Melting and burning solids into liquids and gases.
We propose a novel technique for melting and burning solid materials, including the simulation of the resulting liquid and gas. The solid is simulated with traditional mesh-based techniques (triangles or tetrahedra) which enable robust handling of both deformable and rigid objects, collision and self-collision, rolling, friction, stacking, etc. The subsequently created liquid or gas is simulated with modern grid-based techniques, including vorticity confinement and the particle level set method. The main advantage of our method is that state-of-the-art techniques are used for both the solid and the fluid without compromising simulation quality when coupling them together or converting one into the other. For example, we avoid modeling solids as Eulerian grid-based fluids with high viscosity or viscoelasticity, which would preclude the handling of thin shells, self-collision, rolling, etc. Thus, our method allows one to achieve new effects while still using their favorite algorithms (and implementations) for simulating both solids and fluids, whereas other coupling algorithms require major algorithm and implementation overhauls and still fail to produce rich coupling effects (e.g., melting and burning solids).


Costs analysis and comparison of usefulness of acute MRI and 2 weeks of cast immobilization for clinically suspected scaphoid fractures.
Fractures of the scaphoid are often not detected on initial plain radiographs. Conventional management of clinically suspected scaphoid fractures is cast immobilization for 2 weeks and then reassessment. Early MRI is a diagnostic alternative. We compared the cost and usefulness of the early MRI diagnostic strategy with that of conventional management. This prospective pseudo-randomized study included patients between 18 and 49 years of age who attended Bergen Accident and Emergency Department, Bergen, Norway during 1 year in 2009-2010, after sustaining an acute wrist trauma in the previous week and with a clinically suspected scaphoid fracture. 61 patients were investigated with acute MRI, while 63 patients received standard treatment as a control group. We used cost-minimization analysis to estimate the cost of the 2 patient groups. Concerning cost, there were no statistically significant differences in the total direct medical costs or in indirect costs between the groups. Concerning usefulness, patients in the MRI group without a fracture (n = 35) used a cast for fewer days (mean 1 day) than patients in the control group with no fractures (n = 52) (mean 14 days; p < 0.001). They had less than half the number of days on sick leave than patients in the control group (mean 7 days vs. 15 days; p = 0.002). In a Norwegian setting, an early MRI was of value in patients with clinically suspected scaphoid fracture and normal plain radiographs.


Error-related Persistence of Motor Activity in Resting-state Networks.
The relationship between neural activation during movement training and the plastic changes that survive beyond movement execution is not well understood. Here we ask whether the changes in resting-state functional connectivity observed following motor learning overlap with the brain networks that track movement error during training. Human participants learned to trace an arched trajectory using a computer mouse in an MRI scanner. Motor performance was quantified on each trial as the maximum distance from the prescribed arc. During learning, two brain networks were observed, one showing increased activations for larger movement error, comprising the cerebellum, parietal, visual, somatosensory, and cortical motor areas, and the other being more activated for movements with lower error, comprising the ventral putamen and the OFC. After learning, changes in brain connectivity at rest were found predominantly in areas that had shown increased activation for larger error during task, specifically the cerebellum and its connections with motor, visual, and somatosensory cortex. The findings indicate that, although both errors and accurate movements are important during the active stage of motor learning, the changes in brain activity observed at rest primarily reflect networks that process errors. This suggests that error-related networks are represented in the initial stages of motor memory formation.


Anthropogenic ecosystem fragmentation drives shared and unique patterns of sexual signal divergence among three species of Bahamian mosquitofish.
When confronted with similar environmental challenges, different organisms can exhibit dissimilar phenotypic responses. Therefore, understanding patterns of phenotypic divergence for closely related species requires considering distinct evolutionary histories. Here, we investigated how a common form of human-induced environmental alteration, habitat fragmentation, may drive phenotypic divergence among three closely related species of Bahamian mosquitofish (Gambusia spp.). Focusing on one phenotypic trait (male coloration), having a priori predictions of divergence, we tested whether populations persisting in fragmented habitats differed from those inhabiting unfragmented habitats and examined the consistency of the pattern across species. Species exhibited both shared and unique patterns of phenotypic divergence between the two types of habitats, with shared patterns representing the stronger effect. For all species, populations in fragmented habitats had fewer dorsal-fin spots. In contrast, the magnitude and trajectory of divergence in dorsal-fin color, a sexually selected trait, differed among species. We identified fragmentation-mediated increased turbidity as a possible driver of these trait shifts. These results suggest that even closely related species can exhibit diverse phenotypic responses when encountering similar human-mediated selection regimes. This element of unpredictability complicates forecasting the phenotypic responses of wild organisms faced with anthropogenic change - an important component of biological conservation and ecosystem management.


Forearm vasodilator reactivity in homozygous carriers of the 9p21.3 rs1333049 G>C polymorphism.
Recently, a novel susceptibility locus for coronary artery disease (CAD) has been identified on chromosome 9p21.3, linked to the single-nucleotide polymorphism (SNP) rs1333049 G>C. However, the physiological mechanism through which this locus confers an increased CAD-risk is still unknown. The aim of the present case-control study was to test whether this chromosome 9p21.3 locus, represented by the rs1333049 variant, is associated with altered vasodilator resistance vessel function in healthy young volunteers. A total of 97 healthy male volunteers were screened for homozygous carriers of either the G- or the C-allele, the minor allele in European populations. Forearm blood flow (FBF) reactivity to acetylcholine (ACh) and glycerol trinitrate (GTN) was then studied in 10 C/C-genotype carriers compared with 10 control subjects harbouring the G/G-genotype. FBF responses to ACh and GTN were reduced in subjects homozygous for the C-allele of the rs1333049 SNP (P < 0.05). FBF reactivity to the highest dose of ACh and GTN was 95% and 74% lower when compared with control subjects with the G/G-genotype. Our study revealed a functional impairment in forearm artery vasodilator resistance in carriers of the rs1333049 C/C-genotype, thus providing evidence for a first physiological functional link underlying the genetic association of the 9p21.3 locus with an increased cardiovascular risk.


Costs of village community, residential campus and dispersed housing provision for people with intellectual disability.
In recent years, a growing volume of research evidence has been generated about the relative cost-effectiveness of various types of community-based residential supports for people with intellectual disability (ID) in the UK. However, few reliable data are available to inform planners, commissioners or service providers about the quality and costs of providing support within residential or village communities. The evaluation described in the present paper aimed to fill some of the gaps in knowledge by examining the comparative costs of supporting people in village community settings, in National Health Service (NHS) residential campuses and in dispersed, community-based housing schemes. The complete service package received by each study participant was described and costed, and a series of statistical analyses was undertaken to identify factors associated with variations in the cost of support. The analyses reported in the present paper were based on comparisons of 86 people living in village communities, 133 in residential campuses and 281 in dispersed housing schemes. Wide variations in cost were found, not only between models of accommodation, but between individual organizations, settings and service users. Multivariate analysis revealed that higher costs were associated with supports for people with higher levels of ID and more severe challenging behaviour. The cost of support was affected by the size of the residential setting, with smaller facilities likely to be more expensive. Associations were also found between increased costs, and services for younger users, male users and people who had not moved from a NHS hospital. Generally, more sophisticated service processes within the setting were associated with higher costs; although systematic arrangements for supervision and training of staff had a negative effect on cost. The cost findings should be considered alongside evidence on outcomes. A comparison of village communities and dispersed housing schemes suggests that both models of provision appear be associated with particular benefits, although different types of setting are appropriate for different individuals and therefore, the continued development of a range of residential models is important.


Time-Dependent Mechanical Response of APbX3 (A = Cs, CH3 NH3 ; X = I, Br) Single Crystals.
The ease of processing hybrid organic-inorganic perovskite (HOIPs) films, belonging to a material class with composition ABX3 , from solution and at mild temperatures promises their use in deformable technologies, including flexible photovoltaic devices, sensors, and displays. To successfully apply these materials in deformable devices, knowledge of their mechanical response to dynamic strain is necessary. The authors elucidate the time- and rate-dependent mechanical properties of HOIPs and an inorganic perovskite (IP) single crystal by measuring nanoindentation creep and stress relaxation. The observation of pop-in events and slip bands on the surface of the indented crystals demonstrate dislocation-mediated plastic deformation. The magnitudes of creep and relaxation of both HOIPs and IPs are similar, negating prior hypothesis that the presence of organic A-site cations alters the mechanical response of these materials. Moreover, these samples exhibit a pronounced increase in creep, and stress relaxation as a function of indentation rate whose magnitudes reflect differences in the rates of nucleation and propagation of dislocations within the crystal structures of HOIPs and IP. This contribution provides understanding that is critical for designing perovskite devices capable of withstanding mechanical deformations.


Surgical options for treatment of atrial fibrillation.
If we want to improve the outcomes, increase the success and reduce the complication rate of existing treatment strategies in concomitant and stand-alone atrial fibrillation (AF) procedures, we will have to increase our understanding of the pathophysiology, and of the disease, the limitations of current energy sources and ablation catheters, the different possible lesion sets, as well as improve communication between the electrophysiologist and cardiac surgeon. The technical limitations of percutaneous endocardial ablation procedures and the empirical techniques in surgical AF procedures necessitate new and innovative approaches. Surgeons should aim to improve the quality of the lesion set and minimize the invasiveness of existing techniques. The Maze procedure remains the basis upon which most of the more limited concomitant ablation procedures are and will be designed, but in stand-alone patients, recent progress has directed us towards either a single-step or sequential combined percutaneous endocardial procedure with a thoracoscopic epicardial procedure on the beating heart. A dedicated team of electrophysiologists and cardiothoracic surgeons can now work together to perform AF procedures. This can guide us to determine if there is an additional value of limiting the lesion set of the Maze procedure in concomitant surgery, and of an epicardial access in the treatment of stand-alone AF on the beating heart. If so, we will better understand which energy sources, lesion sets and surgical techniques are able to give us a three-dimensional knowledge and a three-dimensional treatment of AF. As a result, we can expect to obtain a higher single procedure long-term success rate with an acceptable low complication rate.


