bluuebunny/crossref_metadata_2025 huggingface dataset:
“Most people are simply not designed to eat pasta”: evolutionary explanations for obesity in the low-carbohydrate diet movement
Authors: Knight Christine
Published: February 2011

Low-carbohydrate diets, notably the Atkins Diet, were particularly popular in Britain and North America in the late 1990s and early 2000s. On the basis of a discourse analysis of bestselling low-carbohydrate diet books, I examine and critique genetic and evolutionary explanations for obesity and diabetes as they feature in the low-carbohydrate literature. Low-carbohydrate diet books present two distinct neo-Darwinian explanations of health and body-weight. First, evolutionary nutrition is based on the premise that the human body has adapted to function best on the diet eaten in the Paleolithic era. Second, the thrifty gene theory suggests that feast-or-famine conditions during human evolutionary development naturally selected for people who could store excess energy as body fat for later use. However, the historical narratives and scientific arguments presented in the low-carbohydrate literature are beset with generalisations, inconsistencies and errors. These result, I argue, from the use of the primitive as a discursive “blank slate” onto which to project ideals perceived to be lacking in contemporary industrialised life.
Breaking away from Mediocre Complacency to a Prosperous Future
Authors: Loser Claudio , Sood Anil
Published: February 2011

Latin America has been one of the most prosperous regions among the group of emerging economies. However, particularly in recent decades, Latin America has not managed to keep up with the growth of other emerging economies. This article lays out some reasons to explain the region’s lackluster economic growth. It proposes that the region and its leaders need to promote a vision of a vibrant, fastgrowing economic region where more inclusion, higher productivity, and increased competition and openness are the objects of national policy. While no regions are equivalent, the example of East Asia, even with its own vulnerabilities provides important lessons for Latin America, as it devises policies to free it from the middle-income trap.
Requirements for Infrastructure Investment in Latin America Under Alternate Growth Scenarios
Authors: Kohli Harpaul Alberto , Basil Phillip
Published: February 2011

This study estimates requirements for infrastructure investment in 21 Latin American countries for the period 2011–2040 using a structural equation model. Needs total about 4 percent of GDP. Projections are provided for both a high-growth convergence scenario and a low-growth business-as-usual scenario. These costs represent minimum investments necessary to support expected economic growth. Costs are presented separately and in total for new-capacity investment and maintenance for 10 sectors: airports, electricity, fixed broadband, landlines, mobile telephony, ports, rail, paved roads, sanitation, and water. Country coverage comprises Argentina, Belize, Bolivia, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Guyana, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, Suriname, Uruguay, and Venezuela. The model differs from past studies of regionwide long-term infrastructure investment needs in five features: (1) It considers alternate GDP growth scenarios; (2) It employs a structural equation model using instrumental variables to provide unbiased, consistent projections for both GDP growth scenarios (Instrumented variables are urbanization and the shares in GDP of agriculture, manufacturing, and services); (3) Mobile phone investment costs are not constant but instead vary with population density; (4) Two additional, wealthier countries are included in modeling to prevent forecasting outside the range of the independent variables’ values used to construct the model, and; (5) Timing of new-capacity investments is distributed over multiple years and varies by sector.
Transcranial Magnetic Stimulation at the Interface with Other Techniques
Authors: Ziemann Ulf
Published: February 2011

Transcranial magnetic stimulation (TMS) has developed into a very powerful tool in the hands of basic and clinical neuroscientists alike to study function and dysfunction of the human brain noninvasively and painlessly. However, as a stand-alone technique, the potential of TMS to gain knowledge is relatively limited. This potential can be strongly enhanced by combining TMS with simultaneous measurements in other electrophysiological (EEG) or imaging modalities (PET, fMRI, NIRS, MRS) or by combining TMS with exposure to neuroactive drugs (pharmaco-TMS). This review provides an up-to-date synopsis of these combined approaches and highlights important examples that have advanced our understanding of how TMS interacts with neuronal networks in the human brain.
Small Changes, Big Impact
Authors: Ehrnhoefer Dagmar E. , Sutton Liza , Hayden Michael R.
Published: February 2011

Huntington disease (HD) is a neurodegenerative disorder caused by an elongated polyglutamine tract in huntingtin (htt). htt normally undergoes different posttranslational modifications (PTMs), including phosphorylation, SUMOylation, ubiquitination, acetylation, proteolytic cleavage, and palmitoylation. In the presence of the HD mutation, some PTMs are significantly altered and can result in changes in the clinical phenotype. A rate-limiting PTM is defined as one that can result in significant effects on the phenotype in animal models. For example, the prevention of proteolysis at D586 as well as constitutive phosphorylation at S13 and S16 can obviate the expression of phenotypic features of HD. The enzymes involved in these modifications such as caspase-6, the IκB kinase (IKK) complex, and still to be characterized phosphatases therefore represent promising therapeutic targets for HD. Identifying and testing specific modulators of PTMs now constitute the next big challenges in order to further validate these targets and proceed towards the goal of a mechanism-based treatment for HD.
Older Offenders and Homicide: What Can We Learn From the Chicago Homicide Dataset?
Authors: Stanback Brianne , King-Kallimanis Bellinda L.
Published: February 2011

