Systematic review of randomized controlled trials of patch angioplasty versus primary closure and different types of patch materials during carotid endarterectomy.
Patch angioplasty during carotid endarterectomy (CEA) may reduce the risk for perioperative or late carotid artery recurrent stenosis and subsequent ischemic stroke. We performed a systematic review of randomized controlled trials to assess the effect of routine or selective carotid patch angioplasty compared with CEA with primary closure, and the effect of different materials used for carotid patch angioplasty. Randomized trials were included if they compared carotid patch angioplasty with primary closure in any patients undergoing CEA or use of one type of carotid patch with another. Thirteen eligible randomized trials were identified. Seven trials involving 1281 operations compared primary closure with routine patch closure, and 8 trials with 1480 operations compared different patch materials (2 studies compared both). Patch angioplasty was associated with a reduction in risk for stroke of any type (P = .004), ipsilateral stroke (P = .001), and stroke or death during both the perioperative period (P = .007) and long-term follow-up (P = .004). Patching was also associated with reduced risk for perioperative arterial occlusion (P = .0001) and decreased recurrent stenosis during long-term follow-up (P < .0001). Seven trials that compared different patch types showed no difference in the risk for stroke, death, or arterial recurrent stenosis either perioperatively or at 1-year follow-up. One study of 180 patients (200 arteries) compared collagen-impregnated Dacron (Hemashield) patches with polytetrafluoroethylene patches. There was a significant increase in risk for stroke (P = .02), combined stroke and transient ischemic attack (P = .03), and recurrent stenosis (P = .01) at 30 days, and an increased risk for late recurrent stenosis greater than 50% (P < .001) associated with Dacron compared with polytetrafluoroethylene. Carotid patch angioplasty decreases the risk for perioperative death or stroke, and long-term risk for ipsilateral ischemic stroke. More data are required to establish differences between various patch materials.


Exosomes from uninfected cells activate transcription of latent HIV-1.
HIV-1 infection causes AIDS, infecting millions worldwide. The virus can persist in a state of chronic infection due to its ability to become latent. We have previously shown a link between HIV-1 infection and exosome production. Specifically, we have reported that exosomes transport viral proteins and RNA from infected cells to neighboring uninfected cells. These viral products could then elicit an innate immune response, leading to activation of the Toll-like receptor and NF-κB pathways. In this study, we asked whether exosomes from uninfected cells could activate latent HIV-1 in infected cells. We observed that irrespective of combination antiretroviral therapy, both short- and long-length viral transcripts were increased in wild-type HIV-1-infected cells exposed to purified exosomes from uninfected cells. A search for a possible mechanism for this finding revealed that the exosomes increase RNA polymerase II loading onto the HIV-1 promoter in the infected cells. These viral transcripts, which include trans-activation response (TAR) RNA and a novel RNA that we termed TAR-gag, can then be packaged into exosomes and potentially be exported to neighboring uninfected cells, leading to increased cellular activation. To better decipher the exosome release pathways involved, we used siRNA to suppress expression of ESCRT (endosomal sorting complex required for transport) proteins and found that ESCRT II and IV significantly control exosome release. Collectively, these results imply that exosomes from uninfected cells activate latent HIV-1 in infected cells and that true transcriptional latency may not be possible in vivo, especially in the presence of combination antiretroviral therapy.


Intercomparison of in-situ aircraft and satellite aerosol measurements in the stratosphere.
Aerosol composition and optical scattering from particles in the lowermost stratosphere (LMS) have been studied by comparing in-situ aerosol samples from the IAGOS-CARIBIC passenger aircraft with vertical profiles of aerosol backscattering obtained from the CALIOP lidar aboard the CALIPSO satellite. Concentrations of the dominating fractions of the stratospheric aerosol, being sulphur and carbon, have been obtained from post-flight analysis of IAGOS-CARIBIC aerosol samples. This information together with literature data on black carbon concentrations were used to calculate the aerosol backscattering which subsequently is compared with measurements by CALIOP. Vertical optical profiles were taken in an altitude range of several kilometres from and above the northern hemispheric extratropical tropopause for the years 2006-2014. We find that the two vastly different measurement platforms yield different aerosol backscattering, especially close to the tropopause where the influence from tropospheric aerosol is strong. The best agreement is found when the LMS is affected by volcanism, i.e., at elevated aerosol loadings. At background conditions, best agreement is obtained some distance (>2 km) above the tropopause in winter and spring, i.e., at likewise elevated aerosol loadings from subsiding aerosol-rich stratospheric air. This is to our knowledge the first time the CALIPSO lidar measurements have been compared to in-situ long-term aerosol measurements.


Physical-, chemical-, and biological-responsive nanomedicine for cancer therapy.
Cancer therapy is unsatisfactory as it typically has serious side effects, because normal cells in healthy organs are destroyed along with the tumor. Thus, researchers have tried to develop effective therapies with minimal side effects. One such method is to use nanotechnology to carry the drugs or therapeutic agents to the tumor region by secure encapsulation without leakage. Once the nanomedicine enters the target tumor site, it can release therapeutic agents in an effective manner. Accordingly, various nanomedicines have been developed to enhance the efficiency of cancer therapy and minimize the systematic toxicity. Here, we provide an overview and discuss the different types of responsive nanomedicines including physically, chemically, biologically, dual, and multi-responsive nanomedicines, for the in situ release of cargos in recent years. We propose critical considerations that must be considered for the design of excellent stimuli-nanomedicine. Furthermore, the possible directions for the development of successful stimuli-responsive (smart) nanomedicine are highlighted. With the development of responsive nanomedicines, precise and personalized nanomedicine will be realized with great promise in the future. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.


The structure of Mercury's magnetic field from MESSENGER's first flyby.
During its first flyby of Mercury, the MESSENGER spacecraft measured the planet's near-equatorial magnetic field. The field strength is consistent to within an estimated uncertainty of 10% with that observed near the equator by Mariner 10. Centered dipole solutions yield a southward planetary moment of 230 to 290 nanotesla RM3 (where RM is Mercury's mean radius) tilted between 5 degrees and 12 degrees from the rotation axis. Multipole solutions yield non-dipolar contributions of 22% to 52% of the dipole field magnitude. Magnetopause and tail currents account for part of the high-order field, and plasma pressure effects may explain the remainder, so that a pure centered dipole cannot be ruled out.


Ascorbic acid ameliorates oxidative stress and inflammation in dextran sulfate sodium-induced ulcerative colitis in mice.
Ascorbic acid (AA) has been shown to exert beneficial effects, including mitigating oxidative stress and inhibiting inflammation. However, the preventative effect of vitamin C in chronic inflammatory diseases such as inflammatory bowel disease (IBD) remains unclear. In our study, we investigated the anti-inflammatory effects of AA and possible mechanism involved in inhibiting dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. Male C57BL/6 mice were randomly divided to three groups: control group, DSS group, and DSS plus ascorbic acid treated group. Several clinical and inflammatory parameters as well as oxidative stress were evaluated. The results demonstrated that ascorbic acid significantly reduced clinical signs, inflammatory cytokines, myeloperoxidase (MPO) and malonaldehyde (MDA) activities, whereas the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were increased in DSS-induced mice. In addition, ascorbic acid was capable of inhibiting NF-κB, COX-2 and iNOS expression in the colonic. Taken together, these findings suggest that ascorbic acid contributes to the reduction of oxidative stress and inflammatory response in DSS-induced colitis and exerts the potential to prevent and clinical treatment of inflammatory bowel disease.


Survey of patient and public perceptions of electronic health records for healthcare, policy and research: study protocol.
Immediate access to patients' complete health records via electronic databases could improve healthcare and facilitate health research. However, the possible benefits of a national electronic health records (EHR) system must be balanced against public concerns about data security and personal privacy. Successful development of EHR requires better understanding of the views of the public and those most affected by EHR: users of the National Health Service. This study aims to explore the correlation between personal healthcare experience (including number of healthcare contacts and number and type of longer term conditions) and views relating to development of EHR for healthcare, health services planning and policy and health research. A multi-site cross-sectional self-complete questionnaire designed and piloted for use in waiting rooms was administered to patients from randomly selected outpatients' clinics at a university teaching hospital (431 beds) and general practice surgeries from the four primary care trusts within the catchment area of the hospital. All patients entering the selected outpatients clinics and general practice surgeries were invited to take part in the survey during August-September 2011. Statistical analyses will be conducted using descriptive techniques to present respondents' overall views about electronic health records and logistic regression to explore associations between these views and participants' personal circumstances, experiences, sociodemographics and more specific views about electronic health records. The study design and implementation were successful, resulting in unusually high response rates and overall recruitment (85.5%, 5336 responses). Rates for face-to-face recruitment in previous work are variable, but typically lower (mean 76.7%, SD 20). We discuss details of how we collected the data to provide insight into how we obtained this unusually high response rate.


Childhood nutrition education in health promotion and disease prevention.
In the last 10 to 15 years, nutrition has become a major component of health promotion and chronic disease prevention. Two widely recommended strategies for incorporating nutrition education directed toward children and youth into health promotion and disease prevention efforts are school-based nutrition education and the integration of nutritional care into health care. School-based nutrition education programs targeted toward very specific eating behaviors are showing very promising results in regard to behavior and attitude change of children and adolescents. Substantial changes in health care providers' attitudes and practices and in the funding and financing of health care will be needed if nutrition education delivered in the context of routine health care is to be a major force in health promotion and disease prevention for youth.