Management of perineal necrotizing fasciitis (Fournier's gangrene).
Eleven cases of perineal necrotizing fasciitis were treated in the Department of Surgery, University of Turku, Finland. In 10 cases the diagnosis was made on the basis of the fulminating progression of the infection to scrotal gangrene, identification of multiple underlying pathogenic organisms and toxaemia. In one female patient a corresponding infection developed in the labia majora. Each patient suffered nonspecific symptoms before the gangrene became evident. The management included surgical debridement of the necrotic tissue with incisions and drainage of the involved areas, antibiotic therapy and hyperbaric oxygen (HBO) treatment. The infection originated from the anorectal area in 5 patients, 1 patient had sustained scrotal trauma and in 5 cases the underlying condition was unknown. Colostomy was performed in 6 patients. One patient died 2 days after the admission. All the infections proved to be multimicrobial. Hyperbaric oxygenation was employed as a therapeutic adjunct in the present series, but it should neither replace nor delay surgical intervention. The key points in the management include early diagnosis with prompt surgical debridement and antibiotic therapy. After healthy granulation has appeared, the healing time can be shortened with reconstructive surgical procedures.


The current and future global distribution and population at risk of dengue.
Dengue is a mosquito-borne viral infection that has spread throughout the tropical world over the past 60 years and now affects over half the world's population. The geographical range of dengue is expected to further expand due to ongoing global phenomena including climate change and urbanization. We applied statistical mapping techniques to the most extensive database of case locations to date to predict global environmental suitability for the virus as of 2015. We then made use of climate, population and socioeconomic projections for the years 2020, 2050 and 2080 to project future changes in virus suitability and human population at risk. This study is the first to consider the spread of Aedes mosquito vectors to project dengue suitability. Our projections provide a key missing piece of evidence for the changing global threat of vector-borne disease and will help decision-makers worldwide to better prepare for and respond to future changes in dengue risk.


Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules.
Cholangiocarcinoma is an aggressive hepatobiliary malignancy originating from biliary tract epithelium. Whether cholangiocarcinoma is responsive to immune checkpoint antibody therapy is unknown, and knowledge of its tumor immune microenvironment is limited. We aimed to characterize tumor-infiltrating lymphocytes (TILs) in cholangiocarcinoma and assess functional effects of targeting checkpoint molecules on TILs. We isolated TILs from resected tumors of patients with cholangiocarcinoma and investigated their compositions compared with their counterparts in tumor-free liver (TFL) tissues and blood, by flow cytometry and immunohistochemistry. We measured expression of immune co-stimulatory and co-inhibitory molecules on TILs, and determined whether targeting these molecules improved ex vivo functions of TILs. Proportions of cytotoxic T cells and natural killer cells were decreased, whereas regulatory T cells were increased in tumors compared with TFL. While regulatory T cells accumulated in tumors, the majority of cytotoxic and helper T cells were sequestered at tumor margins, and natural killer cells were excluded from the tumors. The co-stimulatory receptor GITR and co-inhibitory receptors PD1 and CTLA4 were over-expressed on tumor-infiltrating T cells compared with T cells in TFL and blood. Antagonistic targeting of PD1 or CTLA4 or agonistic targeting of GITR enhanced effector molecule production and T cell proliferation in ex vivo stimulation of TILs derived from cholangiocarcinoma. The inter-individual variations in TIL responses to checkpoint treatments were correlated with differences in TIL immune phenotype. Decreased numbers of cytotoxic immune cells and increased numbers of suppressor T cells that over-express co-inhibitory receptors suggest that the tumor microenvironment in cholangiocarcinoma is immunosuppressive. Targeting GITR, PD1 or CTLA4 enhances effector functions of tumor-infiltrating T cells, indicating that these molecules are potential immunotherapeutic targets for patients with cholangiocarcinoma. The defense functions of immune cells are suppressed in cholangiocarcinoma tumors. Stimulating or blocking "immune checkpoint" molecules expressed on tumor-infiltrating T cells can enhance the defense functions of these cells. Therefore, these molecules may be promising targets for therapeutic stimulation of immune cells to eradicate the tumors and prevent cancer recurrence in patients with cholangiocarcinoma.


Haplotype block structure is conserved across mammals.
Genetic variation in genomes is organized in haplotype blocks, and species-specific block structure is defined by differential contribution of population history effects in combination with mutation and recombination events. Haplotype maps characterize the common patterns of linkage disequilibrium in populations and have important applications in the design and interpretation of genetic experiments. Although evolutionary processes are known to drive the selection of individual polymorphisms, their effect on haplotype block structure dynamics has not been shown. Here, we present a high-resolution haplotype map for a 5-megabase genomic region in the rat and compare it with the orthologous human and mouse segments. Although the size and fine structure of haplotype blocks are species dependent, there is a significant interspecies overlap in structure and a tendency for blocks to encompass complete genes. Extending these findings to the complete human genome using haplotype map phase I data reveals that linkage disequilibrium values are significantly higher for equally spaced positions in genic regions, including promoters, as compared to intergenic regions, indicating that a selective mechanism exists to maintain combinations of alleles within potentially interacting coding and regulatory regions. Although this characteristic may complicate the identification of causal polymorphisms underlying phenotypic traits, conservation of haplotype structure may be employed for the identification and characterization of functionally important genomic regions.


A Simple Flow-Cytometric Method Measuring B Cell Surface Immunoglobulin Avidity Enables Characterization of Affinity Maturation to Influenza A Virus.
Antibody (Ab) affinity maturation enables an individual to maintain immunity to an increasing number of pathogens within the limits of a total Ig production threshold. A better understanding of this process is critical for designing vaccines that generate optimal Ab responses to pathogens. Our study describes a simple flow-cytometric method that enumerates virus-specific germinal center (GC) B cells as well as their AC50, a measure of Ab avidity, defined as the antigen concentration required to detect 50% of specific B cells. Using a model of mouse Ab responses to the influenza A virus hemagglutinin (IAV HA), we obtained data indicating that AC50 decreases with time postinfection in an affinity maturation-dependent process. As proof of principle of the utility of the method, our data clearly show that relative to intranasal IAV infection, intramuscular immunization against inactivated IAV in adjuvant results in a diminished GC HA B cell response, with increased AC50 correlating with an increased serum Ab off-rate. Enabling simultaneous interrogation of both GC HA B cell quantity and quality, this technique should facilitate study of affinity maturation and rational vaccine design. Though it was first described 50 years ago, little is known about how antibody affinity maturation contributes to immunity. This question is particularly relevant to developing more effective vaccines for influenza A virus (IAV) and other viruses that are difficult vaccine targets. Limitations in methods for characterizing antigen-specific B cells have impeded progress in characterizing the quality of immune responses to vaccine and natural immunogens. In this work, we describe a simple flow cytometry-based approach that measures both the number and affinity of IAV-binding germinal center B cells specific for the IAV HA, the major target of IAV-neutralizing antibodies. Using this method, we showed that the route and form of immunization significantly impacts the quality and quantity of B cell antibody responses. This method provides a relatively simple yet powerful tool for better understanding the contribution of affinity maturation to viral immunity.


A gut-brain axis regulating glucose metabolism mediated by bile acids and competitive fibroblast growth factor actions at the hypothalamus.
Bile acids have been implicated as important regulators of glucose metabolism via activation of FXR and GPBAR1. We have previously shown that FGF19 can modulate glucose handling by suppressing the activity of hypothalamic AGRP/NPY neurons. As bile acids stimulate the release of FGF19/FGF15 into the circulation, we pursued the potential of bile acids to improve glucose tolerance via a gut-brain axis involving FXR and FGF15/FGF19 within enterocytes and FGF receptors on hypothalamic AGRP/NPY neurons. A 5-day gavage of taurocholic acid, mirroring our previous protocol of a 5-day FGF19 treatment, was performed. Oral glucose tolerance tests in mice with genetic manipulations of FGF signaling and melanocortin signaling were used to define a gut-brain axis responsive to bile acids. The taurocholic acid gavage led to increased serum concentrations of taurocholic acid as well as increases of FGF15 mRNA in the ileum and improved oral glucose tolerance in obese (ob/ob) mice. In contrast, lithocholic acid, an FXR antagonist but a potent agonist for GPBAR1, did not improve glucose tolerance. The positive response to taurocholic acid is dependent upon an intact melanocortinergic system as obese MC4R-null mice or ob/ob mice without AGRP did not show improvements in glucose tolerance after taurocholate gavage. We also tested the FGF receptor isoform necessary for the bile acid response, using AGRP:Fgfr1-/- and AGRP:Fgfr2-/- mice. While the absence of FGFR1 in AGRP/NPY neurons did not alter glucose tolerance after taurocholate gavage, manipulations of Fgfr2 caused bidirectional changes depending upon the experimental model. We hypothesized the existence of an endogenous hypothalamic FGF, most likely FGF17, that acted as a chronic activator of AGRP/NPY neurons. We developed two short peptides based on FGF8 and FGF17 that should antagonize FGF17 action. Both of these peptides improved glucose homeostasis after a 4-day course of central and peripheral injections. Significantly, daily average blood glucose from continuous glucose monitoring was reduced in all tested animals but glucose concentrations remained in the euglycemia range. We have defined a gut-brain axis that regulates glucose metabolism mediated by antagonistic fibroblast growth factors. From the intestine, bile acids stimulate FGF15 secretion, leading to activation of the FGF receptors in hypothalamic AGRP/NPY neurons. FGF receptor intracellular signaling subsequently silences AGRP/NPY neurons, leading to improvements of glucose tolerance that are likely mediated by the autonomic nervous system. Finally, short peptides that antagonize homodimeric FGF receptor signaling within the hypothalamus have beneficial effects on glucose homeostasis without inducing hypoglycemia. These peptides could provide a new mode of regulating glucose metabolism.