Older offenders are the fastest growing group in the U.S. prison system, although little is known about older offenders who commit homicides, their v ictims, or the details of the crime. The current study inv estigated cov ariates associated with four categories of homicide: intimate, family, acquaintance, and unrelated v ictims. Using the Chicago Homicide Dataset, a subsample was created of offenders 50 years and older ( n = 972). In a multinomial multiv ariate regression, where unrelated homicides were defined as the base outcome, it was rev ealed in intimate and family comparisons that women were at a significantly higher risk of v ictimization. Crimes that occurred in residences were significantly associated with all three homicides groups compared with unrelated homicides. The use of alcohol was significant in crimes where an acquaintance was the v ictim. The results suggest that earlier identification of at-risk older adults and more social support in the community could be integral in the prev ention of v iolent crimes.
Linking Criminal History to Crime Scene Behavior in Single-Victim and Serial Homicide: Implications for Offender Profiling Research
Authors: Trojan Carrie , Salfati C.Gabrielle
Published: February 2011

Research has consistently shown that the average individual who commits one or more homicides is likely to have a criminal record, but little research has focused on whether individuals behave in a psychologically or thematically consistent way in both their homicide crime scene actions and prior offending. The current study examines the crime scene behaviors of single and serial homicide offenders to identify patterns that can be compared to themes in their prior offending. The results showed that crime scene actions occurred on a continuum from hostile to cognitive actions with serial offenders concentrating at the latter end of this continuum. However, only a small group of the serial homicide offenders committed similarly themed prior offenses and homicide behaviors, which raises questions regarding the hypotheses of behavioral consistency underlying offender profiling.
Measuring TeraGrid: workload characterization for a high-performance computing federation
Authors: Hart David L
Published: February 2011

TeraGrid has deployed a significant monitoring and accounting infrastructure in order to understand its operational success. In this paper, we present an analysis of the jobs reported by TeraGrid for 2008. We consider the workload from several perspectives: traditional high-performance computing (HPC) workload characteristics; grid-oriented workload characteristics; and finally user- and group-oriented characteristics. We use metrics reported in prior studies of HPC and grid systems in order to understand whether such metrics provide useful information for managing and studying resource federations. This study highlights the importance of distinguishing between analyses of job patterns and work patterns; that small sets of users dominate the workload both in terms of job and work patterns; and that aggregate analyses across even loosely coupled federations, with incomplete information for individual systems, reflect patterns seen in more tightly coupled grids and in single HPC systems.
Changing Their Mind About Confessing to Police: The Role of Contextual Factors in Crime Confession
Authors: Deslauriers-Varin Nadine , Beauregard Eric , Wong Jennifer
Published: February 2011

This study aimed to investigate the offender’s decision making in crime confession during police interrogation. On the basis of a sample of 211 incarcerated offenders, the study showed that 21% of offenders changed their mind about confessing or not their crime following police interrogation. Logit regression indicated that contextual factors were associated with the offender’s final decision to confess after controlling for the offender’s initial decision. Multinomial regression further showed that offenders with a lengthy criminal record, advised by a lawyer, and facing drug-related charges characterized by weak police evidence were less likely to confess to the police, even when they initially planned to do so. Findings are discussed in light of the literature on crime confession.
Understanding Community Policing and Legitimacy-Seeking Behavior in Virtual Reality: A National Study of Municipal Police Websites
Authors: Rosenbaum Dennis P. , Graziano Lisa M. , Stephens Cody D. , Schuck Amie M.
Published: February 2011

Using a national probability sample of municipal police departments, this study provides the first systematic look at the prevalence, predictors, and content of municipal police websites in the United States. A content analysis revealed that police agencies with websites (42% of all police agencies nationwide in 2008) were more inclined to use websites to “push out” information rather than “pull in” information from the community. The results support the hypothesis that departments with a greater emphasis on community policing (defined by Law Enforcement Management and Administrative Statistics [LEMAS] data) would be more likely to have a website, exhibit greater transparency in the display of data and provide more opportunities for citizen input. Crime rate and population size were also important determinants of website creation and content, respectively. This study concludes that websites are underutilized by both the police and research communities.
Municipal Contracting With County Sheriffs for Police Services in California: Comparison of Cost and Effectiveness
Authors: Nelligan Peter J. , Bourns William
Published: February 2011

