bluuebunny/crossref_metadata_2025 huggingface dataset:
Falling Short of Highest Life Expectancy: How Many Americans Might Have Been Alive in the Twentieth Century?
Authors: Muszyńska Magdalena M. , Rau Roland
Published: September 2009

Life expectancy at birth in the United States during the twentieth century was lower than in many other highly developed countries. We investigate how this mortality disadvantage in the last 100 years translates into the number of hypothetical lives lost and their sex and age structure. We estimate the hypothetical US population if it had experienced in each decade since 1900 the mortality level of the country with the then highest life expectancy and compare the results to the actual figures in 2000. By 2000, the number of additional people who could have been alive had the mortality levels in the United States been as low as those in countries with the highest life expectancy was 66 million. This number is distributed equally between males and females. Suboptimal mortality at reproductive ages is crucial for the cumulative effect of potential lives lost, resulting from premature deaths of women who could still become first‐time mothers or bear additional children. Out of the 66 million additional persons who could have been alive in 2000, 45 million are attributable to those indirect deaths. Although the differences in the composition of the population by sex and age under the two mortality regimes are minor, the majority of people who might have been alive—54 million—were of working age or younger.
Beyond Just Research: Experiences from Southern Africa in Developing Social Learning Partnerships for Resource Conservation Initiatives
Authors: Shackleton Charlie M. , Cundill Georgina , Knight Andrew T.
Published: September 2009

There is a well‐acknowledged communication or knowledge gap between scientists and decision‐makers. Many scientists who take on the challenge of narrowing this gap operate on the understanding that their role is to communicate their findings in a one‐way flow of information: from science to decision‐makers. However, to be effective scientists must engage in an ongoing social learning process with decision‐makers, and regard themselves as facilitators, and also as one among many stakeholders who have valid and important ecological knowledge. The developing world poses some particular challenges in this regard, specifically in terms of the large number of local level subsistence resources users who are importantde factodecision‐makers. We examine four natural resource management case studies from South Africa that differ in spatial scale and complexity, ranging from a single village to a whole biome. We distil seven lessons to help guide development of social learning processes and organizations in similar situations relating to natural resource planning and management. The lessons pertain to: maintaining ‘key individuals’ within social learning processes; the role of researchers; the formulation of research questions that social learning processes require adaptive long‐term funding and capacity support; that local resource users are key decision‐makers in developing countries; some perspectives on knowledge; and the need to measure research success.
Out of the Loop: Why Research Rarely Reaches Policy Makers and the Public and What Can be Done
Authors: Shanley Patricia , López Citlalli
Published: September 2009

Most of the world's population that derives their livelihoods or part of their livelihoods from forests are out of the information loop. Exclusion of public users of natural resources from access to scientific research results is not an oversight; it is a systemic problem that has costly ramifications for conservation and development. Results of a survey of 268 researchers from 29 countries indicate that institutional incentives support the linear, top‐down communication of results through peer‐reviewed journal articles, which often guarantees positive performance measurement. While the largest percentage of respondents (34%) ranked scientists as the most important audience for their work, only 15 percent of respondents considered peer‐reviewed journals effective in promoting conservation and/or development. Respondents perceived that local initiatives (27%) and training (16%) were likely to lead to success in conservation and development; but few scientists invest in these activities. Engagement with the media (5%), production of training and educational materials (4%) and popular publications (5%) as outlets for scientific findings was perceived as inconsequential (<14%) in measuring scientific performance. Less than 3 percent of respondents ranked corporate actors as an important audience for their work. To ensure science is shared with those who need it, a shift in incentive structures is needed that rewards actual impact rather than only ‘high‐impact’ journals. Widely used approaches and theoretical underpinnings from the social sciences, which underlie popular education and communication for social change, could enhance communication by linking knowledge and action in conservation biology.
Synthesis: Sharing Ecological Knowledge—The Way Forward
Authors: Born Julia , Boreux Virginie , Lawes Michael J.
Published: September 2009

Knowledge sharing between scientists and nonscientist stakeholders is necessary to implement research findings in an appropriate and effective manner within the context of the environment and conservation sectors. Yet scientific ecological knowledge is rarely shared and transferred effectively. This special section has addressed a number of opportunities and barriers to the improvement of scientific communication and knowledge transfer with respect to environmental management in tropical settings. A main challenge is seen in creating a research ‘impact‐metric’ system, which is fundamental to foster knowledge sharing with institutional research incentives. Partnering with local institutions and research centers as well as participatory research methods will promote effective knowledge exchange. Research relevance and impact will be improved by matching interdisciplinary research with local capacity building and support through research activities. We conclude that training the next generation of tropical biologists through more effective knowledge sharing will be crucial to the long term success of scientifically based environmental management in tropical regions.
Turbulent magnetic reconnection in two dimensions
Authors: Loureiro N. F. , Uzdensky D. A. , Schekochihin A. A. , Cowley S. C. , Yousef T. A.
Published: September 2009

Two-dimensional numerical simulations of the effect of background turbulence on two-dimensional resistive magnetic reconnection are presented. For sufficiently small values of the resistivity (η) and moderate values of the turbulent power (ε), the reconnection rate is found to have a much weaker dependence on η than the Sweet–Parker scaling of η1/2 and is even consistent with an η independent value. For a given value of η, the dependence of the reconnection rate on the turbulent power exhibits a critical threshold in ε above which the reconnection rate is significantly enhanced.
Antibiotic Resistance in Bacteria: Novel Metalloenzyme Inhibitors
Authors: Kim Sung‐Kun , Sims Cynthe L. , Wozniak Susan E. , Drude Stephanie H. , Whitson Dustin , Shaw Robert W.
Published: September 2009

β‐Lactam antibiotics are among the most important drugs used to fight bacterial infection. Overuse and misuse of β‐lactam antibiotics has caused the evolution of resistance mechanisms, allowing pathogenic bacteria to survive antibiotic treatment. The major source of resistance to β‐lactam antibiotics occurs through production of enzymes called β‐lactamases capable of catalyzing hydrolysis of the β‐lactam rings in these drug compounds. The metallo‐β‐lactamases have become a major threat due to their broad substrate specificities; there are no clinically useful inhibitors for these metalloenzymes. We have obtained single‐stranded DNA’s that are potent inhibitors of the Bacillus cereus 5/B/6 metallo‐β‐lactamase. These are rapid, reversible, non‐competitive inhibitors of the metalloenzyme, with Ki and Ki′ values in the nanomolar range. The inhibition patterns and metal ion dependence of their inhibition suggest that the oligonucleotides alter the coordination of the active site metal ion(s); inhibition is efficient and highly specific. Microbiological growth experiments, using combinations of ssDNA with the β‐lactam antibiotic cephalexin, reveal that the inhibitor is capable of causing cell death in liquid cultures of both Gram‐positive and Gram‐negative metallo‐β‐lactamase producing bacteria in the micromolar concentration range.
Becoming Bluestockings: Contextualising Hannah More's ‘The Bas Bleu’
Authors: HASLETT MOYRA
Published: September 2009

Hannah More's poem ‘The Bas Bleu’ was the first account of the Bluestockings to be published from within the Bluestocking circle itself. It remained the most significant defence of Bluestocking ideals for many decades thereafter, years in which satirical depictions of the Bluestockings would predominate. This essay locates More's poem in the contexts of its original composition (1783), manuscript circulation and eventual publication (1786). The poem's transformation from a manuscript to a published poem exemplifies its particular significance as a public statement in which the Bluestockings attained prominence and celebrity.
‘Leisure to be Wise’: Edgeworthian Education and the Possibilities of Domesticity
Authors: DE RITTER RICHARD
Published: September 2009

Abstract:  In Letters for Literary Ladies Maria Edgeworth discusses the positive effects of women's exclusion from the division of labour. According to Edgeworth, their exemption from professional life grants women ‘leisure to be wise’. Drawing on Edgeworth's father's Essays on Professional Education, as well as on her novel Belinda, this article considers the extent to which intellectual capital can provide a viable alternative to the possession of either landed estate or professional skills. With reference to previous interrogations of the ‘separate spheres thesis’, this article suggests that domestic education is, in fact, informed by an ethic of professionalism.
The need and total cost of Finnish eyecare services: a simulation model for 2005–2040
Authors: Tuulonen Anja , Salminen Hannu , Linna Miika , Perkola Markku
Published: September 2009

Purpose:  The aims of this study were: (i) to create a structural simulation model capable of predicting the future need and cost of eyecare services in Finland; and (ii) to test and rank different policy alternatives for access to care and the required physician workforce.

Methods:  Using the system dynamics approach, the number and cost of patients with cataract, glaucoma, diabetic retinopathy and age‐related macular degeneration (AMD) were described with causal‐loop diagrams and were then translated into a set of mathematical equations to build a computer simulation model. Mathematically, the problem was formulated as a set of differential equations that were solved numerically with specialized software. The validity of the model was tested against prevalence and administrative historical data. The costs covered by the public sector in Finland were obtained from 2003 from the Finnish Hospital Discharge Register (including outpatient care), the Finnish Social Insurance Institution and a survey of hospital price lists. Different levels of access to public care were then simulated in four eye diseases, for which the model estimated the need for services and resources and their costs in the years 2005–2040.

Results:  The model forecasted that the adoption of the 2005 national ‘access to care’ criteria for cataract surgery would shorten waiting lists. If the workload of Finnish ophthalmologists were kept at the 2003 level, the graduation rate of new ophthalmologists would have to increase by 75% from the current level. If all glaucoma patients were followed in the public sector in future, even this increase in training would not meet the demand for physician workforce. The current model indicated that the screening frequency of diabetes can be increased without large sacrifices in terms of costs. AMD therapy has a significant role in the allocation of future resources in eyecare. The modelling study predicted that ageing alone will increase the costs of eyecare during the next four decades in Finland by about 1% per year in real terms (undiscounted and without inflation of unit costs). The increases in total yearly costs were on average 8.6% between 2001 and 2003.

Conclusions:  The results of this modelling study indicate that policy initiatives, such as defining criteria for access to care, can have substantial implications on the demand for care and waiting times whereas the effect of ageing alone was relatively small. Measures to control several other factors – such as the adoption and price level of new technologies, treatments and practice patterns – will be at least equally important in order to restrain healthcare costs effectively.
The Large Mechanosensitive Channel MscL Determines Bacterial Susceptibility to the Bacteriocin Sublancin 168
Authors: Kouwen Thijs R. H. M. , Trip Erik N. , Denham Emma L. , Sibbald Mark J. J. B. , Dubois Jean-Yves F. , van Dijl Jan Maarten
Published: September 2009

Bacillus subtilis
strain 168 produces the extremely stable and broad-spectrum lantibiotic sublancin 168. Known sublancin 168-susceptible organisms include important pathogens, such as
Staphylococcus aureus
. Nevertheless, since its discovery, the mode of action of sublancin 168 has remained elusive. The present studies were, therefore, aimed at the identification of cellular determinants for bacterial susceptibility toward sublancin 168. Growth inhibition and competition assays on plates and in liquid cultures revealed that sublancin 168-mediated growth inhibition of susceptible
B. subtilis
and
S. aureus
cells is affected by the NaCl concentration in the growth medium. Added NaCl did not influence the production, activity, or stability of sublancin 168 but, instead, lowered the susceptibility of sensitive cells toward this lantibiotic. Importantly, the susceptibility of
B. subtilis
and
S. aureus
cells toward sublancin 168 was shown to depend on the presence of the large mechanosensitive channel of conductance MscL. In contrast, MscL was not involved in susceptibility toward the bacteriocin nisin or Pep5. Taken together, our unprecedented results demonstrate that MscL is a critical and specific determinant in bacterial sublancin 168 susceptibility that may serve either as a direct target for this lantibiotic or as a gate of entry to the cytoplasm.
Pharmacological Inhibition of Transforming Growth Factor β Signaling Decreases Infection and Prevents Heart Damage in Acute Chagas' Disease
Authors: Waghabi Mariana C. , de Souza Elen M. , de Oliveira Gabriel M. , Keramidas Michelle , Feige Jean-Jacques , Araújo-Jorge Tania C. , Bailly Sabine
Published: September 2009

Chagas' disease induced by
Trypanosoma cruzi
infection is an important cause of mortality and morbidity affecting the cardiovascular system for which presently available therapies are largely inadequate. We previously reported that transforming growth factor β (TGF-β) is implicated in several regulatory aspects of
T
.
cruzi
invasion and growth and in host tissue fibrosis. This prompted us to evaluate the therapeutic action of an inhibitor of TGF-β signaling (SB-431542) administered during the acute phase of experimental Chagas' disease. Male Swiss mice were infected intraperitoneally with 10
4
trypomastigotes of
T
.
cruzi
(Y strain) and evaluated clinically for the following 30 days. SB-431542 treatment significantly reduced mortality and decreased parasitemia. Electrocardiography showed that SB-431542 treatment was effective in protecting the cardiac conduction system. By 14 day postinfection, enzymatic biomarkers of tissue damage indicated that muscle injury was decreased by SB-431542 treatment, with significantly lower blood levels of aspartate aminotransferase and creatine kinase. In conclusion, inhibition of TGF-β signaling in vivo appears to potently decrease
T
.
cruzi
infection and to prevent heart damage in a preclinical mouse model. This suggests that this class of molecules may represent a new therapeutic agent for acute and chronic Chagas' disease that warrants further clinical exploration.
Influence of Inoculum Size and Marbofloxacin Plasma Exposure on the Amplification of Resistant Subpopulations of
Klebsiella pneumoniae
in a Rat Lung Infection Model
Authors: Kesteman Anne-Sylvie , Ferran Aude A. , Perrin-Guyomard Agnès , Laurentie Michel , Sanders Pascal , Toutain Pierre-Louis , Bousquet-Mélou Alain
Published: September 2009

We tested the hypothesis that the bacterial load at the infection site could impact considerably on the pharmacokinetic/pharmacodynamic (PK/PD) parameters of fluoroquinolones. Using a rat lung infection model, we measured the influence of different marbofloxacin dosage regimens on selection of resistant bacteria after infection with a low (10
5
CFU) or a high (10
9
CFU) inoculum of
Klebsiella pneumoniae
. For daily fractionated doses of marbofloxacin, prevention of resistance occurred for an area-under-the-concentration-time-curve (AUC)/MIC ratio of 189 h for the low inoculum, whereas for the high inoculum, resistant-subpopulation enrichment occurred for AUC/MIC ratios up to 756 h. For the high-inoculum-infected rats, the AUC/MIC ratio,
C
max
/MIC ratio, and time within the mutant selection window (
T
MSW
) were not found to be effective predictors of resistance prevention upon comparison of fractionated and single administrations. An index corresponding to the ratio of the time that the drug concentrations were above the mutant prevention concentration (MPC) over the time that the drug concentrations were within the MSW (
T
>
MPC
/
T
MSW
) was the best predictor of the emergence of resistance: a
T
>
MPC
/
T
MSW
ratio of 0.54 was associated with prevention of resistance for both fractionated and single administrations. These results suggest that the enrichment of resistant bacteria depends heavily on the inoculum size at the start of an antimicrobial treatment and that classical PK/PD parameters cannot adequately describe the impact of different dosage regimens on enrichment of resistant bacteria. We propose an original index, the
T
>
MPC
/
T
MSW
ratio, which reflects the ratio of the time that the less susceptible bacterial subpopulation is killed over the time that it is selected, as a potentially powerful indicator of prevention of enrichment of resistant bacteria. This ratio is valid only if plasma concentrations achieve the MPC.
In Vitro Activity of Ceftaroline against Methicillin-Resistant
Staphylococcus aureus
and Heterogeneous Vancomycin-Intermediate
S. aureus
in a Hollow Fiber Model
Authors: Vidaillac Céline , Leonard Steve N. , Rybak Michael J.
Published: September 2009

Ceftaroline is a broad-spectrum injectable cephalosporin exhibiting bactericidal activity against a variety of bacteria, including methicillin-resistant
Staphylococcus aureus
(MRSA). Using a two-compartment in vitro pharmacokinetic/pharmacodynamic (PK/PD) model, we evaluated the activity of ceftaroline at 600 mg every 8 h (q8h) and q12h in comparison with that of vancomycin at 1,000 mg q12h over a 72-h time period against six clinical MRSA isolates, including two heterogeneous vancomycin-intermediate
S. aureus
(hVISA) isolates. The MIC and minimum bactericidal concentration ranged between 0.125 to 2 and 0.5 to 2 μg/ml for ceftaroline and vancomycin, respectively. In the PK/PD model, ceftaroline was superior to vancomycin against all isolates (
P
< 0.05), except one to which it was equivalent. No difference in activity was observed between both q8 and q12h dosing regimens of ceftaroline. Bacterial regrowth was observed after 32 h for two isolates treated with ceftaroline. This regrowth was uncorrelated to resistance, instability of the drug, or tolerance. However, subpopulations with higher MICs to ceftaroline were found by population analysis for these two isolates. Finally, and in contrast to ceftaroline, MIC elevations up to 8 to 12 μg/ml were observed with vancomycin for the hVISA isolates. In conclusion, in addition to a lower potential to select resistant mutants, ceftaroline demonstrated activity equal to or greater than vancomycin against MRSA isolates. Although further in vitro and in vivo investigations are warranted, ceftaroline appears to be a promising alternative for the treatment of MRSA infections.
ATP Synthase Inhibition of
Mycobacterium avium
Is Not Bactericidal
Authors: Lounis Nacer , Gevers Tom , Van Den Berg Joke , Vranckx Luc , Andries Koen
Published: September 2009

The efficacy of ATP synthase inhibitor TMC207 was assessed in early and late
Mycobacterium avium
infections in mice. In contrast to what was earlier observed for
M. tuberculosis
, a bacteriostatic effect was obtained. In vitro, the minimal bactericidal concentration (MBC)/MIC ratio was very high. The MBC was more relevant for assessment of pharmacokinetic/pharmacodynamic relationships than the MIC.
Case of Fatal
Blastoschizomyces capitatus
Infection Occurring in a Patient Receiving Empiric Micafungin Therapy
Authors: Chittick Paul , Palavecino Elizabeth L. , Delashmitt Brian , Evans James , Peacock James E.
Published: September 2009

We report the first case, to our knowledge, of
Blastoschizomyces capitatus
infection occurring in a patient receiving empirical echinocandin therapy for neutropenic fevers. Clinicians should consider
B. capitatus
infection in those neutropenic patients who remain febrile despite echinocandin therapy or who develop yeast bloodstream infections while receiving an echinocandin.
Cross-Reactive Immunity to
Mycobacterium tuberculosis
DosR Regulon-Encoded Antigens in Individuals Infected with Environmental, Nontuberculous Mycobacteria
Authors: Lin May Young , Reddy T. B. K. , Arend Sandra M. , Friggen Annemieke H. , Franken Kees L. M. C. , van Meijgaarden Krista E. , Verduyn Marleen J. C. , Schoolnik Gary K. , Klein Michel R. , Ottenhoff Tom H. M.
Published: September 2009

Mycobacterium tuberculosis
DosR regulon-encoded antigens are highly immunogenic in
M. tuberculosis
-infected humans and are associated with latent tuberculosis infection. We have investigated the hypothesis that infection with or exposure to nontuberculous mycobacteria (NTM) can induce cross-reactive immunity to
M. tuberculosis
DosR regulon-encoded antigens since responsiveness has been observed in non-
M. tuberculosis
-exposed but purified protein derivative-responsive individuals.
M. tuberculosis
DosR regulon-encoded antigen-specific T-cell responses were studied in peripheral blood mononuclear cells (PBMCs) of NTM-infected/exposed individuals. BLASTP was used to determine the presence of
M. tuberculosis
DosR regulon-encoded protein orthologs among environmental mycobacteria and nonmycobacteria. Significant gamma interferon production was observed in PBMCs from NTM-infected/exposed individuals in response to
M. tuberculosis
DosR regulon-encoded antigens. DosR regulon-encoded protein orthologs were prominently present in tuberculous and environmental mycobacteria and surprisingly also in nonmycobacteria. The ubiquitous presence of the highly conserved DosR master regulator protein Rv3133c suggests that this is a general adaptive bacterial response regulator. We report a first series of
M. tuberculosis
antigens to which cross-reactive immunity is induced by NTM infection/exposure. The high conservation of
M. tuberculosis
DosR regulon-encoded antigens most likely enables them to induce cross-reactive T-cell responses.
Molecular, Antigenic, and Functional Characteristics of Ferric Enterobactin Receptor CfrA in
Campylobacter jejuni
Authors: Zeng Ximin , Xu Fuzhou , Lin Jun
Published: September 2009

The ferric enterobactin receptor CfrA not only is responsible for high-affinity iron acquisition in
Campylobacter jejuni
but also is essential for
C. jejuni
colonization in animal intestines. In this study, we determined the feasibility of targeting the iron-regulated outer membrane protein CfrA for immune protection against
Campylobacter
colonization. Alignment of complete CfrA sequences from 15
Campylobacter
isolates showed that the levels of amino acid identity for CfrA range from 89% to 98%. Immunoblotting analysis using CfrA-specific antibodies demonstrated that CfrA was dramatically induced under iron-restricted conditions and was widespread and produced in 32
Campylobacter
primary strains from various sources and from geographically diverse areas. The immunoblotting survey results were highly correlated with the results of an enterobactin growth promotion assay and a PCR analysis using
cfrA
-specific primers. Inactivation of the
cfrA
gene also impaired norepinephrine-mediated growth promotion, suggesting that CfrA is required for
C. jejuni
to sense intestinal stress hormones during colonization. Complementation of the
cfrA
mutant with a wild-type
cfrA
allele in
trans
fully restored the production and function of CfrA. A growth assay using purified anti-CfrA immunoglobulin G demonstrated that specific CfrA antibodies could block the function of CfrA, which diminished ferric enterobactin-mediated growth promotion under iron-restricted conditions. The inhibitory effect of CfrA antibodies was dose dependent. Immunoblotting analysis also indicated that CfrA was expressed and immunogenic in chickens experimentally infected with
C. jejuni
. Amino acid substitution mutagenesis demonstrated that R327, a basic amino acid that is highly conserved in CfrA, plays a critical role in ferric enterobactin acquisition in
C. jejuni.
Together, these findings strongly suggest that CfrA is a promising vaccine candidate for preventing and controlling
Campylobacter
infection in humans and animal reservoirs.
Overexpression of CsrA (BB0184) Alters the Morphology and Antigen Profiles ofBorrelia burgdorferi
Authors: Sanjuan Eva , Esteve-Gassent Maria D. , Maruskova Mahulena , Seshu J.
Published: September 2009

Borrelia burgdorferi, the agent of Lyme disease, alters its gene expression in response to highly disparate environmental signals encountered in its hosts. Among the relatively few regulators of adaptive gene expression present in the borrelial genome is an open reading frame (ORF), BB0184, annotated as CsrA (carbonstorageregulatorA). CsrA, in several bacterial species, has been characterized as a small RNA binding protein that functions as a global regulator affecting mRNA stability or levels of translation of multiple ORFs. Consistent with known functions of CsrA, overexpression of CsrA fromB. burgdorferi(CsrABb) inEscherichia coliresulted in reduced accumulation of glycogen. We determined thatcsrABbis part of theflgKmotility operon and that the synthesis of CsrABbwas increased whenB. burgdorferiwas propagated under fed-tick conditions. Overexpression of CsrABbinB. burgdorferistrain B31 (ML23, lp25-negative clonal isolate) resulted in a clone, designated ES25, which exhibited alterations in colony morphology and a significant reduction in the levels of FlaB. Several lipoproteins previously characterized as playing a role in infectivity were also altered in ES25. Real-time reverse transcription-PCR analysis of RNA revealed significant differences in the transcriptional levels ofospCin ES25, while there were no such differences in the levels of other transcripts, suggesting posttranscriptional regulation of expression of these latter genes. These observations indicate that CsrABbplays a role in the regulation of expression of pathophysiological determinants ofB. burgdorferi, and further characterization of CsrABbwill help in better understanding of the regulators of gene expression inB. burgdorferi.
Genome-Wide Study of
Pseudomonas aeruginosa
Outer Membrane Protein Immunogenicity Using Self-Assembling Protein Microarrays
Authors: Montor Wagner R. , Huang Jin , Hu Yanhui , Hainsworth Eugenie , Lynch Susan , Kronish Jeannine-Weiner , Ordonez Claudia L. , Logvinenko Tanya , Lory Stephen , LaBaer Joshua
Published: September 2009

Pseudomonas aeruginosa
is responsible for potentially life-threatening infections in individuals with compromised defense mechanisms and those with cystic fibrosis.
P. aeruginosa
infection is notable for the appearance of a humoral response to some known antigens, such as flagellin C, elastase, alkaline protease, and others. Although a number of immunogenic proteins are known, no effective vaccine has been approved yet. Here, we report a comprehensive study of all 262 outer membrane and exported
P. aeruginosa
PAO1 proteins by a modified protein microarray methodology called the nucleic acid-programmable protein array. From this study, it was possible to identify 12 proteins that trigger an adaptive immune response in cystic fibrosis and acutely infected patients, providing valuable information about which bacterial proteins are actually recognized by the immune system in vivo during the natural course of infection. The differential detections of these proteins in patients and controls proved to be statistically significant (
P
< 0.01). The study provides a list of potential candidates for the improvement of serological diagnostics and the development of vaccines.
Codependent and Independent Effects of Nitric Oxide-Mediated Suppression of PhoPQ andSalmonellaPathogenicity Island 2 on IntracellularSalmonella entericaSerovar Typhimurium Survival
Authors: Bourret Travis J. , Song Miryoung , Vázquez-Torres Andrés
Published: September 2009

Here we show that theSalmonella entericaserovar Typhimurium PhoQ sensor kinase lessens the cytotoxicity of reactive nitrogen species (RNS) generated by inducible nitric oxide synthase (iNOS) in the innate response of mononuclear phagocytic cells. This observation is consistent with the expression patterns of PhoP-activated genes during moderate nitrosative stress in the innate host response. In contrast, RNS synthesized during high-NO fluxes of gamma interferon (IFN-γ)-activated macrophages repress PhoP-activatedlpxO,pagP, andphoPgene transcription. Because PhoP-regulatedSalmonellapathogenicity island 2 (SPI2) genes are also repressed by high-order RNS (39), we investigated whether the NO-mediated inhibition of PhoPQ underlies the repression of SPI2. Our studies indicate that a third of the expression of the SPI2spiCgene recorded in nonactivated macrophages depends on PhoQ. Transcription ofspiCis repressed in IFN-γ-primed macrophages in an iNOS-dependent manner, irrespective of thephoQstatus of the bacteria. Transcription ofspiCis restored in IFN-γ-treated, iNOS-deficient macrophages to levels sustained by aphoQmutant in nonactivated phagocytes, suggesting that most NO-dependent repression ofspiCis due to the inhibition of PhoPQ-independent targets. Comparison of the intracellular fitness ofspiC,phoQ, andspiC phoQmutants revealed that PhoPQ and SPI2 have codependent and independent effects onS. Typhimurium survival during innate nitrosative stress. However, the intracellular survival of mostS.Typhimurium bacteria is conferred by the PhoPQ two-component regulator, and the SPI2 type III secretion system is repressed by high-order RNS of IFN-γ-activated macrophages.
Roles of age, length of service and job in work-related injury: a prospective study of 446 120 person-years in railway workers
Authors: Chau N , Wild P , Dehaene D , Benamghar L , Mur J M , Touron C
Published: September 2009

Objectives

Because work-related injuries are common and yet the mechanisms through which various types of injuries relate to age, length of service and job remain unknown, this study assessed the role of age, length of service and job in work-related injury.

Methods

Prospective study of all 164 814 permanently employed male workers at the French national railway company during 1998–2000, based on the company's injury database: 446 120 person-years, 15 195 injuries with working days lost, coded using the company's injury classification, which is derived from that of the French health insurance scheme. We investigated the incidence of 10 types of injury: fall on same level, fall to lower level, handling materials/machine parts during assembly, handling objects, lifting/handling equipment, collision with/by moving objects, collision with/by vehicles, operating machines/equipment, using hand tools and other injuries. Data were analysed using negative binomial regression.

Results

Workers aged <25 years were subject to a higher injury risk from handling materials/machine parts during assembly, and collision with/by moving objects or vehicles. Older workers, especially those aged 50–55 years, were subject to a higher risk of fall and injury resulting from lifting/handling materials/equipment/objects or from collision with/by moving objects/vehicles. Using hand tools was a risky task for workers aged <30 or ≥40 years. The relative risk decreased steadily with increasing length of service with the company, from 2.6 for 1 year to 1.0 for ≥30 years, and the slope of the trend is stronger for fall to lower level, lifting/handling materials/equipment and collision with/by moving objects.

Conclusion

Younger and older ages and shorter length of service are at risk for various types of injuries. Preventive measures should improve working conditions, especially for younger/older ages, provide knowledge through specific training during the first years in a job and help workers to be more aware of risks associated with their age, years of employment and job.
Effect of a participatory ergonomics intervention on psychosocial factors at work in a randomised controlled trial
Authors: Haukka Eija , Pehkonen Irmeli , Leino-Arjas Päivi , Viikari-Juntura Eira , Takala Esa-Pekka , Malmivaara Antti , Hopsu Leila , Mutanen Pertti , Ketola Ritva , Virtanen Tuija , Holtari-Leino Merja , Nykänen Jaana , Stenholm Sari , Ojajärvi Anneli , Riihimäki Hilkka
Published: September 2009

Objectives

To study the effect of a participatory ergonomics intervention on psychosocial factors among kitchen workers.

Design

A cluster randomised controlled trial.

Setting

Four cities in Finland, 2002–2005.

Participants

504 workers in 119 municipal kitchens.

Intervention

Kitchens were randomised to intervention (n=59) and control (n=60) groups. The intervention lasted 11–14 months and was based on the workers' active participation in work analysis, planning and implementing the ergonomic changes aimed at decreasing the physical and mental workload.

Main outcome measures

Mental stress, mental strenuousness of work, hurry, job satisfaction, job control, skill discretion, co-worker relationships and supervisor support. Data were collected by questionnaire at baseline, at the end of the intervention, and at a 12-month follow-up (PI12).

Results

At the end of the intervention, the OR of job dissatisfaction for the intervention group as compared with the control group was 3.0 (95% CI 1.1 to 8.5), of mental stress 2.3 (1.2 to 4.7) and of poor co-worker relationships 2.3 (1.0 to 5.2). At the PI12, the OR of job dissatisfaction was 3.0 (1.2 to 7.8). Analysis of the independent and joint effects of the intervention and unconnected organisational reforms showed that adverse changes were accentuated among those with exposure to both.

Conclusions

No favourable effects on psychosocial factors at work were found. The adverse changes were due to a joint effect of the intervention and the unconnected organisational reforms. The findings do not support the usefulness of this kind of intervention in changing unsatisfactory psychosocial working conditions.
Occupation and renal cell cancer in Central and Eastern Europe
Authors: Heck J E , Charbotel B , Moore L E , Karami S , Zaridze D G , Matveev V , Janout V , Kollárová H , Foretova L , Bencko V , Szeszenia-Dabrowska N , Lissowska J , Mates D , Ferro G , Chow W-H , Rothman N , Stewart P , Brennan P , Boffetta P
Published: September 2009

Objective:

Central and Eastern Europe has among the highest rates of renal cell cancer worldwide. Few studies have been conducted in these areas to investigate the possible role of occupational exposures in renal cell cancer aetiology. The purpose of this study was to examine the association of renal cell cancer with employment in specific occupations and industries.

Methods:

From 1999 to 2003, we conducted a hospital-based case-control study in seven areas of the Czech Republic, Poland, Romania and Russia. A detailed occupational history was collected from renal cell cancer cases and controls, together with information on potential confounders. Odds ratios (ORs) and 95% CI of cancer risk were calculated for having ever been employed in selected jobs and industries, with follow-up analyses examining duration of employment.

Results:

A total of 992 histologically confirmed incident renal cell cancer cases and 1459 controls were included in the analysis. An increased risk of renal cell cancer was observed for workers in agricultural labour and animal husbandry (OR 1.43; 95% CI 1.05 to 1.93), particularly among women employed as general farm workers (OR 2.73; 95% CI 1.05 to 7.13). Risk gradients for agricultural work increased with longer employment. An overall increased risk of renal cell cancer was seen among architects and engineers (OR 1.89; 95% CI 1.35 to 2.65), and mechanical engineers (OR 1.71; 95% CI 1.03 to 2.84).

Conclusions:

Our data suggest an association between renal cell cancer and agricultural work, particularly among female workers.
NATURE–INSPIRED INTELLIGENCE: A REVIEW OF SELECTED METHODS AND APPLICATIONS
Authors: VASSILIADIS VASSILIOS , DOUNIAS GEORGIOS
Published: September 2009

The successful handling of numerous real–world complex problems has increased the popularity of nature–inspired intelligent (NII) algorithms and techniques. Their successful implementation primarily on difficult and complicated optimization problems, stresses their upcoming importance in the broader area of artificial intelligence. NII techniques take advantage of the way that biological systems deal with real–world situations. Specifically, they simulate the way real biological systems, such as the human brain, ant colonies and human immune system work, when solving complex real–world situations. In this survey paper, we briefly present a number of selected NII approaches and we point particular suitable areas of application for each of them. Specifically, five major categories of nature inspired approaches are presented, namely, Particle Swarm Optimization (PSO), Ant Colony Optimization (ACO), DNA computing, artificial immune systems and membrane computing. Applications include problems related to optimization (financial, industrial and medical), task scheduling, system design (optimization of the system's parameters), image processing and data processing (feature selection and classification). We also refer to collaboration between NII techniques and classical AI methodologies, such as neural networks, genetic algorithms, fuzzy logic, etc. The current survey states that NII techniques are likely to become the next step in the rapid evolution of artificial intelligence tools.
METCO: A PARALLEL PLUGIN-BASED FRAMEWORK FOR MULTI-OBJECTIVE OPTIMIZATION
Authors: LEÓN COROMOTO , MIRANDA GARA , SEGURA CARLOS
Published: September 2009

This paper presents a parallel framework for the solution of multi-objective optimization problems. The framework implements some of the best known multi-objective evolutionary algorithms. The plugin-based architecture of the framework minimizes the end user effort required to incorporate their own problems and evolutionary algorithms, and facilitates tool maintenance. A wide variety of configuration options can be specified to adapt the software behavior to many different parallel models. An innovation of the framework is that it provides a self-adaptive parallel model that is based on the cooperation of a set of evolutionary algorithms. The aim of the new model is to raise the level of generality at which most current evolutionary algorithms operate. This way, a wider range of problems can be tackled since the strengths of one algorithm can compensate for the weaknesses of another. The model proposed is a hybrid algorithm that combines a parallel island-based scheme with a hyperheuristic approach. The model grants more computational resources to those algorithms that show a more promising behavior. The flexibility and efficiency of the framework were tested and demonstrated by configuring standard and self-adaptive models for test problems and real-world applications.
A very low carbohydrate ketogenic diet improves glucose tolerance inob/obmice independently of weight loss
Authors: Badman Michael K. , Kennedy Adam R. , Adams Andrew C. , Pissios Pavlos , Maratos-Flier Eleftheria
Published: September 2009

In mice of normal weight and with diet-induced obesity, a high-fat, low-carbohydrate ketogenic diet (KD) causes weight loss, reduced circulating glucose and lipids, and dramatic changes in hepatic gene expression. Many of the effects of KD are mediated by fibroblast growth factor 21 (FGF21). We tested the effects of KD feeding on ob/ ob mice to determine if metabolic effects would occur in obesity secondarily to leptin deficiency. We evaluated the effect of prolonged KD feeding on weight, energy homeostasis, circulating metabolites, glucose homeostasis, and gene expression. Subsequently, we evaluated the effects of leptin and fasting on FGF21 expression in ob/ ob mice. KD feeding of ob/ ob mice normalized fasting glycemia and substantially reduced insulin and lipid levels in the absence of weight loss. KD feeding was associated with significant increases in lipid oxidative genes and reduced expression of lipid synthetic genes, including stearoyl-coenzyme A desaturase 1, but no change in expression of inflammatory markers. In chow-fed ob/ ob mice, FGF21 mRNA was elevated 10-fold compared with wild-type animals, and no increase from this elevated baseline was seen with KD feeding. Administration of leptin to chow-fed ob/ ob mice led to a 24-fold induction of FGF21. Fasting also induced hepatic FGF21 in ob/ ob mice. Thus, KD feeding improved ob/ ob mouse glucose homeostasis without weight loss or altered caloric intake. These data demonstrate that manipulation of dietary macronutrient composition can lead to marked improvements in metabolic profile of leptin-deficient obese mice in the absence of weight loss.
Tumor Vaccines Expressing Flt3 Ligand Synergize with CTLA-4 Blockade to Reject Preimplanted Tumors
Authors: Curran Michael A. , Allison James P.
Published: September 2009

The transformation of a healthy cell into a malignant neoplasm involves numerous genetic mutations and aberrations in gene expression. As few of these changes are shared between individuals or types of cancer, the best source for eliciting broad-spectrum tumor immunity remains each patient's own tumor. Previously, we have shown that combining blockade of the T-cell–negative costimulatory molecule CTL-associated antigen 4 (CTLA-4) and vaccination with irradiated B16 tumor expressing granulocyte macrophage colony-stimulating factor (GM-CSF; Gvax) promotes rejection of established murine melanomas. Here we show that, like GM-CSF, the cytokine Flt3 ligand (Flt3L) expressed in B16 and coupled with CTLA-4 blockade promotes both prophylactic and therapeutic rejection of B16. When administered at the site of growing tumor, Gvax fails to prevent tumor outgrowth in any mice, whereas the B16-Flt3L vaccine (Fl3vax) induces the rejection of 75% of melanomas implanted 3 days before vaccination. Relative to Gvax, Fl3vax promotes greater infiltration of both the vaccine site and the tumor site by CD8+ T cells and “sentinel” and plasmacytoid dendritic cells. Gvax and Fl3vax did not synergize when used in combination in treating B16 melanoma even in the context of CD25+ regulatory T-cell depletion. Further, we show that a combination of Flt3L expression and CTLA-4 blockade can also promote the rejection of established TRAMP prostate adenocarcinomas, proving that the utility of this treatment extends beyond melanoma. Engineering Flt3L to be constitutively secreted and attaching an IgG2a tail yielded a B16 vaccine that, when combined with CTLA-4 blockade, prevented the outgrowth of significantly more 5-day implanted B16-BL6 tumors than did Gvax. [Cancer Res 2009;69(19):7747–55]
Elevated Epithelial Insulin-like Growth Factor Expression Is a Risk Factor for Lung Cancer Development
Authors: Kim Woo-Young , Jin Quanri , Oh Seung-Hyun , Kim Edward S. , Yang Youn Joo , Lee Dong Hoon , Feng Lei , Behrens Carmen , Prudkin Ludmila , Miller York E. , Lee J. Jack , Lippman Scott M. , Hong Waun Ki , Wistuba Ignacio I. , Lee Ho-Young
Published: September 2009

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has been implicated in several human neoplasms. However, the role of serum levels of IGFs in lung cancer risk is controversial. We assessed the role of tissue-derived IGFs in lung carcinogenesis. We found that IGF-I and IGF-II levels in bronchial tissue specimens containing high-grade dysplasia were significantly higher than in those containing normal epithelium, hyperplasia, and squamous metaplasia. Derivatives of human bronchial epithelial cell lines with activation mutation in KRAS(V12) or loss of p53 overexpressed IGF-I and IGF-II. The transformed characteristics of these cells were significantly suppressed by inactivation of IGF-IR or inhibition of IGF-I or IGF-II expression but enhanced by overexpression of IGF-IR or exposure to the tobacco carcinogens (TC) 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone and benzo(a)pyrene. We further determined the role of IGF-IR signaling in lung tumorigenesis by determining the antitumor activities of the selective IGF-IR tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo [1,5-a]pyrazin-8-ylamine using an in vitro progressive cell system and an in vivo mouse model with a lung-specific IGF-I transgene after exposure to TCs, including 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone plus benzo(a)pyrene. Our results show that airway epithelial cells produce IGFs in an autocrine or paracrine manner, and these IGFs act jointly with TCs to enhance lung carcinogenesis. Furthermore, the use of selective IGF-IR inhibitors may be a rational approach to controlling lung cancer. [Cancer Res 2009;69(18):7439–48]
Advances in Ewing's Sarcoma Research: Where Are We Now and What Lies Ahead?
Authors: Ordóñez José Luis , Osuna Daniel , Herrero David , de Álava Enrique , Madoz-Gúrpide Juan
Published: September 2009

Ewing's sarcoma family tumors (EFT) are characterized by specific chromosomal translocations, which lead to EWS/ETS transcription factors. Elucidation of EWS/ETS target gene networks within the context of other signaling pathways, together with the identification of the initiating cell, and the development of genetically engineered mice will hopefully lead to biology-based therapeutic strategies for these tumors. [Cancer Res 2009;69(18):7140–50]