Impact of Canopy Openness on Spider Communities: Implications for Conservation Management of Formerly Coppiced Oak Forests.
Traditional woodland management created a mosaic of differently aged patches providing favorable conditions for a variety of arthropods. After abandonment of historical ownership patterns and traditional management and the deliberate transformation to high forest after World War II, large forest areas became darker and more homogeneous. This had significant negative consequences for biodiversity. An important question is whether even small-scale habitat structures maintained by different levels of canopy openness in abandoned coppiced forest may constitute conditions suitable for forest as well as open habitat specialists. We investigated the effect of canopy openness in former traditionally coppiced woodlands on the species richness, functional diversity, activity density, conservation value, and degree of rareness of epigeic spiders. In each of the eight studied locations, 60-m-long transect was established consisting of five pitfall traps placed at regular 15 m intervals along the gradient. Spiders were collected from May to July 2012. We recorded 90 spider species, including high proportions of xeric specialists (40%) and red-listed threatened species (26%). The peaks of conservation indicators, as well as spider community abundance, were shifted toward more open canopies. On the other hand, functional diversity peaked at more closed canopies followed by a rapid decrease with increasing canopy openness. Species richness was highest in the middle of the canopy openness gradient, suggesting an ecotone effect. Ordinations revealed that species of conservation concern tended to be associated with sparse and partly opened canopy. The results show that the various components of biodiversity peaked at different levels of canopy openness. Therefore, the restoration and suitable forest management of such conditions will retain important diversification of habitats in formerly coppiced oak forest stands. We indicate that permanent presence of small-scale improvements could be suitable conservation tools to prevent the general decline of woodland biodiversity in the intensified landscape of Central Europe.


Strong second harmonic generation in SiC, ZnO, GaN two-dimensional hexagonal crystals from first-principles many-body calculations.
The second harmonic generation (SHG) intensity spectrum of SiC, ZnO, GaN two-dimensional hexagonal crystals is calculated by using a real-time first-principles approach based on Green's function theory [Attaccalite et al., Phys. Rev. B: Condens. Matter Mater. Phys. 2013 88, 235113]. This approach allows one to go beyond the independent particle description used in standard first-principles nonlinear optics calculations by including quasiparticle corrections (by means of the GW approximation), crystal local field effects and excitonic effects. Our results show that the SHG spectra obtained using the latter approach differ significantly from their independent particle counterparts. In particular they show strong excitonic resonances at which the SHG intensity is about two times stronger than within the independent particle approximation. All the systems studied (whose stabilities have been predicted theoretically) are transparent and at the same time exhibit a remarkable SHG intensity in the range of frequencies at which Ti:sapphire and Nd:YAG lasers operate; thus they can be of interest for nanoscale nonlinear frequency conversion devices. Specifically the SHG intensity at 800 nm (1.55 eV) ranges from about 40-80 pm V(-1) in ZnO and GaN to 0.6 nm V(-1) in SiC. The latter value in particular is 1 order of magnitude larger than values in standard nonlinear crystals.


Sex difference in leukocyte telomere length is ablated in opposite-sex co-twins.
In eutherian mammals and in humans, the female fetus may be masculinized while sharing the intra-uterine environment with a male fetus. Telomere length (TL), as expressed in leukocytes, is heritable and is longer in women than in men. The main determinant of leukocyte TL (LTL) is LTL at birth. However, LTL is modified by age-dependent attrition. We studied LTL dynamics (LTL and its attrition) in adult same-sex (monozygotic, n = 268; dizygotic, n = 308) twins and opposite-sex (n = 144) twins. LTL was measured by Southern blots of the terminal restriction fragments. We observed that in same-sex (both monozygotic and dizygotic) twins, as reported in singletons, LTL was longer in females than in males [estimate ± standard error (SE):163 ± 63 bp, P < 0.01]. However, in opposite-sex twins, female LTL was indistinguishable from that of males (-31 ± 52 bp, P = 0.6), whereas male LTL was not affected. Findings were similar when the comparison was restricted to opposite-sex and same-sex dizygotic twins (females relative to males: same-sex: 188 ± 90 bp, P < 0.05; other-sex: -32 ± 64 bp, P = 0.6). These findings are compatible with masculinization of the female fetus in opposite-sex twins. They suggest that the sex difference in LTL, seen in the general population, is largely determined in utero, perhaps by the intrauterine hormonal environment. Further studies in newborn twins are warranted to test this thesis.


Self-rated health status and cardiorespiratory fitness as predictors of mortality in men.
Self-rated health (SRH) and cardiorespiratory fitness (fitness) are independent risk factors for all-cause mortality. The purpose of this report is to examine the single and joint effects of these exposures on mortality risk. The study included 18 488 men who completed a health survey, clinical examination and a maximal exercise treadmill test during 1987-2003. Cox regression analysis was used to quantify the associations of SRH and fitness with all-cause mortality. There were 262 deaths during 17 years of follow-up. There was a significant inverse trend (p(trend) <0.05) for mortality across SRH categories after adjustment for age, examination year, body mass index, physical activity, smoking, alcohol consumption, abnormal ECG, hypertension, hypercholesterolaemia, cardiovascular disease, diabetes and cancer. Adjustment for fitness attenuated the association (p value =0.09). The authors also observed an inverse association between fitness and mortality after controlling for the same covariates and SRH (p(trend) = 0.006). The combined analysis of SRH and fitness showed that fit men with good or excellent SRH had a 58% lower risk of mortality than their counterparts. SRH and fitness were both associated with all-cause mortality in men. Fit men with good or excellent SRH live longer than unfit men with poor or fair SRH.


Granulocyte elastase cleaves human high molecular weight kininogen and destroys its clot-promoting activity.
Purified human granulocyte elastase cleaved purified human high molecular weight (HMW) kininogen into multiple low molecular weight fragments, and destroyed the clot-promoting activity of the HMW kininogen. Elastase digestion did not release kinin or destroy the bradykinin portion of the HMW kininogen molecule; kallikrein could release kinin from the elastase-induced low molecular weight digestion products of HMW kininogen. Purified alpha 1-antitrypsin prevented the destruction of the clot-promoting activity of HMW kininogen by elastase; it also delayed the clotting of normal plasma. Elastase may play a significant role in altered hemostasis as well as fibrinolysis, in areas of inflammation to which polymorphonuclear leukocytes have been attracted.


Cardiac Rehabilitation Availability and Delivery in Canada: How Does It Compare With Other High-Income Countries?
Canada has insufficient cardiac rehabilitation (CR) capacity, yet unmet need is unknown. Moreover, Canada has CR guidelines, but whether delivery conforms has not been characterized by province/territory. This study aimed to establish (1) CR volumes, capacity, and density, as well as (2) the nature of programs, and (3) compare these (a) by province/territory and (b) with other high-income countries (HICs). In this cross-sectional study, an online survey was administered to CR programs globally. National cardiac associations were engaged to facilitate program identification where available, or local champions. Density was computed using Canada's Chronic Disease Surveillance System ischemic heart disease incidence estimates. Twenty-eight HICs with CR were selected for comparison (N = 619 programs), and multilevel analyses performed. CR was available in 10 of 13 (76.9%) provinces (no programs in Canada's North), with 74 of 182 programs initiating a survey (40.7% response). Program volumes (median = 250) were greatest in Ontario, but ultimately there was only 1 CR spot per 4.55 patients with ischemic heart disease nationally (similar in other HICs), and 186,187 more spots are needed annually. Most programs were funded by government/hospital sources (n = 48, 66.7%), but in 23 (31.5%), patients paid some or all of program costs out-of-pocket. Guideline-indicated conditions were accepted in more than 90% of programs. Programs had a multidisciplinary team of 6.2 ± 2.1 staff, offering 7.7 ± 1.5/10 core components (varied by province, P = 0.001; return-to-work offered less frequently than other HICs; P = 0.03), over 42.0 ± 26.0 hours (provincial and other HIC differences, P < 0.001). Canadian CR capacity must be augmented, but where available, services are consistent with other HICs.


Measuring the implementation of a group-based Lifestyle-integrated Functional Exercise (Mi-LiFE) intervention delivered in primary care for older adults aged 75 years or older: a pilot feasibility study protocol.
Declines in function and quality of life, and an increased risk of cardiovascular events, falls, and fractures occur with aging and may be amenable to exercise intervention. Primary care is an ideal setting for identifying older adults in need of exercise intervention. However, a cost-effective, generalizable model of chronic disease management using exercise in a real-world setting remains elusive. Our objective is to measure the feasibility, potential effectiveness, and implementation of an evidence-based Lifestyle-integrated Functional strength and balance Exercise (LiFE) intervention adapted as a group-based format (Mi-LiFE) for primary care to promote increased physical activity levels in older adults aged 75 years or older. We hypothesize that the intervention will be feasible without modification if ≥30 individuals are recruited over 6 months, ≥75 % of our sample is retained, and ≥50 % of our sample complete exercises ≥3 days per week. A pre-post pilot study design will be used to evaluate feasibility, potential effectiveness, and implementation outcomes over a 6-month period in physically inactive older adults ≥75 years recruited from a local family health team practice. The reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework will be applied to evaluate the public health effects of the intervention including outcomes both at the individual and organizational levels. A physical therapist will teach participants how to integrate strength and balance activities into their daily lives over one individual and four group-based sessions, and two phone calls. Assessments will be completed at baseline and 6 months. Feasibility outcomes include recruitment over 6 months, retention at follow-up, and adherence measured by activity diaries. Change in patient-centered and implementation outcomes that will be evaluated include physical activity levels using accelerometers and International Physical Activity Questionnaire, physical performance using short physical performance battery, quality of life using EQ5D questionnaire, falls and harms using daily calendar diaries and self-report, fidelity using descriptive feedback, barriers and facilitators to implementation using thematic content analysis, and process outcomes. The feasibility and implementation of the Mi-LiFE intervention in primary care for older adults will be evaluated, as well as the effects of the intervention on secondary outcomes. If the intervention appears feasible, we will use the resultant information to design a larger trial. ClinicalTrials.gov: NCTO2266225.