Rather than having a traditional, municipal police department nearly 30%of the 478 cities in California contract with their county sheriff for police services. The usual rationale is that contracting with the sheriff costs less than establishing and operating a city police department. This research investigates this issue by analyzing expenditure, crime, and other relevant data covering the 5-year period 2001-2005. It poses and answers the following questions: (1) Are the cities that contract (contract cities) similar to the cities that have their own police departments (department cities) on a range of characteristics that may affect the cost of policing? (2) Do statewide data show the claimed cost differential? (3) Are there differences in comparative costs between or within regions and counties in the state? and (4) Does contracting cost less because of less effective policing as measured by percentages of violent and property crimes cleared? Contract cities are newer, less populous, less dense, wealthier, have less business activity, have lower numbers and rates of reported crime, and have fewer arrests. It is suggested that there is less police work in the contract cities, and that may affect cost. Mean annual per capita police expenditures are much lower in the contract cities statewide, in both the northern and southern regions, and in three of the four southern California counties where contracting is most prevalent. Finally, contract cities have on average significantly higher clearance rates for violent crimes than department cities (especially in Los Angeles County) and the same clearance rates for property crimes. It does not appear that contract cities are paying less because they are getting lower quality police service, at least as measured by crime clearances. Suggestions are made for further research on the contracting phenomenon.
Emerging diagnostic and therapeutic molecular imaging applications in vascular disease
Authors: Eraso Luis H , Reilly Muredach P , Sehgal Chandra , Mohler Emile R
Published: February 2011

Assessment of vascular disease has evolved from mere indirect and direct measurements of luminal stenosis to sophisticated imaging methods to depict millimeter structural changes of the vasculature. In the near future, the emergence of multimodal molecular imaging strategies may enable robust therapeutic and diagnostic (‘theragnostic’) approaches to vascular diseases that comprehensively consider structural, functional, biological and genomic characteristics of the disease in individualized risk assessment, early diagnosis and delivery of targeted interventions.This review presents a summary of recent preclinical and clinical developments in molecular imaging and theragnostic applications covering diverse atherosclerosis events such as endothelial activation, macrophage inflammatory activity, plaque neovascularization and arterial thrombosis. The main focus is on molecular targets designed for imaging platforms commonly used in clinical medicine including magnetic resonance, computed tomography and positron emission tomography. A special emphasis is given to vascular ultrasound applications, considering the important role this imaging platform plays in the clinical and research practice of the vascular medicine specialty.
Operationalizing and measuring language dominance
Authors: Treffers-Daller Jeanine
Published: February 2011

The aim of this article is to show how measures of lexical richness (Guiraud, 1954; Malvern, Richards, Chipere, & Durán, 2004) can be used to operationalize and measure language dominance among bilinguals. A typology of bilinguals is proposed based on these measures of lexical richness, and the validity of the typology is then investigated in an empirical study among two groups of bilingual informants with different language dominance profiles (25 Dutch—French bilinguals from Brussels and 24 French—English bilinguals from Paris). The most important advantage of the proposed operationalization is that it allows researchers carry out precise measurements of bilingual ability in languages or language varieties for which no standardized tests exist and that these measures can be calculated on oral data that have been collected in an informal and unobtrusive way, in a naturalistic setting.
Assessing bilingual attainment: macrostructural planning in narratives
Authors: Flecken Monique
Published: February 2011

The present study addresses questions concerning bilinguals’ attainment in the two languages by investigating the extent to which early bilinguals manage to apply the information structure required in each language when producing a complex text. In re-narrating the content of a film, speakers have to break down the perceived series of dynamic situations and structure relevant information into units that are suited for linguistic expression. The analysis builds on typological studies of Germanic and Romance languages which investigate the role of grammaticized concepts in determining core features in information structure. It takes a global perspective in that it focuses on factors that determine information selection and information structure that hold in macrostructural terms for the text as a whole (factors driving information selection, the temporal frame used to locate events on the time line, and the means used in reference management). A first comparison focuses on Dutch and German monolingual native speakers and shows that despite overall typological similarities, there are subtle though systematic differences between the two languages in the aforementioned areas of information structure. The analyses of the bilinguals focus on their narratives in both languages, and compares the patterns found to those found in the monolingual narratives. Findings show that the method used provides insights into the individual bilingual’s attainment in the two languages and identifies either balanced levels of attainment, patterns showing higher degrees of conformity with one of the languages, as well as bilingual-specific patterns of performance.
Predicting individual differences in L2 speakers’ gestures
Authors: Nagpal Jaya , Nicoladis Elena , Marentette Paula
Published: February 2011

While it is well known that there is a lot of variability in L2, researchers rarely measure the variability in L1 to predict the variability in L2. In this study we tested two explanations of the rate of gestures used in telling a story in L2: (1) a story-telling style underlying both L1 and L2 and (2) proficiency/fluency in L2. Hindi—English bilingual adults performed a story-telling task in their two languages. There was some support for the second predictor: the participants used more gestures in L2 than L1, consistent with gesturing to aid in accessing language. However, the results were strongly supportive of a story-telling style underlying both languages: the individual differences in gesture rate (along with the story length and the vocabulary variability) were highly correlated across languages but not correlated with L2 proficiency/fluency. These results illustrate the importance of studying L1 variability as an important predictor of L2 gesture use.
Should surfers be ostracized? Basic income, liberal neutrality, and the work ethos
Authors: Birnbaum Simon
Published: February 2011