Harmonic Structure Predicts the Enjoyment of Uplifting Trance Music.
An empirical investigation of how local harmonic structures (e.g., chord progressions) contribute to the experience and enjoyment of uplifting trance (UT) music is presented. The connection between rhythmic and percussive elements and resulting trance-like states has been highlighted by musicologists, but no research, to our knowledge, has explored whether repeated harmonic elements influence affective responses in listeners of trance music. Two alternative hypotheses are discussed, the first highlighting the direct relationship between repetition/complexity and enjoyment, and the second based on the theoretical inverted-U relationship described by the Wundt curve. We investigate the connection between harmonic structure and subjective enjoyment through interdisciplinary behavioral and computational methods: First we discuss an experiment in which listeners provided enjoyment ratings for computer-generated UT anthems with varying levels of harmonic repetition and complexity. The anthems were generated using a statistical model trained on a corpus of 100 uplifting trance anthems created for this purpose, and harmonic structure was constrained by imposing particular repetition structures (semiotic patterns defining the order of chords in the sequence) on a professional UT music production template. Second, the relationship between harmonic structure and enjoyment is further explored using two computational approaches, one based on average Information Content, and another that measures average tonal tension between chords. The results of the listening experiment indicate that harmonic repetition does in fact contribute to the enjoyment of uplifting trance music. More compelling evidence was found for the second hypothesis discussed above, however some maximally repetitive structures were also preferred. Both computational models provide evidence for a Wundt-type relationship between complexity and enjoyment. By systematically manipulating the structure of chord progressions, we have discovered specific harmonic contexts in which repetitive or complex structure contribute to the enjoyment of uplifting trance music.


Contrasting persistence strategies in Salmonella and Mycobacterium.
Long-term survival of persistent bacterial pathogens in mammalian hosts critically depends on their ability to avoid elimination by innate and adaptive immune responses. The persistent human pathogens that cause typhoid fever and tuberculosis exemplify alternative strategies for survival in the host: immune evasion and immune adaptation, respectively. Salmonella enterica serotype Typhi evades host innate immune responses and inflammation by expressing factors that interfere with its detection as a Gram-negative bacterium, enabling persistent colonization of an immunologically privileged niche, the gallbladder. In contrast, Mycobacterium tuberculosis has adapted to survive within phagocytic cells, which typically eliminate invading microbes, by deploying stress resistance mechanisms that counteract the harsh environment of the phagolysosome.


A road map for universal coverage: finding a pass through the financial mountains.
Government already pays for more than half of U.S. health care costs, and nearly all universal health insurance proposals assume continued government involvement through tax subsidies and other means. The question of what specific taxes could be used to finance universal coverage is, however, seldom carefully examined, in part due to efforts by health care reform proponents to downplay tax issues. In this article we undertake such an examination. We argue that the challenges of relying on taxes for universal coverage are even greater than is generally appreciated, but that they can nevertheless be met. A proposal to fund a universal health insurance voucher system with a value-added tax illustrates issues that would arise for tax-financed plans in general and provides a broad framework for a bipartisan approach to universal coverage. We discuss significant problems that such an approach would face and suggest solutions. We outline a long-term political and legislative strategy for enacting universal coverage that draws upon precedents set by comparable legislative initiatives, including tax reform and Medicare. The results are an improved understanding of the relationship between systemic health care finance reform and taxation and a politically realistic plan for universal coverage that employs undisguised taxes.


Quality of family planning services in HIV integrated and non-integrated health facilities in Malawi and Tanzania.
The integration of family planning (FP) and HIV-related services is common in sub-Saharan Africa. Little research has examined how FP quality of care differs between integrated and non-integrated facilities. Using nationally representative data from Malawi and Tanzania, we examined how HIV integration was associated with FP quality of care. Data were drawn from Service Provision Assessments (SPAs) from Malawi (2013-2014) and Tanzania (2014-2015). The analytic sample was restricted to lower-level facilities in Malawi (n = 305) and Tanzania (n = 750) that offered FP services. We matched SPA measures to FP quality of care indicators in the Quick Investigation of Quality (QIQ). We conducted bivariate and multivariate analyses of 22 QIQ indicators to examine how integration status was related to individual QIQ indicators and overall FP quality of care at the facility- and client-level. The prevalence of HIV integration in Malawi (39%) and Tanzania (38%) was similar. Integration of HIV services was significantly associated (p < 0.05) with QIQ indicators in Malawi (n = 3) and Tanzania (n = 4). Except for one negative association in Tanzania, all other associations were positive. At the facility-level, HIV integration was associated with increased odds of being at or above the median in FP quality of care in Malawi (adjusted odd ratio (OR) = 2.24; 95% confidence interval (CI) = 1.32, 3.79) and Tanzania (adjusted OR = 2.10; 95% CI = 1.37, 3.22). At the client-level, HIV integration was not associated with FP quality of care in either country. Based on samples in Malawi and Tanzania, HIV integration appears to be beneficially associated with FP quality of care. Using a spectrum of FP quality of care indicators, we found little evidence to support concerns that HIV integration may strain facilities and providers, and adversely impact quality outcomes. Rather, it appears to strengthen FP service delivery by increasing the likelihood of stocked FP commodities and achievement of other facility-level quality indicators, potentially through HIV-related supply chains. Further research is needed to assess FP quality of care outcomes across the various platforms of FP integration found in sub-Saharan Africa.


Vector bionomics and vectorial capacity as emergent properties of mosquito behaviors and ecology.
Mosquitoes are important vectors for pathogens that infect humans and other vertebrate animals. Some aspects of adult mosquito behavior and mosquito ecology play an important role in determining the capacity of vector populations to transmit pathogens. Here, we re-examine factors affecting the transmission of pathogens by mosquitoes using a new approach. Unlike most previous models, this framework considers the behavioral states and state transitions of adult mosquitoes through a sequence of activity bouts. We developed a new framework for individual-based simulation models called MBITES (Mosquito Bout-based and Individual-based Transmission Ecology Simulator). In MBITES, it is possible to build models that simulate the behavior and ecology of adult mosquitoes in exquisite detail on complex resource landscapes generated by spatial point processes. We also developed an ordinary differential equation model which is the Kolmogorov forward equations for models developed in MBITES under a specific set of simplifying assumptions. While mosquito infection and pathogen development are one possible part of a mosquito's state, that is not our main focus. Using extensive simulation using some models developed in MBITES, we show that vectorial capacity can be understood as an emergent property of simple behavioral algorithms interacting with complex resource landscapes, and that relative density or sparsity of resources and the need to search can have profound consequences for mosquito populations' capacity to transmit pathogens.


An assessment of patient sign-outs conducted by University at Buffalo internal medicine residents.
Internal medicine residents were surveyed regarding patient sign-outs at shift change. Data were used to design and implement interventions aimed at improving sign-out quality. This quasi-experimental project incorporated the Plan, Do, Study, Act methodology. Residents completed an anonymous electronic survey regarding experiences during sign-outs. Survey questions assessed structure, process, and outcome of sign-outs. Analysis of qualitative and quantitative data was performed; interventions were implemented based on survey findings. A total of 120 surveys (89% response) and 115 surveys (83% response) were completed by residents of 4 postgraduate years in response to the first (2008) and second (2009) survey requests, respectively. Approximately 79% of the respondents to the second survey indicated that postintervention sign-out systems were superior to preintervention systems. Results indicated improvement in specific areas of structure, process, and outcome. Survey-based modifications to existing sign-out systems effected measurable quality improvement in structure, process, and outcome.


Serum lipid changes and insulin resistance in familial Mediterranean fever.
Inflammation is known to alter lipid profiles and to induce insulin resistance. This study was planned to test the hypothesis that familial Mediterranean ferver (FMF) patients and their first-degree asymptomatic relatives may have lipid profile changes and/or insulin resistance, similar to other inflammatory diseases. We studied 72 FMF patients, 30 asymptomatic first-degree relatives, and 75 healthy controls. Fasting and 2-hour postprandial glucose, insulin, apolipoprotein (Apo) A1, Apo B, acute phase reactants, and lipid profiles of all subjects were studied. Insulin resistance was determined by the HOMA (Homeostasis Model Assessment) index. There was no difference between the groups with regard to sex, mean systolic and diastolic blood pressure, body mass index, smoking status, fasting and postprandial 2-hour glucose, insulin, acute phase reactants, and HOMA index levels. High-density lipoprotein cholesterol (HDL-C) levels were similar between FMF patients and FMF relatives (48.9±12.4 mg/dL vs 49.3±13.8 mg/dL; p=NS), and both were lower than controls (48.9±12.4 mg/dL vs 59.6±15.1 mg/dL; p<0.001 and 49.3±13.8 mg/dL vs 59.8±15.1 mg/dL; p=0.001, respectively). Apo A1 levels in FMF patients and asymptomatic first-degree FMF relatives were both lower than in controls, similar to the HDL-C levels (126.1±25.7 mg/dL vs 151.2±31.4 mg/dL; p<0.001 and 129.5±29.0 mg/dL vs 151.2±31.4 mg/dL; p=0.002, respectively). TG levels were significantly higher in FMF relatives as compared to controls (113.4±53.6 mg/dL vs 97.1± 54.9 mg/dL; p=0.025). Low HDL-C and low Apo A1 levels are found in FMF patients and their first-degree asymptomatic relatives. Low-grade inflammation caused by MEFV mutations may be responsible for these lipid profile changes.


Upper and lower body functional asymmetries in the newborn: do they have the same lateral biases?
It is still an open question as to whether functional asymmetries in the human newborn derive from a single lateralized system or multiple subsystems based on different neural mechanisms. In the present study, asymmetries in head turning were compared to those in leg movements during stepping and placing, with the latter also being related to differences in leg mass. The effects of an active versus an inactive state or condition were examined for all three behaviors. No overall lateral biases were found for head turning or for the first foot to move in stepping and placing, and there were no concordances among them; however, there was an asymmetry in that the left foot had a shorter onset latency when compared to the right foot for both stepping and placing. Findings are discussed in terms of what they imply about underlying neural systems that have a bearing on expressions of newborn laterality, and also with regard to the impact of methodological differences in this area of study.


