findings in oral ES, demonstrates its sometimes difficult diagnosis and discusses the (dis-)advantages of primary osseous reconstruction in ablative tumour surgery.
Two-term AVO inversion: Equivalences and new methods
Authors: Ursenbach Charles P. , Stewart Robert R.
Published: November 2008

Most amplitude-variation-with-offset (AVO) studies use two-parameter inversion methods that are approximations of a more general three-parameter method based on the Aki-Richards approximation. Two-parameter methods are popular because the three-parameter inversion is often plagued by numerical instability. Reducing the dimensionality of the parameter space stabilizes the inversion. A variety of constraints can accomplish this, and these lead to the multiplicity of current two-parameter methods. It would be useful to understand relationships between various two-parameter methods. To this end, we derive formal expressions for inversion errors of each method. Using these expressions, conversion formulas are obtained that allow the flexibility to convert results of any two-parameter method to those of any other two-parameter method. The only requirement for the equivalence of methods is that the maximum angle of incidence be at least a few degrees less than the critical angle. In addition, error expressions result in a new formulation for a two-parameter AVO tool that combines strengths of two commonly used methods. The expressions also suggest a simple way to incorporate information from well-log calibration into legacy AVO inversions. These results should be helpful in resource exploration.
Crosswell seismic imaging for deep gas reservoir characterization
Authors: Yu Gang , Marion Bruce , Bryans Brad , Carrillo Pedro , Guo Wankui , Pang Yanming , Kong Fanzhong
Published: November 2008

A gas discovery in the Shengping area of the Daqing Oilfield in China was made recently in a large-scale volcanic depositional environment. Because gas in the heterogeneities of formations broken by tectonic activity and localized volcanic eruptions is not common, researchers sought a more detailed reservoir characterization before developing the field. Crosswell seismic data were used to augment existing 3D surface seismic, log, and core data. This provided data at five times the resolution of the surface seismic data to bridge the gap in resolution between surface seismic and well data. Crosswell seismic data were acquired in two wells, [Formula: see text] apart, and processed to provide images of reflectivity, velocity, and formation properties from sections produced by amplitude-versus-angle (AVA) inversion. The state of the art in crosswell seismic is summarized briefly, reviewing progress in data acquisition and data processing over several decades of crosswell technology development. A detailed description of the data acquisition and data processing applied to the data from the Shengping area is also given. An integrated interpretation of the crosswell images with the surface seismic and log data was used to produce a more detailed geologic model. The enhanced geologic model is being used to plan strategic development of the reservoir and to evaluate possible infill well locations.