Neutralists have argued that there is something illiberal about linking access to gift-like resources to work requirements. The central liberal motivation for basic income is to provide greater freedom to choose between different ways of life, including options attaching great importance to non-market activities and disposable time. As argued by Philippe Van Parijs, even those spending their days surfing should be fed. This article examines Van Parijs' dual commitment to a ‘real libertarian’ justification of basic income and the public enforcement of a strong work ethos, which serves to boost the volume of work at a given rate of taxation. It is argued (contra Van Parijs) that this alliance faces the neutrality objection: the work ethos will largely offset the liberal gains of unconditionality by radically restricting the set of permissible options available. A relaxed, non-obligatory ethos might avoid this implication. This view, however, is vulnerable to the structural exploitation objection: feasibility is achieved only because some choose to do necessary tasks to which most people have the same aversion. In light of these objections, the article examines whether there is a morally untainted feasibility path consistent with liberal objectives.
Republican freedom, rights, and the coalition problem
Authors: Dowding Keith
Published: February 2011

Republican freedom is freedom from domination juxtaposed to negative freedom as freedom from interference. Proponents argue that republican freedom is superior since it highlights that individuals lose freedoms even when they are not subject to interference, and claim republican freedom is more ‘resilient’. Republican freedom is trivalent, that is, it includes the idea that someone might be non-free to perform some actions rather than unfree, and in that sense everyone regards republican freedom as different from negative freedom. Trivalence makes republican freedom moralized according to negative libertarians. Beyond that, negative libertarians argue that all the supposed advantages of republican freedom are compatible with those of pure negative-freedom measures. That is, losses and gains of republican freedom are captured in measures of pure negative freedom, and any protection for republican freedom also protects negative freedom, ensuring each is equally resilient. Since republican freedom has no advantages over negative freedom, but has other problems (is moralized and is trivalent), negative freedom is superior. I examine this debate in this article through the ‘coalition problem’ for republican freedom. The coalition problem is that since there is always a coalition of others who could dominate any agent in any sphere, all agents are subject to domination, and hence no one can ever have republican freedom. Pettit’s simple solution to this reductio ad absurdum distinguishes potential from actual coalitions. Individuals are only dominated by actual coalitions, and not by potential ones. The simple solution highlights moralization problems as it demonstrates that domination cannot be purely institutionally defined, but requires consideration of dispositions and expectations about others’ behaviour. I argue that the differences between the ‘free man’ and ‘unfree person’ paradigmatic to republican arguments is best captured not by the difference between domination and interference, but, rather, from familiar distinctions between different types of rights and freedoms. Resilience is a practical matter that might track some of these familiar distinctions.
Taking reasonable pluralism seriously: an internal critique of political liberalism
Authors: Freyenhagen Fabian
Published: February 2011

The later Rawls attempts to offer a non-comprehensive, but nonetheless moral justification in political philosophy. Many critics of political liberalism doubt that this is successful, but Rawlsians often complain that such criticisms rely on the unwarranted assumption that one cannot offer a moral justification other than by taking a philosophically comprehensive route. In this article, I internally criticize the justification strategy employed by the later Rawls. I show that he cannot offer us good grounds for the rational hope that citizens will assign political values priority over non-political values in cases of conflict about political matters. I also suggest an alternative approach to justification in political philosophy (that is, a weak realist, Williams-inspired account) that better respects the later Rawls’s concern with non-comprehensiveness and pluralism than either his own view or more comprehensive approaches. Thus, if we take reasonable pluralism seriously, then we should adopt what Shklar aptly called ‘liberalism of fear’.
Urbanisms, worlding practices and the theory of planning
Authors: Roy Ananya
Published: February 2011

This special issue seeks to return the urban to the heart of planning theory. In doing so, it has three objectives. Firstly, it highlights particular urbanisms: how they are produced, lived and negotiated, from New York to Bogota. The articles thus draw attention to the multiplicity of urbanisms that constitute the contemporary world system, thereby disrupting the rather restricted analytics of global cities and world cities. Secondly, the articles pay careful attention to the forms of worlding at work in such urbanisms, demonstrating how the production of the urban takes place in the crucible of modernizing projects of development, regimes of immigration and governance and experiments with neoliberalism and market rule.Thirdly, this special issue seeks to explore the implications of such research and analysis for the field of ideas currently constituted as planning theory. How does the study of urbanisms allow a rigorous understanding of planning as the organization and transformation of space? How can planning theory make sense of seemingly unplanned spaces that lie outside the grid of visible order? In what ways is planning itself a worlding practice, such that models, best practices, expertise and capital circulate in transnational fashion, creating new worlds of planning common sense?
Deliberate improvisation: Planning highway franchises in Santiago, Chile
Authors: Silva Enrique R.
Published: February 2011