Association of aspirin dose and vorapaxar safety and efficacy in patients with non-ST-segment elevation acute coronary syndrome (from the TRACER Trial).
Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial compared vorapaxar and placebo in 12,944 high-risk patients with non-ST-segment elevation acute coronary syndrome. We explored aspirin (ASA) use and its association with outcomes. Kaplan-Meier event rates were compared in groups defined by ASA dose (low, medium, and high). Landmark analyses with covariate adjustment were performed for 0 to 30, 31 to 180, and 181 to 365 days. Of 12,515 participants, 7,523, 1,049, and 3,943 participants were treated with low-, medium-, and high-dose ASA at baseline, respectively. Participants enrolled in North America versus elsewhere were more often treated with a high dose at baseline (66% vs 19%) and discharge (60% vs 3%). Unadjusted cardiovascular death, myocardial infarction, stroke, hospitalization for ischemia, or urgent revascularization event rates tended to be higher with higher baseline ASA (18.45% low, 19.13% medium, and 20.27% high; p for trend = 0.15573). Unadjusted and adjusted hazard ratios (95% confidence intervals) for effect of vorapaxar on cardiovascular (unadjusted p for interaction = 0.065; adjusted p for interaction = 0.140) and bleeding (unadjusted p for interaction = 0.915; adjusted p for interaction = 0.954) outcomes were similar across groups. Landmark analyses showed similar safety and efficacy outcomes with vorapaxar and placebo by ASA dose at each time point except for 0 to 30 days, when vorapaxar tended to be worse for efficacy (hazard ratio 1.13, 95% confidence interval 0.89 to 1.44, p for interaction = 0.0157). In conclusion, most TRACER participants were treated with low-dose ASA, although a high dose was common in North America. High-dose participants tended to have higher rates of ischemic and bleeding outcomes. Although formal statistical testing did not reveal heterogeneity in vorapaxar's effect across dose subgroups, consistent trends support use of low-dose ASA with other antiplatelet therapies.


Closing the quality gap: revisiting the state of the science (vol. 7: quality improvement measurement of outcomes for people with disabilities).
To examine how health care outcomes for general medical care have been assessed for people with disabilities within the rubrics of care coordination and quality improvement. MEDLINE®, PsychINFO, ERIC, and CIRRIE through March 27, 2012; hand searches of references from relevant literature and journals. A search of high-quality gray literature sources was also conducted. We included all forms of disability except severe and persistent mental illness for all age groups in outpatient and community settings. We focused on outcomes, patient experience, and care coordination process measures. We looked for generic outcome measures rather than disability-condition-specific measures. We also looked for examples of outcomes used in the context of disability as a complicating condition for a set of basic service needs relevant to the general population, and secondary conditions common to disability populations. Two independent reviewers screened all articles; disagreements were resolved through consensus. Included articles were abstracted to evidence tables and quality-checked by a second reviewer. Data synthesis was qualitative. A total of 15,513 articles were screened; 15 articles were included for general outcome measures and 44 studies for care coordination. A large number of outcome measures have been critically assessed and mapped to the International Classification of Functioning, Disability and Health. We found no eligible studies of basic medical needs or secondary conditions that examined mixed populations of disabled and nondisabled participants for disability as a complicating condition. Care coordination literature for people with disabilities is relatively new and focuses on initial implementation of interventions rather than assessing the quality of the implementation. We found very few direct examples of work conducted from the perspective of disability as a complicating condition. The sparse literature indicates the early stages of research development. Capturing the disability perspective will require collaboration and coordination of measurement efforts across medical interventions, rehabilitation, and social support provision.


Partnership for implementation of evidence-based mental health practices in rural federally qualified health centers: theory and methods.
Mental health and substance abuse are among the most commonly reported reasons for visits to Federally Qualified Health Centers (CHCs), yet only 6.5% of encounters are with on-site behavioral health specialists. Rural CHCs are significantly less likely to have on-site behavioral specialists than urban CHCs. Because of this lack of mental health specialists in rural areas, the most promising approach to improving mental health outcomes is to help rural primary care (PC) providers deliver evidence-based practices (EBPs). Despite the scope of these problems, no research has developed an effective implementation strategy for facilitating the adoption of mental health EBPs for rural CHCs. We sought to describe the conceptual components of an implementation partnership that focuses on the adaption and adoption of mental health EBPs by rural CHCs in Arkansas. We present a conceptual model that integrates seven separate frameworks: (1) Jones and Wells' Evidence-Based Community Partnership Model, (2) Kitson's Promoting Action on Research Implementation in Health Services (PARiHS) implementation framework, (3) Sackett's definition of evidence-based medicine, (4) Glisson's organizational social context model, (5) Rubenstein's Evidence-Based Quality Improvement (EBQI) facilitation process, (6) Glasgow's RE-AIM evaluation approach, and (7) Naylor's concept of shared decision making. By integrating these frameworks into a meaningful conceptual model, we hope to develop a successful implementation partnership between an academic health center and small rural CHCs to improve mental health outcomes. Findings from this implementation partnership should have relevance to hundreds of clinics and millions of patients, and could help promote the sustained adoption of EBPs across rural America.


Rational design of highly active and selective ligands for the alpha5beta1 integrin receptor.
The inhibition of integrin function is a major challenge in medicinal chemistry. Potent ligands are currently in different stages of clinical trials for the antiangiogenic therapy of cancer and age-related macula degeneration (AMD). The subtype alpha5beta1 has recently been drawn into the focus of research because of its genuine role in angiogenesis. In our previous work we could demonstrate that the lack of structural information about the receptor could be overcome by a homology model based on the X-ray structure of the alphavbeta3 integrin subtype and the sequence similarities between both receptors. In this work, we describe the rational design and synthesis of high affinity alpha5beta1 binders, and the optimisation of selectivity against alphavbeta3 by means of extensive SAR studies and docking experiments. A first series of compounds based on the tyrosine scaffold resulted in affinities in the low and even subnanomolar range and selectivities of 400-fold against alphavbeta3. The insights about the structure-activity relationship gained from tyrosine-based ligands could be successfully transferred to ligands that bear an aza-glycine scaffold to yield alpha5beta1 ligands with affinities of approximately 1 nm and selectivities that exceed 10(4)-fold. The ligands have already been successfully employed as selective alpha5beta1 ligands in biological research and might serve as lead structures for antiangiogenic cancer therapy.


Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis.
Since 1990, overall breast cancer mortality rates in the United States decreased 24%. This decline has been attributed to mammography screening and adjuvant systemic therapy. However, the efficacy of these modalities may depend on estrogen receptor (ER) expression and age. We therefore examined breast cancer mortality trends in the United States according to ER status and age. Using the Surveillance, Epidemiology, and End Results (SEER) program (1990-2003), we calculated trends in incidence-based mortality (IBM), annual hazard rates for breast cancer deaths after diagnosis, and relative hazard rates for women with ER-positive and ER-negative tumors. Relative hazard rates were assessed with Cox proportional hazards models, adjusted for stage and grade, and stratified by age at diagnosis. During the study period, IBM and annual hazard rates for breast cancer deaths decreased among women with ER-positive and ER-negative tumors, although declines were greater for those with ER-positive tumors. Among women younger than 70 years, relative hazard rates declined 38% for those with ER-positive tumors versus 19% for those with ER-negative tumors. Among women 70 years or older, relative hazard rates declined 14% for those with ER-positive tumors versus no significant decline for those with ER-negative tumors. In the United States, breast cancer mortality rates have declined among women with ER-positive and ER-negative tumors, with greater declines among younger women and those with ER-positive tumors. Although mortality in all groups remains unacceptably high, additional emphasis should be placed on improving outcomes of breast cancer patients older than 70 years and those of all ages with ER-negative tumors.


Asymmetrical gene flow in a hybrid zone of Hawaiian Schiedea (Caryophyllaceae) species with contrasting mating systems.
Asymmetrical gene flow, which has frequently been documented in naturally occurring hybrid zones, can result from various genetic and demographic factors. Understanding these factors is important for determining the ecological conditions that permitted hybridization and the evolutionary potential inherent in hybrids. Here, we characterized morphological, nuclear, and chloroplast variation in a putative hybrid zone between Schiedea menziesii and S. salicaria, endemic Hawaiian species with contrasting breeding systems. Schiedea menziesii is hermaphroditic with moderate selfing; S. salicaria is gynodioecious and wind-pollinated, with partially selfing hermaphrodites and largely outcrossed females. We tested three hypotheses: 1) putative hybrids were derived from natural crosses between S. menziesii and S. salicaria, 2) gene flow via pollen is unidirectional from S. salicaria to S. menziesii and 3) in the hybrid zone, traits associated with wind pollination would be favored as a result of pollen-swamping by S. salicaria. Schiedea menziesii and S. salicaria have distinct morphologies and chloroplast genomes but are less differentiated at the nuclear loci. Hybrids are most similar to S. menziesii at chloroplast loci, exhibit nuclear allele frequencies in common with both parental species, and resemble S. salicaria in pollen production and pollen size, traits important to wind pollination. Additionally, unlike S. menziesii, the hybrid zone contains many females, suggesting that the nuclear gene responsible for male sterility in S. salicaria has been transferred to hybrid plants. Continued selection of nuclear genes in the hybrid zone may result in a population that resembles S. salicaria, but retains chloroplast lineage(s) of S. menziesii.


IgE antibody and resistance to infection. I. Selective suppression of the IgE antibody response in rats diminishes the resistance and the eosinophil response to Trichinella spiralis infection.
Selective suppression of the total IgE antibody response has been achieved in rats by injection of rabbit anti-rat epsilon-chain antibodies. This IgE-specific suppression was maintained during the course of a natural infection by the nematode Trichinella spiralis. Depletion of the IgE antibody response resulted in a marked reduction of the number of eosinophils attracted to the T. spiralis larvae encysted in striated muscle. Blood eosinophilia following T. spiralis infection, although reaching normal peak levels, was abbreviated in IgE-suppressed animals. Moreover, IgE-depleted animals were more susceptible to the infection; they harbored two to three times more larvae encysted in their muscles than their control litter mates.


Photo-induced phosphate released from organic phosphorus degradation in deionized and natural water.
The photodegradation of organic phosphorus is one of the most important processes of the phosphorus cycle by which phosphate is regenerated in the water environment. In this study, the influence of direct photolysis or indirect photolysis of organic phosphorus using natural photosensitizers on the released phosphate was examined in deionized and natural water under ultraviolet (UV) irradiation using diazinon as the organic phosphorus model. Phosphate was released when diazinon was exposed to UV light, and the solution pH also exhibited distinct influences on the phosphate that was released from diazinon photodegradation. When the natural photosensitizers were added, the amount of phosphate released increased significantly because of the diazinon indirect photodegradation by reactive species, such as the hydroxyl radical generated by NO3- and Fe3+. However, humic acid and HCO3- inhibited the phosphate released by a radical scavenging effect. When natural water was spiked with diazinon, the phosphate that was released in natural water was higher than that of the control or deionized water, and the phosphate that was released was inhibited when isopropanol was added to the reaction. In addition, the formation of hydroxyl radicals (˙OH) in the natural water systems was identified from the photoluminescence spectra using coumarin as the trapping molecule, and the steady-state concentration of ˙OH in natural water was 3.07 ± 0.57 × 10-16 M under UV irradiation. All of these results indicated that direct and indirect photolysis degradation of organic phosphorus significantly impacts the release of phosphate in surface waters.


Estimating the Impact of Carbon Dioxide Absorbent Performance Differences on Absorbent Cost During Low-Flow Anesthesia.
Reducing fresh gas flow when using a circle anesthesia circuit is the most effective strategy for reducing both inhaled anesthetic vapor cost and waste. As fresh gas flow is reduced, the amount of exhaled gas rebreathed increases, but the utilization of carbon dioxide absorbent increases as well. Reducing fresh gas flow may not make economic sense if the increased cost of absorbent utilization exceeds the reduced cost of anesthetic vapor. The primary objective of this study was to determine the minimum fresh gas flow at which absorbent costs do not exceed vapor savings. Another objective is to provide a qualitative insight into the factors that influence absorbent performance as fresh gas flow is reduced. A mathematical model was developed to compare the vapor savings with the cost of carbon dioxide absorbent as a function of fresh gas flow. Parameters of the model include patient size, unit cost of vapor and carbon dioxide absorbent, and absorbent capacity and efficiency. Boundaries for fresh gas flow were based on oxygen consumption or a closed-circuit condition at the low end and minute ventilation to approximate an open-circuit condition at the high end. Carbon dioxide production was estimated from oxygen consumption assuming a respiratory quotient of 0.8. For desflurane, the cost of carbon dioxide absorbent did not exceed vapor savings until fresh gas flow was almost equal to closed-circuit conditions. For sevoflurane, as fresh gas flow is reduced, absorbent costs increase more slowly than vapor costs decrease so that total costs are still minimized for a closed circuit. Due to the low cost of isoflurane, even with the most effective absorbent, the rate of absorbent costs increase more rapidly than vapor savings as fresh gas flow is reduced, so that an open circuit is least expensive. The total cost of vapor and absorbent is still lowest for isoflurane when compared with the other agents. The relative costs of anesthetic vapor and carbon dioxide absorbent as fresh gas flow is reduced are dependent on choice of anesthetic vapor and performance of the carbon dioxide absorbent. Absorbent performance is determined by the product selected and strategy for replacement. Clinicians can maximize the performance of absorbents by replacing them based on the appearance of inspired carbon dioxide rather than the indicator. Even though absorbent costs exceed vapor savings as fresh gas flow is reduced, isoflurane is still the lowest cost choice for the environmentally sound practice of closed-circuit anesthesia.


Assessment of social psychological determinants of satisfaction with childbirth in a cross-national perspective.
The fulfilment of expectations, labour pain, personal control and self-efficacy determine the postpartum evaluation of birth. However, researchers have seldom considered the multiple determinants in one analysis. To explore to what extent the results can be generalised between countries, we analyse data of Belgian and Dutch women. Although Belgium and the Netherlands share the same language, geography and political system and have a common history, their health care systems diverge. The Belgian maternity care system corresponds to the ideal type of the medical model, whereas the Dutch system approaches the midwifery model. In this paper we examine multiple determinants, the fulfilment of expectations, labour pain, personal control and self-efficacy, for their association with satisfaction with childbirth in a cross-national perspective. Two questionnaires were filled out by 605 women, one at 30 weeks of pregnancy and one within the first 2 weeks after childbirth either at home or in a hospital. Of these, 560 questionnaires were usable for analysis. Women were invited to participate in the study by independent midwives and obstetricians during antenatal visits in 2004-2005. Satisfaction with childbirth was measured by the Mackey Satisfaction with Childbirth Rating Scale, which takes into account the multidimensional nature of the concept. Labour pain was rated retrospectively using Visual Analogue Scales. Personal control was assessed with the Wijma Delivery Expectancy/Experience Questionnaire and Pearlin and Schooler's mastery scale. A hierarchical linear analysis was performed. Satisfaction with childbirth benefited most consistently from the fulfilment of expectations. In addition, the experience of personal control buffered the lowering impact of labour pain. Women with high self-efficacy showed more satisfaction with self-, midwife- and physician-related aspects of the birth experience. Our findings focus the attention toward personal control, self-efficacy and expectations about childbirth. This study confirms the multidimensionality of childbirth satisfaction and demonstrates that different factors predict the various dimensions of satisfaction. The model applies to both Belgian and Dutch women. Cross-national comparative research should further assess the dependence of the determinants of childbirth satisfaction on the organisation of maternity care.


Coverage and timing of children's vaccination: an evaluation of the expanded programme on immunisation in The Gambia.
To evaluate the coverage and timeliness of the Expanded Programme on Immunisation (EPI) in The Gambia. Vaccination data were obtained between January 2005 and December 2012 from the Farafenni Health and Demographic Surveillance System (FHDSS), the Basse Health and Demographic Surveillance System (BHDSS), the Kiang West Demographic surveillance system (KWDSS), a cluster survey in the more urban Western Health Region (WR) and a cross sectional study in four clinics in the semi-urban Greater Banjul area of WR. Kaplan-Meier survival function was used to estimate the proportion vaccinated by age and to assess timeliness to vaccination. BCG vaccine uptake was over 95% in all regions. Coverage of DPT1 ranged from 93.2% in BHDSS to 99.8% in the WR. Coverage decreased with increasing number of DPT doses; DPT3 coverage ranged from 81.7% in BHDSS to 99.0% in WR. Measles vaccination coverage ranged from 83.3% in BHDSS to 97.0% in WR. DPT4 booster coverage was low and ranged from 43.9% in the WR to 82.8% in KWDSS. Across all regions, delaying on previous vaccinations increased the likelihood of being delayed for the subsequent vaccination. The Gambia health system achieves high vaccine coverage in the first year of life. However, there continues to be a delay to vaccination which may impact on the introduction of new vaccines. Examples of effectively functioning EPI programmes such as The Gambia one may well be important models for other low income countries struggling to achieve high routine vaccination coverage.


Secondary T-cell lymphoproliferation after marrow transplantation.
Secondary lymphoproliferative syndromes in immunosuppressed patients have been characterized as polyclonal or monoclonal B-lineage disorders nearly always associated with Epstein-Barr virus (EBV) infection. The authors now report three patients with a distinctly different lymphoproliferative syndrome. Two patients with common acute lymphoblastic leukemia antigen (CALLA) (CD10)-positive acute lymphoblastic leukemia and one patient with acute myelogenous leukemia, respectively, received high-dose chemoradiotherapy followed by marrow transplantation from either an HLA-identical sibling or HLA-mismatched parent. All three patients developed severe graft-versus-host disease (GVHD), requiring immunosuppressive treatment with corticosteroids. A secondary malignant T-cell lymphoproliferation occurred 2, 21, and 43 months, respectively, after marrow transplantation. In all three cases the lymphoid cells expressed T-cell surface antigens and were morphologically and immunophenotypically distinct from the malignant cells present before transplantation. One tumor was of host cell origin, one was probably of donor origin, and the tumor origin in the third case could not be determined. The authors were unable to find any evidence for EBV, human T-cell lymphotropic virus type I or II, human immunodeficiency virus, or human herpesvirus 6.


Percutaneous balloon angioplasty for acute occlusion of intracranial arteries.
The benefits of intravenous thrombolysis for acute ischemic stroke are still limited. To evaluate the safety and efficacy of double-lumen balloon catheter-based reperfusion therapy with or without intra-arterial thrombolysis for acute occlusion of intracranial arteries. Fifty-nine patients with acute occlusion of intracranial arteries were enrolled. A Gateway balloon catheter was used to disrupt clots or dilate atheromatous plaques in every patient. The technical details, technique-related complications, recanalization rates, and clinical outcomes were analyzed. The occlusion sites were internal carotid arteries in 17 patients, M1 segments in 32 patients, the M2 segment in 1 patient, a vertebral artery in 1 patient, and basilar arteries in 8 patients. Twenty-four patients (41%) were treated with thrombolysis first, and 20 patients (34%) were treated with percutaneous transluminal angioplasty (PTA) followed by thrombolysis. PTA alone was performed in 15 patients (25%). The mean dose of urokinase was 205 x 10 U. The extent of recanalization was complete (Thrombolysis in Myocardial Infarction [TIMI] score of 3) in 17 patients (29%), and partial (TIMI 1/2) in 28 patients (47%). Functional independence at discharge was preserved in 76%, 25%, and 7% of patients with TIMI 3, TIMI 1/2, and TIMI 0, respectively. A combination of PTA and thrombolysis resulted in a significantly higher recanalization rate than PTA only. Seven patients (12%) experienced hemorrhagic events after treatment. Severe parenchymal hemorrhage with neurologic deterioration was observed in 2 patients (4%), and vessel rupture was encountered in 1 atherosclerotic case. Mechanical angioplasty using a Gateway catheter combined with a low-dose thrombolytic agent is a safe and effective treatment for acute intracranial embolic and atherosclerotic occlusion with a low risk of hemorrhagic complications.


Progression of radiological changes in rheumatoid arthritis.
A prospective study over one year of patients who had active rheumatoid arthritis discovered 64 who had received treatment for an adequate time with second-line drugs. In these patients there was evidence of continuing joint destruction as shown by radiological progression. During the year there were highly significant correlations between improvements in clinical and laboratory measurements, but neither group of tests was related to the degree of radiological change. However, in the second 6 months of treatment there was evidence that radiological progression was reduced. In a second prospective study of 88 patients with rheumatoid arthritis given prolonged, intensive therapy with second-line drugs and followed up for 10 years two-thirds showed radiological progression. However, the number of joints damaged per year fell significantly during the study period. There was a divergence between deterioration in radiological features and improvements in the ESR and functional capacity, though patients with a persistently low ESR had less radiological progression. These studies provide evidence that treatment may be associated with a reduced rate of radiological progression but suggest that changes in radiological progression and clinical and laboratory measurements may result from different mechanisms.


Conformational state distributions and catalytically relevant dynamics of a hinge-bending enzyme studied by single-molecule FRET and a coarse-grained simulation.
Over the last few decades, a view has emerged showing that multidomain enzymes are biological machines evolved to harness stochastic kicks of solvent particles into highly directional functional motions. These intrinsic motions are structurally encoded, and Nature makes use of them to catalyze chemical reactions by means of ligand-induced conformational changes and states redistribution. Such mechanisms align reactive groups for efficient chemistry and stabilize conformers most proficient for catalysis. By combining single-molecule Förster resonance energy transfer measurements with normal mode analysis and coarse-grained mesoscopic simulations, we obtained results for a hinge-bending enzyme, namely phosphoglycerate kinase (PGK), which support and extend these ideas. From single-molecule Förster resonance energy transfer, we obtained insight into the distribution of conformational states and the dynamical properties of the domains. The simulations allowed for the characterization of interdomain motions of a compact state of PGK. The data show that PGK is intrinsically a highly dynamic system sampling a wealth of conformations on timescales ranging from nanoseconds to milliseconds and above. Functional motions encoded in the fold are performed by the PGK domains already in its ligand-free form, and substrate binding is not required to enable them. Compared to other multidomain proteins, these motions are rather fast and presumably not rate-limiting in the enzymatic reaction. Ligand binding slightly readjusts the orientation of the domains and feasibly locks the protein motions along a preferential direction. In addition, the functionally relevant compact state is stabilized by the substrates, and acts as a prestate to reach active conformations by means of Brownian motions.


Collective violence caused by climate change and how it threatens health and human rights.
The weight of scientific evidence indicates that climate change is causally associated with collective violence. This evidence arises from individual studies over wide ranges of time and geographic location, and from two extensive meta-analyses. Complex pathways that underlie this association are not fully understood; however, increased ambient temperatures and extremes of rainfall, with their resultant adverse impacts on the environment and risk factors for violence, appear to play key roles. Collective violence due to climate change poses serious threats to health and human rights, including by causing morbidity and mortality directly and also indirectly by damage to the health-supporting infrastructure of society, forcing people to migrate from their homes and communities, damaging the environment, and diverting human and financial resources. This paper also briefly addresses issues for future research on the relationship between climate change and collective violence, the prevention of collective violence due to climate change, and States' obligations to protect human rights, to prevent collective violence, and to promote and support measures to mitigate and adapt to climate change.


Distracted by relatives: Effects of frontal lobe damage on semantic distraction.
When young adults carry out visual search, distractors that are semantically related, rather than unrelated, to targets can disrupt target selection (see Belke, Humphreys, Watson, Meyer, & Telling, 2008; Moores, Laiti, & Chelazzi, 2003). This effect is apparent on the first eye movements in search, suggesting that attention is sometimes captured by related distractors. Here we assessed effects of semantically related distractors on search in patients with frontal-lobe lesions and compared them to the effects in age-matched controls. Compared with the controls, the patients were less likely to make a first saccade to the target and they were more likely to saccade to distractors (whether related or unrelated to the target). This suggests a deficit in a first stage of selecting a potential target for attention. In addition, the patients made more errors by responding to semantically related distractors on target-absent trials. This indicates a problem at a second stage of target verification, after items have been attended. The data suggest that frontal lobe damage disrupts both the ability to use peripheral information to guide attention, and the ability to keep separate the target of search from the related items, on occasions when related items achieve selection.


Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis.
The suprachiasmatic nucleus of the brain is the circadian center, relaying rhythmic environmental and behavioral information to peripheral tissues to control circadian physiology. As such, central clock dysfunction can alter systemic homeostasis to consequently impair peripheral physiology in a manner that is secondary to circadian malfunction. To determine the impact of circadian clock function in organ transplantation and dissect the influence of intrinsic tissue clocks versus extrinsic clocks, we implemented a blood vessel grafting approach to surgically assemble a chimeric mouse that was part wild-type (WT) and part circadian clock mutant. Arterial isografts from donor WT mice that had been anastamosed to common carotid arteries of recipient WT mice (WT:WT) exhibited no pathology in this syngeneic transplant strategy. Similarly, when WT grafts were anastamosed to mice with disrupted circadian clocks, the structural features of the WT grafts immersed in the milieu of circadian malfunction were normal and absent of lesions, comparable to WT:WT grafts. In contrast, aortic grafts from Bmal1 knockout (KO) or Period-2,3 double-KO mice transplanted into littermate control WT mice developed robust arteriosclerotic disease. These lesions observed in donor grafts of Bmal1-KO were associated with up-regulation in T-cell receptors, macrophages, and infiltrating cells in the vascular grafts, but were independent of hemodynamics and B and T cell-mediated immunity. These data demonstrate the significance of intrinsic tissue clocks as an autonomous influence in experimental models of arteriosclerotic disease, which may have implications with regard to the influence of circadian clock function in organ transplantation.


Moving toward more perfect unions: daily and long-term consequences of approach and avoidance goals in romantic relationships.
In 2 daily experience studies and a laboratory study, the authors test predictions from approach-avoidance motivational theory to understand how dating couples can maintain feelings of relationship satisfaction in their daily lives and over the course of time. Approach goals were associated with increased relationship satisfaction on a daily basis and over time, particularly when both partners were high in approach goals. Avoidance goals were associated with decreases in relationship satisfaction over time, and people were particularly dissatisfied when they were involved with a partner with high avoidance goals. People high in approach goals and their partners were rated as relatively more satisfied and responsive to a partner's needs by outside observers in the lab, whereas people with high avoidance goals and their partners were rated as less satisfied and responsive. Positive emotions mediated the link between approach goals and daily satisfaction in both studies, and responsiveness to the partner's needs was an additional behavioral mechanism in Study 2. Implications of these findings for approach-avoidance motivational theory and for the maintenance of satisfying relationships over time are discussed.


Public involvement in research within care homes: benefits and challenges in the APPROACH study.
Public involvement in research (PIR) can improve research design and recruitment. Less is known about how PIR enhances the experience of participation and enriches the data collection process. In a study to evaluate how UK care homes and primary health-care services achieve integrated working to promote older people's health, PIR was integrated throughout the research processes. This paper aims to present one way in which PIR has been integrated into the design and delivery of a multisite research study based in care homes. A prospective case study design, with an embedded qualitative evaluation of PIR activity. Data collection was undertaken in six care homes in three sites in England. Six PIR members participated: all had prior personal or work experience in care homes. Qualitative data collection involved discussion groups, and site-specific meetings to review experiences of participation, benefits and challenges, and completion of structured fieldwork notes after each care home visit. PIR members supported recruitment, resident and staff interviews and participated in data interpretation. Benefits of PIR work were resident engagement that minimized distress and made best use of limited research resources. Challenges concerned communication and scheduling. Researcher support for PIR involvement was resource intensive. Clearly defined roles with identified training and support facilitated involvement in different aspects of the data collection process. This can also ensure that vulnerable older people who participate in research have a positive experience that reinforces the value of their views.


Respiratory Viruses Associated Hospitalization among Children Aged <5 Years in Bangladesh: 2010-2014.
We combined hospital-based surveillance and health utilization survey data to estimate the incidence of respiratory viral infections associated hospitalization among children aged < 5 years in Bangladesh. Surveillance physicians collected respiratory specimens from children aged <5 years hospitalized with respiratory illness and residing in the primary hospital catchment areas. We tested respiratory specimens for respiratory syncytial virus, parainfluenza viruses, human metapneumovirus, influenza, adenovirus and rhinoviruses using rRT-PCR. During 2013, we conducted a health utilization survey in the primary catchment areas of the hospitals to determine the proportion of all hospitalizations for respiratory illness among children aged <5 years at the surveillance hospitals during the preceding 12 months. We estimated the respiratory virus-specific incidence of hospitalization by dividing the estimated number of hospitalized children with a laboratory confirmed infection with a respiratory virus by the population aged <5 years of the catchment areas and adjusted for the proportion of children who were hospitalized at the surveillance hospitals. We estimated that the annual incidence per 1000 children (95% CI) of all cause associated respiratory hospitalization was 11.5 (10-12). The incidences per 1000 children (95% CI) per year for respiratory syncytial virus, parainfluenza, adenovirus, human metapneumovirus and influenza infections were 3(2-3), 0.5(0.4-0.8), 0.4 (0.3-0.6), 0.4 (0.3-0.6), and 0.4 (0.3-0.6) respectively. The incidences per 1000 children (95%CI) of rhinovirus-associated infections among hospitalized children were 5 (3-7), 2 (1-3), 1 (0.6-2), and 3 (2-4) in 2010, 2011, 2012 and 2013, respectively. Our data suggest that respiratory viruses are associated with a substantial burden of hospitalization in children aged <5 years in Bangladesh.


Nurses and IT: a survey of use among community clinical staff.
A survey investigated the use of information technology among community nurses and other staff in one primary care trust. Provision of IT was poor across all the staff studied, with health visitors and community nurses lagging slightly behind others. The reasons for the low levels of use need further research so that barriers to using IT can be overcome.


A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme.
Delta(9)-Tetrahydrocannabinol (THC) and other cannabinoids inhibit tumour growth and angiogenesis in animal models, so their potential application as antitumoral drugs has been suggested. However, the antitumoral effect of cannabinoids has never been tested in humans. Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration. We also evaluated THC action on the length of survival and various tumour-cell parameters. A dose escalation regimen for THC administration was assessed. Cannabinoid delivery was safe and could be achieved without overt psychoactive effects. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks (95% confidence interval: 15-33). Delta(9)-Tetrahydrocannabinol inhibited tumour-cell proliferation in vitro and decreased tumour-cell Ki67 immunostaining when administered to two patients. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.


Frequency of Boiled Potato Consumption and All-Cause and Cardiovascular Disease Mortality in the Prospective Population-Based HUNT Study.
Few studies have assessed the association between potato consumption and mortality, especially cardiovascular disease (CVD) mortality. Our objective was to investigate the association between consumption of boiled potatoes and all-cause and CVD mortality in a Norwegian population. We used data from the population based HUNT3 study in Norway, with data on boiled potato consumption frequency in 2006-2008 from 49,926 males and females aged 20 years or above. All-cause and CVD mortality were identified during 10 years follow-up through the national Cause of Death Registry, which is virtually complete. We used Cox regression to estimate hazard ratio (HR) with a 95% confidence interval (CI) for death controlling for potential confounders, and conducted additional analyses stratified by sex, body mass index (BMI) ±25 kg/m2, and age ±65 years. There were 4,084 deaths and 1,284 of these were due to CVD. Frequency of boiled potato consumption was not associated with all-cause mortality, nor with CVD mortality. Compared to those individuals who consumed boiled potatoes less than once weekly, those who reported to consume boiled potatoes 1-3 times per week had an adjusted HR (95% CI) of 1.12 (0.89, 1.41) for all-cause mortality and 1.20 (0.78, 1.86) for CVD mortality. Individuals who consumed boiled potatoes 4-6 times per week had HRs of 0.97 (0.78, 1.21) and 1.03 (0.68, 1.55), for all-cause and CVD mortality, respectively, whereas those who consumed boiled potatoes more than once daily had HRs of 1.04 (0.83, 1.29) and 1.09 (0.73, 1.63) for all-cause and CVD mortality, respectively. There was no evidence of differential associations for males vs. females, nor between people with BMI ± 25 kg/m2. The associations between frequency of boiled potato consumption and all-cause mortality showed different patterns between those younger vs. older than 65 years, with a tendency of increased risk only in the oldest age group. In conclusion, frequency of consumption of boiled potatoes was not associated with all-cause or CVD mortality in the HUNT population in Norway.


Towards a balanced social psychology: causes, consequences, and cures for the problem-seeking approach to social behavior and cognition.
Mainstream social psychology focuses on how people characteristically violate norms of action through social misbehaviors such as conformity with false majority judgments, destructive obedience, and failures to help those in need. Likewise, they are seen to violate norms of reasoning through cognitive errors such as misuse of social information, self-enhancement, and an over-readiness to attribute dispositional characteristics. The causes of this negative research emphasis include the apparent informativeness of norm violation, the status of good behavior and judgment as unconfirmable null hypotheses, and the allure of counter-intuitive findings. The shortcomings of this orientation include frequently erroneous imputations of error, findings of mutually contradictory errors, incoherent interpretations of error, an inability to explain the sources of behavioral or cognitive achievement, and the inhibition of generalized theory. Possible remedies include increased attention to the complete range of behavior and judgmental accomplishment, analytic reforms emphasizing effect sizes and Bayesian inference, and a theoretical paradigm able to account for both the sources of accomplishment and of error. A more balanced social psychology would yield not only a more positive view of human nature, but also an improved understanding of the bases of good behavior and accurate judgment, coherent explanations of occasional lapses, and theoretically grounded suggestions for improvement.


Heavy metals of the Tibetan top soils: level, source, spatial distribution, temporal variation and risk assessment.
Due to its high elevation, rare human activities and proximity to south Asia where industries are highly developed, it is required to investigate the fragile environment of the Tibetan Plateau. We are aiming to obtain the concentration level, source, spatial distribution, temporal variation and potential environmental risk of Tibetan soils. A total of 128 surf ace soil samples were collected and analyzed f or V, Cr, Mn, Co, Ni, Cu, Zn, As, Cd and Pb, and an additional 111 samples were analyzed f or Hg and total organic carbon. Concentration comparisons coupled with multivariate statistics were used to analysis the sources of elements of soils. We also carried out Risk assessment on the soils. Concentrations of Hg, Cr, Ni, Cd and Pb are slightly higher than those of the late 1970s. Concentrations of Cr and Ni are higher than averaged world background values. Tibetan soils present a high natural As concentration level. Anthropogenic sources may partly contribute to the elevated Hg, Cd and Pb concentrations. Cr and Ni are mainly originated from soil parent materials. Soil elements in Anduo and Qamdo regions may threaten the health of local people. Heavy metal elements of Tibetan Plateau are mainly from the natural source. Arsenic present a high background level. Soil elements in Anduo and Qamdo regions may threaten the health of local people, which should be of concern to scientists and the government.


Fluorescence-based alternative splicing reporters for the study of epithelial plasticity in vivo.
Alternative splicing generates a vast diversity of protein isoforms from a limited number of protein-coding genes, with many of the isoforms possessing unique, and even contrasting, functions. Fluorescence-based splicing reporters have the potential to facilitate studies of alternative splicing at the single-cell level and can provide valuable information on phenotypic transitions in almost real time. Fibroblast growth factor receptor 2 (FGFR2) pre-mRNA is alternatively spliced to form the epithelial-specific and mesenchymal-specific IIIb and IIIc isoforms, respectively, which are useful markers of epithelial-mesenchymal transitions (EMT). We have used our knowledge of FGFR2 splicing regulation to develop a fluorescence-based reporter system to visualize exon IIIc regulation in vitro and in vivo. Here we show the application of this reporter system to the study of EMT in vitro in cell culture and in vivo in transgenic mice harboring these splicing constructs. In explant studies, the reporters revealed that FGFR2 isoform switching is not required for keratinocyte migration during cutaneous wound closure. Our results demonstrate the value of the splicing reporters as tools to study phenotypic transitions and cell fates at single cell resolution. Moreover, our data suggest that keratinocytes migrate efficiently in the absence of a complete EMT.


Cannabis-Derived Compounds Cannabichromene and Δ9-Tetrahydrocannabinol Interact and Exhibit Cytotoxic Activity against Urothelial Cell Carcinoma Correlated with Inhibition of Cell Migration and Cytoskeleton Organization.
Cannabis sativa contains more than 500 constituents, yet the anticancer properties of the vast majority of cannabis compounds remains unknown. We aimed to identify cannabis compounds and their combinations presenting cytotoxicity against bladder urothelial carcinoma (UC), the most common urinary system cancer. An XTT assay was used to determine cytotoxic activity of C. sativa extracts on T24 and HBT-9 cell lines. Extract chemical content was identified by high-performance liquid chromatography (HPLC). Fluorescence-activated cell sorting (FACS) was used to determine apoptosis and cell cycle, using stained F-actin and nuclei. Scratch and transwell assays were used to determine cell migration and invasion, respectively. Gene expression was determined by quantitative Polymerase chain reaction (PCR). The most active decarboxylated extract fraction (F7) of high-cannabidiol (CBD) C. sativa was found to contain cannabichromene (CBC) and Δ9-tetrahydrocannabinol (THC). Synergistic interaction was demonstrated between CBC + THC whereas cannabinoid receptor (CB) type 1 and type 2 inverse agonists reduced cytotoxic activity. Treatments with CBC + THC or CBD led to cell cycle arrest and cell apoptosis. CBC + THC or CBD treatments inhibited cell migration and affected F-actin integrity. Identification of active plant ingredients (API) from cannabis that induce apoptosis and affect cell migration in UC cell lines forms a basis for pre-clinical trials for UC treatment.


Heart disease in marathon runners: a review.
Thirty-six cases of heart attack or sudden death in marathon runners have been reported in the world literature to date. The mean age of the runners was 43.8 yr (range = 18 to 70), the mean years' running was 6.8 yr (range = 0.5 to 29), and the mean best standard 42.2 km marathon time was 3 h 28 min (range = 2 h 33 min to 4 h 28 min). Coronary artery disease was diagnosed either clinically, angiographically, or at autopsy in 27 runners (75%), two of whom also had histological evidence of hypertrophic cardiomyopathy. Seventy-one percent of the runners with coronary artery disease had premonitory symptoms, and most ignored such symptoms and continued to train or race. Fifty percent of all cardiac events occurred either during or within 24 h of competitive running events or long training runs. The marathon running population does not constitute solely persons with excellent cardiovascular health. Marathon runners, especially those with a family history of heart disease and other coronary risk factors, should not consider themselves immune to either sudden death or to coronary heart disease and should seek medical advice immediately if they develop any symptoms suggestive of ischemic heart disease. Physicians should not assume that "physically fit" marathon runners cannot have serious, life-threatening cardiac disease.


Diagnosis and management of the drug hypersensitivity reactions in Coronavirus disease 19: An EAACI Position Paper.
Coronavirus disease 2019 (COVID-19), a respiratory tract infection caused by a novel human coronavirus, the severe acute respiratory syndrome coronavirus 2, leads to a wide spectrum of clinical manifestations ranging from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia. Given the huge influence caused by the overwhelming COVID-19 pandemic affecting over three million people worldwide, a wide spectrum of drugs is considered for the treatment in the concept of repurposing and off-label use. There is no knowledge about the diagnosis and clinical management of the drug hypersensitivity reactions that can potentially occur during the disease. This review brings together all the published information about the diagnosis and management of drug hypersensitivity reactions due to current and candidate off-label drugs and highlights relevant recommendations. Furthermore, it gathers all the dermatologic manifestations reported during the disease for guiding the clinicians to establish a better differential diagnosis of drug hypersensitivity reactions in the course of the disease.


Keeping a large-pupilled eye on high-level visual processing.
The pupillary light response has long been considered an elementary reflex. However, evidence now shows that it integrates information from such complex phenomena as attention, contextual processing, and imagery. These discoveries make pupillometry a promising tool for an entirely new application: the study of high-level vision.


Phase-sensitive optical coherence tomography imaging of the tissue motion within the organ of Corti at a subnanometer scale: a preliminary study.
Hearing loss can mean severe impairment to the quality of life. However, the biomechanical mechanisms of how the hearing organ, i.e., the organ of Corti (OC), responds to sound are still elusive, largely because there is currently no means available to image the 3-D motion characteristics of the OC. We present a novel use of the phase-sensitive spectral domain optical coherence tomography (PSOCT) to characterize the motion of cellular compartments within the OC at a subnanometer scale. The PSOCT system operates at 1310 nm with a spatial resolution of ∼16 μm and an imaging speed of 47,000 A-lines/s. The phase changes of the spectral interferograms induced by the localized tissue motion are used to quantify the vibration magnitude. Fourier transform analysis of the phase changes improves the system sensitivity to sense minute vibrations smaller than 1 nm. We demonstrate that the PSOCT system is feasible to image the meaningful vibration of cellular compartments within the OC with an unprecedented sensitivity down to ∼0.5 Å.


Effect of family background on the educational gradient in lifetime fertility of Finnish women born 1940-50.
An inverse association between education and fertility in women has been found in many societies but the causes of this association remain inadequately understood. We investigated whether observed and unobserved family-background characteristics explained educational differences in lifetime fertility among 35,212 Finnish women born in 1940-50. Poisson and logistic regression models, adjusted for measured socio-demographic family-background characteristics and for unobserved family characteristics shared by siblings, were used to analyse the relationship between education and the number of children, having any children, and fertility beyond the first child. The woman's education and the socio-economic position of the family were negatively associated with fertility. Observed family characteristics moderately (3-28 per cent) explained the association between education and fertility, and results from models including unobserved characteristics supported this interpretation. The remaining association may represent a causal relationship between education and fertility or joint preferences that form independently of our measures of background.


Normal, Regular, and Standard: Scaling the Body through Fecal Microbial Transplants.
In 2013, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) held a workshop to determine the risks and benefits associated with the experimental use of fecal microbial transplants to treat Clostridium difficile and other gastroenterological disorders. By focusing on the proceedings of the NIH-FDA workshop on the treatment of the human microbiome, the question of how medicine colonizes human bodies through microbial transplants raises questions about what an individual body is, how determinative of human health the microbiome is, and what the limits of molecular biomedicine are when the microbiome is taken into consideration. In the workshop presentations and discussion of this emerging treatment, experts used ideas about the normal, regular, and standard to move between scales of bodily analysis, from the microbial to the body politic, demonstrating how the individual and society are deeply influenced by the unruly community of microbial symbiotes that humans host.


Impacts of coal ash on methylmercury production and the methylating microbial community in anaerobic sediment slurries.
Mercury (Hg) associated with coal ash is an environmental concern, particularly if the release of coal ash to the environment is associated with the conversion of inorganic Hg to methylmercury (MeHg), a bioaccumulative form of Hg that is produced by anaerobic microorganisms. In this study, sediment slurry microcosm experiments were performed to understand how spilled coal ash might influence MeHg production in anaerobic sediments of an aquatic ecosystem. Two coal ash types were used: (1) a weathered coal ash; and (2) a freshly collected, unweathered fly ash that was relatively enriched in sulfate and Hg compared to the weathered ash. These ash samples were added to anaerobic sediment slurries constructed with a relatively pristine sediment (containing 0.03 mg kg-1 Hg) and a Hg-contaminated sediment (containing 0.29 mg kg-1 Hg). The results of these experiments showed negligible net production of MeHg in microcosms with no ash and in microcosms amended with the low sulfate/low Hg ash. In contrast, slurry microcosms amended with high sulfate/high Hg ash showed increases in total MeHg content that was 2 to 3 times greater than control microcosms without ash (p < 0.001). 16S amplicon sequencing of microbial communities in the slurries indicated that the coal ash addition generally increased the relative abundance of the methylating microbial community, including sulfate-reducing bacteria and iron-reducing bacteria species that are known to be efficient methylators of Hg. The stimulation of these microorganisms was likely caused by the release of substrates (sulfate and Fe) originating from the ash. Overall, the results highlight the need to incorporate both environmental parameters and coal ash characteristics into risk assessments that guide coal ash management and disposal.


Using heterogeneous data to identify signatures of dengue outbreaks at fine spatio-temporal scales across Brazil.
Dengue virus remains a significant public health challenge in Brazil, and seasonal preparation efforts are hindered by variable intra- and interseasonal dynamics. Here, we present a framework for characterizing weekly dengue activity at the Brazilian mesoregion level from 2010-2016 as time series properties that are relevant to forecasting efforts, focusing on outbreak shape, seasonal timing, and pairwise correlations in magnitude and onset. In addition, we use a combination of 18 satellite remote sensing imagery, weather, clinical, mobility, and census data streams and regression methods to identify a parsimonious set of covariates that explain each time series property. The models explained 54% of the variation in outbreak shape, 38% of seasonal onset, 34% of pairwise correlation in outbreak timing, and 11% of pairwise correlation in outbreak magnitude. Regions that have experienced longer periods of drought sensitivity, as captured by the "normalized burn ratio," experienced less intense outbreaks, while regions with regular fluctuations in relative humidity had less regular seasonal outbreaks. Both the pairwise correlations in outbreak timing and outbreak trend between mesoresgions were best predicted by distance. Our analysis also revealed the presence of distinct geographic clusters where dengue properties tend to be spatially correlated. Forecasting models aimed at predicting the dynamics of dengue activity need to identify the most salient variables capable of contributing to accurate predictions. Our findings show that successful models may need to leverage distinct variables in different locations and be catered to a specific task, such as predicting outbreak magnitude or timing characteristics, to be useful. This advocates in favor of "adaptive models" rather than "one-size-fits-all" models. The results of this study can be applied to improving spatial hierarchical or target-focused forecasting models of dengue activity across Brazil.


Harmful effects of NSAIDs among patients with hypertension and coronary artery disease.
There is limited information about the safety of chronic nonsteroidal anti-inflammatory drugs (NSAIDs) in hypertensive patients with coronary artery disease. This was a post hoc analysis from the INternational VErapamil Trandolapril STudy (INVEST), which enrolled patients with hypertension and coronary artery disease. At each visit, patients were asked by the local site investigator if they were currently taking NSAIDs. Patients who reported NSAID use at every visit were defined as chronic NSAID users, while all others (occasional or never users) were defined as nonchronic NSAID users. The primary composite outcome was all-cause death, nonfatal myocardial infarction, or nonfatal stroke. Cox regression was used to construct a multivariate analysis for the primary outcome. There were 882 chronic NSAID users and 21,694 nonchronic NSAID users (n = 14,408 for never users and n=7286 for intermittent users). At a mean follow-up of 2.7 years, the primary outcome occurred at a rate of 4.4 events per 100 patient-years in the chronic NSAID group, versus 3.7 events per 100 patient-years in the nonchronic NSAID group (adjusted hazard ratio [HR] 1.47; 95% confidence interval [CI], 1.19-1.82; P=.0003). This was due to an increase in cardiovascular mortality (adjusted HR 2.26; 95% CI, 1.70-3.01; P<.0001). Among hypertensive patients with coronary artery disease, chronic self-reported use of NSAIDs was associated with an increased risk of adverse events during long-term follow-up.


Clocks, metabolism, and the epigenome.
Many behaviors and physiological activities in living organisms display circadian rhythms, allowing the organisms to anticipate and prepare for the diurnal changes in the living environment. In this way, metabolic processes are aligned with the periodic environmental changes and behavioral cycles, such as the sleep/wake and fasting/feeding cycles. Disturbances of this alignment significantly increase the risk of metabolic diseases. Meanwhile, the circadian clock receives signals from the environment and feedback from metabolic pathways, and adjusts its activity and function. Growing evidence connects the circadian clock with epigenomic regulators. Here we review the recent advances in understanding the crosstalk between the circadian clock and energy metabolism through epigenomic programming and transcriptional regulation.


Risk adjustment and risk selection in Europe: 6 years later.
In this paper we analyse the developments concerning risk adjustment and risk selection in Belgium, Germany, Israel, the Netherlands and Switzerland in the period 2000-2006. Since 2000 two major trends can be observed. On the one hand the risk adjustment systems have been improved, for example, by adding relevant health-based risk adjusters. On the other hand in all five countries there is evidence of increasing risk selection, which increasingly becomes a problem, in particular in Germany and Switzerland. Some potential explanations are given for these seemingly contradictory observations. Since the mid-1990s citizens in these countries can regularly switch sickness fund, which should stimulate the sickness funds to improve efficiency in health care production and to respond to consumers' preferences. When looking at managed care there are some weak signals of increasing managed care activities by individual sickness funds in all countries (except Belgium). However, with imperfect risk adjustment, such as in Israel and Switzerland, insurers will integrate their managed care activities with their selection activities, which may have adverse effects for society, even if all insurers are equally successful in selection. The conclusion is that good risk adjustment is an essential pre-condition for reaping the benefits of a competitive health insurance market. Without good risk adjustment the disadvantages of a competitive insurance market may outweigh its advantages.


Structuring detergents for extracting and stabilizing functional membrane proteins.
Membrane proteins are privileged pharmaceutical targets for which the development of structure-based drug design is challenging. One underlying reason is the fact that detergents do not stabilize membrane domains as efficiently as natural lipids in membranes, often leading to a partial to complete loss of activity/stability during protein extraction and purification and preventing crystallization in an active conformation. Anionic calix[4]arene based detergents (C4Cn, n=1-12) were designed to structure the membrane domains through hydrophobic interactions and a network of salt bridges with the basic residues found at the cytosol-membrane interface of membrane proteins. These compounds behave as surfactants, forming micelles of 5-24 nm, with the critical micellar concentration (CMC) being as expected sensitive to pH ranging from 0.05 to 1.5 mM. Both by 1H NMR titration and Surface Tension titration experiments, the interaction of these molecules with the basic amino acids was confirmed. They extract membrane proteins from different origins behaving as mild detergents, leading to partial extraction in some cases. They also retain protein functionality, as shown for BmrA (Bacillus multidrug resistance ATP protein), a membrane multidrug-transporting ATPase, which is particularly sensitive to detergent extraction. These new detergents allow BmrA to bind daunorubicin with a Kd of 12 µM, a value similar to that observed after purification using dodecyl maltoside (DDM). They preserve the ATPase activity of BmrA (which resets the protein to its initial state after drug efflux) much more efficiently than SDS (sodium dodecyl sulphate), FC12 (Foscholine 12) or DDM. They also maintain in a functional state the C4Cn-extracted protein upon detergent exchange with FC12. Finally, they promote 3D-crystallization of the membrane protein. These compounds seem promising to extract in a functional state membrane proteins obeying the positive inside rule. In that context, they may contribute to the membrane protein crystallization field.


In vitro selection and in vivo efficacy of piperazine- and alkanediamide-linked bisbenzamidines against Pneumocystis pneumonia in mice.
Bisbenzamidines, such as pentamidine isethionate, are aromatic dicationic compounds that are active against Pneumocystis and other microbes but are oftentimes toxic to the host. To identify potential anti-Pneumocystis agents, we synthesized bisbenzamidine derivatives in which the parent compound pentamidine was modified by a 1,4-piperazinediyl, alkanediamide, or 1,3-phenylenediamide moiety as the central linker. Several of the compounds were more active against P. carinii and less toxic than pentamidine in cytotoxicity assays. For this study, we evaluated nine bisbenzamidine derivatives representing a range of in vitro activities, from highly active to inactive, for the treatment of pneumocystosis in an immunosuppressed mouse model. Six of these in vitro-active compounds, 01, 02, 04, 06, 100, and 101, exhibited marked efficacies against infection at a dose of 10 mg/kg of body weight, and four compounds, 01, 04, 100, and 101, showed significant increases in survival versus that of untreated infected control mice. Compound 100 was highly efficacious against the infection at 20 mg/kg and 40 mg/kg, with > 1,000-fold reductions in burden, and resulted in improved survival curves versus those for pentamidine-treated mice (at the same doses). All six bisbenzamidine compounds that exhibited high in vitro activity significantly decreased the infection in vivo; two compounds, 12 and 102, with marked to moderate in vitro activities had slight or no activity in vivo, while compound 31 was inactive in vitro and was also inactive in vivo. Thus, the selection of highly active compounds from in vitro cytotoxicity assays was predictive of activity in the mouse model of Pneumocystis pneumonia. We conclude that a number of these bisbenzamidine compounds, especially compound 100, may show promise as new anti-Pneumocystis drugs.


Interhospital Transfer of Neurosurgical Patients to a High-Volume Tertiary Care Center: Opportunities for Improvement.
Neurosurgical indications for patient transfer include absence of local or available neurosurgical coverage, subspecialty or interdisciplinary requirements, and family preference. Transfer of patients to regional centers will increase with further centralization of medical care. To report the transfer records of a large tertiary care center to identify trends, failures, and opportunities to improve interhospital transfer of neurosurgical patients. All consecutive, prospectively documented requests for interhospital patient transfer to the adult neurosurgical service of Emory University Hospitals were retrospectively identified from a centralized transfer center database for a 1-year study period. Requests for neurosurgical care constituted 1323 of the 9087 calls (14.6%); 81.1% of these requests were accepted, and a total of 984 patients (74.4%) arrived at our institutions. Patients arrived from 133 unique facilities throughout a catchment area of 66 287 sq miles. Although the median travel time for transfer patients was 36 minutes, the median interval between the request and patient arrival was 4 hours 2 minutes. The most frequent diagnoses were intracranial hemorrhage (31.8%), subarachnoid hemorrhage (31.2%), and intracranial tumor (15.2%). The overall diagnostic error rate was 10.3%. Only 42.5% of patients underwent neurosurgical intervention, and 57 patients admitted to intensive care were immediately transitioned to a lower level of care. Interhospital transfer requires a coordinated effort among hospital administrators, physicians, and staff to make complex decisions that govern this important and costly process. These data suggest common failures and numerous opportunities for improvement in transfer efficiency, diagnostic accuracy, triage, and resource allocation.


Dominance-Driven Autocratic Political Orientations Predict Political Violence in Western, Educated, Industrialized, Rich, and Democratic (WEIRD) and Non-WEIRD Samples.
Given the costs of political violence, scholars have long sought to identify its causes. We examined individual differences related to participation in political violence, emphasizing the central role of political orientations. We hypothesized that individuals with dominance-driven autocratic political orientations are prone to political violence. Multilevel analysis of survey data from 34 African countries (N = 51,587) indicated that autocracy-oriented individuals, compared with democracy-oriented individuals, are considerably more likely to participate in political violence. As a predictor of violence (indexed with attitudinal, intentional, and behavioral measures), autocratic orientation outperformed other variables highlighted in existing research, including socioeconomic status and group-based injustice. Additional analyses of original data from South Africa (N = 2,170), Denmark (N = 1,012), and the United States (N = 1,539) indicated that the link between autocratic orientations and political violence reflects individual differences in the use of dominance to achieve status and that the findings generalize to societies extensively socialized to democratic values.


Core promoter-selective RNA polymerase II transcription.
The initiation of mRNA synthesis in eukaryotic cells is a complex and highly regulated process that requires the assembly of general transcription factors and RNAP II (RNA polymerase II; also abbreviated as Pol II) into a pre-initiation complex at the core promoter. The core promoter is defined as the minimal DNA region that is sufficient to direct low levels of activator-independent (basal) transcription by RNAP II in vitro. The core promoter typically extends approx. 40 bp up- and down-stream of the start site of transcription and can contain several distinct core promoter sequence elements. Core promoters in higher eukaryotes are highly diverse in structure, and each core promoter sequence element is only found in a subset of genes. So far, only TATA box and INR (initiator) element have been shown to be capable of directing accurate RNAP II transcription initiation independent of other core promoter elements. Computational analysis of metazoan genomes suggests that the prevalence of the TATA box has been overestimated in the past and that the majority of human genes are TATA-less. While TATA-mediated transcription initiation has been studied in great detail and is very well understood, very little is known about the factors and mechanisms involved in the function of the INR and other core promoter elements. Here we summarize our current understanding of the factors and mechanisms involved in core promoter-selective transcription and discuss possible pathways through which diversity in core promoter architecture might contribute to combinatorial gene regulation in metazoan cells.


Intracellular gonadotropin-releasing hormone receptors in breast cancer and gonadotrope lineage cells.
Gonadotropin-releasing hormone receptors (GnRHRs) are expressed in gonadotropes and several extra-pituitary sites. They are assumed to be cell surface proteins but the human (h) GnRHR lacks features favoring plasma membrane localization and receptor location varies with cell type. When expressed in mammary (MCF7) cells, cell surface hGnRHR binding was much lower than that of mouse and sheep GnRHRs (type I GnRHRs without C-terminal tails), Xenopus (X) and marmoset type II GnRHRs (type II GnRHRs with C-tails) or chimeric receptors (type I GnRHRs with added XGnRHR C-tails). hGnRHR binding was higher in alphaT4 (gonadotrope-derived) cells and was increased less by C-tail addition. Whole cell levels of tagged human, Xenopus and chimeric GnRHRs were comparable (Western blotting) and confocal microscopy revealed that the hGnRHR is primarily intracellular (distribution similar to the endoplasmic reticulum marker, calreticulin), whereas most XGnRHR is at the plasma membrane, and adding the C-tail increased cell surface hGnRHR levels. A membrane-permeant antagonist increased cell surface hGnRHR number (>4-fold, t1/2 = 4 h) and also increased hGnRHR signaling and hGnRHR-mediated inhibition of proliferation. A more rapid increase in hGnRHR binding occurred when the temperature was raised from 4 to 37 degrees C (>5-fold, t1/2 = 15 min) and this effect was prevented by mutation to prevent signaling. Thus, cell surface GnRHR expression depends on receptor and cell type and the hGnRHR is primarily an intracellular protein that traffics to the cell surface for signaling in MCF7 cells. Manipulations favoring such trafficking may facilitate selective targeting of extra-pituitary GnRHRs.


Ball-milled sulfur-doped graphene materials contain metallic impurities originating from ball-milling apparatus: their influence on the catalytic properties.
Graphene materials have found applications in a wide range of devices over the past decade. In order to meet the demand for graphene materials, various synthesis methods are constantly being improved or invented. Ball-milling of graphite to obtain graphene materials is one of the many versatile methods to easily obtain bulk quantities. In this work, we show that the graphene materials produced by ball-milling are spontaneously contaminated with metallic impurities originating from the grinding bowls and balls. Ball-milled sulfur-doped graphene materials obtained from two types of ball-milling apparatus, specifically made up of stainless steel and zirconium dioxide, were investigated. Zirconium dioxide-based ball-milled sulfur-doped graphene materials contain a drastically lower amount of metallic impurities than stainless steel-based ball-milled sulfur-doped graphene materials. The presence of metallic impurities is demonstrated by their catalytic effects toward the electrochemical catalysis of hydrazine and cumene hydroperoxide. The general impression toward ball-milling of graphite as a versatile method for the bulk production of 'metal-free' graphene materials without the need for post-processing and the selection of ball-milling tools should be cautioned. These findings would have wide-reaching implications for graphene research.