Extracellular DNA and histones: double-edged swords in immunothrombosis.
The existence of extracellular DNA in human plasma, also known as cell-free DNA (cfDNA), was first described in the 1940s. In recent years, there has been a resurgence of interest in the functional significance of cfDNA, particularly in the context of neutrophil extracellular traps (NETs). cfDNA and histones are key components of NETs that aid in the host response to infection and inflammation. However, cfDNA and histones may also exert harmful effects by triggering coagulation, inflammation, and cell death and by impairing fibrinolysis. In this article, we will review the pathologic nature of cfDNA and histones in macrovascular and microvascular thrombosis, including venous thromboembolism, cancer, sepsis, and trauma. We will also discuss the prognostic value of cfDNA and histones in these disease states. Understanding the molecular and cellular pathways regulated by cfDNA and histones may provide novel insights to prevent pathological thrombus formation and vascular occlusion.


Pharmacy students' retention of knowledge of drug-drug interactions.
To evaluate pharmacy students' drug-drug interaction (DDI) knowledge retention over 1 year and to determine whether presenting DDI vignettes increased knowledge retention. A knowledge assessment tool was distributed to fourth-year pharmacy students before and after completing a DDI educational session. The questionnaire was re-administered after 1 year to assess knowledge retention. During the intervening year, students had the option of presenting DDI case vignettes to preceptors and other health professionals as part of their advanced pharmacy practice experiences (APPEs). Thirty-four of 78 pharmacy students completed both the post-intervention and 1-year follow-up assessments. Students' knowledge of 4 DDI pairs improved, knowledge of 3 DDI pairs did not change, and knowledge of the remainder of DDI pairs decreased. Average scores of the 18 students who completed all tests and presented at least 1 vignette during their APPEs were higher on the 1-year follow-up assessment than students who did not, suggesting greater DDI knowledge retention (p = 0.04). Although pharmacy students' overall DDI knowledge decreased in the year following an educational session, those who presented vignettes to health professionals retained more DDI knowledge, particularly on those DDIs for which they gave presentations. Other methods to enhance pharmacy students' retention of DDI knowledge of clinically important DDIs are needed.


Neoadjuvant chemotherapy and surgery of cancer of the esophagus.
Neoadjuvant, or pre-operative, chemotherapy for esophageal cancer has become an area of increasing interest because of the failure of conventional therapy (surgery or radiation) to improve disease-free or overall survival. Several autopsy series have demonstrated that, in many symptomatic Western patients, esophageal cancer is a systemic disease. Neoadjuvant chemotherapy thus, in theory, allows a simultaneous attack on both the primary and metastatic disease. A number of single-arm, phase II multi-modality trials have been completed. Toxicities of chemotherapy, while substantial, have been tolerable. With careful attention to detail, operative morbidity and mortality has not been increased. Large-scale randomized trials, needed to evaluate the impact of this technique on disease-free and overall survival, have been designed and will shortly be activated.


Automated selection of brain regions for real-time fMRI brain-computer interfaces.
Brain-computer interfaces (BCIs) implemented with real-time functional magnetic resonance imaging (rt-fMRI) use fMRI time-courses from predefined regions of interest (ROIs). To reach best performances, localizer experiments and on-site expert supervision are required for ROI definition. To automate this step, we developed two unsupervised computational techniques based on the general linear model (GLM) and independent component analysis (ICA) of rt-fMRI data, and compared their performances on a communication BCI. Approach. 3 T fMRI data of six volunteers were re-analyzed in simulated real-time. During a localizer run, participants performed three mental tasks following visual cues. During two communication runs, a letter-spelling display guided the subjects to freely encode letters by performing one of the mental tasks with a specific timing. GLM- and ICA-based procedures were used to decode each letter, respectively using compact ROIs and whole-brain distributed spatio-temporal patterns of fMRI activity, automatically defined from subject-specific or group-level maps. Letter-decoding performances were comparable to supervised methods. In combination with a similarity-based criterion, GLM- and ICA-based approaches successfully decoded more than 80% (average) of the letters. Subject-specific maps yielded optimal performances. Significance. Automated solutions for ROI selection may help accelerating the translation of rt-fMRI BCIs from research to clinical applications.


Aryl Hydrocarbon Receptor Interacting Protein Maintains Germinal Center B Cells through Suppression of BCL6 Degradation.
B cell lymphoma-6 (BCL6) is highly expressed in germinal center B cells, but how its expression is maintained is still not completely clear. Aryl hydrocarbon receptor interacting protein (AIP) is a co-chaperone of heat shock protein 90. Deletion of Aip in B cells decreased BCL6 expression, reducing germinal center B cells and diminishing adaptive immune responses. AIP was required for optimal AKT signaling in response to B cell receptor stimulation, and AIP protected BCL6 from ubiquitin-mediated proteasomal degradation by the E3-ubiquitin ligase FBXO11 by binding to the deubiquitinase UCHL1, thus helping to maintain the expression of BCL6. AIP was highly expressed in primary diffuse large B cell lymphomas compared to healthy tissue and other tumors. Our findings describe AIP as a positive regulator of BCL6 expression with implications for the pathobiology of diffuse large B cell lymphoma.


Picking the good apples: statistics versus good judgment in choosing stent operators for a multicenter clinical trial.
The Carotid Revascularization Endarterectomy Versus Stenting Trial was completed with a low stroke and death rate. A lead-in series of patients receiving carotid artery stenting was used to select the physician-operators for the study, where performance was evaluated by complication rates and by peer review of cases. Herein, we assess the potential contribution of statistical evaluation of complication rates. The ability to discriminate between stent operators who can successfully meet the published guideline of <3% combined rate of stroke and death is calculated under the binomial distribution, based on a small consecutive case series (n=24 patients). A criterion of ≤2 stroke or death events among the 24 patients (<8% event rate) was required of operators. Setting such a high criterion, however, ensures an inability to exclude operators who cannot meet the criteria. In fact, if a good operator is defined as having a 2% event rate and a poor operator as a 6% event rate, even a series of 240 patients would (on average) still exclude 5.4% of the good operators and include 4.6% of the poor operators. The low periprocedural event rates in the trial suggest success in separating skillful operators from less skillful. However, it seems unlikely that statistical assessment of event rates in the lead-in contributed to successful selection, but rather successful selection was more likely because of peer review of subjective and other factors including patient volume and technical approaches. http://www.clinicaltrials.gov. Unique identifier: NCT00004732.


Evolution of copper resistance in the kiwifruit pathogen Pseudomonas syringae pv. actinidiae through acquisition of integrative conjugative elements and plasmids.
Horizontal gene transfer can precipitate rapid evolutionary change. In 2010 the global pandemic of kiwifruit canker disease caused by Pseudomonas syringae pv. actinidiae (Psa) reached New Zealand. At the time of introduction, the single clone responsible for the outbreak was sensitive to copper, however, analysis of a sample of isolates taken in 2015 and 2016 showed that a quarter were copper resistant. Genome sequences of seven strains showed that copper resistance - comprising czc/cusABC and copABCD systems - along with resistance to arsenic and cadmium, was acquired via uptake of integrative conjugative elements (ICEs), but also plasmids. Comparative analysis showed ICEs to have a mosaic structure, with one being a tripartite arrangement of two different ICEs and a plasmid that were isolated in 1921 (USA), 1968 (NZ) and 1988 (Japan), from P. syringae pathogens of millet, wheat and kiwifruit respectively. Two of the Psa ICEs were nearly identical to two ICEs isolated from kiwifruit leaf colonists prior to the introduction of Psa into NZ. Additionally, we show ICE transfer in vitro and in planta, analyze fitness consequences of ICE carriage, capture the de novo formation of novel recombinant ICEs, and explore ICE host-range.


Construction and analysis of cDNA libraries from the antennae of Batocera horsfieldi and expression pattern of putative odorant binding proteins.
A high-quality cDNA library was constructed from female and male antenna of the longhorned beetle, Batocera horsfieldi (Hope) (Coleoptera: Cerambycidae), a serious pest of Populus (Salicales: Salicaceae). The titer was approximately 2.37 × 106 pfu/mL, and this complies with the test requirement. From the libraries, 692 clones were selected randomly, sequenced, and further analyzed, and the recombinational efficiency reached 93.85%. By alignment and cluster analysis, we identified four odorant binding proteins, two pheromone-binding proteins (have the characteristic six conserved cysteine residues), four Minus-C odorant binding proteins (lost two conserved cysteines), and three chemosensory proteins. In this study, we describe the identification and characterization of four new cDNAs that encode Minus-C odorant binding proteins (Minus-C OBPs) from B. horsfieldi antennal cDNA libraries. Our investigation focused on the expression pattern of the Minus-C OBP genes in various tissues in both sexes at different developmental stages, using reverse transcription PCR (RT-PCR) and realtime PCR (qPCR) strategies. Minus-C OBP1, 2, and 3 were expressed in all tested tissues, with the exception of the head (without antenna, labial palps, and maxillary palps). Minus-C OBP4 was expressed in the antenna, legs, and abdomen, but not in the labial palps, maxillary palps, or head. The qPCR results revealed MinusC OBPs were expressed in the antenna throughout the adult life, and that the transcript levels of these genes depended on the sex, age, and mating status of adults.


Examining the relationship between impulsivity-related personality traits and e-cigarette use in adults.
The present study aimed to investigate the relationship between impulsivity-related personality traits based on the UPPS-P model and e-cigarette use. The study used a sample of mainly European adults and compared e-cigarette users with non-smokers, cigarette smokers and dual users (those who currently smoke cigarettes and use e-cigarettes). Additionally, the relationship between impulsivity-related traits and frequency and intensity of e-cigarette use was examined, while the main reasons for e-cigarette use were also assessed. Participants were 720 adults (234 non-smokers, 164 smokers, 150 e-cigarette users, 172 dual users), who completed online questionnaires regarding sociodemographics, smoking/e-cigarette use behaviour, and impulsivity (UPPS-P scale). Impulsivity-related traits did not significantly differentiate e-cigarette users from non-smokers. E-cigarette users showed lower levels of lack of perseverance than cigarette smokers, and they exhibited lower levels of negative and positive urgency than dual users. Negative urgency also significantly differentiated smokers and non-smokers, with smokers having higher levels of the trait. No significant results were found examining the relationship between the impulsivity-related traits and e-cigarette behaviour (number of days vaping per month, number of times vaping per day, and millilitres of e-liquid used per day). The main reason given for e-cigarette use was the perception that it is less harmful than cigarettes. The present study found that trait impulsivity differentiated e-cigarette users from cigarette smokers and dual users, but did not differentiate e-cigarette users from non-smokers. Such findings are important to not only help us identify factors associated with e-cigarette use, but also to potentially inform treatment plans and decisions.


The centaurin gamma-1 GTPase-like domain functions as an NTPase.
Centaurins are a family of proteins that contain GTPase-activating protein domains, with the gamma family members containing in addition a GTPase-like domain. Centaurins reside mainly in the nucleus and are known to activate phosphoinositide 3-kinase, a key regulator of cell proliferation, motility and vesicular trafficking. In the present study, using X-ray structural analysis, enzymatic assays and nucleotide-binding studies, we show that, for CENTG1 (centaurin gamma-1) the GTPase-like domain has broader trinucleotide specificity. Alterations within the G4 motif of CENTG1 from the highly conserved NKXD found in typical GTPases to TQDR result in the loss of specificity, a lower affinity for the nucleotides and higher turnover rates. These results indicate that the centaurins could be more accurately classified as NTPases and point to alternative mechanisms of cell signalling control.


Carcass disposal: lessons from The Netherlands after the foot and mouth disease outbreak of 2001.
The main logistical problems of the foot and mouth disease (FMD) outbreak that occurred in the Netherlands in 2001 were a lack of culling and rendering capacity. Suppressive vaccination formed the basis for the solution to both problems and was primarily used to halt the possible spread of the virus. This allowed culls to take place on vaccinated farms when sufficient culling capacity eventually became available. In addition, the vaccinated cloven-hoofed animals could be removed alive and then killed in central culling places fourteen or more days after vaccination. Using slaughterhouses as central culling places meant that parts of carcasses could be deep-frozen, which solved the lack of rendering capacity. The deep-frozen carcass parts were destroyed later, when rendering capacity became available. To guarantee that all vaccinated, culled and temporarily deep-frozen cloven-hoofed animals were eventually destroyed, a balanced audit trail, partly based on kilogram records, was vital in this situation.


Mapping of γ/δ T cells reveals Vδ2+ T cells resistance to senescence.
Immune adaptation with aging is a major of health outcomes. Studies in humans have mainly focus on αβ T cells while γδ T cells have been neglected despite their role in immunosurveillance. We investigated the impact of aging on γδ T cell subsets phenotypes, functions, senescence and their molecular response to stress. Peripheral blood of young and old donors in Singapore have been used to assess the phenotype, functional capacity, proliferation capacity and gene expression of the various γδ T cell subsets. Peripheral blood mononuclear cells from apheresis cones and young donors have been used to characterize the telomere length, epigenetics profile and DNA damage response of the various γδ T cell subsets phenotype. Our data shows that peripheral Vδ2+ phenotype, functional capacity (cytokines, cytotoxicity, proliferation) and gene expression profile are specific when compared against all other αβ and γδ T cells in aging. Hallmarks of senescence including telomere length, epigenetic profile and DNA damage response of Vδ2+ also differs against all other αβ and γδ T cells. Our results highlight the differential impact of lifelong stress on γδ T cells subsets, and highlight possible mechanisms that enable Vδ2+ to be resistant to cellular aging. The new findings reinforce the concept that Vδ2+ have an "innate-like" behavior and are more resilient to the environment as compared to "adaptive-like" Vδ1+ T cells.


Caregiving Self-efficacy and Knowledge Regarding Patient Positioning Among Malaysian Caregivers of Stroke Patients.
Background Most family caregivers of stroke patients in Malaysia do not receive adequate prior preparation or training. This study aimed to determine levels of patient positioning knowledge and caregiving self-efficacy among caregivers of stroke patients. Methods This cross-sectional study was conducted at an urban teaching hospital involving 128 caregivers of stroke patients. The caregivers were conveniently sampled and completed the data collection forms, which comprised their socio-demographic data, patients' functional status, the Caregiving Knowledge For Stroke Questionnaire: Patient Positioning (CKQ-My© Patient Positioning) to measure caregiver's knowledge on patient positioning, and the Family Caregiver Activation Tool (FCAT©) to measure caregivers' self-efficacy in managing the patient. Descriptive and multivariate inferential statistics were used for data analysis. Results Among the caregivers sampled, 87.3% had poor knowledge of positioning (mean score 14.9 ± 4.32). The mean score for FCAT was 49.7 ± 6.0 from a scale of 10 to 60. There was no significant association between knowledge on positioning and self-efficacy. Multiple linear regression showed that caregivers' age (B = 0.146, p = 0.003) and caregiver training (B = 3.302, p = 0.007) were independently associated with caregivers' self-efficacy. Conclusion Caregivers' knowledge on the positioning of stroke patients was poor, despite a fairly good level of self-efficacy. Older caregivers and receiving caregiver training were independently associated with better caregiver self-efficacy. This supports the provision of caregiver training to improve caregiver self-efficacy.


Monocytes and macrophages regulate immunity through dynamic networks of survival and cell death.
Monocytes and macrophages are central cells of the innate immune system, responsible for defending against diverse pathogens. While they originate from a common myeloid precursor and share functions in innate immunity, each has a very distinct life span finely tuned by the apoptotic caspases. Normally, circulating monocytes are short-lived and undergo spontaneous apoptosis on a daily basis. Macrophages, however, have a longer life span. In chronic inflammatory diseases and, as recently recognized, in the tumor microenvironment, the inhibition of the apoptotic program promotes monocyte survival contributing to the accumulation of macrophages and the persistence of an inflammatory milieu. A complex network of differentiation factors and inflammatory stimuli determine monocyte/macrophage life span by blocking the apoptotic pathway and activating a myriad of survival pathways. Our understanding of apoptosis has flourished over the last decade, and its relevance in the regulation of the immune system is now indisputable. Nevertheless, how the complicated networks of survival and apoptotic regulators are integrated to determine cellular life span remains elusive. This review summarizes the contribution of the caspases and their regulators in monocyte/macrophage cell fate and discusses how these molecules orchestrate the initiation, maintenance, and resolution of inflammation. More provocatively, we discuss possible strategies to control inflammation by manipulating leukocyte life span.


Claims of potential expansion throughout the U.S. by invasive python species are contradicted by ecological niche models.
Recent reports from the United States Geological Survey (USGS) suggested that invasive Burmese pythons in the Everglades may quickly spread into many parts of the U.S. due to putative climatic suitability. Additionally, projected trends of global warming were predicted to significantly increase suitable habitat and promote range expansion by these snakes. However, the ecological limitations of the Burmese python are not known and the possible effects of global warming on the potential expansion of the species are also unclear. Here we show that a predicted continental expansion is unlikely based on the ecology of the organism and the climate of the U.S. Our ecological niche models, which include variables representing climatic extremes as well as averages, indicate that the only suitable habitat in the U.S. for Burmese pythons presently occurs in southern Florida and in extreme southern Texas. Models based on the current distribution of the snake predict suitable habitat in essentially the only region in which the snakes are found in the U.S. Future climate models based on global warming forecasts actually indicate a significant contraction in suitable habitat for Burmese pythons in the U.S. as well as in their native range. The Burmese python is strongly limited to the small area of suitable environmental conditions in the United States it currently inhabits due to the ecological niche preferences of the snake. The ability of the Burmese python to expand further into the U.S. is severely limited by ecological constraints. Global warming is predicted to significantly reduce the area of suitable habitat worldwide, underscoring the potential negative effects of climate change for many species.


The gut microbiota and its correlations with the central nervous system disorders.
A mutual impact of gastrointestinal tract (GIT) and central nervous system (CNS) functions has been recognized since the mid-twentieth century. It is accepted that the so-called gut-brain axis provides a two-way homeostatic communication, through immunological, hormonal and neuronal signals. A dysfunction of this axis has been associated with the pathogenesis of some diseases both within and outside the GIT, that have shown an increase in incidence over the last decades. Studies comparing germ-free animals and animals exposed to pathogenic bacterial infections, probiotics or antibiotics suggest the participation of the microbiota in this communication and a role in host defense, regulation of immunity and autoimmune disease appearance. The GIT could represent a vulnerable area through which pathogens influence all aspects of physiology and even induce CNS neuro-inflammation. All those concepts may suggest the modulation of the gut microbiota as an achievable strategy for innovative therapies in complex disorders. Moving from this background, the present review discusses the relationship between intestinal microbiota and CNS and the effects in health and disease. We particularly look at how the commensal gut microbiota influences systemic immune response in some neurological disorders, highlighting its impact on pain and cognition in multiple sclerosis, Guillain-Barrè Syndrome, neurodevelopmental and behavioral disorders and Alzheimer's disease. In this review we discuss recent studies showing that the potential microbiota-gut-brain dialogue is implicated in neurodegenerative diseases. Gaining a better understanding of the relationship between microbiota and CNS could provide an insight on the pathogenesis and therapeutic strategies of these disorders.


Observed increase in local cooling effect of deforestation at higher latitudes.
Deforestation in mid- to high latitudes is hypothesized to have the potential to cool the Earth's surface by altering biophysical processes. In climate models of continental-scale land clearing, the cooling is triggered by increases in surface albedo and is reinforced by a land albedo-sea ice feedback. This feedback is crucial in the model predictions; without it other biophysical processes may overwhelm the albedo effect to generate warming instead. Ongoing land-use activities, such as land management for climate mitigation, are occurring at local scales (hectares) presumably too small to generate the feedback, and it is not known whether the intrinsic biophysical mechanism on its own can change the surface temperature in a consistent manner. Nor has the effect of deforestation on climate been demonstrated over large areas from direct observations. Here we show that surface air temperature is lower in open land than in nearby forested land. The effect is 0.85 ± 0.44 K (mean ± one standard deviation) northwards of 45° N and 0.21 ± 0.53 K southwards. Below 35° N there is weak evidence that deforestation leads to warming. Results are based on comparisons of temperature at forested eddy covariance towers in the USA and Canada and, as a proxy for small areas of cleared land, nearby surface weather stations. Night-time temperature changes unrelated to changes in surface albedo are an important contributor to the overall cooling effect. The observed latitudinal dependence is consistent with theoretical expectation of changes in energy loss from convection and radiation across latitudes in both the daytime and night-time phase of the diurnal cycle, the latter of which remains uncertain in climate models.


Spatially engineered polarization states and optical vortices in uniaxial crystals.
We describe how the propagation of light through uniaxial crystals can be used as a versatile tool towards the spatial engineering of polarization and phase, thereby providing an all-optical technique for vectorial and scalar singular beam shaping in optics. Besides the prominent role played by the linear birefringence, the influence of circular birefringence (the optical activity) is discussed as well and both the monochromatic and polychromatic singular beam shaping strategies are addressed. Under cylindrically symmetric light-matter interaction, the radially, azimuthally, and spirally polarized eigen-modes for the light field are revealed to be of a fundamental interest to describe the physical mechanisms at work when dealing with scalar and vectorial optical singularities. In addition, we also report on nontrivial effects arising from cylindrical symmetry breaking, e.g. tilting the incident beam with respect to the crystal optical axis.


Oral delivery of double-stranded RNA in larvae of the yellow fever mosquito, Aedes aegypti: implications for pest mosquito control.
RNA interference has already proven itself to be a highly versatile molecular biology tool for understanding gene function in a limited number of insect species, but its widespread use in other species will be dependent on the development of easier methods of double-stranded RNA (dsRNA) delivery. This study demonstrates that RNA interference can be induced in the mosquito Aedes aegypti L. (Diptera: Culicidae) simply by soaking larvae in a solution of dsRNA for two hours. The mRNA transcripts for β-tubulin, chitin synthase-1 and -2, and heat shock protein 83 were reduced between 30 and 50% three days post-dsRNA treatment. The dsRNA was mixed with a visible dye to identify those individuals that fed on the dsRNA, and based on an absence of RNA interference in those individuals that contained no dye within their guts, the primary route of entry of dsRNA is likely through the gut epithelium. RNA interference was systemic in the insects, inducing measurable knock down of gene expression in tissues beyond the gut. Silencing of the β-tubulin and chitin synthase-1 genes resulted in reduced growth and/or mortality of the larvae, demonstrating the utility of dsRNA as a potential mosquito larvicide. Silencing of chitin synthase-2 did not induce mortality in the larvae, and silencing of heat shock protein 83 only induced mortality in the insects if they were subsequently subjected to a heat stress. Drosophila melanogaster Meigen (Diptera: Drosophilidae) larvae were also soaked in dsRNA designed to specifically target either their own β-tubulin gene, or that of A. aegypti, and significant mortality was only seen in larvae treated with dsRNA targeting their own gene, which suggests that dsRNA pesticides could be designed to be species-limited.


The lipid-reactive oxygen species phenotype of breast cancer. Raman spectroscopy and mapping, PCA and PLSDA for invasive ductal carcinoma and invasive lobular carcinoma. Molecular tumorigenic mechanisms beyond Warburg effect.
Vibrational signatures of human breast tissue (invasive ductal carcinoma and invasive lobular carcinoma) were used to identify, characterize and discriminate structures in normal (noncancerous) and cancerous tissues by confocal Raman imaging, Raman spectroscopy and IR spectroscopy. The most important differences between normal and cancerous tissues were found in regions characteristic for vibrations of carotenoids, fatty acids, proteins, and interfacial water. Particular attention was paid to the role played by unsaturated fatty acids and their derivatives. K-means clustering and basis analysis followed by PCA and PLSDA is employed to analyze Raman spectroscopic maps of human breast tissue and for a statistical analysis of the samples (82 patients, 164 samples). Raman maps successfully identify regions of carotenoids, fatty acids, and proteins. The intensities, frequencies and profiles of the average Raman spectra differentiate the biochemical composition of normal and cancerous tissues. The paper demonstrates that Raman imaging has reached a clinically relevant level in regard to breast cancer diagnosis applications. The sensitivity and specificity obtained directly from PLSLD and cross validation are equal to 90.5% and 84.8% for calibration and 84.7% and 71.9% for cross-validation respectively.


Genetic mapping of quantitative trait loci for growth and fatness in pigs.
The European wild boar was crossed with the domesticated Large White pig to genetically dissect phenotypic differences between these populations for growth and fat deposition. The most important effects were clustered on chromosome 4, with a single region accounting for a large part of the breed difference in growth rate, fatness, and length of the small intestine. The study is an advance in genome analyses and documents the usefulness of crosses between divergent outbred populations for the detection and characterization of quantitative trait loci. The genetic mapping of a major locus for fat deposition in the pig could have implications for understanding human obesity.


Nighttime driving: visual, lighting and visibility challenges.
Nighttime driving is dangerous and is one of the most challenging driving situations for most drivers. Fatality rates are higher at night than in the day when adjusted for distances travelled, particularly for crashes involving pedestrians and cyclists. Although there are multiple contributory factors, the low light levels at night are believed to be the major cause of collisions with pedestrians and cyclists at night, most likely due to their reduced visibility. Understanding the visibility problems involved in nighttime driving is thus critical, given the increased risk to road safety. This review discusses research that highlights key differences in the nighttime road environment compared to the day and how this affects visual function and driving performance, together with an overview of studies investigating how driver age and visual status affect nighttime driving performance. Research that has focused on the visibility of vulnerable road users at nighttime (pedestrians and cyclists) is also included. Collectively, the research evidence suggests that visual function is reduced under the mesopic lighting conditions of night driving and that these effects are exacerbated by increasing age and visual impairment. Light and glare from road lighting and headlights have significant impacts on vision and night driving and these effects are likely to change with evolving technologies, such as LED streetlighting and headlights. Research also highlights the importance of the visibility of vulnerable road users at night and the role of retroreflective clothing in the 'biomotion' configuration for improving their conspicuity and hence safety.


Agricultural peatland restoration: effects of land-use change on greenhouse gas (CO2 and CH4) fluxes in the Sacramento-San Joaquin Delta.
Agricultural drainage of organic soils has resulted in vast soil subsidence and contributed to increased atmospheric carbon dioxide (CO2) concentrations. The Sacramento-San Joaquin Delta in California was drained over a century ago for agriculture and human settlement and has since experienced subsidence rates that are among the highest in the world. It is recognized that drained agriculture in the Delta is unsustainable in the long-term, and to help reverse subsidence and capture carbon (C) there is an interest in restoring drained agricultural land-use types to flooded conditions. However, flooding may increase methane (CH4) emissions. We conducted a full year of simultaneous eddy covariance measurements at two conventional drained agricultural peatlands (a pasture and a corn field) and three flooded land-use types (a rice paddy and two restored wetlands) to assess the impact of drained to flooded land-use change on CO2 and CH4 fluxes in the Delta. We found that the drained sites were net C and greenhouse gas (GHG) sources, releasing up to 341 g C m(-2) yr(-1) as CO2 and 11.4 g C m(-2) yr(-1) as CH4. Conversely, the restored wetlands were net sinks of atmospheric CO2, sequestering up to 397 g C m(-2) yr(-1). However, they were large sources of CH4, with emissions ranging from 39 to 53 g C m(-2) yr(-1). In terms of the full GHG budget, the restored wetlands could be either GHG sources or sinks. Although the rice paddy was a small atmospheric CO2 sink, when considering harvest and CH4 emissions, it acted as both a C and GHG source. Annual photosynthesis was similar between sites, but flooding at the restored sites inhibited ecosystem respiration, making them net CO2 sinks. This study suggests that converting drained agricultural peat soils to flooded land-use types can help reduce or reverse soil subsidence and reduce GHG emissions.


Comparison of Two Commercial ELISA Kits for the Detection of Anti-Dengue IgM for Routine Dengue Diagnosis in Laos.
The endemicity of Dengue virus (DENV) infection remains a major public health problem in Lao PDR. In this study, we compared two commercial anti-dengue IgM ELISA kits, Panbio® Dengue IgM Capture ELISA (Panbio Kit, Alere, Waltham, MA, USA) and DEN DetectTM MAC-ELISA (InBios kit, InBios International, Inc., Seattle, WA, USA), in the context of diagnosis of patients admitted to hospital with clinical dengue presentation. Two panels of paired blood samples were tested. Panel A was composed of 54 dengue confirmed patients (by DENV real-time RT-PCR) and 11 non-dengue dengue patients (other infections confirmed by corresponding PCR results). Panel B included 74 patients randomly selected from consecutive patients admitted to Mahosot Hospital in 2008 with suspicion of dengue fever according to WHO criteria. Results from panel A showed significantly better sensitivity for Panbio kit (64.8%; 95%CI: 50.6-77.3%) than for InBios kit (18.5%; 95%CI: 9.3-31.4%) when testing admission sera. Sensitivity was increased for both kits when combining results from admission and convalescent sera. Concordant results were obtained from panel B with fair agreement (κ = 0.29) between both kits when testing single admission samples, and moderate agreement (κ = 0.5) when combining results from admission and convalescent sera.


Effect of nitro-functionalization on the cross-linking and bioadhesion of biomimetic adhesive moiety.
Dopamine mimics the exceptional moisture-resistant adhesive properties of the amino acid, DOPA, found in adhesive proteins secreted by marine mussels. The catechol side chain of dopamine was functionalized with a nitro-group, and the effect of the electron withdrawing group modification on the cross-linking chemistry and bioadhesive properties of the adhesive moiety was evaluated. Both nitrodopamine and dopamine were covalently attached as a terminal group onto an inert, 4-armed poly(ethylene glygol) (PEG-ND and PEG-D, respectively). PEG-ND and PEG-D exhibited different dependence on the concentration of NaIO4 and pH, which affected the curing rate, mechanical properties, and adhesive performance of these biomimetic adhesives differently. PEG-ND cured instantly and its bioadhesive properties were minimally affected by the change in pH (5.7-8) within the physiological range. Under mildly acidic conditions (pH 5.7 and 6.7), PEG-ND outperformed PEG-D in lap shear adhesion testing using wetted pericardium tissues. However, nitrodopamine only formed dimers, which resulted in the formation of loosely cross-linked network and adhesive with reduced cohesive properties. UV-vis spectroscopy further confirmed nitrodopamine's ability for rapid dimer formation. The ability for nitrodopamine to rapidly cure and adhere to biological substrates in an acidic pH make it suitable for designing adhesive biomaterials targeted at tissues that are more acidic (i.e., subcutaneous, dysoxic, or tumor tissues).


Poor sleep in patients with multiple sclerosis.
Poor sleep is a frequent symptom in patients with multiple sclerosis (MS). Sleep may be influenced by MS-related symptoms and adverse effects from immunotherapy and symptomatic medications. We aimed to study the prevalence of poor sleep and the influence of socio-demographic and clinical factors on sleep quality in MS- patients. A total of 90 MS patients and 108 sex-and age- matched controls were included in a questionnaire survey. Sleep complaints were evaluated by Pittsburgh Sleep Quality Index (PSQI) and a global PSQI score was used to separate good sleepers (≤ 5) from poor sleepers (>5). Excessive daytime sleepiness, the use of immunotherapy and antidepressant drugs, symptoms of pain, depression, fatigue and MS-specific health related quality of life were registered. Results were compared between patients and controls and between good and poor sleepers among MS patients. MS patients reported a higher mean global PSQI score than controls (8.6 vs. 6.3, p = 0.001), and 67.1% of the MS patients compared to 43.9% of the controls (p = 0.002) were poor sleepers. Pain (p = 0.02), fatigue (p = 0.001), depression (p = 0.01) and female gender (p = 0.04) were associated with sleep disturbance. Multivariate analyses showed that female gender (p = 0.02), use of immunotherapy (p = 005) and a high psychological burden of MS (p = 0.001) were associated with poor sleep among MS patients. Poor sleep is common in patients with MS. Early identification and treatment of modifiable risk factors may improve sleep and quality of life in MS.


Apathy in Alzheimer's disease.
Apathy is the most common neuropsychiatric symptom in patients with Alzheimer's disease (AD). The presence of apathy has been related to greater caregiver distress, decreased quality of life, and increased morbidity. Here we review the most recent studies on this neuropsychiatric syndrome, focusing on prevalence, impact on quality of life, behavioural and neuroimaging studies, and treatment options. The results of some investigations on the behavioural and neuroanatomical profile of apathy in AD point to a role of frontostriatal circuits, specifically involving the anterior cingulate cortex. However, small and heterogeneous samples, lack of control for disease severity, and non-specific apathy scales complicate interpretation of results. Future studies might benefit from studying multiple dimensions of apathy within conceptual frameworks which allow for a deconstruction of underlying mechanisms.


Mechanisms of lead, copper, and zinc retention by phosphate rock.
The solid-liquid interface reaction between phosphate rock (PR) and metals (Pb, Cu, and Zn) was studied. Phosphate rock has the highest affinity for Pb, followed by Cu and Zn, with sorption capacities of 138, 114, and 83.2 mmol/kg PR, respectively. In the Pb-Cu-Zn ternary system, competitive metal sorption occurred with sorption capacity reduction of 15.2%, 48.3%, and 75.6% for Pb, Cu, and Zn, respectively compared to the mono-metal systems. A fractional factorial design showed the interfering effect in the order of Pb>Cu>Zn. Desorption of Cu and Zn was sensitive to pH change, increasing with pH decline, whereas Pb desorption was decreased with a strongly acidic TCLP extracting solution (pH = 2.93). The greatest stability of Pb retention by PR can be attributed to the formation of insoluble fluoropyromorphite [Pb(10)(PO(4))(6)F(2)], which was primarily responsible for Pb immobilization (up to 78.3%), with less contribution from the surface adsorption or complexation (21.7%), compared to 74.5% for Cu and 95.7% for Zn. Solution pH reduction during metal retention and flow calorimetry analysis both supported the hypothesis of retention of Pb, Cu, and Zn by surface adsorption or complexation. Flow calorimetry indicated that Pb and Cu adsorption onto PR was exothermic, while Zn sorption was endothermic. Our research demonstrated that PR can effectively remove Pb from solutions, even in the presence of other heavy metals (e.g. Cu, Zn).


Probing the mechanism of incorporation of fluorescently labeled actin into stress fibers.
The mechanism of actin incorporation into and association with stress fibers of 3T3 and WI38 fibroblasts was examined by fluorescent analog cytochemistry, fluorescence recovery after photobleaching (FRAP), image analysis, and immunoelectron microscopy. Microinjected, fluorescein-labeled actin (AF-actin) became associated with stress fibers as early as 5 min post-injection. There was no detectable cellular polarity in the association of AF-actin with pre-existing stress fibers relative to perinuclear or peripheral regions. The rate of incorporation was quantified by image analysis of images generated with a two-dimensional photon counting microchannel plate camera. After equilibration of up to 2 h post-injection, FRAP demonstrated that actin subunits exchanged rapidly between filaments in stress fibers and the surrounding cytoplasm. When co-injected with rhodamine-labeled bovine serum albumin as a control, only actin was detected in the phase-dense stress fibers. The control protein was excluded from fibers and any linear fluorescence of the control was demonstrated as a pathlength artifact. The incorporation of AF-actin into stress fibers was studied by immunoelectron microscopy using anti-fluorescein as the primary antibody and goat anti-rabbit IgG coupled to peroxidase as the secondary antibody. At 5 min post-injection, reaction product was localized periodically in some fibers with a periodicity of approximately 0.75 microns. In large diameter fibers at 5 min post-injection, the analog was seen first on the surface of fibers, with individual filaments resolvable within the core. In the same cell, thinner diameter fibers were labeled uniformly throughout the diameter. By 20 min post-injection, most fibers were uniformly labeled. We conclude that the rate of actin subunit exchange in vivo is extremely rapid with molecular incorporation into actin filaments of stress fibers occurring as early as a few minutes post-injection. Exchange appears to first occur in filaments along the surface of stress fibers and then into more central regions in a periodic manner. We suggest that the periodic localization of actin at very early time points is due to a local microheterogeneity in which microdomains of fast vs. slower incorporation result from the periodic localization of actin-binding protein, such as alpha-actinin, along the length of the fiber.


Do donor oocyte cycles comply with ASRM/SART embryo transfer guidelines? An analysis of 13,393 donor cycles from the SART registry.
To analyze donor oocyte cycles in the Society for Assisted Reproductive Technology (SART) registry to determine: 1) how many cycles complied with the 2009 American Society for Reproductive Medicine/SART embryo transfer guidelines; and 2) cycle outcomes according to the number of embryos transferred. For donor oocyte IVF with donor age <35 years, the consideration of single-embryo transfer was strongly recommended. Retrospective cohort study of United States national registry information. Not applicable. A total of 13,393 donor-recipient cycles from 2011 to 2012. Embryos transferred in donor IVF cycles. Percentage of compliant cycles, multiple pregnancy rate. There were 3,157 donor cleavage-stage transfers and 10,236 donor blastocyst transfers. In the cleavage-stage cycles, 88% met compliance criteria. The multiple pregnancy rate (MPR) was significantly higher in the noncompliant cycles. In a subanalysis of compliant cleavage-stage cycles, 91% transferred two embryos and only 9% single embryos. In those patients transferring two embryos, the MPR was significantly higher (33% vs. 1%). In blastocyst transfers, only 28% of the cycles met compliance criteria. The MPR was significantly higher in the noncompliant blastocyst cohort at 53% (compared with 2% in compliant cycles). The majority of donor cleavage-stage transfers are compliant with current guidelines, but the transfer of two embryos results in a significantly higher MPR compared with single-embryo transfer. The majority of donor blastocyst cycles are noncompliant, which appears to be driving an unacceptably high MPR in these cycles.


Egalitarian policies and social determinants of health in Bolivarian Venezuela.
In 1999, newly-elected Venezuelan President Hugo Chávez initiated a far-reaching social movement as part of a political project known as the Bolivarian Revolution. Inspired by the democratic ideologies of Simón Bolívar, this movement was committed to reducing intractable inequalities that defined Venezuela's Fourth Republic (1958-1998). Given the ambitious scope of these reforms, Venezuela serves as an instructive example to understand the political context of social inequalities and population health. In this article, we provide a brief overview of the impact of egalitarian policies in Venezuela, stressing: (a) the socialist reforms and social class changes initiated by the Bolivarian Movement; (b) the impact of these reforms and changes on poverty and social determinants of health; (c) the sustainability of economic growth to continue pro-poor policies; and (d) the implications of egalitarian policies for other Latin American countries. The significance and implications of Chávez's achievements are now further underscored given his recent passing, leading one to ask whether political support for Bolivarianism will continue without its revolutionary leader.


White matter MR hyperintensities in adult patients with congenital rubella.
To observe and quantify white matter hyperintensities on MR images in adults with schizophrenialike symptoms who had had congenital rubella, in order to elucidate the neuropathologic sequelae of this perinatal viral infection and to explore the potential relationship of these lesions to schizophrenia. Eleven deaf adult patients with documented prenatal rubella virus infection and schizophrenialike symptoms were compared with 19 age-matched patients with early-onset schizophrenia who did not have congenital rubella and with 18 age-matched control subjects. All MR images (obtained at 1.5 T) were evaluated by a neuroradiologist who was blinded to diagnosis and were rated for white matter lesions on a five-point scale: 0 = no lesions; 1 = 1 lesion less than 1 mm in diameter; 2 = 1 to 4 lesions 1 mm or greater; 3 = 5 to 10 lesions; 4 = more than 10 lesions or a single lesion more than 1 cm in diameter. In addition, the white matter hyperintensities were volumed objectively with a manual threshold technique. Ratings of white matter lesions were significantly higher in the rubella patients than in the control subjects: 6 of the 11 patients had ratings greater than 1 compared with 1 of the 18 control subjects and none of the 19 schizophrenic patients. Also, MR images in five rubella patients received ratings at the highest end of the scale of abnormality (3 or 4). The white matter hyperintensities were characterized as bilateral T2 signal hyperintensities in periventricular and subcortical regions, punctate or linear in shape; they were observed predominantly in parietal lobes. This quantitative MR study of adult rubella patients disclosed abnormal white matter lesions that may correspond to neurovascular lesions known neuropathologically. They do not appear to be directly related to schizophrenialike symptoms.


The ethics of anonymized HIV testing of pregnant women: a reappraisal.
Seroprevalence monitoring of HIV in pregnant women by anonymized unlinked testing has been widely adopted in the UK and other countries. The scientific rationale is to eliminate participation and selection bias. The ethical justification is that the public good outweighs any harm to individuals. The assumption has been that individuals have had their autonomy respected by the offer of informed consent. In the light of new scientific evidence, it is doubtful that the public good is best served by the continuation of anonymously testing women receiving antenatal care. It is submitted that it is no longer ethical for health professionals to refrain from informing pregnant women of the benefits of voluntary named testing, or to request their consent to anonymized testing. The legal and moral concept of duty of care is examined, and the abrogation of this duty through anonymization is explained.


Suppression of defense response in plants by the avrBs3/pthA gene family of Xanthomonas spp.
Effector genes of some plant-pathogenic bacteria, including some members of the avrBs3/pthA effector gene family from Xanthomonas spp., confer not only genotype-specific disease resistance but also pathogen aggressiveness or virulence. In addition, some effector gene products suppress induction of a nonspecific (or general) hypersensitive response (HR). To determine whether the Xanthomonas avrBs3/pthA gene family members apl1, avrXa7, or avrXa10 also confer suppressor activity, we introduced constructs with each effector gene into Pseudomonas fluorescens 55 that expressed the entire hrp cluster from P. syringae pv. syringae in cosmid pHIR11. When inoculated to tobacco 'Bright Yellow', P fluorescens (pHIR11) induces the HR and expression of four tobacco defense response genes: HIN1, RbohB, PAL, and PR1. When P. fluorescens double transformants that contained pHIR11 and constructs with apl1, avrXa7, or avrXa10 were infiltrated into tobacco, the HR and expression of three defense response genes, RbohB, PAL, and PR1, were suppressed. The suppression of the HR and defense gene expression was more efficient in the transformants with the apl1 and avrXa7 than the transformant with avrXa10. Although expression of other defense genes was suppressed by the double transformants, HIN1 expression was the same level as was observed after infiltration with P. fluorescens (pHIR11), suggesting that HIN1 may not be involved directly in HR. Taken together, our data suggest that avrXa7, avrXa10, and apl1, when delivered to plant cells by the P. syringae pv. syringae hrp secretion system, can suppress nonhost HR and associated phenotypes.


The biomechanical significance of washer use with screw fixation.
Washers can be used with lag screws during fracture fixation to optimize compression and minimize the risk of unintentional intrusion of the screw head through cortical bone during screw insertion. The concept of using washers to optimize screw fixation is particularly applicable to iliosacral screw fixation and screw fixation of the femoral neck, distal femur, as well as the proximal and distal tibia. However, there is a paucity of literature on this topic. The purpose of this study was to detail the biomechanical consequences of washer use and screw intrusion. Partially threaded 7.0-mm cannulated screws with and without washers were placed through synthetic bone blocks fabricated to simulate cortical and cancellous bone. A load cell was used to measure the compressive force before and after screw intrusion. Screws were tested with a washer (n = 8), without a washer (n = 8), and with a washer after initially being intruded (n = 8). Screws inserted with washers generated significantly more compressive force than screws inserted without washers before screw intrusion. After intrusion, compressive force decreased significantly under all conditions, but screws inserted with washers maintained greater compressive force than screws inserted without washers. Screws with washers reinserted after intrusion without a washer, produced almost as much compressive force as screws inserted with washers primarily. Screw intrusion during fracture fixation results in a loss of compressive force that may compromise fixation quality. Washers are advantageous in that they allow for more compression to be generated before intrusion occurs and can be used to salvage compressive force of intruded screws.


Production of tissue-engineered three-dimensional human bronchial models.
We have reported morphological and functional features of cells isolated from human bronchial biopsies. Both epithelial and fibroblastic cells were isolated from the same biopsies using collagenase. A few models have been established to study normal bronchial response to various agents and to understand the mechanisms responsible for some disorders, such as asthma. We produced three-dimensional bronchial equivalents in culture, using human epithelial and fibroblastic cells. We previously showed that peripheral anchorage can prevent the dramatic collagen contraction in gels seeded with fibroblasts when properly adapted to the size and type of cultured tissues. Our bilayered bronchial constructs were anchored and cultured under submerged conditions and at the air-liquid interface. Three culture media were compared. Serum-free medium supplemented with retinoic acid (5 x 10(-8) M) was found to be the best for maintenance of bronchial cell properties in the reconstructed bronchial tissue. Immunohistological and ultrastructural analyses showed that these equivalents present good structural organization, allowing ciliogenesis to occur in culture. Moreover, human bronchial goblet cells could differentiate and secrete mucus with culture time. Laminin, a major constituent of the basement membrane and basal cells, was also detected at the mesenchymoepithelial interface. Such models will be useful for studying human bronchial properties in vitro.


HBV lamivudine resistance among hepatitis B and HIV coinfected patients starting lamivudine, stavudine and nevirapine in Kenya.
Widespread use of lamivudine in antiretroviral therapy may lead to hepatitis B virus resistance in HIV-HBV coinfected patients from endemic settings where tenofovir is not readily available. We evaluated 389 Kenyan HIV-infected adults before and for 18 months after starting highly active antiretroviral therapy with stavudine, lamivudine and nevirapine. Twenty-seven (6.9%) were HBsAg positive and anti-HBs negative, 24 were HBeAg negative, and 18 had HBV DNA levels ≤ 10,000 IU/mL. Sustained HBV suppression to <100 IU/mL occurred in 89% of 19 evaluable patients. Resistance occurred in only two subjects, both with high baseline HBV DNA levels. Lamivudine resistance can emerge in the setting of incomplete HBV suppression but was infrequently observed among HIV-HBV coinfected patients with low baseline HBV DNA levels.


Tuberculosis of sacrum mimicking as malignancy.
Tuberculosis has always been a menace for both clinicians and radiologists due to its often non-specific and protean manifestations. Isolated tubercular involvement of sacrum is very rare. The authors present the case of a 38-year-old man with history of low-grade fever, pain and swelling in the sacral region. Skiagram revealed an osteolytic lesion of sacrum leading to the provisional diagnosis of chordoma and osteoclastoma. However, MRI was suggestive of a chronic infective condition like tuberculosis and fine needle aspiration cytology was positive for acid-fast bacilli and revealed epitheloid granulomas with caseous necrosis. Culture was positive for Mycobacterium tuberculosis. Antitubercular therapy was commenced and surgical decompression of cold abscess was done and with good clinical response. This case highlights the importance of remaining cognisant of the manifestations and the importance of considering tuberculosis as a diagnosis at unusual sites of involvement.


Is the US AIDS drug assistance program cost-effective?
Each year, the US AIDS drug assistance program (ADAP) provides access to prescription drugs-including antiretrovirals-to more than 110,000 persons living with HIV (PLWH) who lack adequate medical insurance. PLWH on effective antiretroviral therapy live longer lives, with enhanced quality of life, and are less likely to transmit HIV to others. There are thus significant benefits associated with the ADAP program. But there also are substantial costs. A mathematical model was used to assess the cost-effectiveness of the US ADAP program. Findings indicate that by providing antiretrovirals to underinsured persons, the ADAP program prevented 3,191 secondary infections and saved 24,922 quality-adjusted life years in 2008. The net cost per quality-adjusted life year saved was $11,955, which suggests that the ADAP program is cost-effective by conventional standards.


Targeting mutant p53 protein and the tumor vasculature: an effective combination therapy for advanced breast tumors.
Breast cancer progression depends upon the elaboration of a vasculature sufficient for the nourishment of the developing tumor. Breast tumor cells frequently contain a mutant form of p53 (mtp53), a protein which promotes their survival. The aim of this study was to determine whether combination therapy targeting mtp53 and anionic phospholipids (AP) on tumor blood vessels might be an effective therapeutic strategy for suppressing advanced breast cancer. We examined the therapeutic effects, singly, or in combination, of p53 reactivation and induction of massive apoptosis (PRIMA-1), which reactivates mtp53 and induces tumor cell apoptosis, and 2aG4, a monoclonal antibody that disrupts tumor vasculature by targeting AP on the surface of tumor endothelial cells and causes antibody-dependent destruction of tumor blood vessels, leading to ischemia and tumor cell death. Xenografts from two tumor cell lines containing mtp53, BT-474 and HCC-1428, were grown in nude mice to provide models of advanced breast tumors. After treatment with PRIMA-1 and/or 2aG4, regressing tumors were analyzed for vascular endothelial growth factor (VEGF) expression, blood vessel loss, and apoptotic markers. Individual drug treatment led to partial suppression of breast cancer progression. In contrast, combined treatment with PRIMA-1 and 2aG4 was extremely effective in suppressing tumor growth in both models and completely eradicated approximately 30% of tumors in the BT-474 model. Importantly, no toxic effects were observed in any treatment group. Mechanistic studies determined that PRIMA-1 reactivated mtp53 and also exposed AP on the surface of tumor cells as determined by enhanced 2aG4 binding. Combination treatment led to significant induction of tumor cell apoptosis, loss of VEGF expression, as well as destruction of tumor blood vessels. Furthermore, combination treatment severely disrupted tumor blood vessel perfusion in both tumor models. The observed in vitro PRIMA-1-induced exposure of tumor epithelial cell AP might provide a target for 2aG4 and contribute to the increased effectiveness of such combination therapy in vivo. We conclude that the combined targeting of mtp53 and the tumor vasculature is a novel effective strategy for combating advanced breast tumors.


An automatic service for the personalization of ventricular cardiac meshes.
Computational cardiac physiology has great potential to improve the management of cardiovascular diseases. One of the main bottlenecks in this field is the customization of the computational model to the anatomical and physiological status of the patient. We present a fully automatic service for the geometrical personalization of cardiac ventricular meshes with high-order interpolation from segmented images. The method is versatile (able to work with different species and disease conditions) and robust (fully automatic results fulfilling accuracy and quality requirements in 87% of 255 cases). Results also illustrate the capability to minimize the impact of segmentation errors, to overcome the sparse resolution of dynamic studies and to remove the sometimes unnecessary anatomical detail of papillary and trabecular structures. The smooth meshes produced can be used to simulate cardiac function, and in particular mechanics, or can be used as diagnostic descriptors of anatomical shape by cardiologists. This fully automatic service is deployed in a cloud infrastructure, and has been made available and accessible to the scientific community.


The Accuracy of Imaging Techniques in the Assessment of Periprosthetic Hip Infection: A Systematic Review and Meta-Analysis.
Various imaging techniques are used for excluding or confirming periprosthetic hip infection, but there is no consensus regarding the most accurate technique. The objective of this study was to determine the accuracy of current imaging modalities in diagnosing periprosthetic hip infection. A systematic review and meta-analysis of the literature was conducted with a comprehensive search of MEDLINE and Embase to identify clinical studies in which periprosthetic hip infection was investigated with different imaging modalities. The sensitivity and specificity of each imaging technique were determined and compared with the results of microbiological and histological analysis, intraoperative findings, and clinical follow-up of >6 months. A total of 31 studies, published between 1988 and 2014, were included for meta-analysis, representing 1,753 hip prostheses. Quality assessment of the included studies identified low concerns with regard to external validity but more concerns with regard to internal validity including risk of bias (>50% of studies had insufficient information). No meta-analysis was performed for radiography, ultrasonography, computed tomography, and magnetic resonance imaging because of insufficient available clinical data. The pooled sensitivity and specificity were 88% (95% confidence interval [CI], 81% to 94%) and 92% (95% CI, 88% to 96%), respectively, for leukocyte scintigraphy; 86% (95% CI, 80% to 90%) and 93% (95% CI, 90% to 95%) for fluorodeoxyglucose positron emission tomography (FDG PET); 69% (95% CI, 58% to 79%) and 96% (95% CI, 93% to 98%) for combined leukocyte and bone marrow scintigraphy; 84% (95% CI, 70% to 93%) and 75% (95% CI, 66% to 82%) for antigranulocyte scintigraphy; and 80% (95% CI, 72% to 86%) and 69% (95% CI, 64% to 73%) for bone scintigraphy. Of the currently used imaging techniques, leukocyte scintigraphy has satisfactory accuracy in confirming or excluding periprosthetic hip infection. Although not significantly different, combined leukocyte and bone marrow scintigraphy was the most specific imaging technique. FDG PET has an appropriate accuracy in confirming or excluding periprosthetic hip infection, but may not yet be the preferred imaging modality because of limited availability and relatively higher cost. Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Comparison of three-dimensional soft-tissue evaluations between skeletal and pseudo-class III malocclusions.
The aim of our study was to compare soft tissue measurements with 3D imaging methods in individuals with untreated skeletal and pseudo-Class III malocclusions. The study sample consisted of 75 patients (38 males, 37 females, mean age 12.41 ± 2.35 years) with pseudo- and true skeletal Class III malocclusions and skeletal Class I malocclusions. Soft tissue evaluations of all patients were performed using 3D stereophotogrammetric facial images. In our study, 26 landmarks, 17 linear measurements, 13 angular measurements, and 5 volume measurements were made using the 3dMD Vultus software. The significance was determined to be p < 0.05 in ANOVA, Tukey tests. No significant differences were found among the groups in terms of demographic data (p > 0.05). The skeletal Class I control group had a significantly more extended upper lip and vermillion length as compared to the Class III groups. The soft tissue convexity angle and upper nasal angle were found to be wider in the Class III malocclusion group compared to those in the Class I control group. While the pseudo-Class III group had a significantly lower midface volume, chin volume was significantly higher in the skeletal class group. Upper lip volume was significantly higher in the Class I group. Using 3dMD for guiding clinicians in the differential soft and hard tissue diagnosis of pseudo-Class III malocclusions, differences were revealed in Class I patients in the middle part of the face. In the differential diagnosis of true Class III malocclusions, chin volume was found to be different from that of Class I patients.


A sequence variation: 713-8delC in the transforming growth factor beta 1 gene polymorphism in thalassemia major patients.
Osteoporosis remains an important cause of morbidity in β-thalassemia major. Although several factors have been implicated to play an important role in the pathogenesis of osteoporosis and several candidate gene polymorphisms have been found to regulate this process, its pathogenesis has not been completely elucidated. Deletion of a C in the fourth intron sequence 8 base before exon 5 (713-8delC) of transforming growth factor beta 1 (TGF-β1) gene which has been reported significantly higher in the osteoporotic group was studied for its prevalence and association with bone mineral density (BMD) in thalassemia major patients. The aim of this study was to find out the distribution of TGF-β1 (713-8delC) sequence variation and its relationship with BMD in thalassemia major patients. 713-8delC Sequence variation polymorphism was detected in 150 β-thalassemia major patients and their BMD was measured by dual-energy X-ray absorptiometry. Biochemical levels were estimated by enzyme-linked immunosorbent assay. We have found a remarkable incidence (90%) of osteopenia and osteoporosis among regularly transfused patients. We have found no association of 713-8delC variant of TGF-β1 gene with Z-score of BMD at lumbar spine (p = 0.061) and hips (p = 0.773). However, Cc genotype of TGF-β1 gene was found as a risk factor (odds ratio: 3.3) for low bone density in these patients.


Effect of a yoga programme on an individual with Parkinson's disease: a single-subject design.
To investigate the effect of eight weekly yoga sessions on balance, mobility and reported quality of life of an individual with Parkinson's disease (PD). Furthermore, to test the methodology in order to inform future research. A 69-year-old female with an 8-year history of PD (Hoehn and Yahr rating two) was selected for the study, which had a single subject ABA design. A 1-week baseline was followed by an 8-week period of weekly 60 min yoga classes and a further 5 weeks of treatment withdrawal. Main outcome measures used were Berg Balance Scale (BBS), Timed Up and Go (TUG) and the Parkinson's Disease Questionnaire-39 (PDQ-39); collected at baseline, before, during and after the intervention and at follow-up. An improvement was noted in the BBS and TUG during the intervention phase; although these changes did not appear to be clinically significant. No change in quality of life as measured by the PDQ-39 was noted. The objective improvements in functional activities during the intervention period were not clinically significant. Subjectively, the participant gained much enjoyment and relaxation from the yoga classes. This study justifies the need for further studies using a larger sample size. Additionally, it will inform the methodological design.


Comparison of burst pacing, autodecremental (ramp) pacing, and universal pacing for termination of ventricular tachycardia.
This study was designed to test the comparative efficacy of burst pacing, autodecremental (ramp) pacing, and universal (steep ramp) pacing for termination of ventricular tachycardia. A prospective, randomized sequence cross-over design was used to achieve comparisons of the pacing modalities that were matched for patient, day, and ventricular tachycardia characteristics. Thirty eight patients were enrolled, whose ventricular tachycardia was well-enough tolerated to be reinduced, and tested with 3 pacing modalities. There were 27 series 1 patients in which the pacing modalities were nonsynchronized burst pacing, synchronized burst pacing, and ramp pacing. The 11 patients in series 2 were tested with synchronized burst pacing, ramp pacing, and universal pacing. All pacing methods proved to be comparable in their ability to terminate ventricular tachycardia (p = NS). The 2 burst methods required the fewest number of attempts (significant vs ramp pacing). Universal pacing required the fewest number of stimuli. The mean paced cycle length was similar will all methods. The shortest paced cycle lengths were found with the autodecremental and universal methods because of their ramp patterns. It is concluded that burst, ramp, and universal pacing are of similar efficacy, although ramps were least efficient. Choice of a modality depends on operator preference, and individual patient response.


Reliability of data on caesarean sections in developing countries.
To examine the reliability of reported rates of caesarean sections from developing countries and make recommendations on how data collection for surveys and health facility-based studies could be improved. Population-based rates for caesarean section obtained from two sources: Demographic and Health Surveys (DHS) and health facility-based records of caesarean sections from the Unmet Obstetric Need Network, together with estimates of the number of live births, were compared for six developing countries. Sensitivity analyses were conducted using several different definitions of the caesarean section rate, and the rates obtained from the two data sources were compared. The DHS rates for caesarean section were consistently higher than the facility-based rates. However, in three quarters of the cases, the facility-based rates for caesarean sections fell within the 95% confidence intervals for the DHS estimate. The importance of the differences between these two series of rates depends on the analyst's perspective. For national and global monitoring, DHS data on caesarean sections would suffice, although the imprecision of the rates would make the monitoring of trends difficult. However, the imprecision of DHS data on caesarean sections precludes their use for the purposes of programme evaluation at the regional level.


Genome-Wide Search for Translated Upstream Open Reading Frames in Arabidopsis Thaliana.
Upstream open reading frames (uORFs) are open reading frames that occur within the 5' UTR of an mRNA. uORFs have been found in many organisms. They play an important role in gene regulation, cell development, and in various metabolic processes. It is believed that translated uORFs reduce the translational efficiency of the main coding region. However, only few uORFs are experimentally characterized. In this paper, we use ribosome footprinting together with a semi-supervised approach based on stacking classification models to identify translated uORFs in Arabidopsis thaliana. Our approach identified 5360 potentially translated uORFs in 2051 genes. GO terms enriched in genes with translated uORFs include catalytic activity, binding, transferase activity, phosphotransferase activity, kinase activity, and transcription regulator activity. The reported uORFs occur with a higher frequency in multi-isoform genes, and some uORFs are affected by alternative transcript start sites or alternative splicing events. Association rule mining revealed sequence features associated with the translation status of the uORFs. We hypothesize that uORF translation is a complex process that might be regulated by multiple factors. The identified uORFs are available online at:https://www.dropbox.com/sh/zdutupedxafhly8/AABFsdNR5zDfiozB7B4igFcja?dl=0. This paper is the extended version of our research presented at ISBRA 2015.


Cultural influences on the neural correlate of moral decision making processes.
This study compares the neural substrate of moral decision making processes between Korean and American participants. By comparison with Americans, Korean participants showed increased activity in the right putamen associated with socio-intuitive processes and right superior frontal gyrus associated with cognitive control processes under a moral-personal condition, and in the right postcentral sulcus associated with mental calculation in familiar contexts under a moral-impersonal condition. On the other hand, American participants showed a significantly higher degree of activity in the bilateral anterior cingulate cortex (ACC) associated with conflict resolution under the moral-personal condition, and in the right medial frontal gyrus (MFG) associated with simple cognitive branching in non-familiar contexts under the moral-impersonal condition when a more lenient threshold was applied, than Korean participants. These findings support the ideas of the interactions between the cultural background, education, and brain development, proposed in the field of cultural psychology and educational psychology. The study introduces educational implications relevant to moral psychologists and educators.


Sleep state organization in normal infants and victims of the sudden infant death syndrome.
Infants at increased risk of the sudden infant death syndrome (SIDS) show abnormal patterning of sleep-waking states. It was hypothesized that infants who were to die of SIDS would show abnormalities of sleep state distribution prior to their deaths. Twenty-two 12-hour recordings were obtained from infants who subsequently died of SIDS, and sleep state patterns were compared in these records and 66 records of age-matched control infants. Each 1-minute epoch was classified as quiet sleep, rapid eye movement (REM) sleep, waking, indeterminate state, or artifact-contaminated. Victims of SIDS showed less waking and more sleep than control infants during the early-morning hours. Victims of SIDS younger than 1 month of age showed significantly more epochs classified as REM sleep across the night and significantly fewer epochs contaminated by artifacts relative to control infants. Further analysis indicated that the increased number of REM epochs resulted from fewer artifact-contaminated epochs, suggesting reduced motility during REM sleep in the SIDS victims compared with the control infants. The finding of decreased waking time during the early morning is of particular importance since most SIDS deaths occur during this portion of the day. The findings of altered sleep patterns in SIDS victims suggest that central neural changes are associated with SIDS risk.


Enemy of the people/enemy of the state: two great(lyiInfamous) doctors, passions, and the judgment of history.
If the aphorism "history will be the judge" is deployed, the active agent of this formulation is the historian. Comparing two great(ly infamous) doctors,John C. Cutler and Alan Berkman, the article considers how historians balance digging for sources, creating meaningful narrative, and acknowledging our own beliefs that embed in the judgments we make. The article explores our responsibility for balance and moral judgment at the same time. Cutler, admonished for his role in the infamous sexually transmitted diseases studies in Tuskegee and Guatemala, also was a well-respected researcher and teacher. Berkman, renowned for his success in global HIV/AIDs activism, was also only the second physician in U.S. history to be charged with accessory to murder after the fact and who served seven hard years for bombings and robbery. The author considers her relationship to these physicians and the effort to create a passionate historical practice.


A trial of a 7-valent pneumococcal conjugate vaccine in HIV-infected adults.
Streptococcus pneumoniae is a leading and serious coinfection in adults with human immunodeficiency virus (HIV) infection, particularly in Africa. Prevention of this disease by vaccination with the current 23-valent polysaccharide vaccine is suboptimal. Protein conjugate vaccines offer a further option for protection, but data on their clinical efficacy in adults are needed. In this double-blind, randomized, placebo-controlled clinical efficacy trial, we studied the efficacy of a 7-valent conjugate pneumococcal vaccine in predominantly HIV-infected Malawian adolescents and adults who had recovered from documented invasive pneumococcal disease. Two doses of vaccine were given 4 weeks apart. The primary end point was a further episode of pneumococcal infection caused by vaccine serotypes or serotype 6A. From February 2003 through October 2007, we followed 496 patients (of whom 44% were male and 88% were HIV-seropositive) for 798 person-years of observation. There were 67 episodes of pneumococcal disease in 52 patients, all in the HIV-infected subgroup. In 24 patients, there were 19 episodes that were caused by vaccine serotypes and 5 episodes that were caused by the 6A serotype. Of these episodes, 5 occurred in the vaccine group and 19 in the placebo group, for a vaccine efficacy of 74% (95% confidence interval [CI], 30 to 90). There were 73 deaths from any cause in the vaccine group and 63 in the placebo group (hazard ratio in the vaccine group, 1.18; 95% CI, 0.84 to 1.66). The number of serious adverse events within 14 days after vaccination was significantly lower in the vaccine group than in the placebo group (3 vs. 17, P = 0.002), and the number of minor adverse events was significantly higher in the vaccine group (41 vs. 13, P = 0.003). The 7-valent pneumococcal conjugate vaccine protected HIV-infected adults from recurrent pneumococcal infection caused by vaccine serotypes or serotype 6A. (Current Controlled Trials number, ISRCTN54494731.).


Antiinflammatory effects of long-acting beta2-agonists in patients with asthma: a systematic review and metaanalysis.
Long-acting beta(2)-agonists (LABAs) are recommended as add-on therapy to antiinflammatory treatment in patients with chronic persistent asthma. Results from individual studies evaluating the in vivo antiinflammatory effect of LABAs are conflicting. The purpose of this metaanalysis was to determine whether LABAs have an in vivo antiinflammatory effect compared to placebo and whether the addition of a LABA to therapy with inhaled corticosteroids (ICSs) has a synergistic or additive antiinflammatory effect. A systematic search was performed of online databases for randomized controlled trials evaluating the antiinflammatory effects of the following: (1) LABAs compared to placebo; and (2) a LABA plus ICS vs ICS alone in adults and children with asthma. Inflammatory outcome measures included cell counts and markers of cell activation in sputum, BAL fluid, bronchial biopsy specimens, serum, and exhaled nitric oxide (ENO). Data were independently extracted by two study investigators and analyzed to generate standardized mean differences using either a fixed or random-effects metaanalysis depending on the degree of heterogeneity. Thirty-two studies (n = 1,105 participants) met the inclusion criteria. The mean number of participants and mean number of studies for each inflammatory outcome in the metaanalysis was 113.1 (SD, 46.2) and 3.5 (SD, 1.3), respectively. There was no effect of LABA therapy on sputum, BAL fluid, or mucosal inflammatory cells in adults or in children. LABA therapy decreased ENO levels and BAL fluid albumin levels in adults. In children, LABA therapy was associated with a small decrease in serum eosinophils and interleukin-4. LABA therapy does not appear to have any clinically important antiinflammatory or proinflammatory effect. LABA therapy decreases BAL fluid albumin levels, suggesting a possible modulating effect on microvascular leakage.


Movement preparation improves touch perception without awareness.
Movements are often directed at external objects, such as when reaching out for a glass to drink from. Surprisingly, however, it is largely unknown how movement plans influence the identification of such external somatosensory stimuli. To address this, we cued participants to prepare for a speeded button press with their left/right thumb and presented a spatially-patterned somatosensory stimulus at either the same or the opposite thumb with equal probability. In contrast to many previous investigations that focused on self-produced somatosensory input and reported attenuated perception, we show that the identification of external stimuli (touch perception) is facilitated by movement preparation. In line with analogous studies in vision, this suggests that movement preparation automatically allocates processing resources (attention) to the location and/or body part of the planned movement. We further show that, in contrast to deliberate somatosensory preparation, participants do not become more confident in their touch perception following movement preparation. These data suggest that the perceptual improvement during movement preparation occurs outside of awareness. Such an unconscious facilitatory process will ensure that relevant parts of the environment are processed with high fidelity, while sparing conscious resources for monitoring other processes in the course of action.


Role of Ca2+ and L-Phe in regulating functional cooperativity of disease-associated "toggle" calcium-sensing receptor mutations.
The Ca(2+)-sensing receptor (CaSR) regulates Ca(2+) homeostasis in the body by monitoring extracellular levels of Ca(2+) ([Ca(2+)]o) and amino acids. Mutations at the hinge region of the N-terminal Venus flytrap domain (VFTD) produce either receptor inactivation (L173P, P221Q) or activation (L173F, P221L) related to hypercalcemic or hypocalcemic disorders. In this paper, we report that both L173P and P221Q markedly impair the functional positive cooperativity of the CaSR as reflected by [Ca(2+)]o-induced [Ca(2+)]i oscillations, inositol-1-phosphate (IP1) accumulation and extracellular signal-regulated kinases (ERK1/2) activity. In contrast, L173F and P221L show enhanced responsiveness of these three functional readouts to [Ca(2+)]o. Further analysis of the dynamics of the VFTD mutants using computational simulation studies supports disruption in the correlated motions in the loss-of-function CaSR mutants, while these motions are enhanced in the gain-of-function mutants. Wild type (WT) CaSR was modulated by L-Phe in a heterotropic positive cooperative way, achieving an EC50 similar to those of the two activating mutations. The response of the inactivating P221Q mutant to [Ca(2+)]o was partially rescued by L-Phe, illustrating the capacity of the L-Phe binding site to enhance the positive homotropic cooperativity of CaSR. L-Phe had no effect on the other inactivating mutant. Moreover, our results carried out both in silico and in intact cells indicate that residue Leu(173), which is close to residues that are part of the L-Phe-binding pocket, exhibited impaired heterotropic cooperativity in the presence of L-Phe. Thus, Pro(221) and Leu(173) are important for the positive homo- and heterotropic cooperative regulation elicited by agonist binding.


Cost of interacting with sexual partners in a facultative sexual microbe.
The widespread occurrence of sexual organisms despite the high costs of sex has long intrigued biologists. The best-known costs are the twofold cost of producing males and the cost associated with producing traits to attract mates and to interact with mating partners, such as exaggerated sexual behaviors and morphological modifications. These costs have been inferred from studies of plants and animals but are thought to be absent in facultative sexual microbes. Here, using the facultative sexual fungus Cryptococcus neoformans, I provide experimental evidence showing that: (i) interactions with active sexual partners can be costly for vegetative fitness in a facultative sexual microbe; (ii) this cost is positively correlated to mating ability; (iii) this cost is composed of at least two distinct components, the cost of producing mating signals that exert effects on mating partners and that associated with responding to active mating partners; and (iv) extended asexual reproduction can reduce both components of the cost. This cost must have been compensated for by the production of zygotes and sexual spores to allow the initial evolution and spread of sexual reproduction in eukaryotes.


Sensitive and simultaneous surface plasmon resonance detection of free and p53-bound MDM2 proteins from human sarcomas.
Murine double minute 2 (MDM2) is an oncoprotein mediating the degradation of the tumor suppressor p53 protein. The physiological levels of MDM2 protein are closely related to malignant transformation and tumor growth. In this work, the simultaneous and label-free determination of free and p53-bound MDM2 proteins from sarcoma tissue extracts was conducted using a dual-channel surface plasmon resonance (SPR) instrument. Free MDM2 protein was measured in one fluidic channel covered with the consensus double-stranded (ds)-DNA/p53 conjugate, while MDM2 bound to p53 was captured by the consensus ds-DNA immobilized onto the other channel. To achieve higher sensitivity and to confirm specificity, an MDM2-specific monoclonal antibody (2A10) was used to recognize both the free and p53-bound MDM2 proteins. The resultant method afforded a detection limit of 0.55 pM of MDM2. The amenability of the method to the analysis of free and p53-bound MDM2 proteins was demonstrated for normal and sarcoma tissue extracts from three patients. Our data reveal that both free and total MDM2 (free and bound forms combined) proteins from sarcoma tissue extracts are of much higher concentrations than those from normal tissue extracts and the p53-bound MDM2 protein only constitutes a small fraction of the total MDM2 concentration. In comparison with enzyme-linked immunosorbent assay (ELISA), the proposed method possesses higher sensitivity, is more cost-effective, and is capable of determining free and p53-bound MDM2 proteins in clinical samples.


CDC's Lead Poisoning Prevention Program: A Long-standing Responsibility and Commitment to Protect Children From Lead Exposure.
The Centers for Disease Control and Prevention's (CDC's) Childhood Lead Poisoning Prevention Program (CLPPP) serves as the nation's public health leader and resource on strategies, policies, and practices aimed at preventing lead exposure in young children. CDC supports and advises state and local public health agencies and works with other federal agencies and partners to achieve the Healthy People 2020 objective of eliminating childhood lead exposure as a public health concern. Primary prevention-the removal of lead hazards from the environment before a child is exposed-is the most effective way to ensure that children do not experience the harmful effects of lead exposure. Blood lead screening tests and secondary prevention remain an essential safety net for children who may be exposed to lead. CDC's key programmatic strategy is to strengthen blood lead surveillance by supporting state and local programs to improve blood lead screening test rates, identify high-risk populations, and ensure effective follow-up for children with elevated blood lead levels. Surveillance plays a central role in helping measure the collective progress of federal, state, and local public health agencies in protecting children from lead, as well as enhancing our ability to target population-based interventions for primary prevention to those areas at highest risk. The CDC CLPPP has been at the front line of efforts to protect children from lead exposure and the resulting adverse health effects over the last 3 decades. As we chart our path for the future, we will continue to learn from past successes and challenges, incorporate new evidence and lessons learned, and work closely with federal, state, local, and nonprofit partners, experts in academia, and the community to advance the overarching goal of eliminating lead exposure in children.


The utility of ancient human DNA for improving allele age estimates, with implications for demographic models and tests of natural selection.
The age of polymorphic alleles in humans is often estimated from population genetic patterns in extant human populations, such as allele frequencies, linkage disequilibrium, and rate of mutations. Ancient DNA can improve the accuracy of such estimates, as well as facilitate testing the validity of demographic models underlying many population genetic methods. Specifically, the presence of an allele in a genome derived from an ancient sample testifies that the allele is at least as old as that sample. In this study, we consider a common method for estimating allele age based on allele frequency as applied to variants from the US National Institutes of Health (NIH) Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project. We view these estimates in the context of the presence or absence of each allele in the genomes of the 5300 year old Tyrolean Iceman, Ötzi, and of the 50,000 year old Altai Neandertal. Our results illuminate the accuracy of these estimates and their sensitivity to demographic events that were not included in the model underlying age estimation. Specifically, allele presence in the Iceman genome provides a good fit of allele age estimates to the expectation based on the age of that specimen. The equivalent based on the Neandertal genome leads to a poorer fit. This is likely due in part to the older age of the Neandertal and the older time of the split between modern humans and Neandertals, but also due to gene flow from Neandertals to modern humans not being considered in the underlying demographic model. Thus, the incorporation of ancient DNA can improve allele age estimation, demographic modeling, and tests of natural selection. Our results also point to the importance of considering a more diverse set of ancient samples for understanding the geographic and temporal range of individual alleles.


Growth inhibition of pathogenic bacteria and some yeasts by selected essential oils and survival of L. monocytogenes and C. albicans in apple-carrot juice.
Food safety is a fundamental concern of both consumers and the food industry. The increasing incidence of foodborne diseases increases the demand of using antimicrobials in foods. Spices and plants are rich in essential oils and show inhibition activity against microorganisms, which are composed of many compounds. In this research, effects of garlic, bay, black pepper, origanum, orange, thyme, tea tree, mint, clove, and cumin essential oils on Listeria monocytogenes AUFE 39237, Escherichia coli ATCC 25922, Salmonella enteritidis ATCC 13076, Proteus mirabilis AUFE 43566, Bacillus cereus AUFE 81154, Saccharomyces uvarum UUFE 16732, Kloeckera apiculata UUFE 10628, Candida albicans ATCC 10231, Candida oleophila UUPP 94365, and Metschnikowia fructicola UUPP 23067 and effects of thyme oil at a concentration of 0.5% on L. monocytogenes and C. albicans in apple-carrot juice during +4 degrees C storage (first to fifth day) were investigated. Strong antibacterial and antifungal activities of some essential oils were found. Thyme, origanum, clove, and orange essential oils were the most inhibitory against bacteria and yeasts. Cumin, tea tree, and mint oils inhibited the yeasts actively. It is concluded that some essential oils could be used as potential biopreservatives capable of controlling foodborne pathogens and food spoilage yeasts.


Identification of a novel clade of group A rotaviruses in fatally diseased domestic pigeons in Europe.
Rotaviruses are well-known causative agents of enteric disorders in humans and other mammals, but little is known about their virulence and pathogenic role in pigeons and other birds. Starting in summer 2017, a series of outbreaks of an acute disease with high mortalities was reported in domestic pigeons in Germany, Belgium and Denmark. The clinical picture was characterized by diarrhoea, vomiting, hepatic necrosis and sudden fatalities. From these severe outbreaks, we discovered several previously unknown group A rotavirus (RVA) lineages of genotype G18P[17]-I4-R4-C4-M4-A4-T4-N4-E19-H4, which were closely related but not identical to an RVA variant identified in cases of fatal hepatic necrosis in Australian pigeon lofts in 2016. Retrospective analysis demonstrated that the predecessors of the highly virulent variants have circulated in Europe since at least 2010. Our data indicate that reassortment and intercontinental spread has led to the emergence of novel RVA variants, which may constitute a major threat to animal welfare and health of domestic pigeon populations worldwide.


Failure to deactivate medial prefrontal cortex in people at high risk for psychosis.
Impaired working memory is a core feature of schizophrenia and is linked with altered engagement the lateral prefrontal cortex. Although altered PFC activation has been reported in people with increased risk of psychosis, at present it is not clear if this neurofunctional alteration differs between familial and clinical risk states and/or increases in line with the level of psychosis risk. We addressed this issue by using functional MRI and a working memory paradigm to study familial and clinical high-risk groups. We recruited 17 subjects at ultra-high-risk (UHR) for psychosis, 10 non-affected siblings of patients with schizophrenia (familial high risk [FHR]) and 15 healthy controls. Subjects were scanned while performing the N-back working memory task. There was a relationship between the level of task-related deactivation in the medial PFC and precuneus and the level of psychosis risk, with deactivation weakest in the UHR group, greatest in healthy controls, and at an intermediate level in the FHR group. In the high-risk groups, activation in the precuneus was associated with the level of negative symptoms. These data suggest that increased vulnerability to psychosis is associated with a failure to deactivate in the medial PFC and precuneus during a working memory task, and appears to be most evident in subjects at clinical, as opposed to familial high risk.


Kbtbd2 inhibits the cytotoxic activity of immortalized NK cells through down-regulating mTOR signaling in a mouse hepatocellular carcinoma model.
Natural killer cell (NK cell)-based immunotherapy is a promising therapeutic strategy for hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the regulation of NK cell function in the tumor sites are not completely elucidated. In this study, we identified the enhanced expression of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) in intratumoral NK cells in a mouse HCC implantation model as a negative regulator of NK cells. To investigate this interaction, we used a Tet-on inducible expression system to control Kbtbd2 expression in an immortalized mouse NK cell line KIL C.2. With this approach, we found that overexpression of Kbtbd2 reduced KIL C.2 cell proliferation, decreased expression certain of Ly49 receptor family members, and substantially impaired cytotoxic activity of KIL C.2 cells in vitro. Moreover, phosphorylation of mTOR and its target 4E-binding protein 1 was reduced in Kbtbd2-expressing KIL C.2 cells, along with down-regulated phosphorylation of Erk1/2. Adoptively transferred Kbtbd2-expressing KIL C.2 cells exhibited weaker tumoricidal effect on hepatocellular carcinoma cells in the HCC implantation model, in comparison with transferred control KIL C.2 cells. Taken together, our investigation indicates that Kbtbd2 is an inhibitory molecule for the tumoricidal activity of KIL C.2 cells and perhaps intratumoral NK cells.


Effect of leukoreduction treatment on vascular endothelial growth factor concentration in stored canine blood transfusion products.
To evaluate vascular endothelial growth factor (VEGF) concentrations in canine blood products treated with or without a leukoreduction filter. 10 canine blood donors. Dogs underwent blood collection. Five of 10 units were leukoreduced prior to separation into packed RBCs and fresh frozen plasma (FFP). Concentrations of VEGF were measured by ELISA in plasma supernatants from aliquots of packed RBCs obtained immediately after separation and on days 7, 14, and 21 of storage. Fresh frozen plasma samples of 2 filtered and 2 nonfiltered units were examined after storage. RBC counts in whole blood before and after leukoreduction did not differ significantly, but WBCs and platelets were removed effectively. The VEGF concentration was lower than the detection limit (9 pg/mL) in 9 of 10 plasma samples and in all packed RBC and FFP units immediately after separation. The median VEGF concentrations in 5 nonfiltered packed RBC units were 37, 164, and 110 pg/mL on days 7, 14, and 21 of storage, respectively. In 5 filtered packed RBC and all FFP units, VEGF concentrations remained lower than the detection limit. Leukoreduction filters were effective in preventing the release of VEGF during storage of canine RBC products.


Statistical analysis of the bioassay of continuous carcinogens.
In an experiment consisting of the continuous constant application of various carcinogenic regimens to a pure strain of experimental animals for a long period, the cancer incidence rates so caused may be studied and compared by the fit of an appropriate class of statistical distributions. In this paper we show that a Weibull distribution in which the age-specific cancer incidence rate rises as a power of time since first risk is more appropriate than a lognormal distribution. If the Weibull family of distributions is used, more information can be extracted from the data, and differences of toxicity between various regimens will not bias the comparison of their carcinogenic forces.