In the 1990s Chile and its capital, Santiago, experienced a transformative wave of large infrastructural development thanks to a post-authoritarian commitment to growth with equity. Celebrated as progressive neoliberalism, growth with equity signaled Chile’s political commitment to market-led development but with targeted forms of state-led resource distribution and interventions in the public realm. This meant the adoption of public—private partnerships (franchises) as the preferred instrument for developing public works, namely highways. Despite political fallout over the projects, especially in cities, franchise planning has been successful — it has produced a country and capital city with a world-class infrastructure. The program’s success, however, is not entirely rooted in its market approach to public works delivery. Franchise planning has worked thanks to a tightly planned business model and a political will to improvise plans to address the social dimensions of large projects. Franchised highways and the protests they have triggered are analyzed as an instance of deliberate improvisation. Deliberate improvisation is the conscious decision to plan without a plan, a political choice that signals the power of the state to define what should be planned, how and when. Deliberate improvisation highlights three key aspects of contemporary Chilean development: the state’s belief in its own power to manage people and place; the privileged position of markets in urban development and the political vulnerability of communities directly affected by large projects. Theoretically, deliberate improvisation bridges the analytical and procedural traditions in planning theory.
‘An area that governs itself ’: Informality, uncertainty and the management of street vending in New York City
Authors: Devlin Ryan Thomas
Published: February 2011

Laws governing street vending in New York City are confusing, convoluted, at times contradictory and difficult to enforce with any sort of consistency. In this context of uncertainty and illegibility, the practice of street vending in New York and particularly in central areas of Manhattan, is managed in decentralized, privatized and informal ways. The result is a variegated landscape of street vending that is less a function of the rights that the city grants to vendors or the restrictions the city puts on them and more a reflection of the power, influence, resources and resolve of property owners and business improvement districts to exert control over vending and manage public space using techniques of surveillance, intimidation and physical interventions in the streetscape. This article describes how this landscape is produced and lived, while demonstrating the ways in which uncertainty, legal ambiguity and informal practice are intrinsic to the current regime of spatial management in New York.
Hand–arm vibration syndrome: a common occupational hazard in industrialized countries
Authors: Heaver C. , Goonetilleke K. S. , Ferguson H. , Shiralkar S.
Published: February 2011

Regular exposure to hand-transmitted vibration can result in symptoms and signs of peripheral vascular, neurological and other disorders collectively known as the hand–arm vibration syndrome (HAVS). A significant proportion of workers can suffer from HAVS after using vibrating power tools. HAVS is a chronic and progressive disorder. Early recognition and prevention is the key to managing vibrating tool exposures and health effects. This article gives a broad overview of the condition with a detailed account of its pathogenesis, identification and management.
Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14)
Authors: Bochtler Tilmann , Hegenbart Ute , Heiss Christiane , Benner Axel , Moos Marion , Seckinger Anja , Pschowski-Zuck Stephanie , Kirn Désirée , Neben Kai , Bartram Claus R. , Ho Anthony D. , Goldschmidt Hartmut , Hose Dirk , Jauch Anna , Schonland Stefan O.
Published: February 2011

In multiple myeloma (MM) pathogenesis, hyperdiploidy and nonhyperdiploidy are recognized as 2 major cytogenetic pathways. Here, we assessed the role of hyperdiploidy in 426 patients with monoclonal plasma cell disorders, among them 246 patients with AL amyloidosis (AL), by interphase fluorescence in situ hybridization. Hyperdiploidy was defined by a well-established score requiring trisomies for at least 2 of the 3 chromosomes 5, 9, and 15. The hyperdiploidy frequency in AL was a mere 11% compared with 30% in monoclonal gammopathy of undetermined significance (P < .001) and 46% in AL with concomitant MM I (P < .001). Overall, hyperdiploidy was associated with an intact immunoglobulin, κ light chain restriction, higher age, and bone marrow plasmacytosis, but was unrelated to the organ involvement pattern in AL. Clustering of 6 major cytogenetic aberrations in AL by an oncogenetic tree model showed that hyperdiploidy and t(11;14) were almost mutually exclusive, whereas gain of 1q21 favored hyperdiploidy. Deletion 13q14 and secondary IgH translocations were equally distributed between ploidy groups. We conclude that the interphase fluorescence in situ hybridization–based hyperdiploidy score is also a feasible tool to delineate hyperdiploid patients in early-stage monoclonal gammopathies and that the cytogenetic pathogenetic concepts developed in MM are transferable to AL.
Development of IL-22–producing NK lineage cells from umbilical cord blood hematopoietic stem cells in the absence of secondary lymphoid tissue
Authors: Tang Qin , Ahn Yong-Oon , Southern Peter , Blazar Bruce R. , Miller Jeffery S. , Verneris Michael R.
Published: February 2011