Perspectives on care and communication involving incurably ill Turkish and Moroccan patients, relatives and professionals: a systematic literature review.
Our aim was to obtain a clearer picture of the relevant care experiences and care perceptions of incurably ill Turkish and Moroccan patients, their relatives and professional care providers, as well as of communication and decision-making patterns at the end of life. The ultimate objective is to improve palliative care for Turkish and Moroccan immigrants in the Netherlands, by taking account of socio-cultural factors in the guidelines for palliative care. A systematic literature review was undertaken. The data sources were seventeen national and international literature databases, four Dutch journals dedicated to palliative care and 37 websites of relevant national and international organizations. All the references found were checked to see whether they met the structured inclusion criteria. Inclusion was limited to publications dealing with primary empirical research on the relationship between socio-cultural factors and the health or care situation of Turkish or Moroccan patients with an oncological or incurable disease. The selection was made by first reading the titles and abstracts and subsequently the full texts. The process of deciding which studies to include was carried out by two reviewers independently. A generic appraisal instrument was applied to assess the methodological quality. Fifty-seven studies were found that reported findings for the countries of origin (mainly Turkey) and the immigrant host countries (mainly the Netherlands). The central themes were experiences and perceptions of family care, professional care, end-of-life care and communication. Family care is considered a duty, even when such care becomes a severe burden for the main female family caregiver in particular. Professional hospital care is preferred by many of the patients and relatives because they are looking for a cure and security. End-of-life care is strongly influenced by the continuing hope for recovery. Relatives are often quite influential in end-of-life decisions, such as the decision to withdraw or withhold treatments. The diagnosis, prognosis and end-of-life decisions are seldom discussed with the patient, and communication about pain and mental problems is often limited. Language barriers and the dominance of the family may exacerbate communication problems. This review confirms the view that family members of patients with a Turkish or Moroccan background have a central role in care, communication and decision making at the end of life. This, in combination with their continuing hope for the patient's recovery may inhibit open communication between patients, relatives and professionals as partners in palliative care. This implies that organizations and professionals involved in palliative care should take patients' socio-cultural characteristics into account and incorporate cultural sensitivity into care standards and care practices.


A novel pink-pigmented facultative methylotroph, Methylobacterium thiocyanatum sp. nov., capable of growth on thiocyanate or cyanate as sole nitrogen sources.
The isolation and properties of a novel species of pink-pigmented methylotroph, Methylobacterium thiocyanatum, are described. This organism satisfied all the morphological, biochemical, and growth-substrate criteria to be placed in the genus Methylobacterium. Sequencing of the gene encoding its 16S rRNA confirmed its position in this genus, with its closest phylogenetic relatives being M. rhodesianum, M. zatmanii and M. extorquens, from which it differed in its ability to grow on several diagnostic substrates. Methanol-grown organisms contained high activities of hydroxypyruvate reductase -3 micromol NADH oxidized min-1 (mg crude extract protein)-1], showing that the serine pathway was used for methylotrophic growth. M. thiocyanatum was able to use thiocyanate or cyanate as the sole source of nitrogen for growth, and thiocyanate as the sole source of sulfur in the absence of other sulfur compounds. It tolerated high concentrations (at least 50 mM) of thiocyanate or cyanate when these were supplied as nitrogen sources. Growing cultures degraded thiocyanate to produce thiosulfate as a major sulfur end product, apparently with the intermediate formation of volatile sulfur compounds (probably hydrogen sulfide and carbonyl sulfide). Enzymatic hydrolysis of thiocyanate by cell-free extracts was not demonstrated. Cyanate was metabolized by means of a cyanase enzyme that was expressed at approximately sevenfold greater activity during growth on thiocyanate [Vmax 634 +/- 24 nmol NH3 formed min-1 (mg protein)-1] than on cyanate [89 +/- 9 nmol NH3 min-1 (mg protein)-1]. Kinetic study of the cyanase in cell-free extracts showed the enzyme (1) to exhibit high affinity for cyanate (Km 0.07 mM), (2) to require bicarbonate for activity, (3) to be subject to substrate inhibition by cyanate and competitive inhibition by thiocyanate (Ki 0.65 mM), (4) to be unaffected by 1 mM ammonium chloride, (5) to be strongly inhibited by selenocyanate, and (6) to be slightly inhibited by 5 mM thiosulfate, but unaffected by 0.25 mM sulfide or 1 mM thiosulfate. Polypeptides that might be a cyanase subunit (mol.wt. 17.9 kDa), a cyanate (and/or thiocyanate) permease (mol.wt. 25.1 and 27.2 kDa), and a putative thiocyanate hydrolase (mol.wt. 39.3 kDa) were identified by SDS-PAGE. Correlation of the growth rate of cultures with thiocyanate concentration (both stimulatory and inhibitory) and the kinetics of cyanase activity might indicate that growth on thiocyanate involved the intermediate formation of cyanate, hence requiring cyanase activity. The very high activity of cyanase observed during growth on thiocyanate could be in compensation for the inhibitory effect of thiocyanate on cyanase. Alternatively, thiocyanate may be a nonsubstrate inducer of cyanase, while thiocyanate degradation itself proceeds by a carbonyl sulfide pathway not involving cyanate. A formal description of the new species (DSM 11490) is given.


Platelet myosin light chain phosphatase: keeping it together.
MLCP (myosin light chain phosphatase) regulates platelet function through its ability to control myosin IIa phosphorylation. Recent evidence suggests that MLCP is a de facto target for signalling events stimulated by cAMP. In the present mini-review, we discuss the mechanisms by which cAMP signalling maintains MLCP in an active state to control platelet contractile machinery.


Positive effect of yoga on cardiorespiratory fitness: A pilot study.
Cardiovascular disease (CVD) is the leading cause of death in developed countries. An integral part of primary prevention is physical activity. One form of physical activity to be potentially used is yoga, but this activity is associated with lower energy expenditure than that recommended for prevention. The study aimed at assessing the effect of regular yoga sessions on the aerobic capacity of the practitioners and comparing it with the normal population performing physical activity recommended by guidelines. Fifty-eight persons (16 males) with a mean age of 50.0 ± 11.06 years comprising the yoga group practiced yoga for at least 1 h a day for over 2 years. They underwent spiroergometry under maximal exercise testing to assess basic performance parameters. Their results were compared with those in 54 age-matched controls (16 males mean age of 48 ± 11.86 years performing a regular aerobic physical activity for at least 7 h a week. The yoga group had statistically significantly higher maximum performance per kilogram (P = 0.007) and maximum oxygen consumption per kilogram per minute (P = 0.028). Despite low energy expenditure, yoga practices are better in some cardiorespiratory fitness parameters than other aerobic activities recommended by current guidelines for CVD prevention.


Serum levels of sex hormones in men with acute myocardial infarction.
To compare the serum levels of total testosterone(TT), free testosterone (FT), estradiol, sex hormone binding globulin (SHBG), and androstenedione (AS) in patients with acute myocardial infarction (AMI) at the time of hospitalization, patients with old myocardial infarction (OMI), and patients with normal coronary arteries (NC) admitted for diagnostic coronary angiography. Serum sex hormones and lipid profile were measured in 79 male patients; 30 patients with AMI, 21 patient with OMI and 28 patients with NC. Ages ranged from 33-68 years. Androstenedione, estrogen, both total and free testosterone levels were quantified using coat-a-count radioimmunoassay kits. Sex hormone binding globulin was analyzed using immunoradiometric assay (IRMA)-count kits. The levels of serum estradiol in the AMI were significantly higher and serum levels of TT, FT, and SHBG were significantly lower in AMI than in OMI and NC but there was no difference found for the levels of AS in all groups. Estradiol level was also higher in OMI than in control group but no significant changes found for other sex hormones in OMI and control group. Also triglyceride, high density and low density lipoprotein in AMI were significantly different from that in OMI and control groups. Serum estradiol and low density lipoprotein levels are increased but TT, FT and SHBG levels are decreased in men with AMI compared with patients with NC.


Membrane organization and cell fusion during mating in fission yeast requires multipass membrane protein Prm1.
The involvement of Schizosaccharomyces pombe prm1(+) in cell fusion during mating and its relationship with other genes required for this process have been addressed. S. pombe prm1Δ mutant exhibits an almost complete blockade in cell fusion and an abnormal distribution of the plasma membrane and cell wall in the area of cell-cell interaction. The distribution of cellular envelopes is similar to that described for mutants devoid of the Fig1-related claudin-like Dni proteins; however, prm1(+) and the dni(+) genes act in different subpathways. Time-lapse analyses show that in the wild-type S. pombe strain, the distribution of phosphatidylserine in the cytoplasmic leaflet of the plasma membrane undergoes some modification before an opening is observed in the cross wall at the cell-cell contact region. In the prm1Δ mutant, this membrane modification does not take place, and the cross wall between the mating partners is not extensively degraded; plasma membrane forms invaginations and fingers that sometimes collapse/retract and that are sometimes strengthened by the synthesis of cell-wall material. Neither prm1Δ nor prm1Δ dniΔ zygotes lyse after cell-cell contact in medium containing and lacking calcium. Response to drugs that inhibit lipid synthesis or interfere with lipids is different in wild-type, prm1Δ, and dni1Δ strains, suggesting that membrane structure/organization/dynamics is different in all these strains and that Prm1p and the Dni proteins exert some functions required to guarantee correct membrane organization that are critical for cell fusion.


