bluuebunny/crossref_metadata_2025 huggingface dataset:
Erythropoietin Protects against Murine Cerebral Malaria through Actions on Host Cellular Immunity
Authors: Wei Xu , Li Ying , Sun Xiaodan , Zhu Xiaotong , Feng Yonghui , Liu Jun , Jiang Yongjun , Shang Hong , Cui Liwang , Cao Yaming
Published: October 2013

Cerebral malaria (CM) is associated with excessive host proinflammatory responses and endothelial activation. The hematopoietic hormone erythropoietin (EPO) possesses neuroprotective functions in animal models of ischemic-hypoxic, traumatic, and inflammatory injuries. In thePlasmodium bergheiANKA model of experimental CM (ECM), recombinant human EPO (rhEPO) has shown evident protection against ECM. To elucidate the mechanism of EPO in this ECM model, we investigated the effect of rhEPO on host cellular immune responses. We demonstrated that improved survival of mice with ECM after rhEPO treatment was associated with reduced endothelial activation and improved integrity of the blood-brain barrier. Our results revealed that rhEPO downregulated the inflammatory responses by directly inhibiting the levels and functions of splenic dendritic cells. Conversely, rhEPO treatment led to significant expansion of regulatory T cells and increased expression of the receptor cytotoxic T lymphocyte antigen 4 (CTLA-4). The data presented here provide evidence of the direct effect of rhEPO on host cellular immunity during ECM.
Bacterially Expressed Full-Length Recombinant Plasmodium falciparum RH5 Protein Binds Erythrocytes and Elicits Potent Strain-Transcending Parasite-Neutralizing Antibodies
Authors: Reddy K. Sony , Pandey Alok K. , Singh Hina , Sahar Tajali , Emmanuel Amlabu , Chitnis Chetan E. , Chauhan Virander S. , Gaur Deepak
Published: October 2013

Plasmodium falciparum
reticulocyte binding-like homologous protein 5 (PfRH5) is an essential merozoite ligand that binds with its erythrocyte receptor, basigin. PfRH5 is an attractive malaria vaccine candidate, as it is expressed by a wide number of
P. falciparum
strains, cannot be genetically disrupted, and exhibits limited sequence polymorphisms. Viral vector-induced PfRH5 antibodies potently inhibited erythrocyte invasion. However, it has been a challenge to generate full-length recombinant PfRH5 in a bacterial-cell-based expression system. In this study, we have produced full-length recombinant PfRH5 in
Escherichia coli
that exhibits specific erythrocyte binding similar to that of the native PfRH5 parasite protein and also, importantly, elicits potent invasion-inhibitory antibodies against a number of
P. falciparum
strains. Antibasigin antibodies blocked the erythrocyte binding of both native and recombinant PfRH5, further confirming that they bind with basigin. We have thus successfully produced full-length PfRH5 as a functionally active erythrocyte binding recombinant protein with a conformational integrity that mimics that of the native parasite protein and elicits potent strain-transcending parasite-neutralizing antibodies.
P. falciparum
has the capability to develop immune escape mechanisms, and thus, blood-stage malaria vaccines that target multiple antigens or pathways may prove to be highly efficacious. In this regard, antibody combinations targeting PfRH5 and other key merozoite antigens produced potent additive inhibition against multiple worldwide
P. falciparum
strains. PfRH5 was immunogenic when immunized with other antigens, eliciting potent invasion-inhibitory antibody responses with no immune interference. Our results strongly support the development of PfRH5 as a component of a combination blood-stage malaria vaccine.
Rapid Nutritional Remodeling of the Host Cell upon Attachment of Legionella pneumophila
Authors: Bruckert William M. , Price Christopher T. , Abu Kwaik Yousef
Published: October 2013

Upon entry of
Legionella pneumophila
into amoebas and macrophages, host-mediated farnesylation of the AnkB effector enables its anchoring to the
Legionella
-containing vacuole (LCV) membrane. On the LCV, AnkB triggers docking of K
48
-linked polyubiquitinated proteins that are degraded by the host proteasomes to elevate cellular levels of amino acids needed for intracellular proliferation. Interference with AnkB function triggers
L. pneumophila
to exhibit a starvation response and differentiate into the nonreplicative phase in response to the basal levels of cellular amino acids that are not sufficient to power intracellular proliferation of
L. pneumophila
. Therefore, we have determined whether the biological function of AnkB is temporally and spatially triggered upon bacterial attachment to the host cell to circumvent a counterproductive bacterial differentiation into the nonreplicative phase upon bacterial entry. Here, we show that upon attachment of
L. pneumophila
to human monocyte-derived macrophages (hMDMs), the host farnesylation and ubiquitination machineries are recruited by the Dot/Icm system to the plasma membrane exclusively beneath sites of bacterial attachment. Transcription and injection of
ankB
is triggered by attached extracellular bacteria followed by rapid farnesylation and anchoring of AnkB to the cytosolic side of the plasma membrane beneath bacterial attachment, where K
48
-linked polyubiquitinated proteins are assembled and degraded by the proteasomes, leading to a rapid rise in the cellular levels of amino acids. Our data represent a novel strategy by an intracellular pathogen that triggers rapid nutritional remodeling of the host cell upon attachment to the plasma membrane, and as a result, a gratuitous surplus of cellular amino acids is generated to support proliferation of the incoming pathogen.
Factor H-Dependent Alternative Pathway Inhibition Mediated by Porin B Contributes to Virulence of Neisseria meningitidis
Authors: Lewis Lisa A. , Vu David M. , Vasudhev Shreekant , Shaughnessy Jutamas , Granoff Dan M. , Ram Sanjay
Published: October 2013