Human secondary lymphoid tissues (SLTs) contain interleukin-22 (IL-22)–producing cells with an immature NK phenotype. Given their location, these cells are difficult to study. We have generated large numbers of NK22 cells from hematopoietic stem cells. HSC-derived NK22 cells show a CD56+CD117highCD94− phenotype, consistent with stage III NK progenitors. Like freshly isolated SLT stage III cells, HSC-derived NK22 cells express NKp44, CD161, CCR6, IL1 receptor, AHR, and ROR-γτ. IL-1β and IL-23 stimulation results in significant IL-22 but not interferon-γ production. Supernatant from these cells increases CD54 expression on mesenchymal stem cells. Thus, IL-22–producing NK cells can be generated in the absence of SLT. HSC-derived NK22 cells will be valuable in understanding this rare NK subset and create the opportunity for human translational clinical trials.
LDOC1 mRNA is differentially expressed in chronic lymphocytic leukemia and predicts overall survival in untreated patients
Authors: Duzkale Hatice , Schweighofer Carmen D. , Coombes Kevin R. , Barron Lynn L. , Ferrajoli Alessandra , O'Brien Susan , Wierda William G. , Pfeifer John , Majewski Tadeusz , Czerniak Bogdan A. , Jorgensen Jeffrey L. , Medeiros L. Jeffrey , Freireich Emil J , Keating Michael J. , Abruzzo Lynne V.
Published: February 2011

We previously identified LDOC1 as one of the most significantly differentially expressed genes in untreated chronic lymphocytic leukemia (CLL) patients with respect to the somatic mutation status of the immunoglobulin heavy-chain variable region genes. However, little is known about the normal function of LDOC1, its contribution to the pathophysiology of CLL, or its prognostic significance. In this study, we have investigated LDOC1 mRNA expression in a large cohort of untreated CLL patients, as well as in normal peripheral blood B-cell (NBC) subsets and primary B-cell lymphoma samples. We have confirmed that LDOC1 is dramatically down-regulated in mutated CLL cases compared with unmutated cases, and have identified a new splice variant, LDOC1S. We show that LDOC1 is expressed in NBC subsets (naive > memory), suggesting that it may play a role in normal B-cell development. It is also expressed in primary B-cell lymphoma samples, in which its expression is associated with somatic mutation status. In CLL, we show that high levels of LDOC1 correlate with biomarkers of poor prognosis, including cytogenetic markers, unmutated somatic mutation status, and ZAP70 expression. Finally, we demonstrate that LDOC1 mRNA expression is an excellent predictor of overall survival in untreated CLL patients.
KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia
Authors: He Jin , Nguyen Anh Tram , Zhang Yi
Published: February 2011

The histone H3 lysine 36 dimethyl–specific demethylase KDM2b/JHDM1b, which is highly expressed in various human leukemias, was previously found to be important in regulating cell proliferation and cellular senescence. However, its functions in leukemia development and maintenance are unclear. Here, we demonstrate that ectopic expression of Kdm2b/Jhdm1b is sufficient to transform hematopoietic progenitors. Conversely, depletion of Kdm2b/Jhdm1b in hematopoietic progenitors significantly impairs Hoxa9/Meis1-induced leukemic transformation. In leukemic stem cells, knockdown of Kdm2b/Jhdm1b impairs their self-renewing capability in vitro and in vivo. The functions of Kdm2b/Jhdm1b are mediated by its silencing of p15Ink4b expression through active demethylation of histone H3 lysine 36 dimethyl. Thus, our study suggests that Kdm2b/Jhdm1b functions as an oncogene and plays a critical role in leukemia development and maintenance.
Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria
Authors: Troadec Marie-Berengere , Warner David , Wallace Jared , Thomas Kirk , Spangrude Gerald J. , Phillips John , Khalimonchuk Oleh , Paw Barry H. , Ward Diane McVey , Kaplan Jerry
Published: February 2011

Mitoferrin1 is 1 of 2 homologous mitochondrial iron transporters and is required for mitochondrial iron delivery in developing erythroid cells. We show that total deletion of Mfrn1 in embryos leads to embryonic lethality. Selective deletion of Mfrn1 in adult hematopoietic tissues leads to severe anemia because of a deficit in erythroblast formation. Deletion of Mfrn1 in hepatocytes has no phenotype or biochemical effect under normal conditions. In the presence of increased porphyrin synthesis, however, deletion of Mfrn1 in hepatocytes results in a decreased ability to convert protoporphyrin IX into heme, leading to protoporphyria, cholestasis, and bridging cirrhosis. Our results show that the activity of mitoferrin1 is required to manage an increase in heme synthesis. The data also show that alterations in heme synthesis within hepatocytes can lead to protoporphyria and hepatotoxicity.
Increased arginase activity contributes to airway remodelling in chronic allergic asthma
Authors: Maarsingh H. , Dekkers B.G.J. , Zuidhof A.B. , Bos I.S.T. , Menzen M.H. , Klein T. , Flik G. , Zaagsma J. , Meurs H.
Published: February 2011

Airway remodelling, characterised by increased airway smooth muscle (ASM) mass, subepithelial fibrosis, goblet cell hyperplasia and mucus gland hypertrophy, is a feature of chronic asthma. Increased arginase activity could contribute to these featuresviaincreased formation of polyamines andl-proline downstream of the arginase productl-ornithine, andviareduced nitric oxide synthesis.