Photonic cancer nanomedicine using the near infrared-II biowindow enabled by biocompatible titanium nitride nanoplatforms.
Light-activated photoacoustic imaging (PAI) and photothermal therapy (PTT) using the second near-infrared biowindow (NIR-II, 1000-1350 nm) hold great promise for efficient tumor detection and diagnostic imaging-guided photonic nanomedicine. In this work, we report on the construction of titanium nitride (TiN) nanoparticles, with a high photothermal-conversion efficiency and desirable biocompatibility, as an alternative theranostic agent for NIR-II laser-excited photoacoustic (PA) imaging-guided photothermal tumor hyperthermia. Working within the NIR-II biowindow provides a larger maximum permissible exposure (MPE) and desirable penetration depth of the light, which then allows detection of the tumor to the full extent using PA imaging and complete tumor ablation using photothermal ablation, especially in deeper regions. After further surface polyvinyl-pyrrolidone (PVP) modification, the TiN-PVP photothermal nanoagents exhibited a high photothermal conversion efficiency of 22.8% in the NIR-II biowindow, and we further verified their high penetration depth using the NIR-II biowindow and their corresponding therapeutic effect on the viability of tumor cells in vitro. Furthermore, these TiN-PVP nanoparticles were developed as a contrast agent for NIR-II-activated PA imaging both in vitro and in vivo for the first time and realized efficient photothermal ablation of the tumor in vivo within both the NIR-I and NIR-II biowindows. This work not only provides a paradigm for TiN-PVP photothermal nanoagents working in the NIR-II biowindow both in vitro and in vivo, but also proves the feasibility of PAI and PTT cancer theranostics using NIR-II laser excitation.


Pulsed radio-frequency electromagnetic fields: dose-dependent effects on sleep, the sleep EEG and cognitive performance.
To establish a dose-response relationship between the strength of electromagnetic fields (EMF) and previously reported effects on the brain, we investigated the influence of EMF exposure by varying the signal intensity in three experimental sessions. The head of 15 healthy male subjects was unilaterally exposed for 30 min prior to sleep to a pulse-modulated EMF (GSM handset like signal) with a 10 g-averaged peak spatial specific absorption rate of (1) 0.2 W kg(-1), (2) 5 W kg(-1), or (3) sham exposed in a double-blind, crossover design. During exposure, subjects performed two series of three computerized cognitive tasks, each presented in a fixed order [simple reaction time task, two-choice reaction time task (CRT), 1-, 2-, 3-back task]. Immediately after exposure, night-time sleep was polysomnographically recorded for 8 h. Sleep architecture was not affected by EMF exposure. Analysis of the sleep electroencephalogram (EEG) revealed a dose-dependent increase of power in the spindle frequency range in non-REM sleep. Reaction speed decelerated with increasing field intensity in the 1-back task, while accuracy in the CRT and N-back task were not affected in a dose-dependent manner. In summary, this study reveals first indications of a dose-response relationship between EMF field intensity and its effects on brain physiology as demonstrated by changes in the sleep EEG and in cognitive performance.


The effect of Valerian root extract on the severity of pre menstrual syndrome symptoms.
Premenstrual syndrome (PMS) is a common disorder. Due to the knowledge lack of the precise etiology of this syndrome, different treatment methods are recommended, one of them is the use of medicinal herbs. This study aimed to investigate the effect of Valerian ( xié cǎo) root extract on the intensity of PMS symptoms. In this double-blind clinical trial, 100 female students of Islamic Azad University, Tonekabon Branch, Mazandaran Province, Iran, with PMS were randomly divided into groups receiving Valerian (scientific name: Valeriana officinalis) and placebo in 2013. The participants received 2 pills daily in the last seven days of their menstrual cycle for 3 cycles and recorded their symptoms. The data collection tools included demographic information questionnaire, daily symptom severity questionnaire, and a provisional diagnosis of premenstrual syndrome questionnaire. Data were compared previous, one, two, and three cycles after student's intervention using and analyzed by independent t-test, paired t-test, chi-squared test, and repeated measures ANOVA in SPSS 16. A significant difference was seen in mean emotional, behavioral and physical premenstrual symptom severity in the intervention group before and after the intervention (P < 0.001). However, this difference was not statistically significant in the control group. The results of this study showed that Valerian root extract may reduce emotional, physical, and behavioral symptoms of premenstrual syndrome.


Identification and purification of glial growth factor.
Cultured rat Schwann cells are stimulated to divide by a protein growth factor, present in extracts of bovine brain and pituitary, which we have named glial growth factor (GGF). Two lines of evidence indicate that GGF activity in both brain and pituitary resides in a protein of Mr = 31,000. (1) Four independently isolated monoclonal antibodies that immunoprecipitate the activity react with an antigen of this molecular weight in sodium dodecyl sulfate (SDS)-polyacrylamide gels. (2) After SDS-polyacrylamide gel electrophoresis of partially purified preparations, mitogenic activity on Schwann cells is recovered at this molecular weight. GGF has been purified approximately 10(5)-fold to apparent homogeneity from bovine pituitary anterior lobes by a combination of column chromatography steps and preparative SDS gel electrophoresis. Purified human platelet-derived growth factor, a molecule with properties similar to those of GGF, is inactive on Schwann cells and therefore appears to be distinct.


Spectinomycin as initial treatment for gonorrhoea.
The prevalence of penicillinase producing Neisseria gonorrhoeae at this hospital increased exponentially from less than 0.5% in 1978 to 6.5% of all isolates in 1982. In January 1983 first line treatment for uncomplicated heterosexual anogenital gonorrhoea was therefore changed from ampicillin and probenecid to spectinomycin. This subsequently cured 95% of cases seen at the Praed Street Clinic. Although there was an initial fall in the monthly isolation rate of penicillinase producing N gonorrhoeae after the introduction of spectinomycin, this was not maintained. The exponential increase in the prevalence of the strain did slow in 1983, rising to only 8.7%. This, however, may have reflected a general decline in the rate of increase of penicillinase producing N gonorrhoeae throughout Britain. The failure to influence the prevalence of penicillinase producing N gonorrhoeae to any great degree may have been due in part to spectinomycin resistance in both penicillinase producing and non-penicillinase-producing N gonorrhoeae. All of the isolates appeared identical, apart from the presence of the 4.4 megadalton plasmid in penicillinase producing N gonorrhoeae, but they could not be linked epidemiologically. Changing treatment in only one of the many venereal diseases clinics in London, where patients have open access to all such clinics, is unlikely to affect the prevalence of penicillinase producing N gonorrhoeae. This has probably been more important than spectinomycin resistance in limiting the effectiveness of spectinomycin in reducing the prevalence of the strain.


Small-signal analysis of bidirectional operating characteristics in a Raman ring laser with external optical injections.
Employing the small-signal analysis, we study the bidirectional operating characteristics in a Raman ring laser. Bidirectional operation is found not stable in a silicon ring because of the existence of two-photon absorption. Using polar crystals which have different forward and backward Raman gain or introducing external optical injections helps to establish stable bidirectional operation in a Raman ring laser.


Intimate partner abuse among couples during pregnancy and its predictors as reported by pregnant women visiting governmental health care centres in Tabriz, Iran.
Little is known about intimate partner abuse (IPA) among couples during pregnancy in Iran. This study aimed to compare the rates of IPA by pregnant women towards their husbands (perpetration), and women's experience of IPA from their husbands (victimization) and determine the predictors of the two behaviours. The cross-sectional study was conducted on 525 pregnant women at 24-30 weeks of gestation visiting governmental health care centres/posts in Tabriz, Iran, in 2014. The study sample was selected using random cluster sampling. The Revised Conflict Tactics Scale (CTS2) was used to assess IPA perpetration and victimization. The McNemar test was employed to compare the prevalences of IPA perpetration and victimization, and adjusted logistic regression was utilized to determine the socio-demographic predictors of overall IPA perpetration and victimization. The overall rates of women's reported abuse of their husbands (perpetration) and women's experience of abuse from their husbands (victimization) were 70% and 67%, respectively, but the difference was not statistically significant (p=0.086). The prevalence of psychological aggression perpetrated by women towards their husbands was significantly higher than that experienced by the women from their husbands (65% vs 58%, p<0.001). The prevalences of sexual coercion (15% vs 30%) and injury (8% vs 16%) perpetrated by women on their husbands were significantly lower those they experienced by the women from their husbands (p<0.001). There was no statistically significant difference between the prevalence of perpetration of physical violence towards husbands by women (19%) and that experienced by women from their husbands (22%) (p=0.072). Women's and husbands' satisfaction with their own occupations were predictors of both perpetration and victimization of IPA. The observed high rates of IPA perpetration by, women and victimization of, women during pregnancy, and the significantly higher rate of violence towards women compared with that perpetrated by women, especially for sexual coercion and injury, require health policymakers and care providers to make serious efforts to identify such violence, and take appropriate measures to reduce it, during pregnancy in women in Iran.


Breeding latitude predicts timing but not rate of spring migration in a widespread migratory bird in South America.
Identifying the processes that determine avian migratory strategies in different environmental contexts is imperative to understanding the constraints to survival and reproduction faced by migratory birds across the planet.We compared the spring migration strategies of Fork-tailed Flycatchers (Tyrannus s. savana) that breed at south-temperate latitudes (i.e., austral migrants) vs. tropical latitudes (i.e., intratropical migrants) in South America. We hypothesized that austral migrant flycatchers are more time-selected than intratropical migrants during spring migration. As such, we predicted that austral migrants, which migrate further than intratropical migrants, will migrate at a faster rate and that the rate of migration for austral migrants will be positively correlated with the onset of spring migration.We attached light-level geolocators to Fork-tailed Flycatchers at two tropical breeding sites in Brazil and at two south-temperate breeding sites in Argentina and tracked their movements until the following breeding season.Of 286 geolocators that were deployed, 37 were recovered ~1 year later, of which 28 provided useable data. Rate of spring migration did not differ significantly between the two groups, and only at one site was there a significantly positive relationship between date of initiation of spring migration and arrival date.This represents the first comparison of individual migratory strategies among conspecific passerines breeding at tropical vs. temperate latitudes and suggests that austral migrant Fork-tailed Flycatchers in South America are not more time-selected on spring migration than intratropical migrant conspecifics. Low sample sizes could have diminished our power to detect differences (e.g., between sexes), such that further research into the mechanisms underpinning migratory strategies in this poorly understood system is necessary.


Dual role of macrophages in tumor growth and angiogenesis.
During the neoplastic progression, macrophages as well as dendritic and NK cells are attracted into the tumor site and initiate the immune response against transformed cells. They activate and present tumor antigens to T cells, which are then activated to kill tumor cells. However, tumor cells are often capable of escaping the immune machinery. As the immune surveillance is not sufficient anymore, tumor-associated macrophages contribute to tumor progression. It is notable that tumor-associated macrophages promote the proliferation of tumor cells directly by secreting growth factors. They also participate in tumor progression by acting on endothelial cells and thus promoting the neovascularization of the tumor. Tumor-associated macrophages are indeed key protagonists during angiogenesis and promote each step of the angiogenesis cascade.


Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells.
Helicobacter pylori strains that express the oncoprotein CagA augment risk for gastric cancer. However, the precise mechanisms through which cag(+) strains heighten cancer risk have not been fully delineated and model systems that recapitulate the gastric niche are critical for understanding pathogenesis. Gastroids are three-dimensional organ-like structures that provide unique opportunities to study host-H. pylori interactions in a preclinical model. We used gastroids to inform and direct in vitro studies to define mechanisms through which H. pylori modulates expression of the cancer-associated tight junction protein claudin-7. Gastroids were infected by luminal microinjection, and MKN28 gastric epithelial cells were cocultured with H. pylori wild-type cag(+) strains or isogenic mutants. β-catenin, claudin-7 and snail localisation was determined by immunocytochemistry. Proliferation was assessed using 5-ethynyl-2'-deoxyuridine, and levels of claudin-7 and snail were determined by western blot and flow cytometry. Gastroids developed into a self-organising differentiation axis and H. pylori induced mislocalisation of claudin-7 and increased proliferation in a CagA- and β-catenin-dependent manner. In MKN28 cells, H pylori-induced suppression of claudin-7 was regulated by β-catenin and snail. Similarly, snail expression was increased and claudin-7 levels were decreased among H. pylori-infected individuals. H. pylori increase proliferation in a strain-specific manner in a novel gastroid system. H. pylori also alter expression and localisation of claudin-7 in gastroids and human epithelial cells, which is mediated by β-catenin and snail activation. These data provide new insights into molecular interactions with carcinogenic potential that occur between H. pylori and epithelial cells within the gastric niche.


Cell cycle inhibition preserves endothelial function in genetically engineered rabbit vein grafts.
We have recently shown that ex vivo gene therapy of rabbit autologous vein grafts with antisense oligodeoxynucleotides (AS ODN) blocking cell cycle regulatory gene expression inhibits not only neointimal hyperplasia, but also diet-induced, accelerated graft atherosclerosis. We observed that these grafts remained free of macrophage invasion and foam cell deposition. Since endothelial dysfunction plays an important role in vascular disease, the current study examined the effect of this genetic engineering strategy on graft endothelial function and its potential relationship to the engineered vessels' resistance to atherosclerosis. Rabbit vein grafts transfected with AS ODN against proliferating cell nuclear antigen (PCNA) and cell division cycle 2 (cdc2) kinase elaborated significantly more nitric oxide and exhibited greater vasorelaxation to both calcium ionophore and acetylcholine than did untreated or control ODN-treated grafts. This preservation of endothelial function was associated with a reduction in superoxide radical generation, vascular cell adhesion molecule-1 (VCAM-1) expression, and monocyte binding activity in grafts in both normal and hypercholesterolemic rabbits. Our data demonstrate that AS ODN arrest of vascular cell cycle progression results in the preservation of normal endothelial phenotype and function, thereby influencing the biology of the vessel wall towards a reduction of its susceptibility to occlusive disease.


Can Elevated Air [CO2] Conditions Mitigate the Predicted Warming Impact on the Quality of Coffee Bean?
Climate changes, mostly related to high temperature, are predicted to have major negative impacts on coffee crop yield and bean quality. Recent studies revealed that elevated air [CO2] mitigates the impact of heat on leaf physiology. However, the extent of the interaction between elevated air [CO2] and heat on coffee bean quality was never addressed. In this study, the single and combined impacts of enhanced [CO2] and temperature in beans of Coffea arabica cv. Icatu were evaluated. Plants were grown at 380 or 700 μL CO2 L-1 air, and then submitted to a gradual temperature rise from 25°C up to 40°C during ca. 4 months. Fruits were harvested at 25°C, and in the ranges of 30-35 or 36-40°C, and bean physical and chemical attributes with potential implications on quality were then examined. These included: color, phenolic content, soluble solids, chlorogenic, caffeic and p-coumaric acids, caffeine, trigonelline, lipids, and minerals. Most of these parameters were mainly affected by temperature (although without a strong negative impact on bean quality), and only marginally, if at all, by elevated [CO2]. However, the [CO2] vs. temperature interaction strongly attenuated some of the negative impacts promoted by heat (e.g., total chlorogenic acids), thus maintaining the bean characteristics closer to those obtained under adequate temperature conditions (e.g., soluble solids, caffeic and p-coumaric acids, trigonelline, chroma, Hue angle, and color index), and increasing desirable features (acidity). Fatty acid and mineral pools remained quite stable, with only few modifications due to elevated air [CO2] (e.g., phosphorous) and/or heat. In conclusion, exposure to high temperature in the last stages of fruit maturation did not strongly depreciate bean quality, under the conditions of unrestricted water supply and moderate irradiance. Furthermore, the superimposition of elevated air [CO2] contributed to preserve bean quality by modifying and mitigating the heat impact on physical and chemical traits of coffee beans, which is clearly relevant in a context of predicted climate change and global warming scenarios.


Endoscopic antireflux therapy: the Stretta procedure.
The Stretta procedure is safe and effective for the treatment of GERD. There are well-documented clinical trial data supporting its use, including a randomized sham-controlled study, single- and multi-center prospective trials, and community practice reports. The complication rate is within the acceptable range for therapeutic endoscopic procedures and less than the published complication rate for laparoscopic fundoplication. The durability of effect also is established beyond 2 years in several studies. Stretta should be added to the GERD management algorithm specifically for patients considering an antireflux surgical procedure but who are not accepting of the risks of surgery and anesthesia. These patients typically present with incomplete GERD control, despite optimal antisecretory drug therapy, or intolerance to medical therapy. Stretta should be considered only for patients who fit the anatomic inclusion criteria, whereas antireflux surgery should be reserved for those who do not. The decision to undergo antireflux surgery or Stretta must be based on the relative risks and benefits of each procedure. Although antireflux surgery provides better control of esophageal acid exposure than Stretta, the outcomes for GERD symptoms, quality of life, and reduction in PPI use are comparable. Stretta has a low risk of acute adverse events, has no reported cases of long-term dysphagia, and obviates general anesthesia and hospitalization, whereas antireflux surgery has a reported adverse event rate of approximately 2%, a considerable incidence of dysphagia, and requires general anesthesia and 1 to 2 days in the hospital. Another advantage of the Stretta procedure is that antireflux surgery still can be performed in the case of failures. In conclusion, the Stretta procedure offers a minimally invasive, safe, and effective alternative to antireflux surgery for those patients who have GERD who are controlled unsatisfactorily on antisecretory medications, who are considering surgery, and who meet the anatomic criteria that make the procedure technically feasible and safe.


Interventions to promote repeat breast cancer screening with mammography: a systematic review and meta-analysis.
Various interventions to promote repeat use of mammography have been evaluated, but the efficacy of such interventions is not well understood. We searched electronic databases through August 15, 2009, and extracted data to calculate unadjusted effect estimates (odds ratios [ORs] and 95% confidence intervals [CIs]). Eligible studies were those that reported estimates of repeat screening for intervention and control groups. We tested homogeneity and computed summary odds ratios. To explore possible causes of heterogeneity, we performed stratified analyses, examined meta-regression models for 15 a priori explanatory variables, and conducted influence analyses. We used funnel plots and asymmetry tests to assess publication bias. Statistical tests were two-sided. The 25 eligible studies (27 effect estimates) were statistically significantly heterogeneous (Q = 69.5, I(2) = 63%, P < .001). Although there were homogeneous subgroups in some categories of the 15 explanatory variables, heterogeneity persisted after stratification. For all but one explanatory variable, subgroup summary odds ratios were similar with overlapping confidence intervals. The summary odds ratio for the eight heterogeneous reminder-only studies was the largest observed (OR = 1.79, 95% CI = 1.41 to 2.29) and was statistically significantly greater than the summary odds ratio (P(diff) = .008) for the homogeneous group of 17 studies that used the more intensive strategies of education/motivation or counseling (OR = 1.27, 95% CI = 1.17 to 1.37). However, reminder-only studies remained statistically significantly heterogeneous, whereas the studies classified as education/motivation or counseling were homogeneous. Similarly, in meta-regression modeling, the only statistically significant predictor of the intervention effect size was intervention strategy (reminder-only vs the other two combined as the referent). Publication bias was not apparent. The observed heterogeneity precludes a summary effect estimate. We also cannot conclude that reminder-only intervention strategies are more effective than alternate strategies. Additional studies are needed to identify methods or strategies that could increase repeat mammography.


Commensal-bacteria-derived butyrate promotes the T-cell-independent IgA response in the colon.
Secretory immunoglobulin A (SIgA), the most abundant antibody isotype in the body, maintains a mutual relationship with commensal bacteria and acts as a primary barrier at the mucosal surface. Colonization by commensal bacteria induces an IgA response, at least partly through a T-cell-independent process. However, the mechanism underlying the commensal-bacteria-induced T-cell-independent IgA response has yet to be fully clarified. Here, we show that commensal-bacteria-derived butyrate promotes T-cell-independent IgA class switching recombination (CSR) in the mouse colon. Notably, the butyrate concentration in human stools correlated positively with the amount of IgA. Butyrate up-regulated the production of transforming growth factor β1 and all-trans retinoic acid by CD103+CD11b+ dendritic cells, both of which are critical for T-cell-independent IgA CSR. This effect was mediated by G-protein-coupled receptor 41 (GPR41/FFA3) and GPR109a/HCA2, and the inhibition of histone deacetylase. The butyrate-induced IgA response reinforced the colonic barrier function, preventing systemic bacterial dissemination under inflammatory conditions. These observations demonstrate that commensal-bacteria-derived butyrate contributes to the maintenance of the gut immune homeostasis by facilitating the T-cell-independent IgA response in the colon.


Nano-mechanics of ionic liquids at dielectric and metallic interfaces.
Using a dynamic surface force apparatus, we investigate the nano-mechanics and the nano-rheology of an ionic liquid at dielectric and metallic solid surfaces. On smooth dielectric Pyrex surfaces, we find an ordered interfacial phase extending over less than 3 nm away from the top of the layer, with a compression modulus of 15 MPa extracted from the profile of the oscillatory forces. We discuss the boundary flow of the Newtonian bulk phase on this ordered interfacial layer. On metallic platinum surfaces, our hydrodynamic measurements evidence an interfacial soft solid layer extending up to 20 nm away from the top of the layer. The elastic modulus of this interfacial layer, derived from elasto-hydrodynamic measurements, is similar to the one found on Pyrex surfaces. Both on the dielectric and on the metal surfaces, the thickness of the interfacial phases is not found to change upon approach of the opposite surface, and does not exhibit a capillary-freezing transition.


Factors intrinsic and extrinsic to blood hamper the development of a routine blood test for human prion diseases.
Development of numerous advanced techniques in recent years have allowed detection of the pathological prion protein (PrP(TSE)), the unique marker of transmissible spongiform encephalopathies (TSEs, or prion diseases), in the blood of animals and humans; however, an ante mortem screening test that can be used for the routine diagnosis of human prion diseases remains unavailable. A critical, analytical review of all the diagnostic assays developed to date will allow an evaluation of progress in this field and may facilitate the identification of the possible reasons for this delay. Thus, in this review, I provide a detailed overview of the techniques currently available for detecting PrP(TSE) and other markers of the disease in blood, as well as an analysis of the significance, feasibility, reliability and application spectrum for these methods. I highlight that factors intrinsic and extrinsic to blood may interfere with the detection of PrP(TSE)/prions, and that this is not yet taken into account in current tests. This may inspire researchers in this field to not only aspire to increase test sensitivity, but also to adopt other strategies in order to identify and overcome the limitations that hamper the development of a successful routine blood test for prion diseases.


Drinking in transition: trends in alcohol consumption in Russia 1994-2004.
Heavy alcohol consumption is widespread in Russia, but studying changes in drinking during the transition from Communism has been hampered previously by the lack of frequent data. This paper uses 1-2 yearly panel data, comparing consumption trends with the rapid concurrent changes in economic variables (notably around the "Rouble crisis", shortly preceding the 1998 survey round), and mortality. Data were from 9 rounds (1994-2004) of the 38-centre Russia Longitudinal Monitoring Survey. Respondents aged over 18 were included (>7,000 per round). Trends were measured in alcohol frequency, quantity per occasion (by beverage type) and 2 measures of potentially hazardous consumption: (i) frequent, heavy spirit drinking (≥80 g per occasion of vodka or samogon and >weekly) (ii) consuming samogon (cheap home-distilled spirit). Trends in consumption, mean household income and national mortality rates (in the same and subsequent 2 years) were compared. Finally, in a subsample of individual male respondents present in both the 1996 and 1998 rounds (before and after the financial crash), determinants of changes in harmful consumption were studied using logistic regression. Frequent, heavy spirit drinking (>80 g each time, ≥weekly) was widespread amongst men (12-17%) throughout, especially in the middle aged and less educated; with the exception of a significant, temporary drop to 10% in 1998. From 1996-2000, samogon drinking more than doubled, from 6% to 16% of males; despite a decline, levels were significantly higher in 2004 than 1996 in both sexes. Amongst women, frequent heavy spirit drinking rose non-significantly to more than 1% during the study. Heavy frequent male drinking and mortality in the same year were correlated in lower educated males, but not in women. Individual logistic regression in a male subsample showed that between 1996 and1998, those who lost their employment were more likely to cease frequent, heavy drinking; however, men who commenced drinking samogon in 1998 were more likely to be rural residents, materially poor, very heavy drinkers or pessimistic about their finances. These changes were unexplained by losses to follow-up. Sudden economic decline in late 1990s Russia was associated with a sharp, temporary fall in heavy drinking, and a gradual and persistent increase in home distilled spirit consumption, with the latter more common amongst disadvantaged groups. The correlation between heavy drinking and national mortality in lower educated men is interesting, but the timing of RLMS surveys late in the calendar year, and the absence of any correlation between drinking and the subsequent year's mortality, makes these data hard to interpret. Potential study limitations include difficulty in measuring multiple beverages consumed per occasion, and not specifically recording "surrogate" (non-beverage) alcohols.


Oscillatory compressional behavior of articular cartilage and its associated electromechanical properties.
The compressive stiffness of articular cartilage was examined in oscillatory confined compression over a wide frequency range including high frequencies relevant to impact loading. Nonlinear behavior was found when the imposed sinusoidal compression amplitude exceeded a threshold value that depended on frequency. Linear behavior was attained only by suitable control of the compression amplitude. This was enabled by real time Fourier analysis of data which provided an accurate assessment of the extent of nonlinearity. For linear viscoelastic behavior, a stiffness could be defined in the usual sense. The dependence of the stiffness on ionic strength and proteoglycan content showed that electrostatic forces between matrix charge groups contribute significantly to cartilage's compressive stiffness over the 0.001 to 20 Hz frequency range. Sinusoidal streaming potentials were also generated by oscillatory compression. A theory relating the streaming potential field to the fluid velocity field is derived and used to interpret the data. The observed magnitude of the streaming potential suggests that interstitial fluid flow is significant to cartilage behavior over the entire frequency range. The use of simultaneous streaming potential and stiffness data with an appropriate theory appears to be an important tool for assessing the relative contribution of fluid flow, intrinsic matrix viscoelasticity, or other molecular mechanisms to energy dissipation in cartilage. This method is applicable in general to hydrated, charged polymers.


Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV.
Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells contribute to the body's immune defenses. Current chimeric antigen receptor (CAR)-modified T cell immunotherapy shows strong promise for treating various cancers and infectious diseases. Although CAR-modified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use. To alleviate these disadvantages of CAR-modified T cell immunotherapy, additional cytotoxic cell-mediated immunotherapies are urgently needed. The unique biology of NK cells allows them to serve as a safe, effective, alternative immunotherapeutic strategy to CAR-modified T cells in the clinic. While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood, the formation of the immunological synapse (IS) between CAR-modified T or NK cells and their susceptible target cells is known to be essential. The role of the IS in CAR T and NK cell immunotherapies will allow scientists to harness the power of CAR-modified T and NK cells to treat cancer and infectious diseases. In this review, we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus (HIV), and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy, as well as the importance of understanding the molecular mechanisms of CAR-modified T cell- or NK cell-mediated cytotoxicity and side effects, with a focus on the CAR-modified NK cell IS.


Systematic Review: Classification Accuracy of Behavioral Screening Measures for Use in Integrated Primary Care Settings.
OBJECTIVE : To examine the classification accuracy of measures of overall psychopathology recommended for pediatric primary care screening. METHOD : A systematic review identified relevant instruments described in the literature. Subsequent systematic reviews identified studies of sensitivity (SE) and specificity (SP) of each measure for various cutoffs and different criteria for disorder (e.g., caseness determined by structured interview, exceeding a cutoff score, referral for psychiatric evaluation). RESULTS : Measures include the Child Behavior Checklist (CBCL), Pediatric Symptom Checklist (PSC), Strengths and Difficulties Questionnaire (SDQ), Brief Infant-Toddler Social Emotional Assessment (BITSEA), and the Ages and Stages Questionnaire: Social-Emotional scale (ASQ:SE). For three measures (CBCL, PSC, and SDQ) studied extensively, achieving relatively high SE and SP values (≥ .70) simultaneously occurred in only 30-55% of the studies reviewed. There are relatively few studies of the ASQ:SE and BITSEA, or of relatively new measures. DISCUSSION : Documented utility of these measures as screening instruments is limited.


Biomass characteristics in three sequencing batch reactors treating a wastewater containing synthetic organic chemicals.
The physical and biochemical characteristics of the biomass in three lab-scale sequencing batch reactors (SBR) treating a synthetic wastewater at a 20-day target solids retention time (SRT) were investigated. The synthetic wastewater feed contained biogenic compounds and 22 organic priming compounds, chosen to represent a wide variety of chemical structures with different N, P and S functional groups. At a two-day hydraulic retention time (HRT), the oxidation-reduction potential (ORP) cycled between -100 (anoxic) and 100 mV (aerobic) in the anoxic/aerobic SBR, while it remained in a range of 126+/-18 and 249+/-18 mV in the aerobic sequencing batch biofilm reactor (SBBR) and the aerobic SBR reactor, respectively. A granular activated sludge with excellent settleability (SVI=98+/-31 L mg(-1)) developed only in the anoxic/aerobic SBR, compared to a bulky sludge with poor settling characteristics in the aerobic SBR and SBBR. While all reactors had very good COD removal (>90%) and displayed nitrification, substantial nitrogen removal (74%) was only achieved in the anoxic/aerobic SBR. During the entire operational period, benzoate, theophylline and 4-chlorophenol were completely removed in all reactors. In contrast, effluent 3-nitrobenzoate was recorded when its influent concentration was increased to 5 mg L(-1) and dropped only to below 1 mg L(-1) after 300 days of operation. The competent (active) biomass fractions for these compounds were between 0.04% and 5.52% of the total biomass inferred from substrate-specific microbial enumerations. The measured competent biomass fractions for 4-chlorophenol and 3-nitrobenzoate degradation were significantly lower than the influent COD fractions of these compounds. Correspondent to the highest competent biomass fraction for benzoate degradation among the test SOCs, benzoate oxidation could be quantified with an extant respirometric technique, with the highest specific oxygen uptake rate (SOUR(benzoate), 0.026 g O2 h(-1) g(-1) XCOD) in the anoxic/aerobic SBR. These combined results suggest that operating SBRs with alternative anoxic/aerobic cycles might facilitate the formation of granular sludge with good settleability, and retain comparable removal of nitrogen and synthetic organic compounds. Hence, the practice of anoxic/aerobic cycling should be considered in wastewater treatment systems whenever possible.


Experiences of teens living in the shadow of Huntington Disease.
Research on families with Huntington Disease (HD) has primarily focused on adult decision-making surrounding predictive genetic testing and caregiver stress. Little is known about the experiences of teens living in these families. This qualitative study explored the experiences of 32 teens living in families with HD. Six focus groups were conducted across the U.S. and Canada. Data were analyzed using descriptive qualitative analysis. Huntington disease appeared to cast a shadow over the experiences described by teens. Four themes were identified: watching and waiting; alone in the midst of others; family life is kind of hard; and having to be like an adult. These experiences highlight the need for genetic counselors, health care providers, and school personnel to be aware of issues facing teens living in families with HD. Recognizing patterns of teen experiences may help health care providers develop strategies to support coping by teens in HD families.


Telehealth follow-up in lieu of postoperative clinic visit for ambulatory surgery: results of a pilot program.
Telehealth encounters can safely substitute for routine postoperative clinic visits in selected ambulatory surgical procedures. To examine whether an allied health professional telephone visit could safely substitute for an in-person clinic visit. Prospective case series during a 10-month study period from October 2011 to October 2012 (excluding July and August 2012). University-affiliated veterans hospital. Ambulatory surgery patients who underwent elective open hernia repair or laparoscopic cholecystectomy during the 10-month study period. Patients were called 2 weeks after surgery by a physician assistant and assessed using a scripted template. Assessment variables included overall health, pain, fever, incision appearance, activity level, and any patient concerns. If the telephone assessment was consistent with absence of infection and return to baseline activities, the patient was discharged from follow-up. Patients who preferred a clinic visit were seen accordingly. Percentage of patients who accepted telehealth follow-up and complications that presented in telehealth patients within 30 days of surgery. One hundred fifteen open herniorrhaphy and 26 laparoscopic cholecystectomy patients had attempted telehealth follow-up. Seventy-eight percent (110) of all patients were successfully contacted; of those, 70.8% (63) of hernia patients and 90.5% (19) of cholecystectomy patients accepted telehealth as the sole means of follow-up. Complications in the telehealth patients were zero for cholecystectomy and 4.8% (3) for herniorrhaphy. Nearly all patients expressed great satisfaction with the telephone follow-up method. Telehealth can be safely used in selected ambulatory patients as a substitute for the standard postoperative clinic visit with a high degree of patient satisfaction. Time and expense for travel (7-866 miles) were reduced and the freed clinic time was used to schedule new patients.


Anti-RhD antibody therapy modulates human natural killer cell function.
Anti-RhD antibodies are widely used in clinical practice to prevent immunization against RhD, principally in hemolytic disease of the fetus and newborn. Intriguingly, this disease is induced by production of the very same antibodies when an RhD negative woman is pregnant with an RhD positive fetus. Despite over five decades of use, the mechanism of this treatment is, surprisingly, still unclear. Here we show that anti-RhD antibodies induce human natural killer (NK) cell degranulation. Mechanistically, we demonstrate that NK cell degranulation is mediated by binding of the Fc segment of anti-RhD antibodies to CD16, the main Fcγ receptor expressed on NK cells. We found that this CD16 activation is dependent upon glycosylation of the anti-RhD antibodies. Furthermore, we show that anti-RhD antibodies induce NK cell degranulation in vivo in patients who receive this treatment prophylactically. Finally, we demonstrate that the anti-RhD drug KamRho enhances the killing of dendritic cells. We suggest that this killing leads to reduced activation of adaptive immunity and may therefore affect the production of anti-RhD antibodies.


Effects of trait anxiety and situational stress on attentional shifting are buffered by working memory capacity.
Attentional Control Theory (ACT) predicts that trait anxiety and situation stress combine to reduce performance efficiency on tasks requiring rapid shifts in attention. Recent evidence has also suggested that working memory capacity (WMC) might moderate this relationship. We controlled for methodological difficulties in the existing literature to investigate the relationships between trait anxiety, situational stress, and WMC on attentional shifting. Seventy undergraduate students participated in the study. Trait anxiety was operationalized using questionnaire scores, situational stress was manipulated through a pressured counting task, and WMC was based on performance on the Automated Operation Span Task (AOSPAN). The shifting task involved a modified version of the Sternberg paradigm as the primary task and an oddball tone-discrimination task as the secondary task. Dependent variables were performance effectiveness (accuracy) and processing efficiency (accuracy divided by response time) on the secondary task. There was no effect of anxiety, stress, or WMC in predicting performance effectiveness; however, a significant three-way interaction on processing efficiency was observed. At higher WMC, anxiety and situational stress were not associated with processing efficiency. Conversely, at lower WMC, higher trait anxiety was associated with poorer efficiency but only for those who reported higher situational stress; for those who reported lower situational stress higher trait anxiety predicted facilitated efficiency. Results are interpreted with respect to ACT and directions for future research are discussed.


Association of elevated E6 oncoprotein with grade of cervical neoplasia using PDZ interaction-mediated precipitation of E6.
To determine the expression of human papillomavirus (HPV) type 16 E6 oncoprotein in cervical specimens of women with and without cervical intraepithelial neoplasia (CIN). Cervical specimens from 2,530 unscreened women aged 30 to 54 years from Shanxi, China, were obtained. All women were assessed by liquid-based cytology, high-risk HPV DNA tests, and colposcopy with directed biopsy and endocervical curettage as necessary. Women with abnormal cytologic results or positive HPV DNA results were recalled for colposcopy, 4-quadrant cervical biopsies, and endocervical curettage. Women with biopsy-proven CIN and cancer and a convenience sample of HC2-positive, disease-negative women were tested for the presence of HPV-16 infection via HPV-16 E6 DNA-specific polymerase chain reaction. A PDZ interaction-mediated E6 oncoprotein precipitation method followed by E6-specific Western blot was performed on specimens from women with HPV-16 infections. Associations between elevated expression of E6 oncoprotein and CIN 2 and 3 were determined using logistic regression and a reference category of CIN 1 and disease-negative. A significant trend for the detection of HPV-16 E6 oncoprotein in specimen of women with proven HPV-16 infection was determined: 0% (0/12), 12.5% (1/8), 36.4% (4/11), and 42.9% (3/7) of those with negative findings, CIN 1, 2, and 3, respectively (p = .01). Compared with the category combining negative findings and CIN 1, detection of E6 oncoprotein was associated with CIN 2 (odds ratio = 10.9, p = .05) and CIN 3 (odds ratio = 14.3, p = .04). There is a significant association between elevated expression of E6 oncoprotein and grade of CIN. This finding seems consistent with the role played by E6 oncoprotein in carcinogenesis.


Mesothelin is overexpressed in pancreaticobiliary adenocarcinomas but not in normal pancreas and chronic pancreatitis.
Mesothelin, a cell surface glycoprotein present on normal mesothelial cells, has been reported to be expressed in pancreatic adenocarcinomas. We conducted this study to fully characterize mesothelin expression in surgically resected, formalin-fixed, paraffin-embedded tissue specimens of 18 pancreatic adenocarcinomas, 9 adenocarcinomas of the ampulla of Vater, 12 adenocarcinomas of the common bile duct, and 17 cases of chronic pancreatitis. Mesothelin immunostaining was performed using the antimesothelin monoclonal antibody 5B2. All 18 cases (100%) of pancreatic adenocarcinomas showed mesothelin expression, as did 8 (89%) of 9 cases of ampullar adenocarcinoma and all 12 cases (100%) of common bile duct adenocarcinoma. In all cases of pancreaticobiliary adenocarcinoma, the adjacent normal pancreas did not stain for mesothelin. Of 17 specimens of chronic pancreatitis, 16 were negative for mesothelin expression, and 1 case showed weak mesothelin staining of fewer than 5% of normal pancreatic ducts. Our results demonstrated mesothelin expression in the majority of pancreaticobiliary adenocarcinomas and no expression in normal pancreatic tissues and in chronic pancreatitis.


CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment.
Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.


Cortical networks recruited for time perception: a monkey positron emission tomography (PET) study.
The presence of an "internal clock" in the brain has been assumed to underlie the information processing related to time. This clock plays a critical role in time keeping and time perception, which are closely associated with integrated functions in the brain. To identify the brain areas recruited for time keeping and time perception, we performed positron emission tomography (PET) studies with rhesus monkeys to measure regional cerebral blood flow (rCBF) as an index of neural activity during time discrimination tasks of different durations ranging from 400 to 1500 ms. Changes in rCBF that covaried significantly with the durations of the target being perceived by subjects were found in the dorsolateral prefrontal cortex (DLPFC), the posterior part of the inferior parietal cortex, basal ganglia, and posterior cingulate cortex. Furthermore, a loss of neuronal function in the DLPFC caused by a local application of bicuculline resulted in the selective reduction of performance in time discrimination tasks. The results indicate that a neural network composed of the posterior inferior parietal cortex to the DLPFC plays a crucial role in the temporal monitoring process in time perception.