The identification of “factor H binding protein (fHbp)-null” invasive meningococcal isolates and the realization that widespread use of fHbp-based vaccines could herald selection of such strains prompted us to characterize novel mechanisms of alternative pathway (AP) inhibition on meningococci. Of seven strains engineered to lack four known AP-inhibiting molecules, capsular polysaccharide, lipooligosaccharide sialic acid, fHbp, and neisserial surface protein A (quadruple mutants), four strains inhibited human AP-mediated C3 deposition. All four expressed the porin B2 (PorB2) molecule, and three strains belonged to the hypervirulent ST-11 lineage. Consistent with reduced C3 deposition, the rate of C3a generation by a PorB2 isolate was lower than that by a PorB3 strain. Allelic replacement of PorB3 with PorB2, in both encapsulated and unencapsulated strains, confirmed the role of PorB2 in AP inhibition. Expression of PorB2 increased resistance to complement-dependent killing relative to that seen in an isogenic PorB3-expressing strain. Adult rabbit and mouse APs were unimpeded on all mutants, and human fH inhibited nonhuman C3 deposition on PorB2-expressing strains, which provided functional evidence for human fH-dependent AP regulation by PorB2. Low-affinity binding of full-length human fH to quadruple mutants expressing PorB2 was demonstrated. fH-like protein 1 (FHL-1; contains fH domains 1 through 7) and fH domains 6 and 7 fused to IgG Fc bound to one PorB2-expressing quadruple mutant, which suggested that fH domains 6 and 7 may interact with PorB2. These results associate PorB2 expression with serum resistance and presage the appearance of fHbp-null and hypervirulent ST-11 isolates that may evade killing by fHbp-based vaccines.

IMPORTANCEThe widespread use of antimeningococcal vaccines based on factor H (fH) binding protein (fHbp) is imminent. Meningococci that lack fHbp were recently isolated from persons with invasive disease, and these fHbp-null strains could spawn vaccine failure. Our report provides a molecular basis for an explanation of how fHbp-null strains may evade the host immune system. Meningococci possess several mechanisms to subvert killing by the alternative pathway (AP) of complement, including production of the fHbp and NspA fH binding proteins. Here we show that a meningococcal protein called porin B2 (PorB2) contributes to inhibition of the AP on the bacterial surface. A majority of the “fHbp-null” isolates identified, as well as all members of a “hypervirulent” lineage (called ST-11), express PorB2. Our findings highlight the potential for the emergence of fHbp-negative strains that are able to regulate the AP and may be associated with fHbp vaccine failure.
The General Phosphotransferase System Proteins Localize to Sites of Strong Negative Curvature in Bacterial Cells
Authors: Govindarajan Sutharsan , Elisha Yair , Nevo-Dinur Keren , Amster-Choder Orna
Published: October 2013

The bacterial cell poles are emerging as subdomains where many cellular activities take place, but the mechanisms for polar localization are just beginning to unravel. The general phosphotransferase system (PTS) proteins, enzyme I (EI) and HPr, which control preferential use of carbon sources in bacteria, were recently shown to localize near the
Escherichia coli
cell poles. Here, we show that EI localization does not depend on known polar constituents, such as anionic lipids or the chemotaxis receptors, and on the cell division machinery, nor can it be explained by nucleoid occlusion or localized translation. Detection of the general PTS proteins at the budding sites of endocytotic-like membrane invaginations in spherical cells and their colocalization with the negative curvature sensor protein DivIVA suggest that geometric cues underlie localization of the PTS system. Notably, the kinetics of glucose uptake by spherical and rod-shaped
E. coli
cells are comparable, implying that negatively curved “pole-like” sites support not only the localization but also the proper functioning of the PTS system in cells with different shapes. Consistent with the curvature-mediated localization model, we observed the EI protein from
Bacillus subtilis
at strongly curved sites in both
B. subtilis
and
E. coli
. Taken together, we propose that changes in cell architecture correlate with dynamic survival strategies that localize central metabolic systems like the PTS to subcellular domains where they remain active, thus maintaining cell viability and metabolic alertness.

IMPORTANCE
Despite their tiny size and the scarcity of membrane-bounded organelles, bacteria are capable of sorting macromolecules to distinct subcellular domains, thus optimizing functionality of vital processes. Understanding the cues that organize bacterial cells should provide novel insights into the complex organization of higher organisms. Previously, we have shown that the general proteins of the phosphotransferase system (PTS) signaling system, which governs utilization of carbon sources in bacteria, localize to the poles of
Escherichia coli
cells. Here, we show that geometric cues, i.e., strong negative membrane curvature, mediate positioning of the PTS proteins. Furthermore, localization to negatively curved regions seems to support the PTS functionality.
The Gravity Anomaly Map of North America
Authors: Hanna W. F. , Sweeney R. E. , Hildenbrand T. G. , Tanner J. G. , McConnell R. K. , Godson R. H.
Published: October 2013

The recently developed Gravity Anomaly Map of North America is the product of a 12-year multinational effort to compile, critically edit, and merge gravity anomaly data on a continental and global scale (Gravity Anomaly Map Committee, 1987). This color-pixel map is printed on four quadrant sheets at a scale of 1:5,000,000 and includes a fifth sheet showing a color index map and data references. This map is the first at such a global scale to include several hundreds of thousands of precise bits of surface data of Canada, the United States, Mexico, and Central America, as well as other high-quality surface data from neighboring continental and oceanic areas. A 1:20,000,000 version of the map is shown on Plate 1A.

The prospect of producing a gravity anomaly map of North America was formally advanced in 1975 by way of a cooperative agreement between the U.S. Geological Survey and the Society of Exploration Geophysicists. Before these cooperators linked to specialists of Canada, Mexico, and other countries, they agreed that an updated version of the gravity anomaly map of the United States should first be developed. In 1983, following publication of the U.S. map, the Society of Exploration Geophysicists and the U.S. Geological Survey concluded that the planned Centennial Map Series of the Decade of North American Geology program would be an excellent medium for publication of the gravity anomaly map of North America as well as the magnetic anomaly map of North America. The cooperating groups subsequently coordinated with the Geological Society of America, and the map was published in 1988.
Umbilical paracentesis for acute hernia reduction in cirrhotic patients
Authors: Russell Katie W , Mone Mary C , Scaife Courtney L
Published: October 2013

Emergent repair of umbilical hernias in cirrhotic patients is associated with a high risk for morbidity and mortality. We propose a new technique, umbilical paracentesis, for reduction of incarcerated hernias in the patient with ascites. Under ultrasound guidance, removal of ascitic fluid from the umbilical hernia sac can reduce the local pressure and thereby allow for easy hernia reduction, thus avoiding the need for an emergent operation.
Independent appraiser assessment of the quality, methodological rigour and transparency of the development of the 2008 international consensus statement on concussion in sport
Authors: White Peta E , Shee Anna Wong , Finch Caroline F
Published: October 2013

Aim

In recent years, considerable effort has been devoted to the development and revisions to an international consensus statement on concussion in sport (ICSCS). The aim of this study was to obtain expert views on the methodological rigour and transparency with which the 2008 ICSCS was developed, as a precursor to the development of the 2012 update.

Methods

Delegates registered for the 2012 fourth International Conference on Concussion in Sport, selected local concussion researchers not involved in any prior international consensus meetings, and all authors of the 2008 ICSCS published paper were invited to assess the methodological rigour and transparency with which the 2008 ICSCS was developed. The online Appraisal of Guidelines for Research and Evaluation (AGREE) II assessment tool, with six quality domains, was used and domain scores were expressed as a percentage of the maximum possible score for that domain.

Results

18 appraisers completed the online AGREE II assessment. Ten appraisers said they would recommend the 2008 ICSCS for use (without modification) and seven said they would recommend its use with some modification. The ‘scope and purpose’ and ‘clarity of presentation’ were rated highest, both scoring 78%. The lowest scoring domain was ‘applicability’ with a score of 55%.

Conclusions

The quality of the ICSCS is important because it is used to guide return-to-play decisions and the management of sport-related concussions. This appraisal of the 2008 ICSCS suggests that a greater focus is needed on the actual implementation of future ICSCS and the relationship between implementation and desired health outcomes.
Declining incidence of surgery for Achilles tendon rupture follows publication of major RCTs: evidence-influenced change evident using the Finnish registry study
Authors: Mattila Ville M , Huttunen Tuomas T , Haapasalo Heidi , Sillanpää Petri , Malmivaara Antti , Pihlajamäki Harri
Published: October 2013

Objectives

Acute Achilles tendon ruptures are common among highly active people. Recently published studies have provided increasing evidence to support non-surgical treatment. This study aimed to assess the incidence trends of surgically treated, acute Achilles tendon ruptures. Our hypothesis, based on the recent literature showing no difference in functional results between surgical and non-surgical treatment, was that the incidence of surgery would be declining.

Methods

We conducted a nationwide hospital register-based study. All patients 18 years of age or older with a diagnosis of acute Achilles tendon injury, and treated with Achilles tendon repair from 1987 to 2011 in Finland were included in the study.

Results

During the 25-year study period in Finland, a total of 15 252 patients received surgical treatment for an acute Achilles tendon rupture. The incidence of surgical treatment of acute Achilles tendon rupture in men was 11.1/100 000 person-years in 1987 and 20.5/100 000 person-years in 2011. The corresponding figures in women were 2.5/100 000 person-years in 1987 and 4.2/100 000 person-years in 2011. The highest rates occurred in 2008 in men and 2007 in women, and since then the decrease has been 42% in men and 55% in women.

Conclusions

During the past few years, the rate of surgically treated acute Achilles tendon ruptures has declined remarkably. The findings of the present study indicate that orthopaedic surgeons have chosen more often non-surgical treatment option for acute Achilles ruptures. This can be considered as an example, how high-quality scientific evidence can lead to a rapid change in clinical practice.
Knee Arthroscopy Cohort Southern Denmark (KACS): protocol for a prospective cohort study
Authors: Thorlund Jonas Bloch , Christensen Robin , Nissen Nis , Jørgensen Uffe , Schjerning Jeppe , Pørneki Jens Christian , Englund Martin , Lohmander L Stefan
Published: October 2013

Background

Meniscus surgery is a high-volume surgery carried out on 1 million patients annually in the USA. The procedure is conducted on an outpatient basis and the patients leave the hospital a few hours after surgery. A critical oversight of previous studies is their failure to account for the type of meniscal tears. Meniscus tears can be categorised as traumatic or non-traumatic. Traumatic tears (TT) are usually observed in younger, more active individuals in an otherwise ‘healthy’ meniscus and joint. Non-traumatic tears (NTT) (ie, degenerative tears) are typically observed in the middle-aged (35–55 years) and older population but the aetiology is largely unclear. Knowledge about the potential difference of the effect of arthroscopic meniscus surgery on patient symptoms between patients with traumatic and NTT is sparse. Furthermore, little is known about the natural time course of patient perceived pain, function and quality of life after meniscus surgery and factors affecting these outcomes. The aim of this prospective cohort study is to investigate the natural time course of patient-reported outcomes in patients undergoing meniscus surgery, with particular emphasis on the role of type of symptom onset.

Methods/design

This prospective cohort study enrol patients assigned for meniscus surgery. At the baseline (PRE surgery), patient characteristics are assessed using an email-based questionnaire also comprising several validated questionnaires assessing general health, knee-specific characteristics and patient's expectations of the surgery. Follow-up will be conducted at 12 and 52 weeks after meniscus surgery. The major outcomes will be differences in changes, from before to 52 weeks after surgery, in each of the five domains on the Knee injury and Osteoarthritis Outcome Score (KOOS) between patients undergoing surgery for traumatic compared with non-traumatic meniscus tears.

Dissemination

The study findings will be disseminated in peer-reviewed journals and presented at national and international conferences.

Trial registration number

ClinicalTrials.gov Identifier:NCT01871272.
Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis
Authors: Kalil Andre C , Klompas Michael , Haynatzki Gleb , Rupp Mark E
Published: October 2013

Objective

Hospital-acquired pneumonia remains the most lethal and expensive nosocomial infection worldwide. Optimal therapy remains controversial. We aimed to compare mortality and clinical response outcomes in patients treated with either linezolid or vancomycin.

Design

Systematic review and meta-analysis.

Data sources

PubMed, EMBASE, Cochrane Library, American College of Physicians Journal Club, Evidence-based Medicine BMJ and abstracts from infectious diseases and critical care meetings were searched through April 2013.

Eligibility criteria for selecting studies

All randomised clinical trials comparing linezolid to vancomycin for hospital-acquired pneumonia.

Data extraction

Preferred reporting items for systematic reviews and meta-analyses guidelines were followed. One author extracted the data and two authors rechecked and verified all data.

Results

Nine randomised trials with a total of 4026 patients were included. The adjusted absolute mortality risk difference (RD) between linezolid and vancomycin was 0.01% (95% CI −2.1% to 2.1%; p=0.992; I2=13.5%. The adjusted absolute clinical response difference was 0.9% (95% CI −1.2% to 3.1%; p=0.409; I2=0%. The risk of both microbiological (RD=5.6%, 95% CI −2.2% to 13.3%; p=0.159; I2=0%) and methicillin-resistantStaphylococcus aureus(RD=6.4%, 95% CI −4.1% to 16.9%; p=0.230; I2=0%) eradication were not different between linezolid and vancomycin. Gastrointestinal side effects were more frequent with linezolid (RD=0.8% (95% CI 0% to 1.5%; p=0.05), but no differences were found with renal failure, thrombocytopenia and drug discontinuation due to adverse events. Our sample size provided 99.9% statistical power to detect differences between drugs regarding clinical response and mortality.

Conclusions

Linezolid and vancomycin have similar efficacy and safety profiles. The high statistical power and the near-zero efficacy difference between both antibiotics demonstrates that no drug is superior for the treatment of hospital-acquired pneumonia.
Firebase medicine: extending the Role I aid station
Authors: Wilson Ramey L , Truesdell A G
Published: October 2013

The unique nature of counterinsurgency warfare in Afghanistan highlights the tactical and technical challenges of the non-contiguous battlefield. Although remote military outposts distant from their support hubs help project NATO power, they also operate without the advantages of a secure rear area or interior lines of communication. Commonly referred to as ‘firebases’, these outposts typically house a platoon or company-sized element and present numerous challenges to the delivery of medical care and support. Medical planners and providers can mitigate many of these inherent risks through targeted interventions designed to increase the capabilities of these remote outposts. These interventions include focused higher-level trauma and non-trauma medical training for both medical and non-medical personnel, expanded equipment lists, ongoing medical education, training and rehearsals, and a proven and redundant communications plan.
Republished: Interprofessional education in team communication: working together to improve patient safety
Authors: Brock Douglas , Abu-Rish Erin , Chiu Chia-Ru , Hammer Dana , Wilson Sharon , Vorvick Linda , Blondon Katherine , Schaad Douglas , Liner Debra , Zierler Brenda
Published: October 2013

Background

Communication failures in healthcare teams are associated with medical errors and negative health outcomes. These findings have increased emphasis on training future health professionals to work effectively within teams. The Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) communication training model, widely employed to train healthcare teams, has been less commonly used to train student interprofessional teams. The present study reports the effectiveness of a simulation-based interprofessional TeamSTEPPS training in impacting student attitudes, knowledge and skills around interprofessional communication.

Methods

Three hundred and six fourth-year medical, third-year nursing, second-year pharmacy and second-year physician assistant students took part in a 4 h training that included a 1 h TeamSTEPPS didactic session and   three 1 h team simulation and feedback sessions. Students worked in groups balanced by a professional programme in a self-selected focal area (adult acute, paediatric, obstetrics). Preassessments and postassessments were used for examining attitudes, beliefs and reported opportunities to observe or participate in team communication behaviours.

Results

One hundred and forty-nine students (48.7%) completed the preassessments and postassessments. Significant differences were found for attitudes toward team communication (p<0.001), motivation (p<0.001), utility of training (p<0.001) and self-efficacy (p=0.005). Significant attitudinal shifts for TeamSTEPPS skills included, team structure (p=0.002), situation monitoring (p<0.001), mutual support (p=0.003) and communication (p=0.002). Significant shifts were reported for knowledge of TeamSTEPPS (p<0.001), advocating for patients (p<0.001) and communicating in interprofessional teams (p<0.001).

Conclusions

Effective team communication is important in patient safety. We demonstrate positive attitudinal and knowledge effects in a large-scale interprofessional TeamSTEPPS-based training involving four student professions.
Novel cancer therapies: treatments driven by tumour biology
Authors: Ramaswami Ramya , Harding Victoria , Newsom-Davis Thomas
Published: October 2013

The traditional view is that treatments within oncology largely consist of chemotherapy, which aims to maximise damage to the rapidly dividing cancer cells but often at the expense of normal cells and overall quality of life for the patient. The development of anticancer drugs has changed from the serendipitous discoveries of the past, to today's purposeful targeting of cancer cells which takes advantage of novel technological developments and a greater understanding of tumour biology. The aim of these new treatments is to affect the essential function of the cancer cell while sparing normal cells, and limiting side effects. The phenotypic characteristics of tumours, such as unregulated growth signalling, development of new vascular systems and the evasion of immune destruction are used to identify potential drug targets. Here we review the clinical evidence and molecular mechanisms for novel therapies that are currently in use and those that are in development.
Republished: Whipple's disease
Authors: Puéchal Xavier
Published: October 2013

Whipple's disease is a chronic, systemic infection caused by Tropheryma whipplei. Gene amplification, isolation and DNA sequencing of T whipplei have extended our knowledge of this pathogen, which is now recognised as a ubiquitous commensal bacterium. The spectrum of signs associated with T whipplei has now been extended beyond the classic form, which affects middle-aged men, and begins with recurrent arthritis followed several years later by digestive problems associated with other diverse clinical signs. Children may present an acute primary infection, but only a small number of people with a genetic predisposition subsequently develop authentic Whipple's disease. This bacterium may also cause localised chronic infections with no intestinal symptoms: endocarditis, central nervous system involvement, arthritis, uveitis and spondylodiscitis. An impaired TH1 immune response is seen. T whipplei replication in vitro is dependent on interleukin 16 and is accompanied by the apoptosis of host cells, facilitating dissemination of the bacterium. In patients with arthritis, PCR with samples of joint fluid, saliva and stools has become the preferred examination for diagnosis. Immunohistochemical staining is also widely used for diagnosis. Treatment is based on recent microbiological data, but an immune reconstitution syndrome and recurrence remain possible. The future development of serological tests for diagnosis and the generalisation of antigen detection by immunohistochemistry should make it possible to obtain a diagnosis earlier and thus to decrease the morbidity, and perhaps also the mortality, associated with this curable disease which may, nonetheless, be fatal if diagnosed late or in an extensive systemic form.
Ecological correlates of stress for a habitat generalist in a biofuels landscape
Authors: Fredebaugh-Siller S.L. , Suski C.D. , Zuckerman Z.C. , Schooley R.L.
Published: October 2013

Understanding the success of habitat generalist species requires knowledge of how individuals respond to stressors that vary across habitats within landscapes. Habitat structure can affect stress by altering predation risk, conspecific densities, and densities of heterospecific competitors. Increased demand for biofuels will alter habitat structure for species in agroecosystems worldwide. We measured stress responses of deer mice (Peromyscus maniculatus (Wagner, 1845)), a widespread habitat generalist, in a biofuels landscape. We quantified fecal corticosterone concentrations for individuals in four biofuel crops: switchgrass (Panicum virgatum L.), miscanthus (Miscanthus × giganteus Greef & Deuter ex Hodkinson & Renvoize), mixed prairie, and corn (Zea mays L.). We also evaluated stress responses of deer mice to the annual harvesting of corn. Deer mice inhabiting switchgrass and mixed prairie had higher fecal corticosterone concentrations compared with mice in corn and miscanthus. Fecal corticosterone concentrations correlated positively with abundances of conspecifics and behaviorally dominant voles (prairie vole, Microtus ochrogaster (Wagner, 1842); meadow vole, Microtus pennsylvanicus (Ord, 1815)) across habitats. Stress levels of deer mice depended on how habitat structure modified the competitive environment. Deer mice did not exhibit increased fecal corticosterone concentrations in response to corn harvest, a rapid and extensive habitat disturbance common to agroecosystems. Our research is the first to investigate how landscape change due to biofuels expansion can affect stress levels of individuals.
Understanding and controlling the ingress of driven rain through exposed, solid wall masonry structures
Authors: Laycock Elizabeth A. , Wood Christopher
Published: October 2013

Long-term performance of historic buildings can be affected by many environmental factors, some of which become more apparent as the competence of the fabric deteriorates. Many tall historic buildings suffer from water ingress when exposed to driving rain conditions, particularly church towers in the SW of England. It is important to recognize that leakage can occur not only through flaws in the roof of a building but also through significant thicknesses of solid masonry. Identification of the most appropriate intervention requires an understanding of the way in which water might enter the structure and the assessment of potential repair options. While the full work schedule used an integrated assessment involving laboratory, field and archival work to assess the repairs that might be undertaken on these solid wall structures, this paper focuses on the laboratory work carried out to inform the writing of a Technical Advice Note on the effects of wind-driven rain and moisture movement in historic structures. The laboratory work showed that grouting and rendering were effective at reducing water penetration without retarding drying rates, and that use of internal plastering also had a very beneficial effect.
Building stone as a part of a World Heritage Site: ‘Piedra Pajarilla’ Granite and the city of Salamanca, Spain
Authors: Pereira Dolores , Cooper Barry J.
Published: October 2013

Building stone is a significant product in most human communities. While some civilizations paid more attention to the aesthetics of the stone, others focused more on physical properties, especially durability, as well as the ease of transportation to construction sites. These latter issues determined which rocks were exploited, in preference to others, for centuries. Ancient Roman society became expert in constructing durable engineering projects (e.g. roads, bridges and aqueducts). Most of their projects were realized using local granites and most remain in excellent condition today. The historic cores of many European cities need to preserve their integrity, using the original building stone of the city both for new construction and for restoration. A supply of the original material should be preserved in order to avoid use of alternative building stones when restoring old monuments. In Salamanca, a specific unique granite was used to build many of its monuments that are now preserved as part of the UNESCO World Heritage Site. An attempt to preserve this architecture and restore it, when needed, with the original material is the main focus of our paper, as some experiences using other types of rocks have led to unfortunate results.
Impact of cement repointing on rates of sandstone decay in medieval churches of the French Massif Central
Authors: André Marie-Françoise , Voldoire Olivier , Vautier Franck , Roussel Erwan , Phalip Bruno , Morel David
Published: October 2013

Three Romanesque churches of the Bourbonnais region in the French Massif Central have been investigated. These date back to the twelfth century, and are mainly built of red and white sandstones. Their ashlar blocks were extensively repointed in the mid-twentieth century with cement-rich mortar. In order to quantitatively assess the impact of repointing on the decay rates of the sandstones, the following methods have been used: dating of reference surfaces (‘zero datum levels’) based on stone-dressing marks, stone-by-stone and terrestrial LiDAR (Light Detection And Ranging) surveys, and petrographical analyses including on-site non-destructive tests. This study reveals that, between the twelfth century and the mid-twentieth century, intrinsic geological factors have been a key control on weathering rates. Stone surface recession has proceeded, on average, 500 times faster in the poorly cemented soft white sandstone compared to the iron-cemented red sandstone (4 mm/century v. 0.008 mm/century). Since the mid-twentieth century, the replacement of the original lime mortar with a cement-rich mortar has resulted in a marked increase in weathering rates and resulting surface recession of the poorly cemented white sandstone: this increase is fivefold where cement-lime mortar (‘bastard mortar’) has been used and 10-fold where harder cement-rich mortar has been applied. By contrast, the application of cement-lime mortar between the ashlars composed of iron-cemented red sandstone had no deleterious effects. This study confirms that the use of cement-based mortar should be avoided on soft and porous masonries. It also stresses the fact that accelerated stone surface recession rates are systematically associated with heritage sites that are subject to significant anthropogenic effects caused by inappropriate interventions or excessive pressure on the monuments or their environment.
Low PIP4K2B Expression in Human Breast Tumors Correlates with Reduced Patient Survival: A Role for PIP4K2B in the Regulation of E-Cadherin Expression
Authors: Keune Willem-Jan , Sims Andrew H. , Jones David R. , Bultsma Yvette , Lynch James T. , Jirström Karin , Landberg Goran , Divecha Nullin
Published: October 2013

Phosphatidylinositol-5-phosphate (PtdIns5P) 4-kinase β (PIP4K2B) directly regulates the levels of two important phosphoinositide second messengers, PtdIns5P and phosphatidylinositol-(4,5)-bisphosphate [PtdIns(4,5)P2]. PIP4K2B has been linked to the regulation of gene transcription, to TP53 and AKT activation, and to the regulation of cellular reactive oxygen accumulation. However, its role in human tumor development and on patient survival is not known. Here, we have interrogated the expression of PIP4K2B in a cohort (489) of patients with breast tumor using immunohistochemical staining and by a meta-analysis of gene expression profiles from 2,999 breast tumors, both with associated clinical outcome data. Low PIP4K2B expression was associated with increased tumor size, high Nottingham histological grade, Ki67 expression, and distant metastasis, whereas high PIP4K2B expression strongly associated with ERBB2 expression. Kaplan–Meier curves showed that both high and low PIP4K2B expression correlated with poorer patient survival compared with intermediate expression. In normal (MCF10A) and tumor (MCF7) breast epithelial cell lines, mimicking low PIP4K2B expression, using short hairpin RNA interference-mediated knockdown, led to a decrease in the transcription and expression of the tumor suppressor protein E-cadherin (CDH1). In MCF10A cells, knockdown of PIP4K2B enhanced TGF-β–induced epithelial to mesenchymal transition (EMT), a process required during the development of metastasis. Analysis of gene expression datasets confirmed the association between low PIP4K2B and low CDH1expression. Decreased CDH1 expression and enhancement of TGF-β–induced EMT by reduced PIP4K2B expression might, in part, explain the association between low PIP4K2B expression and poor patient survival. Cancer Res; 73(23); 6913–25. ©2013 AACR.
Prostate-Specific Membrane Antigen Protein Expression in Tumor Tissue and Risk of Lethal Prostate Cancer
Authors: Kasperzyk Julie L. , Finn Stephen P. , Flavin Richard , Fiorentino Michelangelo , Lis Rosina , Hendrickson Whitney K. , Clinton Steven K. , Sesso Howard D. , Giovannucci Edward L. , Stampfer Meir J. , Loda Massimo , Mucci Lorelei A.
Published: October 2013

Background: Overexpression of prostate-specific membrane antigen (PSMA) in tumor tissue and serum has been linked to increased risk of biochemical recurrence in surgically treated prostate cancer patients, but none of the studies have assessed its association with disease-specific mortality.

Methods: We examined whether high PSMA protein expression in prostate tumor tissue was associated with lethal disease, and with tumor biomarkers of progression, among participants of two U.S.-based cohorts (n = 902, diagnosed 1983–2004). We used Cox proportional hazards regression to calculate multivariable HRs and 95% confidence intervals (CI) of lethal prostate cancer, defined as disease-specific death or development of distant metastases (n = 95). Partial Spearman rank correlation coefficients were used to correlate PSMA with tumor biomarkers.

Results: During an average 13 years of follow-up, higher PSMA expression at prostatectomy was significantly associated with lethal prostate cancer (age-adjusted HRQuartile(Q)4vs.Q1 = 2.42; Ptrend < 0.01). This association was attenuated and nonsignificant (multivariable-adjusted HRQ4vs.Q1 = 1.01; Ptrend = 0.52) after further adjusting for Gleason score and prostate-specific antigen (PSA) at diagnosis. High PSMA expression was significantly (P < 0.05) correlated with higher Gleason score and PSA at diagnosis, increased tumor angiogenesis, lower vitamin D receptor and androgen receptor expression, and absence of ets-related gene (ERG) expression.

Conclusions: High tumor PSMA expression was not an independent predictor of lethal prostate cancer in the current study. PSMA expression likely captures, in part, malignant features of Gleason grade and tumor angiogenesis.

Impact: PSMA is not a strong candidate biomarker for predicting prostate cancer–specific mortality in surgically treated patients. Cancer Epidemiol Biomarkers Prev; 22(12); 2354–63. ©2013 AACR.
Redirecting Apoptosis to Aponecrosis Induces Selective Cytotoxicity to Pancreatic Cancer Cells through Increased ROS, Decline in ATP Levels, and VDAC
Authors: Dinnen Richard D. , Mao Yuehua , Qiu Wanglong , Cassai Nicholas , Slavkovich Vesna N. , Nichols Gwen , Su Gloria H. , Brandt-Rauf Paul , Fine Robert L.
Published: October 2013

Pancreatic cancer cell lines with mutated ras underwent an alternative form of cell death (aponecrosis) when treated concomitantly with clinically achievable concentrations of arsenic trioxide, ascorbic acid, and disulfiram (Antabuse; AAA). AAA's major effects are mediated through generation of intracellular reactive oxygen species (ROS) and more than 50% decline in intracellular ATP. N-acetyl cysteine and a superoxide dismutase mimetic prevented aponecrosis and restored intracellular ATP levels. DIDS (4,4′-diisothiocyanatostilbene-2, 2′ disulfonic acid), the pan- Voltage-Dependent Anion Channel (VDAC), -1, 2, 3 inhibitor and short hairpin RNA (shRNA) to VDAC-1 blocked cell death and ROS accumulation. In vivo exposure of AAA led to a 62% reduction in mean tumor size and eliminated tumors in 30% of nude mice with PANC-1 xenografts. We concluded that early caspase-independent apoptosis was shifted to VDAC-mediated “targeted” aponecrosis by the addition of disulfiram to arsenic trioxide and ascorbic acid. Conceptually, this work represents a paradigm shift where switching from apoptosis to aponecrosis death pathways, also known as targeted aponecrosis, could be utilized to selectively kill pancreatic cancer cells resistant to apoptosis. Mol Cancer Ther; 12(12); 2792–803. ©2013 AACR.
Long Pentraxin-3 Inhibits Epithelial–Mesenchymal Transition in Melanoma Cells
Authors: Ronca Roberto , Di Salle Emanuela , Giacomini Arianna , Leali Daria , Alessi Patrizia , Coltrini Daniela , Ravelli Cosetta , Matarazzo Sara , Ribatti Domenico , Vermi William , Presta Marco
Published: October 2013

During melanoma progression, malignant melanocytes are reprogrammed into mesenchymal-like cells through to an epithelial–mesenchymal transition (EMT) process associated with the acquisition of an invasive, prometastatic phenotype. The fibroblast growth factor-2 (FGF2)/FGF receptor (FGFR) system plays a pivotal role in melanoma, leading to autocrine/paracrine induction of tumor cell proliferation and angiogenesis. Long pentraxin-3 (PTX3) interacts with FGF2, and other FGF family members, inhibiting FGF-dependent neovascularization and tumor growth. Here, PTX3 protein and the PTX3-derived acetylated pentapeptide Ac-ARPCA-NH2 inhibit FGF2-driven proliferation and downstream FGFR signaling in murine melanoma B16-F10 cells. Moreover, human PTX3-overexpressing hPTX_B16-F10 cells are characterized by the reversed transition from a mesenchymal to an epithelial-like appearance, inhibition of cell proliferation, loss of clonogenic potential, reduced motility and invasive capacity, downregulation of various mesenchymal markers, and upregulation of the epithelial marker E-cadherin. Accordingly, PTX3 affects cell proliferation and EMT transition in human A375 and A2058 melanoma cells. Also, hPTX_B16-F10 cells showed a reduced tumorigenic and metastatic activity in syngeneic C57BL/6 mice. In conclusion, PTX3 inhibits FGF/FGFR-driven EMT in melanoma cells, hampering their tumorigenic and metastatic potential. These data represent the first experimental evidence about a nonredundant role of the FGF/FGFR system in the modulation of the EMT process in melanoma and indicate that PTX3 or its derivatives may represent the basis for the design of novel therapeutic approaches in FGF/FGFR-dependent tumors, including melanoma. Mol Cancer Ther; 12(12); 2760–71. ©2013 AACR.
Paradoxical Activation of T Cells via Augmented ERK Signaling Mediated by a RAF Inhibitor
Authors: Callahan Margaret K. , Masters Gregg , Pratilas Christine A. , Ariyan Charlotte , Katz Jessica , Kitano Shigehisa , Russell Valerie , Gordon Ruth Ann , Vyas Shachi , Yuan Jianda , Gupta Ashok , Wigginton Jon M. , Rosen Neal , Merghoub Taha , Jure-Kunkel Maria , Wolchok Jedd D.
Published: October 2013

RAF inhibitors selectively block extracellular signal–regulated kinase (ERK) signaling in BRAF-mutant melanomas and have defined a genotype-guided approach to care for this disease. RAF inhibitors have the opposite effect in BRAF wild-type tumor cells, where they cause hyperactivation of ERK signaling. Here, we predict that RAF inhibitors can enhance T-cell activation, based on the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells. To test this hypothesis, we have evaluated the effects of the RAF inhibitor BMS908662 on T-cell activation and signaling in vitro and in vivo. We observe that T-cell activation is enhanced in a concentration-dependent manner and that this effect corresponds with increased ERK signaling, consistent with paradoxical activation of the pathway. Furthermore, we find that the combination of BMS908662 with cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade in vivo potentiates T-cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Finally, this combination demonstrates superior antitumor activity, compared with either agent alone, in two transplantable tumor models. This study provides clear evidence that RAF inhibitors can modulate T-cell function by potentiating T-cell activation in vitro and in vivo. Paradoxical activation of ERK signaling in T cells offers one mechanism to explain the enhanced antitumor activity seen when RAF inhibitors are combined with CTLA-4 blockade in preclinical models. Cancer Immunol Res; 2(1); 70–79. ©2013 AACR.
Treatment of Intractable Anorexia Nervosa with Inactivation of the Nucleus Accumbens Using Stereotactic Surgery
Authors: Wang Jing , Chang Chongwang , Geng Ning , Wang Xuelian , Gao Guodong
Published: October 2013

Background: For 30% of anorexia nervosa (AN) patients, conventional treatments are unsuccessful; this is termed intractable AN. Objectives: This study investigates whether ablation of the nucleus accumbens (NAc) using stereotactic surgery can arouse the physiological drive to eat in intractable AN patients. Methods: Eight patients with intractable AN were included: 6 patients underwent bilateral stereotactic radio frequency ablation in the NAc and 2 patients received bilateral NAc deep brain stimulation (DBS). Observations were made for basic vital signs, body mass index (BMI), menstruation, depression, anxiety, obsessive-compulsive disorder, personality, intelligence, memory, quality of life, social functioning, as well as complications and adverse events associated with the treatment. Results: Basic vital signs, BMI and menstruation had recovered 1 year after the operation. Depression, anxiety and obsessive-compulsive disorder were improved 1 year postoperatively. There were changes in personality scores for psychoticism, neuroticism and lie tendencies that seemed to be helpful to the recovery from AN. Intelligence and memory improved after 6 months postoperatively. Quality of life and social functioning were dramatically improved at 1 year postoperatively. Conclusions: The results of this study reveal that ablation of the NAc can increase the AN patients' physiological drive to eat. Furthermore, there were no severe and/or life-influencing complications associated with the treatment.
Accuracy of Frame-Based Stereotactic Depth Electrode Implantation during Craniotomy for Subdural Grid Placement
Authors: Munyon Charles N. , Koubeissi Mohamad Z. , Syed Tanvir U. , Lüders Hans O. , Miller Jonathan P.
Published: October 2013

Background: Frame-based stereotaxy and open craniotomy may seem mutually exclusive, but invasive electrophysiological monitoring can require broad sampling of the cortex and precise targeting of deeper structures. Objectives: The purpose of this study is to describe simultaneous frame-based insertion of depth electrodes and craniotomy for placement of subdural grids through a single surgical field and to determine the accuracy of depth electrodes placed using this technique. Methods: A total of 6 patients with intractable epilepsy underwent placement of a stereotactic frame with the center of the planned cranial flap equidistant from the fixation posts. After volumetric imaging, craniotomy for placement of subdural grids was performed. Depth electrodes were placed using frame-based stereotaxy. Postoperative CT determined the accuracy of electrode placement. Results: A total of 31 depth electrodes were placed. Mean distance of distal electrode contact from the target was 1.0 ± 0.15 mm. Error was correlated to distance to target, with an additional 0.35 mm error for each centimeter (r = 0.635, p < 0.001); when corrected, there was no difference in accuracy based on target structure or method of placement (prior to craniotomy vs. through grid, p = 0.23). Conclusion: The described technique for craniotomy through a stereotactic frame allows placement of subdural grids and depth electrodes without sacrificing the accuracy of a frame or requiring staged procedures.