Using the specific arginase inhitibor 2(S)-amino-6-boronohexanoic acid (ABH), we studied the role of arginase in airway remodelling using a guinea pig model of chronic asthma. Ovalbumin-sensitised guinea pigs were treated with ABH or PBSviainhalation before each of 12 weekly allergen or saline challenges, and indices of arginase activity, and airway remodelling, inflammation and responsiveness were studied 24 h after the final challenge.

Pulmonary arginase activity of repeatedly allergen-challenged guinea pigs was increased. Allergen challenge also increased ASM mass and maximal contraction of denuded tracheal rings, which were prevented by ABH. ABH also attenuated allergen-induced pulmonary hydroxyproline (fibrosis) and putrescine, mucus gland hypertrophy, goblet cell hyperplasia, airway eosinophilia and interleukin-13, whereas an increasedl-ornithine/l-citrulline ratio in the lung was normalised. Moreover, allergen-induced hyperresponsiveness of perfused tracheae was fully abrogated by ABH.

These findings demonstrate that arginase is prominently involved in allergen-induced airway remodelling, inflammation and hyperresponsiveness in chronic asthma.
Effects of cigarette smoke and hypoxia on pulmonary circulation in the guinea pig
Authors: Ferrer E. , Peinado V.I. , Castañeda J. , Prieto-Lloret J. , Olea E. , González-Martín M.C. , Vega-Agapito M.V. , Díez M. , Domínguez-Fandos D. , Obeso A. , González C. , Barberà J.A.
Published: February 2011

Cigarette smoke (CS) and chronic hypoxia (CH) can produce pulmonary hypertension. Similarities and differences between both exposures and their interaction have not been explored. The aim of the present study was to investigate the effects of CS and CH, as single factors or in combination, on the pulmonary circulation in the guinea pig.

51 guinea pigs were exposed to CS for 12 weeks and 32 were sham-exposed. 50% of the animals in each group were additionally exposed to CH for the final 2 weeks. We measured pulmonary artery pressure (Ppa), and the weight ratio between the right ventricle (RV) and left ventricle plus the septum. Pulmonary artery contractility in response to noradrenaline (NA), endothelium-dependent vasodilatation and distensibility were evaluated in organ bath chambers. The number of small intrapulmonary vessels showing immunoreactivity to smooth muscle (SM) α-actin and double elastic laminas was assessed microscopically.

CS and CH induced similar increases ofPpaand RV hypertrophy (p<0.05 for both), effects that were further enhanced when both factors were combined. CH increased the contractility to NA (p<0.01) and reduced the distensibility (p<0.05) of pulmonary arteries. Animals exposed to CS showed an increased number of small vessels with positive immunoreactivity to SM α-actin (p<0.01) and those exposed to CH a greater proportion of vessels with double elastic laminas (p<0.05).

We conclude that CH amplifies the detrimental effects of CS on the pulmonary circulation by altering the mechanical properties of pulmonary arteries and enhancing the remodelling of pulmonary arterioles.
Elemental carbon exposure and lung function in schoolchildren from Mexico City
Authors: Barraza-Villarreal A. , Escamilla-Nuñez M.C. , Hernández-Cadena L. , Texcalac-Sangrador J.L. , Sienra-Monge J.J. , del Río-Navarro B.E. , Cortez-Lugo M. , Sly P.D. , Romieu I.
Published: February 2011

Though exposure to air pollution has a detrimental effect on respiratory health, few studies have examined the association between elemental carbon exposure and lung function among schoolchildren. The aim of the present study was to present the association between short-term elemental carbon exposure and lung function in schoolchildren from Mexico City.

55 asthmatic and 40 non-asthmatic children were followed for an average of 22 weeks. A spirometry test was performed every 15 days during follow-up. Portable air samplers collected particulate matter onto Teflon filters. Gravimetric analysis was conducted and elemental carbon was quantified using transmission densitometry. The association between the main variables was analysed using linear mixed effects models.

The mean±sdof elemental carbon light absorption was 92.7±54.7 Mm−1. An increase of one interquartile range in the 24-h average of elemental carbon (100.93 Mm−1) was associated with a significant negative impact on forced expiratory volume in 1 s (FEV1) (-62.0 (95% CI -123.3– -1.2) mL) and forced expiratory flow at 25–75% of forced vital capacity (FVC) (FEF25–75%) (-111 (95% CI -228.3– -4.1) mL) among asthmatic children, equal to 3.3% and 5.5%, respectively; and on FEV1(-95.0 (95% CI -182.3– -8.5) mL) and FVC (-105.0 (95% CI -197.0– -13.7) mL) among non-asthmatic children.

Exposure to elemental carbon resulted in an important negative effect on lung function in atopic schoolchildren, regardless of asthma status.
Multi-symptom asthma as an indication of disease severity in epidemiology
Authors: Ekerljung L. , Bossios A. , Lötvall J. , Olin A-C. , Rönmark E. , Wennergren G. , Torén K. , Lundbäck B.
Published: February 2011

Epidemiological questionnaires have failed to identify individuals with severe asthma. The extent of symptoms of asthma can, however, be easily established in epidemiology, by identification of multiple symptoms. We hypothesise that reporting of multiple symptoms of asthma reflects uncontrolled disease and is a sign of more severe asthma. The aims of the current study were, therefore, to determine the prevalence and determinants of multi-symptom asthma.

A postal questionnaire was sent to 30,000 randomly selected individuals aged 16–75 yrs. A subgroup underwent clinical examinations. Multi-symptom asthma was defined as reported physician-diagnosed asthma, use of asthma medication, recurrent wheeze, attacks of shortness of breath and at least one additional respiratory symptom.

The prevalence of multi-symptom asthma was 2.0%, and it was more common among females (2.4versus1.5%; p<0.001) and those with a body mass index >30 kg·m-2. Multi-symptom asthmatics had lower forced expiratory volume in 1 s, higher exhaled nitric oxide fraction and more pronounced hyperresponsiveness. Family history of both asthma and allergy (OR 7.3), and occupational exposure to gas dust or fumes (OR 2.0) were also significant risk factors.

Multi-symptom asthmatics comprise 2% of the general population; multi-symptom asthma is related to signs of more severe disease and could be used as an epidemiological marker of disease severity.
Outcomes of hospitalisation for right heart failure in pulmonary arterial hypertension
Authors: Campo A. , Mathai S.C. , Le Pavec J. , Zaiman A.L. , Hummers L.K. , Boyce D. , Housten T. , Lechtzin N. , Chami H. , Girgis R.E. , Hassoun P.M.
Published: February 2011

The aim of this study was to examine the causes and outcomes of hospitalisation in patients with pulmonary arterial hypertension (PAH).

205 consecutive hospitalisations occurring between 2000 and 2009 in 90 PAH patients were studied.

The leading causes for hospitalisation were right heart failure (RHF; 56%), infection (16%) and bleeding disorders (8%). For patients with RHF, in-hospital mortality was 14% overall, 46% for patients receiving inotropes and 48% for those admitted to the intensive care unit. The predictors for in-hospital mortality were the presence of connective tissue disease (CTD) (OR 4.92), systolic blood pressure <100 mmHg (OR 4.32) and Na ≤136 mEq·L−1(OR 4.29). Mortality after discharge was 13, 26 and 35% at 3, 6 and 12 months, respectively. World Health Organization functional class prior to admission, renal dysfunction, Charlson comorbidity index, and the presence of CTD were all predictors of mortality after discharge.

Hyponatraemia and low systolic blood pressure upon admission and underlying CTD are the main prognostic factors for in-hospital mortality in patients with PAH admitted for RHF. The short-term outcomes after discharge are poor and remarkably worse in patients with underlying CTD or renal impairment. Early recognition of these factors may guide decisions regarding more aggressive therapy, including consideration for lung transplantation.
In uterocigarette smoke exposure impairs somatic and lung growth in BALB/c mice
Authors: Larcombe A.N. , Foong R.E. , Berry L.J. , Zosky G.R. , Sly P.D.
Published: February 2011

The aim of this study was to assess whetherin uterotobacco smoke exposure alone affects early-life lung growth and development.

Pregnant BALB/c mice were exposed to cigarette smoke from six cigarettes per day, or air, from day 8 to 20 of gestation. At 2 weeks of age, pups were weighed and had their lung volumes and lung mechanics measured.

Pups born from mothers exposed to cigarette smoke (CS pups; n=17) were significantly lighter (6.76±0.76versus7.72±0.68 g) and had lower lung volumes (0.123±0.02versus0.149±0.02 mL) than control pups (n=20). Respiratory mechanics were adversely impacted by cigarette smoke exposure. CS pups had higher baseline airway resistance, tissue damping and tissue elastance. These differences were largely due to lower lung volumes. Both tissue damping and elastance were increased excessively in CS pups at high transrespiratory pressures, while other parameters were not affected. There were no histological differences between groups.

In uterotobacco smoke exposure significantly affects growth and development in BALB/c mice. These impacts may partially explain the susceptibility of infants born to smoking mothers to early respiratory disease and chronic respiratory disease as adults.
What the pulmonary specialist should know about the new inhalation therapies
Authors: Laube B.L. , Janssens H.M. , de Jongh F.H.C. , Devadason S.G. , Dhand R. , Diot P. , Everard M.L. , Horvath I. , Navalesi P. , Voshaar T. , Chrystyn H.
Published: February 2011

A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient-use aspect of the aerosol delivery devices that are currently available.

The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel.

Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patient's inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient.