Solution structure and siRNA-mediated knockdown analysis of the mitochondrial disease-related protein C12orf65.
Loss of function of the c12orf65 gene causes a mitochondrial translation defect, leading to encephalomyopathy. The C12orf65 protein is thought to play a role similar to that of ICT1 in rescuing stalled mitoribosomes during translation. Both proteins belong to a family of Class I peptide release factors (RFs), all characterized by the presence of a GGQ motif. Here, we determined the solution structure of the GGQ-containing domain (GGQ domain) of C12orf65 from mouse by NMR spectroscopy, and examined the effect of siRNA-mediated knockdown of C12orf65 on mitochondria in HeLa cells using flow cytometry. The GGQ domain, comprising residues 60-124 of the 184-residue full-length protein, forms a structure with a 3(10) -β1-β2-β3-α1 topology that resembles the GGQ domain structure of RF more closely than that of ICT1. Thus, the GGQ domain structures of this protein family can be divided into two types, depending on the region linking β2 and β3; the C12orf65/RF type having a 6-residue π-HB turn and the ICT1 type having an α-helix. Knockdown of C12orf65 resulted in increased ROS production and apoptosis, leading to inhibition of cell proliferation. Substantial changes in mitochondrial membrane potential and mass in the C12orf65-knockdown cells were observed compared with the control cells. These results indicate that the function of C12orf65 is essential for cell vitality and mitochondrial function. Although similar effects were observed in ICT1-downregulated cells, there were significant differences in the range and pattern of the effects between C12orf65- and ICT1-knockdown cells, suggesting different roles of C12orf65 and ICT1 in rescuing stalled mitoribosomes.


A genome-wide view of transcription factor gene diversity in chordate evolution: less gene loss in amphioxus?
Previous studies of gene diversity in the homeobox superclass have shown that the Florida amphioxus Branchiostoma floridae has undergone remarkably little gene family loss. Here we use a combined BLAST and HMM search strategy to assess the family level diversity of four other transcription factor superclasses: the Paired/Pax genes, Tbx genes, Fox genes and Sox genes. We apply this across genomes from five chordate taxa, including B. floridae and Ciona intestinalis, plus two outgroup taxa. Our results show scattered gene family loss. However, as also found for homeobox genes, B. floridae has retained all ancient Pax, Tbx, Fox and Sox gene families that were present in the common ancestor of living chordates. We conclude that, at least in terms of transcription factor gene complexity, the genome of amphioxus has experienced remarkable stasis compared to the genomes of other chordates.


Shape-enhanced photocatalytic activity of single-crystalline anatase TiO(2) (101) nanobelts.
Particle size is generally considered to be the primary factor in the design of nanocrystal photocatalysts, because the reduction of particle size increases the number of active sites. However, the benefit from the size reduction can be canceled by a higher electron-hole recombination rate due to the confined space in sphere-shaped nanoparticles. Here we report a mechanistic study on a novel nanobelt structure that overcomes the drawback of sphere-shaped nanoparticles. Single-crystalline anatase TiO(2) nanobelts with two dominant surfaces of (101) facet exhibit enhanced photocatalytic activity over the nanosphere counterparts with an identical crystal phase and similar specific surface area. The ab initio density functional theory (DFT) calculations show that the exposed (101) facet of the nanobelts yields an enhanced reactivity with molecular O(2), facilitating the generation of superoxide radical. Moreover, the nanobelts exhibit a lower electron-hole recombination rate than the nanospheres due to the following three reasons: (i) greater charge mobility in the nanobelts, which is enabled along the longitudinal dimension of the crystals; (ii) fewer localized states near the band edges and in the bandgap due to fewer unpassivated surface states in the nanobelts; and (iii) enhanced charge separation due to trapping of photogenerated electrons by chemisorbed molecular O(2) on the (101) facet. Our results suggest that the photocatalysis efficiency of nanocrystals can be significantly improved by tailoring the shape and the surface structure of nanocrystals, which provides a new concept for rational design and development of high-performance photocatalysts.


Prevalence of Smoking and Provision of Smoking Cessation Advice during Hospitalization
Aim We aimed to determine the prevalence of smoking and smoking cessation advice received by inpatients in Beaumont Hospital and compared results to previous similar studies. Method Cross-sectional survey where we interviewed eligible in-patients over a two-week period. Results 14.8% (30/203) of participants were current smokers, which is lower than the smoking prevalence found by previous studies. The rate of cessation advice delivery was 53.3% (16/30). An increasing socioeconomic gap between smokers and non-smokers over time was found. Discussion There remains limited provision of smoking cessation advice to inpatients.


Combat Vascular Access: A Scoping Review.
Medical leadership must decide how to obtain vascular access in a combat environment. Adequate combat trauma resuscitation requires efficient vascular access. A search of the Medline and EMBASE databases was conducted to find articles on combat vascular access. The primary dataset of interest was the type of vascular access obtained. Other data reviewed included who performed the intervention and the success rate of the intervention. The search strategy produced 1,339 results, of which 24 were included in the final analysis. Intravenous (IV), intraosseous (IO), and central venous access have all been used in the prehospital combat environment. This review summarizes the available combat literature to help commanders make an evidence-based decision about their prehospital vascular access strategy.


Resistance Gene Carriage Predicts Growth of Natural and Clinical Escherichia coli Isolates in the Absence of Antibiotics.
Bacterial pathogens that carry antibiotic resistance alleles sometimes pay a cost in the form of impaired growth in antibiotic-free conditions. This cost of resistance is expected to be a key parameter for understanding how resistance spreads and persists in pathogen populations. Analysis of individual resistance alleles from laboratory evolution and natural isolates has shown they are typically costly, but these costs are highly variable and influenced by genetic variation at other loci. It therefore remains unclear how strongly resistance is linked to impaired antibiotic-free growth in bacteria from natural and clinical scenarios, where resistance alleles are likely to coincide with other types of genetic variation. To investigate this, we measured the growth of 92 natural and clinical Escherichia coli isolates across three antibiotic-free environments. We then tested whether variation of antibiotic-free growth among isolates was predicted by their resistance to 10 antibiotics, while accounting for the phylogenetic structure of the data. We found that isolates with similar resistance profiles had similar antibiotic-free growth profiles, but it was not simply that higher average resistance was associated with impaired growth. Next, we used whole-genome sequences to identify antibiotic resistance genes and found that isolates carrying a greater number of resistance gene types grew relatively poorly in antibiotic-free conditions, even when the resistance genes they carried were different. This suggests that the resistance of bacterial pathogens is linked to growth costs in nature, but it is the total genetic burden and multivariate resistance phenotype that predict these costs, rather than individual alleles or mean resistance across antibiotics.IMPORTANCE Managing the spread of antibiotic resistance in bacterial pathogens is a major challenge for global public health. Central to this challenge is understanding whether resistance is linked to impaired bacterial growth in the absence of antibiotics, because this determines whether resistance declines when bacteria are no longer exposed to antibiotics. We studied 92 isolates of the key bacterial pathogen Escherichia coli; these isolates varied in both their antibiotic resistance genes and other parts of the genome. Taking this approach, rather than focusing on individual genetic changes associated with resistance as in much previous work, revealed that growth without antibiotics was linked to the number of specialized resistance genes carried and the combination of antibiotics to which isolates were resistant but was not linked to average antibiotic resistance. This approach provides new insights into the genetic factors driving the long-term persistence of antibiotic-resistant bacteria, which is important for future efforts to predict and manage resistance.


5-fluorouracil and low-dose leucovorin in the treatment of recurrent epithelial ovarian carcinoma. A phase II trial of the Gynecologic Oncology Group.
Twenty-one patients with recurrent epithelial ovarian carcinoma not amenable to cure with further surgery or radiotherapy were entered into a Phase II trial utilizing i.v. leucovorin at 20 mg/m2 followed by i.v. 5-fluorouracil at 425 mg/m2 administered daily for 5 days every 4 weeks for the first two courses and then every 5 weeks. Twenty-one patients were entered. Of these, 20 were eligible for toxicity assessment and 19 for response. Five had received prior radiotherapy, and all had received prior cisplatin-based chemotherapy. There was one patient response (5.3%; 95% confidence intervals for response of 0% to 26%). Toxicity was moderate with 5 of 20 (25%) grade 3 or 4 leukopenia, 12 of 20 (60%) grade 3 or 4 granulocytopenia, 1 of 20 (5%) grade 3 thrombocytopenia, 5 of 20 (25%) grade 3 GI toxicity, and 2 of 20 (10%) grade 3 neurotoxicity. There was one toxic death in a patient who developed granulocytopenia and pneumonia after her third course of treatment. This dose schedule of 5-fluorouracil and leucovorin has minimal activity in patients with recurrent epithelial ovarian carcinoma who have received prior cisplatin chemotherapy.


Local administration of AAV-BDNF to subventricular zone induces functional recovery in stroke rats.
Migration of new neuroprogenitor cells (NPCs) from the subventricular zone (SVZ) plays an important role in neurorepair after injury. Previous studies have shown that brain derived neurotrophic factor (BDNF) enhances the migration of NPCs from SVZ explants in neonatal mice in vitro. The purpose of this study was to identify the role of BDNF in SVZ cells using AAV-BDNF in an animal model of stroke. BDNF protein production after AAV-BDNF infection was verified in primary neuronal culture. AAV-BDNF or AAV-RFP was injected into the left SVZ region of adult rats at 14 days prior to right middle cerebral artery occlusion (MCAo). SVZ tissues were collected from the brain and placed in Metrigel cultures 1 day after MCAo. Treatment with AAV-BDNF significantly increased the migration of SVZ cells in the stroke brain in vitro. In another set of animals, AAV-GFP was co-injected with AAV-BDNF or AAV-RFP to label cells in left SVZ prior to right MCAo. Local administration of AAV-BDNF significantly enhanced recovery of locomotor function and migration of GFP-positive cells from the SVZ toward the lesioned hemisphere in stroke rats. Our data suggest that focal administration of AAV-BDNF to the SVZ increases behavioral recovery post stroke, possibly through the enhancement of migration of cells from SVZ in stroke animals. Regional manipulation of BDNF expression through AAV may be a novel approach for neurorepair in stroke brains.


National Cancer Institute Workshop on Proton Therapy for Children: Considerations Regarding Brainstem Injury.
Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury. Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016. The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning. Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.


Incretin-based therapy and risk of acute pancreatitis: a nationwide population-based case-control study.
To investigate whether the use of incretin-based drugs (GLP-1 receptor agonists and dipeptidyl peptidase 4 [DPP4] inhibitors) is associated with acute pancreatitis. The study was a nationwide population-based case-control study using medical databases in Denmark. Participants were 12,868 patients with a first-time hospitalization for acute pancreatitis between 2005 and 2012 and a population of 128,680 matched control subjects. The main outcome measure was the odds ratio (OR) for acute pancreatitis associated with different antihyperglycemic drugs. We adjusted for history of gallstones, alcoholism, obesity, and other pancreatitis-associated comorbidities and medications. A total of 89 pancreatitis patients (0.69%) and 684 control subjects (0.53%) were ever users of incretins. The crude OR for acute pancreatitis among incretin users was 1.36 (95% CI 1.08-1.69), while it was 1.44 (95% CI 1.34-1.54) among users of other antihyperglycemic drugs. After confounder adjustment, the risk of acute pancreatitis was not increased among incretin users (OR 0.95 [95% CI 0.75-1.21]), including DPP4 inhibitor users (OR 1.04 [95% CI 0.80-1.37]) or GLP-1 receptor agonist users (OR 0.82 [95% CI 0.54-1.23]), or among nonincretin antihyperglycemic drug users (OR 1.05 [95% CI 0.98-1.13]), compared with nonusers of any antihyperglycemic drugs. Findings were similar in current versus ever drug users and in patients with pancreatitis risk factors. The adjusted OR comparing incretin-based therapy with other antihyperglycemic therapy internally while also adjusting for diabetes duration and complications was 0.97 (95% CI 0.76-1.23). Our findings suggest that the use of incretin-based drugs appears not to be associated with an increased risk of acute pancreatitis.


On the Emergence of Candida auris: Climate Change, Azoles, Swamps, and Birds.
The most enigmatic aspect of the rise of Candida auris as a human pathogen is that it emerged simultaneously on three continents, with each clade being genetically distinct. Although new pathogenic fungal species are described regularly, these are mostly species associated with single cases in individuals who are immunosuppressed. In this study, we used phylogenetic analysis to compare the temperature susceptibility of C. auris with those of its close relatives and to use these results to argue that it may be the first example of a new fungal disease emerging from climate change, with the caveat that many other factors may have contributed.


Role of antibodies in immunity to Bordetella infections.
The persistence of Bordetella pertussis and B. parapertussis within vaccinated populations and the reemergence of associated disease highlight the need to better understand protective immunity. The present study examined host immunity to bordetellae and addressed potential concerns about the mouse model by using a comparative approach including the closely related mouse pathogen B. bronchiseptica. As previously observed with B. pertussis, all three organisms persisted throughout the respiratory tracts of B-cell-deficient mice, indicating that B cells are required for bacterial clearance. However, adoptively transferred antibodies rapidly cleared B. bronchiseptica but not human pathogens. These results obtained with the mouse model are consistent with human clinical observations, including the lack of correlation between antibody titers and protection, as well as the limited efficacy of intravenous immunoglobulin treatments against human disease. Together, this evidence suggests that the mouse model accurately reflects substantial differences between immunities to these organisms. Although both B. pertussis and B. parapertussis are more closely related to B. bronchiseptica than they are to each other, they share the ability to resist rapid clearance from the lower respiratory tract by adoptively transferred antibodies, an adaptation that correlates with their emergence as human pathogens that circulate within vaccinated populations.


Fiber chirped-pulse amplification system emitting 3.8 GW peak power.
We report on the experimental demonstration of a fiber chirped- pulse amplification system capable of generating nearly transform-limited sub 500 fs pulses with 2.2 mJ pulse energy at 11 W average power. The resulting record peak power of 3.8 GW could be achieved by combining active phase shaping with an efficient reduction of the acquired nonlinear phase. Therefore, we used an Ytterbium-doped large-pitch fiber with a mode field diameter of 105 µm as the main amplifier.


Prevalence of paratuberculosis in cattle and control measures within the herd influence the performance of ELISA tests.
Commercial ELISA kits are widely used in the diagnosis of paratuberculosis of dairy cattle. It is critically important to understand the influences on these test results and their relation to faecal culture (FC) results in order to interpret the findings and to make decisions concerning serial testing and control measures. A total of 1021 cattle (423 FC positive, 598 FC negative) from 14 Mycobacterium avium subspecies paratuberculosis (MAP) positive herds were tested with four ELISA systems and FC simultaneously to calculate the kappa coefficients for the agreement of the different ELISA systems as well as find influencing factors. For the agreement of FC and ELISA, the kappa coefficients were low and ranged from 0.19 to 0.24, whereas, results of the different ELISA were consistently high (0.74-0.90). Agreement with FC was enhanced with the duration of control (P≤0.001) and the lactation number (P≤0.01), and reduced with within-herd prevalence (P≤0.001). There were substantial differences in the detection rate of low (15-24 per cent) and high (85-100 per cent) MAP shedders. In conclusion, the factors shown to influence test sensitivity, should be taken into account for validation and interpretation of ELISA tests. The benefit of serial ELISA testing is low.


Bose-Glass phases of ultracold atoms due to cavity backaction.
We determine the quantum ground-state properties of ultracold bosonic atoms interacting with the mode of a high-finesse resonator. The atoms are confined by an external optical lattice, whose period is incommensurate with the cavity mode wavelength, and are driven by a transverse laser, which is resonant with the cavity mode. While for pointlike atoms photon scattering into the cavity is suppressed, for sufficiently strong lasers quantum fluctuations can support the buildup of an intracavity field, which in turn amplifies quantum fluctuations. The dynamics is described by a Bose-Hubbard model where the coefficients due to the cavity field depend on the atomic density at all lattice sites. Quantum Monte Carlo simulations and mean-field calculations show that, for large parameter regions, cavity backaction forces the atoms into clusters with a checkerboard density distribution. Here, the ground state lacks superfluidity and possesses finite compressibility, typical of a Bose glass. This system constitutes a novel setting where quantum fluctuations give rise to effects usually associated with disorder.


Neurobehavioral effects of aspartame consumption.
Despite its widespread use, the artificial sweetener aspartame remains one of the most controversial food additives, due to mixed evidence on its neurobehavioral effects. Healthy adults who consumed a study-prepared high-aspartame diet (25 mg/kg body weight/day) for 8 days and a low-aspartame diet (10 mg/kg body weight/day) for 8 days, with a 2-week washout between the diets, were examined for within-subject differences in cognition, depression, mood, and headache. Measures included weight of foods consumed containing aspartame, mood and depression scales, and cognitive tests for working memory and spatial orientation. When consuming high-aspartame diets, participants had more irritable mood, exhibited more depression, and performed worse on spatial orientation tests. Aspartame consumption did not influence working memory. Given that the higher intake level tested here was well below the maximum acceptable daily intake level of 40-50 mg/kg body weight/day, careful consideration is warranted when consuming food products that may affect neurobehavioral health.


Multispectral integral imaging acquisition and processing using a monochrome camera and a liquid crystal tunable filter.
This paper presents an acquisition system and a procedure to capture 3D scenes in different spectral bands. The acquisition system is formed by a monochrome camera, and a Liquid Crystal Tunable Filter (LCTF) that allows to acquire images at different spectral bands in the [480, 680]nm wavelength interval. The Synthetic Aperture Integral Imaging acquisition technique is used to obtain the elemental images for each wavelength. These elemental images are used to computationally obtain the reconstruction planes of the 3D scene at different depth planes. The 3D profile of the acquired scene is also obtained using a minimization of the variance of the contribution of the elemental images at each image pixel. Experimental results show the viability to recover the 3D multispectral information of the scene. Integration of 3D and multispectral information could have important benefits in different areas, including skin cancer detection, remote sensing and pattern recognition, among others.


A systematic review of high quality diagnostic tests for Chagas disease.
There is significant heterogeneity in reported sensitivities and specificities of diagnostic serological assays for Chagas disease, as might be expected from studies that vary widely according to setting, research design, antigens employed, and reference standard. The purpose of this study is to summarize the reported accuracy of serological assays and to identify sources of heterogeneity including quality of research design. To avoid associated spectrum bias, our analysis was limited to cohort studies. We completed a search of PubMed, a bibliographic review of potentially relevant articles, and a review of articles identified by a study author involved in this area of research. Studies were limited to prospective cohort studies of adults published since 1985. Measures of diagnostic accuracy were pooled using a Der Simonian Laird Random Effects Model. A subgroup analysis and meta regression were employed to identify sources of heterogeneity. The QUADAS tool was used to assess quality of included studies and Begg's funnel plot was used to assess publication bias. Eighteen studies and 61 assays were included in the final analysis. Significant heterogeneity was found in all pre-determined subgroups. Overall sensitivity was 90% (95% CI: 89%-91%) and overall specificity was 98% (95% CI: 98%-98%). Sensitivity and specificity of serological assays for the diagnosis of Chagas disease appear less accurate than previously thought. Suggestions to improve the accuracy of reporting include the enrollment of patients in a prospective manner, double blinding, and providing an explicit method of addressing subjects that have an indeterminate diagnosis by either the reference standard or index test.


Rescue of collapsed replication forks is dependent on NSMCE2 to prevent mitotic DNA damage.
NSMCE2 is an E3 SUMO ligase and a subunit of the SMC5/6 complex that associates with the replication fork and protects against genomic instability. Here, we study the fate of collapsed replication forks generated by prolonged hydroxyurea treatment in human NSMCE2-deficient cells. Double strand breaks accumulate during rescue by converging forks in normal cells but not in NSMCE2-deficient cells. Un-rescued forks persist into mitosis, leading to increased mitotic DNA damage. Excess RAD51 accumulates and persists at collapsed forks in NSMCE2-deficient cells, possibly due to lack of BLM recruitment to stalled forks. Despite failure of BLM to accumulate at stalled forks, NSMCE2-deficient cells exhibit lower levels of hydroxyurea-induced sister chromatid exchange. In cells deficient in both NSMCE2 and BLM, hydroxyurea-induced double strand breaks and sister chromatid exchange resembled levels found in NSCME2-deficient cells. We conclude that the rescue of collapsed forks by converging forks is dependent on NSMCE2.


Inhibitory effect of chinese propolis on phosphatidylcholine-specific phospholipase C activity in vascular endothelial cells.
To understand the mechanisms underlying the anti-inflammatory action of Chinese propolis, we investigated its effect on the activity of phosphatidylcholine-specific phospholipase C (PC-PLC) that plays critical roles in control of vascular endothelial cell (VEC) function and inflammatory responses. Furthermore, p53 and reactive oxygen species (ROS) levels and mitochondrial membrane potential (Δψm) were investigated. Our data indicated that treatment of Chinese propolis 6.25 and 12.5 μg/ml for 12 hours increased VEC viability obviously. Exposure to Chinese propolis 6.25, 12.5, and 25 μg/ml for 6 and 12 hours significantly decreased PC-PLC activity and p53 level, and ROS levels were depressed by Chinese propolis 12.5 μg/ml and 25 μg/ml dramatically. The Δψm of VECs was not affected by Chinese propolis at low concentration but disrupted by the propolis at 25 μg/ml significantly, which indicated that Chinese propolis depressed PC-PLC activity and the levels of p53 and ROS in VECs but disrupted Δψm at a high concentration.


Hidden evolutionary complexity of Nucleo-Cytoplasmic Large DNA viruses of eukaryotes.
The Nucleo-Cytoplasmic Large DNA Viruses (NCLDV) constitute an apparently monophyletic group that consists of at least 6 families of viruses infecting a broad variety of eukaryotic hosts. A comprehensive genome comparison and maximum-likelihood reconstruction of the NCLDV evolution revealed a set of approximately 50 conserved, core genes that could be mapped to the genome of the common ancestor of this class of eukaryotic viruses. We performed a detailed phylogenetic analysis of these core NCLDV genes and applied the constrained tree approach to show that the majority of the core genes are unlikely to be monophyletic. Several of the core genes have been independently acquired from different sources by different NCLDV lineages whereas for the majority of these genes displacement by homologs from cellular organisms in one or more groups of the NCLDV was demonstrated. A detailed study of the evolution of the genomic core of the NCLDV reveals substantial complexity and diversity of evolutionary scenarios that was largely unsuspected previously. The phylogenetic coherence between the core genes is sufficient to validate the hypothesis on the evolution of all NCLDV from a common ancestral virus although the set of ancestral genes might be smaller than previously inferred from patterns of gene presence-absence.


Evening primrose oil.
Evening primrose oil (Oenothera biennis) is a commonly used alternative therapy and a rich source of omega-6 essential fatty acids. It is best known for its use in the treatment of systemic diseases marked by chronic inflammation, such as atopic dermatitis and rheumatoid arthritis. It is often used for several women's health conditions, including breast pain (mastalgia), menopausal and premenstrual symptoms, cervical ripening, and labor induction or augmentation. However, there is insufficient evidence to make a reliable assessment of its effectiveness for most clinical indications. The current evidence suggests that oral evening primrose oil does not provide clinically significant improvement in persons with atopic dermatitis, and that it is also likely ineffective for the treatment of cyclical mastalgia and premenstrual syndrome. However, most trials to date have significant methodologic flaws and must be considered preliminary. The use of evening primrose oil during pregnancy is not supported in the literature and should be avoided. Evening primrose oil is generally well tolerated, with reported minor adverse effects, including gastrointestinal upset and headaches. Optimal dosing standards and treatment regimens await clarification in adequately powered clinical trials.


Integrin expression profiles during erythroid differentiation.
To study the expression of integrins at the erythroid progenitor level we isolated selected populations of cells from human fetal liver after immunoadherence to anti-beta 2 integrin (CD18) coated plates. These CD18 adherent cells (CD18-Ad), in contrast to CD18 nonadherent cells (CD18-NAd), have a blastlike cell morphology and are highly enriched in all progenitor types (14% to 37% progenitors). By several criteria progenitor cells present in CD18-Ad cells appear to have a higher proliferative potential and diversity than the ones found in CD18-NAd, which were mostly later erythroid progenitors. Positivity of CD18-Ad cells with the common beta 2 integrin (CD18) is largely attributable to expression of alpha L (CD11a) chain, rather than alpha M (CD11b). CD11a is present in all types of progenitors, but it is selectively lost at later stages of erythroid differentiation/maturation. By contrast, CD11b appears to be virtually absent from all progenitors but it has an enhanced expression during granulomonocytic differentiation/maturation. In addition to beta 2 integrins, CD18-Ad cells express several other cytoadhesion molecules (VLA-4, VLA-5, I-CAM, H-CAM) as well as other progenitor cell antigens (CD34, HLA-DR, CD38). Cells expressing all these antigens were selectively enriched in CD18-Ad cells. Our data add new information on the regulation of CD11a and CD11b molecules in hematopoiesis and on the composite profile of integrin expression at several stages of erythroid differentiation.


Comparing the Precision of Information Retrieval of MeSH-Controlled Vocabulary Search Method and a Visual Method in the Medline Medical Database.
Medline is one of the most important databases in the biomedical field. One of the most important hosts for Medline is Elton B. Stephens CO. (EBSCO), which has presented different search methods that can be used based on the needs of the users. Visual search and MeSH-controlled search methods are among the most common methods. The goal of this research was to compare the precision of the retrieved sources in the EBSCO Medline base using MeSH-controlled and visual search methods. This research was a semi-empirical study. By holding training workshops, 70 students of higher education in different educational departments of Kashan University of Medical Sciences were taught MeSH-Controlled and visual search methods in 2012. Then, the precision of 300 searches made by these students was calculated based on Best Precision, Useful Precision, and Objective Precision formulas and analyzed in SPSS software using the independent sample T Test, and three precisions obtained with the three precision formulas were studied for the two search methods. The mean precision of the visual method was greater than that of the MeSH-Controlled search for all three types of precision, i.e. Best Precision, Useful Precision, and Objective Precision, and their mean precisions were significantly different (P <0.001). Sixty-five percent of the researchers indicated that, although the visual method was better than the controlled method, the control of keywords in the controlled method resulted in finding more proper keywords for the searches. Fifty-three percent of the participants in the research also mentioned that the use of the combination of the two methods produced better results. For users, it is more appropriate to use a natural, language-based method, such as the visual method, in the EBSCO Medline host than to use the controlled method, which requires users to use special keywords. The potential reason for their preference was that the visual method allowed them more freedom of action.


Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity.
Mitochondria contribute to cellular innate immunity against RNA viruses. Mitochondrial-mediated innate immunity is regulated by signalling molecules that are recruited to the mitochondrial membrane, and depends on the mitochondrial inner membrane potential (Δψm). Here we examine the physiological relevance of Δψm and the mitochondrial-associating influenza A viral protein PB1-F2 in innate immunity. When expressed in host cells, PB1-F2 completely translocates into the mitochondrial inner membrane space via Tom40 channels, and its accumulation accelerates mitochondrial fragmentation due to reduced Δψm. By contrast, PB1-F2 variants lacking a C-terminal polypeptide, which is frequently found in low pathogenic subtypes, do not affect mitochondrial function. PB1-F2-mediated attenuation of Δψm suppresses the RIG-I signalling pathway and activation of NLRP3 inflammasomes. PB1-F2 translocation into mitochondria strongly correlates with impaired cellular innate immunity, making this translocation event a potential therapeutic target.


A screening-level assessment of the pollinator-attractiveness of ornamental nursery stock using a honey bee foraging assay.
In urban and suburban landscapes characterized by extensive designed greenspaces, the support of pollinator communities hinges significantly on floral resources provided by ornamental plants. The attractiveness of ornamental plants to pollinators, however, cannot be presumed, and some studies suggest that a majority of ornamental plant varieties receive little or no pollinator visitation. Here, we harness the sampling power of the western honey bee, a generalist pollinator whose diet breadth overlaps substantially with that of other pollinators, to survey the utilization of ornamental plants grown at three commercial nurseries in Connecticut, USA. Using a combination of DNA metabarcoding and microscopy, we identify, to genus-level, pollen samples from honey bee colonies placed within each nursery, and we compare our results with nursery plant inventories to identify the subset of cultivated genera that were visited during pollen foraging. Samples were collected weekly from May to September, encompassing the majority of the growing season. Our findings show that some plant genera known to be cultivated as ornamentals in our system, particularly ornamental trees and shrubs (e.g. Hydrangea, Rosa, Spiraea, Syringa, Viburnum), functioned as major pollen sources, but the majority of plants inventoried at our nurseries provided little or no pollen to honey bees. These results are in agreement with a growing body of literature highlighting the special importance of woody plants as resources for flower-visiting insects. We encourage further exploration of the genera highlighted in our data as potential components of pollinator-friendly ornamental greenspace.


The trans-sialidase from the african trypanosome Trypanosoma brucei.
Trypanosoma brucei is the cause of the diseases known as sleeping sickness in humans (T. brucei ssp. gambiense and ssp. rhodesiense) and ngana in domestic animals (T. brucei brucei) in Africa. Procyclic trypomastigotes, the tsetse vector stage, express a surface-bound trans-sialidase that transfers sialic acid to the glycosylphosphatidylinositol anchor of procyclin, a surface glycoprotein covering the parasite surface. Trans-sialidase is a unique enzyme expressed by a few trypanosomatids that allows them to scavenge sialic acid from sialylated compounds present in the infected host. The only enzyme extensively characterized is that of the American trypanosome T. cruzi (TcTS). In this work we identified and characterized the gene encoding the trans-sialidase from T. brucei brucei (TbTS). TbTS genes are present at a small copy number, at variance with American trypanosomes where a large gene family is present. The recombinant TbTS protein has both sialidase and trans-sialidase activity, but it is about 10 times more efficient in transferring than in hydrolysing sialic acid. Its N-terminus contains a region of 372 amino acids that is 45% identical to the catalytic domain of TcTS and contains the relevant residues required for catalysis. The enzymatic activity of mutants at key positions involved in the transfer reaction revealed that the catalytic sites of TcTS and TbTS are likely to be similar, but are not identical. As in the case of TcTS and TrSA, the substitution of a conserved tryptophanyl residue changed the substrate specificity rendering a mutant protein capable of hydrolysing both alpha-(2,3) and alpha-(2,6)-linked sialoconjugates.


Immobilized amines and basic amino acids as mimetic heparin-binding domains for cell surface proteoglycan-mediated adhesion.
Diamines covalently coupled to glass substrates promoted human foreskin fibroblast adhesion in the absence of serum. These diamine-derivatized substrates were produced by coupling ethylene diamine, N-methylaminoethylamine, and N,N-dimethylaminoethylamine (NNDMAEA), to sulfonyl chloride-activated glass. Electron spectroscopy for chemical analysis demonstrated that the diamines were coupled via their primary amine ends to produce a surface-bound secondary amine linked to a free amino moiety via a two-carbon spacer. NNDMAEA-modified substrates containing free tertiary amines supported the highest degree of cell spreading (73 +/- 7% actively spreading cells) and the most extensive cytoskeletal organization. Both the free tertiary and surface-bound secondary amines were shown to be required for cell spreading. Lysine- and arginine-grafted substrates supported cell spreading and cytoskeletal organization similar to that on NNDMAEA-modified substrates. Although some stress fibers were observed within spread cells on these substrates, focal contacts did not form. Heparinase treatment did not inhibit cell attachment or spreading to the diamine-derivatized substrates, however chondroitinase ABC inhibited cell attachment and spreading on all substrates; heparinase inhibited spreading on lysine- and arginine-derivatized substrates to a lesser extent. These results imply that cell attachment to these substrates was mediated primarily by cell surface chondroitin sulfate proteoglycans. This study demonstrates that covalently grafted NNDMAEA, lysine, and arginine can mimic the adhesion-promoting activity of the glycosaminoglycan-binding domains of cell adhesion proteins. This study also demonstrates that the interaction with these proteoglycans depends in a very sensitive manner on the particular structure of the immobilized amine.


Receptor-based design of dihydrofolate reductase inhibitors: comparison of crystallographically determined enzyme binding with enzyme affinity in a series of carboxy-substituted trimethoprim analogues.
By the use of molecular models of Escherichia coli dihydrofolate reductase (DHFR), analogues of trimethoprim (TMP) were designed which incorporated various 3'-carboxyalkoxy moieties in order to acquire ionic interactions with positively charged active-site residues. Certain of these compounds have shown exceptionally high affinity for this enzyme. For example, the 3'-(carboxypentyl)oxy analogue was found to be 55-fold more inhibitory than TMP toward E. coli DHFR (Ki = 0.024 nM vs. 1.32 nM for TMP). X-ray crystallographic studies of E. coli DHFR in binary complexes with TMP and two members of this acid-containing series of compounds defined the binding of these inhibitors and showed the carboxyl group of the latter two inhibitors to be ionically bound to Arg-57. These observations were in agreement with postulated binding modes that were based on receptor modeling.


HIV protease inhibitors in pulmonary hypertension: rationale and design of a pilot trial in idiopathic pulmonary arterial hypertension.
We propose an exploratory clinical study, the first of its kind to our knowledge, to determine the safety and potential clinical benefit of the combination of the HIV protease inhibitors (HIV-PIs) saquinavir and ritonavir (SQV+RIT) in patients with idiopathic pulmonary arterial hypertension (IPAH). This study is based on evidence that (1) HIV-PIs can improve pulmonary hemodynamics in experimental models; (2) both Toll-like receptor 4 and high-mobility group box 1 (HMGB1) participate in the pathogenesis of experimental pulmonary hypertension; and (3) a high-throughput screen for inhibitors of HMGB1-induced macrophage activation yielded HIV-PIs as potent inhibitors of HMGB1-induced cytokine production. In this proposed open-label, pre-post study, micro, low, and standard doses of SQV+RIT will be given to IPAH patients for 14 days. Patients will receive follow-up for the next 14 days. The primary outcome to be evaluated is change in HMGB1 level from baseline at 14 days. The secondary outcome is changes in tumor necrosis factor α, interleukin 1β, interleukin 6, C-reactive protein, pulmonary arterial pressure based on echocardiography parameters and New York Heart Association/World Health Organization functional class, and Brog dyspnea scale index from baseline at 14 days. Other secondary measurements will include N-terminal pro-brain natriuretic peptide, atrial natriuretic peptide, and 6-minute walk distance. We propose that SQV+RIT treatment will improve inflammatory disorders and pulmonary hemodynamics in IPAH patients. If the data support a potentially useful therapeutic effect and suggest that SQV+RIT is safe in IPAH patients, the study will warrant further investigation. (ClinicalTrials.gov identifier: NCT02023450.).


Neural network analysis for evaluating cancer risk in thyroid nodules with an indeterminate diagnosis at aspiration cytology: identification of a low-risk subgroup.
Thyroid nodules with a predominant follicular structure are often diagnosed as indeterminate at fine-needle aspiration biopsy (FNAB). We studied 453 patients with a thyroid nodule diagnosed as indeterminate at FNAB by using a feed-forward artificial neural network (ANN) analysis to integrate cytologic and clinical data, with the goal of subgrouping patients into a high-risk and in a low-risk category. Three hundred seventy-one patients were used to train the network and 82 patients were used to validate the model. The cytologic smears were blindly reviewed and classified in a high-risk and a low-risk subgroup on the basis of standard criteria. Neural network analysis subdivided the 371 lesions of the first series into a high-risk group (cancer rate of approximately 33% at histology) and a low-risk group (cancer rate of 3%). Only cytologic parameters contributed to this classification. Analysis of the receiver operating characteristic (ROC) curves demonstrated that the ANN model discriminated with higher sensitivity and specificity between benign and malignant nodules compared to standard cytologic criteria (p < 0.001). This value did not show degradation when ANN predictions were applied to the validation series of 82 nodules. In conclusion, neural network analysis of cytologic data may be a useful tool to refine the risk of cancer in patients with lesions diagnosed as indeterminate by FNAB.


The Diagnostic Value of Urine Lipoarabinomannan (LAM) Antigen in Childhood Tuberculosis.
Diagnosis of Tuberculosis (TB) in children is difficult because the clinical presentation is not specific, the chest X-ray interpretation has low accuracy and sputum sample is difficult to obtain. Antigen detection test such as rapid urine LAM is a non-invasive alternative for diagnosing TB . Lipoarabinomannan (LAM) is the main component of M.tuberculosis cell wall. To determine the diagnostic value of urinary LAM antigen for diagnosis of childhood TB. In the present cross-sectional study, subjects were included using consecutive sampling method. All the children aged 0-14 years Suspected of pulmonary or extra pulmonary TB suffering from cough more than two weeks, fever without clear aetiology, loss of body weight or poor weight gain, fatigue, malaise, chronic lymph node enlargement, spine angulation, joint swelling and had history of contact with positive sputum smear adult TB patient were enrolled in the study. Pulmonary and extra pulmonary diagnosis was based on clinical presentation, Tuberculin Skin Test (TST), chest X-ray, Acid Fast Bacillus (AFB) staining and or sputum culture. Urinary LAM level was measured by using Enzyme-Linked Immunosorbent Assay (ELISA). Cut off value and Area Under the Curve (AUC) were determined using ROC statistical analysis (SPSS 21.0). Sensitivity and specificity was measured from 2x2 cross table. Out of 61 subjects suspected as TB, 49 (80.3%) were eventually diagnosed with TB. Of those diagnosed with TB, 21 (42.9%) were microbiologically confirmed cases either by sputum microscopy (34.7%) or culture (8.2%), whereas 28 subjects were unconfirmed cases (57.1%). The urinary LAM level was higher in subjects with TB (1.80+1.02) mg/l compared to non-TB group (0.46+0.3) mg/l; p<0.001(independent t-test). Urine LAM had 83% sensitivity and 85% specificity with cut off value 0.98 mg/l using microbiological and clinical confirmation as standard reference and 33% sensitivity and 60% specificity with cut off value 1.69 mg/l using microbiological confirmation only. Urinary LAM has good diagnostic value for childhood TB diagnosis.


Simultaneous measurement of velocity and length of moving surfaces by a speckle velocimeter with two self-mixing laser diodes.
A novel laser speckle velocimeter with two self-mixing laser diodes (SM-LD's) for velocity and length measurements of moving surfaces is reported. The mean frequency of the speckle signal obtained in the measurement system depends on the surface path illuminated by the SM-LD. This behavior of the speckle signal in the SM-LD's is exploited to detect the front and the end edges of a target surface by sampling continuously the number of intensity changes in a speckle signal waveform. Once the edges are determined, the velocity and the length of the surface are calculated easily. The error for length and velocity measurements of a target with a homogeneous rough plane surface of 60-mm length, moving at a velocity of 200 mm/s, can be as low as 2.1% and 1.75%, respectively.


Genetic diversity of canine olfactory receptors.
Evolution has resulted in large repertoires of olfactory receptor (OR) genes, forming the largest gene families in mammalian genomes. Knowledge of the genetic diversity of olfactory receptors is essential if we are to understand the differences in olfactory sensory capability between individuals. Canine breeds constitute an attractive model system for such investigations. We sequenced 109 OR genes considered representative of the whole OR canine repertoire, which consists of more than 800 genes, in a cohort of 48 dogs of six different breeds. SNP frequency showed the overall level of polymorphism to be high. However, the distribution of SNP was highly heterogeneous among OR genes. More than 50% of OR genes were found to harbour a large number of SNP, whereas the rest were devoid of SNP or only slightly polymorphic. Heterogeneity was also observed across breeds, with 25% of the SNP breed-specific. Linkage disequilibrium within OR genes and OR clusters suggested a gene conversion process, consistent with a mean level of polymorphism higher than that observed for introns and intergenic sequences. A large proportion (47%) of SNP induced amino-acid changes and the Ka/Ks ratio calculated for all alleles with a complete ORF indicated a low selective constraint with respect to the high level of redundancy of the olfactory combinatory code and an ongoing pseudogenisation process, which affects dog breeds differently. Our demonstration of a high overall level of polymorphism, likely to modify the ligand-binding capacity of receptors distributed differently within the six breeds tested, is the first step towards understanding why Labrador Retrievers and German Shepherd Dogs have a much greater potential for use as sniffer dogs than Pekingese dogs or Greyhounds. Furthermore, the heterogeneity in OR polymorphism observed raises questions as to why, in a context in which most OR genes are highly polymorphic, a subset of these genes is not? This phenomenon may be related to the nature of their ligands and their importance in everyday life.


Infinite hidden Markov models for unusual-event detection in video.
We address the problem of unusual-event detection in a video sequence. Invariant subspace analysis (ISA) is used to extract features from the video, and the time-evolving properties of these features are modeled via an infinite hidden Markov model (iHMM), which is trained using "normal"/"typical" video. The iHMM retains a full posterior density function on all model parameters, including the number of underlying HMM states. Anomalies (unusual events) are detected subsequently if a low likelihood is observed when associated sequential features are submitted to the trained iHMM. A hierarchical Dirichlet process framework is employed in the formulation of the iHMM. The evaluation of posterior distributions for the iHMM is achieved in two ways: via Markov chain Monte Carlo and using a variational Bayes formulation. Comparisons are made to modeling based on conventional maximum-likelihood-based HMMs, as well as to Dirichlet-process-based Gaussian-mixture models.


Epstein-Barr virus nuclear antigen 2 transactivates latent membrane protein LMP1.
Several lines of evidence are compatible with the hypothesis that Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA-2) or leader protein (EBNA-LP) affects expression of the EBV latent infection membrane protein LMP1. We now demonstrate the following. (i) Acute transfection and expression of EBNA-2 under control of simian virus 40 or Moloney murine leukemia virus promoters resulted in increased LMP1 expression in P3HR-1-infected Burkitt's lymphoma cells and the P3HR-1 or Daudi cell line. (ii) Transfection and expression of EBNA-LP alone had no effect on LMP1 expression and did not act synergistically with EBNA-2 to affect LMP1 expression. (iii) LMP1 expression in Daudi and P3HR-1-infected cells was controlled at the mRNA level, and EBNA-2 expression in Daudi cells increased LMP1 mRNA. (iv) No other EBV genes were required for EBNA-2 transactivation of LMP1 since cotransfection of recombinant EBNA-2 expression vectors and genomic LMP1 DNA fragments enhanced LMP1 expression in the EBV-negative B-lymphoma cell lines BJAB, Louckes, and BL30. (v) An EBNA-2-responsive element was found within the -512 to +40 LMP1 DNA since this DNA linked to a chloramphenicol acetyltransferase reporter gene was transactivated by cotransfection with an EBNA-2 expression vector. (vi) The EBV type 2 EBNA-2 transactivated LMP1 as well as the EBV type 1 EBNA-2. (vii) Two deletions within the EBNA-2 gene which rendered EBV transformation incompetent did not transactivate LMP1, whereas a transformation-competent EBNA-2 deletion mutant did transactivate LMP1. LMP1 is a potent effector of B-lymphocyte activation and can act synergistically with EBNA-2 to induce cellular CD23 gene expression. Thus, EBNA-2 transactivation of LMP1 amplifies the biological impact of EBNA-2 and underscores its central role in EBV-induced growth transformation.


Psychoeducation (brief) for people with serious mental illness.
Those with serious/severe mental illness, especially schizophrenia and schizophrenic-like disorders, often have little to no insight regarding the presence of their illness. Psychoeducation may be defined as the education of a person with a psychiatric disorder regarding the symptoms, treatments, and prognosis of that illness. Brief psychoeducation is a short period of psychoeducation; although what constitutes 'brief psychoeducation' can vary. A previous systematic review has shown that the median length of psychoeducation is around 12 weeks. In this current systematic review, we defined 'brief psychoeducation' as programmes of 10 sessions or less. To assess the efficacy of brief psychoeducational interventions as a means of helping severely mentally ill people when added to 'standard' care, compared with the efficacy of standard care alone.The secondary objective is to investigate whether there is evidence that a particular kind (individual/ family/group) of brief psychoeducational intervention is superior to others. We searched the Cochrane Schizophrenia Group register September 2013 using the phrase:[*Psychoeducat* in interventions of STUDY]. Reference lists of included studies were also inspected for further relevant studies. We also contacted authors of included study for further information regarding further data or details of any unpublished trials. All relevant randomised controlled trials (RCTs) comparing brief psychoeducation with any other intervention for treatment of people with severe mental illness. If a trial was described as 'double blind' but implied randomisation, we entered such trials in a sensitivity analysis. At least two review authors extracted data independently from included papers. We contacted authors of trials for additional and missing data. We calculated risk ratios (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data. For continuous data, we calculated the mean difference (MD), again with 95% CIs. We used a fixed-effect model for data synthesis, and also assessed data using a random-effects model in a sensitivity analysis. We assessed risk of bias for each included study and created 'Summary of findings' tables using GRADE (Grading of Recommendations Assessment, Development and Evaluation). We included twenty studies with a total number of 2337 participants in this review. Nineteen studies compared brief psychoeducation with routine care or conventional delivery of information. One study compared brief psychoeducation with cognitive behavior therapy.Participants receiving brief psychoeducation were less likely to be non-compliant with medication than those receiving routine care in the short term (n = 448, 3 RCTs, RR 0.63 CI 0.41 to 0.96, moderate quality evidence) and medium term (n = 118, 1 RCT, RR 0.17 CI 0.05 to 0.54, low quality evidence).Compliance with follow-up was similar between the two groups in the short term (n = 30, 1 RCT, RR 1.00, CI 0.24 to 4.18), medium term (n = 322, 4 RCTs, RR 0.74 CI 0.50 to 1.09) and long term (n = 386, 2 RCTs, RR 1.19, CI 0.83 to 1.72).Relapse rates were significantly lower amongst participants receiving brief psychoeducation than those receiving routine care in the medium term (n = 406, RR 0.70 CI 0.52 to 0.93, moderate quality evidence), but not in the long term.Data from a few individual studies supported that brief psychoeducation: i) can improve the long-term global state (n = 59, 1 RCT, MD -6.70 CI -13.38 to -0.02, very low quality evidence); ii) promote improved mental state in short term (n = 60, 1 RCT, MD -2.70 CI -4.84 to -0.56,low quality evidence) and medium term; iii) can lower the incidence and severity of anxiety and depression.Social function such as rehabilitation status (n = 118, 1 RCT, MD -13.68 CI -14.85 to -12.51, low quality evidence) and social disability (n = 118, 1 RCT, MD -1.96 CI -2.09 to -1.83, low quality evidence) were also improved in the brief psychoeducation group. There was no difference found in quality of life as measured by GQOLI-74 in the short term (n = 62, 1 RCT, MD 0.63 CI -0.79 to 2.05, low quality evidence), nor the death rate in either groups (n = 154, 2 RCTs, RR 0.99, CI 0.15 to 6.65, low quality evidence). Based on mainly low to very low quality evidence from a limited number of studies, brief psychoeducation of any form appears to reduce relapse in the medium term, and promote medication compliance in the short term. A brief psychoeducational approach could potentially be effective, but further large, high-quality studies are needed to either confirm or refute the use of this approach.


Behavioral risk factor and preventive health care practice survey of immigrants in the emergency department.
To compare the demographic profiles, behavioral risk factors, and preventive health care practices of adult immigrant and non-immigrant patients while considering the effects of various socioeconomic variables. This was a prospective survey administered at a large urban emergency department in New York City. Study subjects were adult immigrant patients presenting in an eight-week period in 1998. One non-immigrant control patient was recruited concurrently with every two immigrant patients. Differences between immigrants and non-immigrants were evaluated using the chi-square test. Multivariate logistic regression models were used to adjust for confounding variables. Eight hundred sixty-nine immigrant patients from 80 countries and 354 non-immigrant patients completed surveys. Immigrants were more likely not to have reached high school (28.9% vs 8.5%; p < 0.001), to have annual family incomes less than $20,000 (73.8% vs 64.5%; p < 0.01), and to have no health coverage (51.7% vs 30.8%; p < 0.001). Immigrant women were more likely never to have had a Papanicolaou test (16.1% vs 1.4%; OR 11.24, 95% CI = 2.70 to 46.8) and never to have performed a self-breast examination (20.8% vs 7.5%; OR 2.03, 95% CI = 1.29 to 3.20). Immigrants were more likely not to use condoms (63.4% vs 42.8%; OR 1.61, 95% CI = 1.20 to 2.15) and never to have visited a dentist (21.2% vs 7.8; OR 2.54, 95% CI = 1.60 to 4.04). Immigrants were more likely never to have received a purified protein derivative (PPD) skin test (30.3% vs 9.1%; OR 3.85, 95% CI = 2.56 to 5.80) and never to have received a tetanus immunization (48.1% vs 13.5%; OR 3.09, 95% CI = 2.17 to 4.42). These differences were independent of age, gender, marital status, employment, education, income, and health insurance status. When analyzing the immigrant group alone, region of origin, length of time in the United States, and English ability were significant independent predictors of higher-risk behavioral profiles and poor preventive health care practices. Differences exist between the socioeconomic profiles, behavioral risk profiles, and preventive health care practices of immigrant and non-immigrant patients presenting to a large inner-city municipal emergency department. Different populations within a heterogeneous group of immigrants have distinct health risks and public health needs.


A Role for the Non-Receptor Tyrosine Kinase Abl2/Arg in Experimental Neuroinflammation.
Multiple sclerosis is a neuroinflammatory degenerative disease, caused by activated immune cells infiltrating the CNS. The disease etiology involves both genetic and environmental factors. The mouse genetic locus, Eae27, linked to disease development in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis, was studied in order to identify contributing disease susceptibility factors and potential drug targets for multiple sclerosis. Studies of an Eae27 congenic mouse strain, revealed that genetic variation within Eae27 influences EAE development. The Abl2 gene, encoding the non-receptor tyrosine kinase Arg, is located in the 4,1 megabase pair long Eae27 region. The Arg protein plays an important role in cellular regulation and is, in addition, involved in signaling through the B- and T-cell receptors, important for the autoimmune response. The presence of a single nucleotide polymorphism causing an amino acid change in a near actin-interacting domain of Arg, in addition to altered lymphocyte activation in the congenic mice upon immunization with myelin antigen, makes Abl2/Arg a candidate gene for EAE. Here we demonstrate that the non-synonymous SNP does not change Arg's binding affinity for F-actin but suggest a role for Abl kinases in CNS inflammation pathogenesis by showing that pharmacological inhibition of Abl kinases ameliorates EAE, but not experimental arthritis.


Gene expression in the human intestine and correlation with oral valacyclovir pharmacokinetic parameters.
The transport of valacyclovir, the l-valyl ester of acyclovir, has been suggested to be mediated by several carrier-mediated pathways in cell culture and animal models. The role and importance of these transporters in modulating valacyclovir absorption in humans has not been determined, however. Recent advances in genomic technology have facilitated the rapid and simultaneous determination of global mRNA expression profiles for thousands of genes in tissue biopsies directly associated with the absorption process, thereby dramatically increasing the value of studies in humans. In this article, we describe correlations of pharmacokinetic parameters following oral valacyclovir or acyclovir administration with expression levels of intestinal genes in humans. Highly positive and significant correlations were observed with 4F2hc, an activator of cation-preferring amino acid transport systems, and human oligopeptide transporter (HPT1), an oligopeptide transporter expressed at higher levels in the human intestine compared with oligopeptide transporter (PEPT1). The validation of HPT1 microarray data with reverse transcription-polymerase chain reaction and the enhanced valacyclovir uptake in HeLa/HPT1 cells suggest that the role of HPT1 in transport of peptides and peptidomimetics drugs needs to be examined in more detail. The interrelation of 4F2hc and HPT1 in transport may be of interest. No significant correlations of valacyclovir pharmacokinetic parameters with PEPT1 and with organic cation or anion transporter expression levels were observed. The highly negative correlations observed with known efflux pumps such as MDR1 (P-glycoprotein) and MRP2 (cMOAT), as well as with the CYP450 IIIA subfamily may indicate that these proteins may regulate the cellular accumulation and metabolism of acyclovir.


Early peri-operative hyperglycaemia and renal allograft rejection in patients without diabetes.
Patients with diabetes have an increased risk for allograft rejection, possibly related to peri-operative hyperglycaemia. Hyperglycaemia is also common following transplantation in patients without diabetes. We hypothesise that exposure of allograft tissue to hyperglycaemia could influence the risk for rejection in any patient with high sugars. To investigate the relationship of peri-operative glucose control to acute rejection in renal transplant patients without diabetes, all patients receiving their first cadaveric graft in a single center were surveyed and patients without diabetes receiving cyclosporin-based immunosuppression were reviewed (n = 230). Records of the plasma blood glucose concentration following surgery and transplant variables pertaining to allograft rejection were obtained. All variables suggestive of association were entered into multivariate logistic regression analysis, their significance analysed and modeled. Hyperglycaemia (>8.0 mmol/L) occurs in over 73% of non-diabetic patients following surgery. Glycaemic control immediately following renal transplantation independently predicted acute rejection (Odds ratio=1.08). 42% of patients with a glucose < 8.0 mmol/L following surgery developed rejection compared to 71% of patients who had a serum glucose above this level. Hyperglycaemia was not associated with any delay of graft function. Hyperglycaemia is associated with an increased risk for allograft rejection. This is consistent with similar findings in patients with diabetes. We hypothesise a causal link concordant with epidemiological and in vitro evidence and propose further clinical research.


Use of artificial neural networks to predict quaternery phase systems from limited experimental data.
The aim of the present work was to develop a method for predicting the phase behaviour of four component systems consisting of oil, water and two surfactants from a limited number of screening experiments. Investigations were conducted to asses the potential of artificial neural networks (ANNs) with back-propagation training algorithm to predict the phase behaviour of four component systems. Three inputs only (percentages of oil and water and HLB of the surfactant blend) and four outputs (oil in water emulsion, water in oil emulsion, microemulsion, and liquid crystals containing regions) were used. Samples used for training represented about 15% of the sampling space within the tetrahedron body. The network was trained by performing optimization of the number and size of the weights for neuron interconnections. The lowest error was obtained with 15 hidden neurons and after 4,500 training cycles. The trained ANN was tested on validation data and had an accuracy of 85.2-92.9%. In most cases the errors in the prediction were confined to points lying along the boundaries of regions and for the extrapolated predictions outside the ANNs 'experience'. This approach is shown to be highly successful and the ANNs have proven to be a useful tool for the prediction of the phase behaviour of quaternary systems with less experimental effort.


Prenatal findings in patients with prolonged QT interval in the neonatal period.
To describe prenatal abnormalities of cardiac rhythm in patients with prolonged QT interval in the neonatal period. A retrospective analysis of the results of fetal echocardiography and the outcome in patients with prolonged QT interval in the neonatal period who had been referred for prenatal evaluation. Two university hospitals. Nine patients with prolonged QT interval in the neonatal period who had been referred for prenatal evaluation. Fetal echocardiograms were obtained from 24 to 40 weeks of gestation. Indications were fetal bradycardia (five patients), a family history of long QT syndrome (two patients), and complex arrhythmias (two patients). Seven fetuses had persistent sinus bradycardia without ventricular arrhythmias (heart rates 70-120 beats/ min). Five patients were treated with propranolol, after the diagnosis had been established by postnatal electrocardiogram (ECG). One of these patients died suddenly at the age of 3 weeks, after the treatment had been stopped because of profound bradycardia. One of the remaining two patients who did not receive propranolol had a syncope at the age of 6 weeks. Two fetuses presented with frequent runs of ventricular tachycardia and intermittent bradycardia caused by intermittent, functional second degree atrioventricular block. Both patients died on the first day of life despite treatment with propranolol and transvenous temporary pacing. Sinus bradycardia in an otherwise normal fetus may be a symptom of long QT syndrome. Postnatal ECGs and a family examination are strongly recommended in these children. In fetuses with frequent runs of ventricular tachycardia and intermittent second degree atrioventricular block long QT syndrome should be suspected prenatally. These high risk patients should be delivered in centres with a paediatric cardiology unit.


The calmodulin binding domain of chicken smooth muscle myosin light chain kinase contains a pseudosubstrate sequence.
Smooth muscle myosin light chain kinase contains a 64 residue sequence that binds calmodulin in a Ca2+-dependent manner (Guerriero, V., Jr., Russo, M. A., and Means, A. R. (1987) Biochemistry, in press). Within this region is a sequence with homology to the corresponding sequence reported for the calmodulin binding region of skeletal muscle myosin light chain kinase (Blumenthal, D. K., Takio, K., Edelman, A. M., Charbonneau, H., Titani, L., Walsh, K. A., and Krebs, E. G. (1985) Proc. Natl. Acad. Sci. U.S.A. 82, 3187-3191). Inspection of these sequences reveals that they both share a similar number and spatial arrangement of basic residues with those present in the myosin light chain substrate. We have synthesized a 22-residue peptide corresponding to residues 480-501 (determined from the cDNA) of the smooth muscle myosin light chain kinase. This peptide, Ala-Lys-Lys-Leu-Ser-Lys-Asp-Arg-Met-Lys-Lys-Tyr-Met-Ala-Arg-Arg-Lys-Trp- Gln-Lys-Thr-Gly, inhibited calmodulin-dependent activation of the smooth muscle myosin light chain kinase with an IC50 of 46 nM. At saturating concentrations of calmodulin, the 22-residue peptide inhibited myosin light chain and synthetic peptide substrate phosphorylation competitively with IC50 values of 2.7 and 0.9 microM, respectively. An 11-residue synthetic peptide analog, corresponding to part of the calmodulin-binding sequence in skeletal muscle myosin light chain kinase, Lys-Arg-Arg-Trp-Lys-Lys-Asn-Phe-Ile-Ala-Val, also competitively inhibited synthetic peptide substrate phosphorylation with a Ki of 1 microM. The competitive inhibitory activity of the calmodulin binding regions is similar to the apparent Km of 2.7 microM for phosphorylation of the 23-residue peptide analog of the smooth muscle myosin light chain and raises the possibility that the calmodulin binding region of the myosin light chain kinase may act as a pseudosubstrate inhibitor of the enzyme.


The mediating effect of dietary patterns on the association between mother's education level and the physical aggression of five-year-old children: a population-based cohort study.
Relatively few studies have investigated the effects of diet on behavior problems among preschoolers, particularly, physical aggression. In addition, children raised by poorly educated mothers usually have a higher probability of developing negative outcomes. Additionally, highly educated mothers have a higher probability of providing more healthy foods for their children. Thus, mothers providing healthy foods might mitigate children's behavior problems. The study aims to examine whether preschoolers' dietary pattern, as a manipulable factor, mediates the association between maternal education level and physical aggression. Data came from the Taiwan Birth Cohort Study (TBCS), a nationally representative population-based cohort study, which included 18,513 five-year-old Taiwanese children. Mothers and primary caregivers reported the information on preschoolers' physical aggression and food consumption at age 5 and maternal education level at age 6 months. Two dietary patterns, namely a healthy diet and a high-fat-sugar-salt (HFSS) diet, were retrieved by exploratory factor analysis. Mediation hypotheses were tested by a series of multiple regression models conducted using the PROCESS macro of SAS 9.4. All models were adjusted for children's sex, parental marital status, household income, mental distress at age 5 and children's physical aggression at age 3. Maternal education positively linked to healthy dietary patterns (B = 0.014, p = 0.002) which was negatively associated with preschoolers' physical aggression (B = -0.096, p = 0.013), and it is negatively related to the HFSS dietary pattern (B = -0.042, p = 0.002) which was directly positively associated with preschoolers' physical aggression (B = 0.123, p = 0.008). The association between maternal education and preschoolers' physical aggression was partially mediated by preschoolers' healthy (B = -0.001, p < .001) and HFSS (B = -0.005, p = <.001) dietary patterns, respectively. The R-square of the mediation model is 0.178. Preschoolers' dietary patterns directly associate with their physical aggression. In addition, mothers with poor education may provide less healthy foods and more unhealthy foods to their children, which may increase the level of physical aggression. The results imply partial mediating effects of dietary patterns between maternal education and physical aggression. It is suggested that a parent-based nutritional education program focusing on healthy meal preparation for poor educated mothers might be beneficial for preschoolers' healthy development.


Parechovirus: an important emerging infection in young infants.
Epidemics of human parechovirus (HPeV) causing disease in young children have occurred every 2 years in Australia since 2013. HPeV genotype 3 caused the epidemic from late 2017 to early 2018. Most HPeV infections cause no or mild symptoms including gastroenteritis or influenza-like illness. Characteristically, young infants present with fever, irritability and on occasions a diffuse rash ("red, hot and angry" babies). Severe disease can manifest as meningoencephalitis, seizures or sepsis-like presentations (including septic shock), or less common presentations including signs of surgical abdomen. Testing for HPeV by specific molecular tests is indicated in children younger than 6 months of age with characteristic presentations without another confirmed diagnosis including febrile illnesses with other suggestive features (eg, rash, seizures), sepsis syndromes (including shock), and suspected meningoencephalitis (which may be detected by magnetic resonance imaging only). There are no effective antiviral therapies. Treatment is primarily supportive, including management of complications. Some infants with severe HPeV infection may have adverse neurodevelopment. Follow-up by a paediatrician is recommended.


Calnexin controls the STAT3-mediated transcriptional response to EGF.
Calnexin is a well-characterized transmembrane chaperone involved in the folding of newly synthesized glycoproteins in the lumen of the endoplasmic reticulum (ER). Here, we reveal a previously unrecognized function of calnexin in regulating the transcriptional response downstream of epidermal growth factor receptor (EGF), the product of a well-known human oncogene. We find that cell stimulation with EGF leads to the caspase-8-dependent cleavage of the calnexin cytoplasmic domain, preferentially at ER-mitochondria interaction sites. The released fragment translocates into the nucleus, binds to PIAS3--a natural inhibitor of activated STAT3--and, thus, acts as an enhancer of the STAT3-mediated transcriptional response to EGF. Also, we reveal the unsuspected capacity of calnexin to sense ER stress and, in response, prevent the EGF-induced processing of its cytosolic domain. Thus, cells integrate the health status of the ER to determine the amplitude of their response to EGF.


The efficacy of sodium benzoate as an adjunctive treatment in early psychosis - CADENCE-BZ: study protocol for a randomized controlled trial.
Psychotic disorders affect up to 3% of the population and are often chronic and disabling. Innovation in the pharmacological treatment of psychosis has remained stagnant in recent decades. In order to improve outcomes for those with psychotic disorders, we present a protocol for the trial of a common food preservative, sodium benzoate, as an adjunctive treatment in early psychosis. Persons experiencing early psychosis (n = 160) will be recruited through hospitals and community mental health services in Queensland, Australia. Patients will be randomized to receive either 12-week treatment with 1000 mg (500 mg twice daily (BD)) sodium benzoate or placebo. Patients will undergo fortnightly outcome assessments, in addition to weekly ongoing capacity to consent, drug compliance and safety assessments. The primary outcome measure is the Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcomes are Global Assessment of Function (GAF), Assessment of Quality of Life Scale (AQOL), the Activity and Participation Questionnaire (APQ6), International Physical Activity Questionnaires (IPAQ), Simple Physical Activity Questionnaire (SIMPAQ), Physical Activity Questionnaire, Clinical Global Impression (CGI), Hamilton Depression rating Scale-17 items (HDRS), Opiate Treatment Index (OTI) and the Patients' Global Impression of Improvement (PGI-I). As a tertiary objective, changes from baseline to endpoint in to serum markers related to D-alanine, L-alanine, D-serine, L-serine, glycine and glutamate will be investigated. Consumers and clinicians are keen to help develop better treatments for those with psychosis. This study, part of the wider Cadence clinical trials platform will examine if a safe and accessible food preservative can help optimize outcomes in those with psychosis. Australian New Zealand Clinical Trials registry (ANZCTR), ACTRN12615000187549 . Registered on 26 February 2015.


Generic method for aero-optic evaluations.
The effect of aerodynamic flow on the performance of an airborne optical system is becoming a critical issue in the development of electro-optic systems. A novel technique for aero-optic calculations that is based on commercially available software is presented. The optically relevant data from the computational fluid dynamics results are transformed into an index-of-refraction field and introduced as an input to the optical code. The data do not necessarily have to be presented in analytical form; instead it is introduced in a most general form as a discrete set of values located at a nonuniform grid of points. The modified quadratic Shepard method has been adopted for data interpolation, enabling a simple interface with virtually any software output. Several numerical simulations that demonstrate the technique are presented.


Flat-panel CT arthrography: feasibility study and comparison to multidetector CT arthrography.
To show the feasibility of flat-panel computed tomography (FPCT) arthrography and quantitatively and qualitatively compare different FPCT protocols with standard multidetector computed tomography (MDCT). First, a phantom simulating joint space with increasing iodine concentrations was scanned using a standard MDCT and 3 different FPCT protocols. Quantitative analyses were performed by measuring CT numbers of iodine dilutions, radiation dose, and image noise as well as signal-to-noise ratio and contrast-to-noise ratio. Second, FPCT arthrographies of 4 animal joint specimens were performed and analyzed qualitatively by 2 independent readers who evaluated image artifacts, image noise, overall image quality and anatomic depiction of bone, cartilage, and soft tissue. Kappa values were calculated for inter-reader agreement. Pearson's correlation coefficient (r) and Wilcoxon signed-ranks test with Bonferroni corrections for multiple comparisons were used to compare MDCT and FPCT. In phantoms, all CT scans showed a linear correlation between increasing iodine concentrations and mean HU values of contrast media and radiation dose, respectively (r = 0.98-0.99, P < 0.01). Dose-length product remained constant for MDCT scans. Signal-to-noise ratio for phantom water linearly decreased in all FPCT scans with increasing iodine concentrations. Contrast-to-noise ratio curves showed reduced slope at iodine concentrations higher than 75 mg/mL. FPCT arthrography after intra-articular administration of 5 to 6 mL of a 25% dilution of iopromide (Ultravist 300 mg/mL, Bayer HealthCare, Berlin, Germany) was successfully performed in all 4 animal joint specimens. Kappa values for inter-reader agreement of qualitative image analyses were 0.62 to 0.91. Image and depiction quality of 20-s FPCT scans were similar or superior compared with standard MDCT (P < 0.005). FPCT arthrography is feasible and may allow similar image quality compared with standard MDCT arthrography.


Fast and Efficient XML Data Access for Next-Generation Mass Spectrometry.
In mass spectrometry-based proteomics, XML formats such as mzML and mzXML provide an open and standardized way to store and exchange the raw data (spectra and chromatograms) of mass spectrometric experiments. These file formats are being used by a multitude of open-source and cross-platform tools which allow the proteomics community to access algorithms in a vendor-independent fashion and perform transparent and reproducible data analysis. Recent improvements in mass spectrometry instrumentation have increased the data size produced in a single LC-MS/MS measurement and put substantial strain on open-source tools, particularly those that are not equipped to deal with XML data files that reach dozens of gigabytes in size. Here we present a fast and versatile parsing library for mass spectrometric XML formats available in C++ and Python, based on the mature OpenMS software framework. Our library implements an API for obtaining spectra and chromatograms under memory constraints using random access or sequential access functions, allowing users to process datasets that are much larger than system memory. For fast access to the raw data structures, small XML files can also be completely loaded into memory. In addition, we have improved the parsing speed of the core mzML module by over 4-fold (compared to OpenMS 1.11), making our library suitable for a wide variety of algorithms that need fast access to dozens of gigabytes of raw mass spectrometric data. Our C++ and Python implementations are available for the Linux, Mac, and Windows operating systems. All proposed modifications to the OpenMS code have been merged into the OpenMS mainline codebase and are available to the community at https://github.com/OpenMS/OpenMS.


Tetrahydrobiopterin supplementation reduces atherosclerosis and vascular inflammation in apolipoprotein E-knockout mice.
BH4 (tetrahydrobiopterin) supplementation improves endothelial function in models of vascular disease by maintaining eNOS (endothelial nitric oxide synthase) coupling and NO (nitric oxide) bioavailability. However, the cellular mechanisms through which enhanced endothelial function leads to reduced atherosclerosis remain unclear. We have used a pharmaceutical BH4 formulation to investigate the effects of BH4 supplementation on atherosclerosis progression in ApoE-KO (apolipoprotein E-knockout) mice. Single oral dose pharmacokinetic studies revealed rapid BH4 uptake into plasma and organs. Plasma BH4 levels returned to baseline by 8 h after oral dosing, but remained markedly increased in aorta at 24 h. Daily oral BH4 supplementation in ApoE-KO mice from 8 weeks of age, for a period of 8 or 12 weeks, had no effect on plasma lipids or haemodynamic parameters, but significantly reduced aortic root atherosclerosis compared with placebo-treated animals. BH4 supplementation significantly reduced VCAM-1 (vascular cell adhesion molecule 1) mRNA levels in aortic endothelial cells, markedly reduced the infiltration of T-cells, macrophages and monocytes into plaques, and reduced T-cell infiltration in the adjacent adventitia, but importantly had no effect on circulating leucocytes. GCH (GTP cyclohydrolase I)-transgenic mice, with a specific increase in endothelial BH4 levels, exhibited a similar reduction in vascular immune cell infiltration compared with BH4-deficient controls, suggesting that BH4 reduces vascular inflammation via endothelial cell signalling. In conclusion, BH4 supplementation reduces vascular immune cell infiltration in atherosclerosis and may therefore be a rational therapeutic approach to reduce the progression of atherosclerosis.


Attention grabbing in red deer sexual calls.
Identifying the respective functions of distinct call types is an important step towards understanding the diversification of mammal vocal repertoires. Red deer (Cervus elaphus) stags give two distinct types of roars during the rut, termed 'common roars' and 'harsh roars'. This study tests the hypothesis that harsh roars function to raise and maintain female attention to calling males. To this end, we examined the response of female red deer to playback sequences of common roar bouts including a bout of harsh roars midway through the sequence. We found that females not only substantially increased their attention to the bout of harsh roars but also then maintained overall higher attention levels to subsequent common roar bouts. Our results suggest that the specific acoustic characteristics of male red deer harsh roar bouts may have evolved to engage and maintain the attention of female receivers during the breeding season. More generally, they indicate a possible evolutionary path for the diversification of male sexual vocal repertoires.


Effects of norepinephrine on the renal vasculature in normal and endotoxemic dogs.
Septic shock is often complicated by systemic hypotension despite normal or increased cardiac output. Restoration of arterial pressure usually requires the administration of systemic vasopressor agents, such as norepinephrine. However, because norepinephrine induces vasoconstriction in other vascular beds, it may decrease visceral blood flow, impairing visceral organ function. Because sepsis is often associated with impaired peripheral vascular responsiveness, we hypothesized that, unlike in normal circulatory conditions, norepinephrine would improve visceral organ blood flow in sepsis by selectively increasing organ perfusion pressure. Thus, in nine pentobarbital-anesthetized, mechanically ventilated dogs, we measured the effect of norepinephrine infusion (0.3 microgram/kg/min) on renal, hepatic, and portal steady-state pressure-flow relations (P/Q) and the dynamic vascular P/Q, created by transient inferior vena caval occlusion, under basal and endotoxic conditions. Norepinephrine increased organ perfusion pressures during both control and endotoxemic conditions. However, even after controlling for the pressure effect using a general linear model, NE was associated with an increase in renal blood flow both before and after endotoxin administration. We conclude that, unlike the effects of administering norepinephrine under baseline conditions, norepinephrine infusion during endotoxic shock actually increases renal blood flow and that this effect is not the result of an increase in perfusion pressure alone.


Adenoviral delivery of recombinant hepatitis B virus expressing foreign antigenic epitopes for immunotherapy of persistent viral infection.
We previously reported a proof-of-concept study for curing chronic hepatitis B virus (HBV) infection using a foreign-antigen recombinant HBV (rHBV) as a gene therapy vector. Targeted elimination of wild-type HBV (wtHBV)-infected cells could be achieved by functionally activating an in situ T-cell response against the foreign antigen. However, as chronic HBV infection spreads to all hepatocytes, specific targeting of virus-infected cells is thought to be less critical. It is also feared that rHBV may not induce active immunization in a setting resembling natural infection. For this immunotherapeutic approach to be practically viable, in the present study, we used a recombinant adenovirus (rAd) vector for rHBV delivery. The rAd vector allowed efficient transduction of wtHBV-producing HepG2 cells, with transferred rHBV undergoing dominant viral replication. Progeny rHBV virions proved to be infectious, as demonstrated in primary tupaia hepatocytes. These results greatly expanded the antiviral capacity of the replication-defective rAd/rHBV in wtHBV-infected liver tissue. With prior priming in the periphery, transduction with rAd/rHBV attracted a substantial influx of the foreign-antigen-specific T-effector cells into the liver. Despite the fully activated T-cell response, active expression of rHBV was observed for a prolonged time, which is essential for rHBV to achieve sustained expansion. In a mouse model of HBV persistence established by infection with a recombinant adeno-associated virus carrying the wtHBV genome, rAd/rHBV-based immunotherapy elicited a foreign-antigen-specific T-cell response that triggered effective viral clearance and subsequent seroconversion to HBV. It therefore represents an efficient strategy to overcome immune tolerance, thereby eliminating chronic HBV infection. Adenovirus-delivered rHBV activated a foreign-antigen-specific T-cell response that abrogated HBV persistence in a mouse model. Our study provides further evidence of the potential of foreign-antigen-based immunotherapy for the treatment of chronic HBV infection.


Aneusomies of chromosomes 8 and Y detected by fluorescence in situ hybridization are prognostic markers for pathological stage C (pt3N0M0) prostate carcinoma.
In an attempt to identify new prognostic markers, we performed fluorescence in situ hybridization (FISH) ploidy analysis of tumor tissue from patients with a targeted stage and histological grade of prostate carcinoma. We identified all 227 patients from the Mayo Clinic radical prostatectomy data base who had a high histological grade pathological stage C (pT3N0M0) tumor removed between 1966 and 1987. After histological review of the paraffin-embedded specimen blocks, 181 cases were suitable for FISH analysis using chromosome enumeration probes for chromosomes 7, 8, 10, 12, X, and Y. FISH detected 80 (44%) diploid, 22 (12%) tetraploid, and 79 (44%) aneuploid tumors. The common aneusomies were of chromosomes 7 and 8, which were present in 51 (28%) and 46 (25%) tumors, respectively. Aneusomies of chromosomes 10, 12, X, and Y were observed in 11 (6%), 15 (8%) 12 (7%) and 16 (9%) tumors, respectively. FISH aneuploid tumors showed a trend of more frequent systemic prostate cancer progression than nonaneuploid tumors (P = 0.060). For individual chromosome anomalies, gains of chromosome 8, aneusomy of chromosome 8, and aneusomy of chromosome Y correlated highly with systemic cancer progression (P = 0.006, 0.013, and 0.021, respectively). Gains of chromosome Y and aneusomy of chromosome Y were associated with an increased prostate cancer death rate (P < 0.001 for both). Multivariate analysis showed that gains of chromosome 8 and aneusomy of chromosome Y were significant independent "predictors" of systemic cancer progression (P = 0.008) and cancer death (P < 0.001), respectively. These results demonstrate that aneuploidy and specific aneusomies detected by FISH are potential markers for a poor prognosis in histological high-grade pathological stage C (pT3N0M0) prostate carcinoma.


Managing malignant cerebral infarction.
Managing patients with malignant cerebral infarction remains one of the foremost challenges in medicine. These patients are at high risk for progressive neurologic deterioration and death due to malignant cerebral edema, and they are best cared for in the intensive care unit of a comprehensive stroke center. Careful initial assessment of neurologic function and of findings on MRI, coupled with frequent reassessment of clinical and radiologic findings using CT or MRI are mandatory to promote the prompt initiation of treatments that will ensure the best outcome in these patients. Significant deterioration in either neurologic function or radiologic findings or both demand timely treatment using the best medical management, which may include osmotherapy (mannitol or hypertonic saline), endotracheal intubation, and mechanical ventilation. Under appropriate circumstances, decompressive craniectomy may be warranted to improve outcome or to prevent death.


Getting the balance right-tackling the obesogenic environment by reducing unhealthy options in a hospital shop without affecting profit.
UK hospitals have been criticized for fuelling obesity by allowing contracts with food retailers selling high fat and high-sugar products on hospital premises. We assessed the impact for a major retailer of increasing healthy food choices at their Royal Free London NHS Foundation Trust outlet. To assess the impact on sales, profit and acceptability to customers, a multi-component intervention based on behavioural insights theory was enacted over 2 months (November-December 2014) at the Royal Free site WHSmith. Sales data on all food and drink were assessed over three time periods: (i) 2 months immediately prior to, and (ii) immediately after the intervention, and (iii) the equivalent period 10 months later. Acceptability to customers was assessed via questionnaires, and profit assessed as a proxy for retailer satisfaction. Compared to the pre-intervention period, total sales increased immediately after the intervention, and again 10 months after the intervention. Sales of healthier options increased as a proportion of total sales following the intervention, sales of sweets and chocolates decreased, while the relative sales of other items remained similar. We demonstrated that healthier alternatives could be provided in a hospital retail premises without negatively affecting total sales, retailer or customer satisfaction.


Microbiota Profile and Impact of Fusobacterium nucleatum in Colorectal Cancer Patients of Barretos Cancer Hospital.
Microbial diversity has been pointed out as a major factor in the development and progression of colorectal cancer (CRC). We sought to explore the richness and abundance of the microbial community of a series of colorectal tumor samples treated at Barretos Cancer Hospital, Brazil, through 16S rRNA sequencing. The presence and the impact of Fusobacterium nucleatum (Fn) DNA in CRC prognosis was further evaluated by qPCR in a series of 152 CRC cases. An enrichment for potentially oncogenic bacteria in CRC was observed, with Fusobacterium being the most abundant genus in the tumor tissue. In the validation dataset, Fn was detected in 35/152 (23.0%) of fresh-frozen tumor samples and in 6/57 (10.5%) of paired normal adjacent tissue, with higher levels in the tumor (p = 0.0033). Fn DNA in the tumor tissue was significantly associated with proximal tumors (p = 0.001), higher depth of invasion (p = 0.014), higher clinical stages (p = 0.033), poor differentiation (p = 0.011), MSI-positive status (p < 0.0001), BRAF mutated tumors (p < 0.0001), and the loss of expression of mismatch-repair proteins MLH1 (p < 0.0001), MSH2 (p = 0.003), and PMS2 (p < 0.0001). Moreover, the presence of Fn DNA in CRC tissue was also associated with a worse patient cancer-specific survival (69.9 vs. 82.2% in 5 years; p = 0.028) and overall survival (63.5 vs. 76.5%; p = 0.037). Here we report, for the first time, the association of F. nucleatum presence with important clinical and molecular features in a Brazilian cohort of CRC patients. Tumor detection and classification based on the gut microbiome might provide a promising approach to improve the prediction of patient outcome.


Excitation of dark plasmonic modes in symmetry broken terahertz metamaterials.
Plasmonic structures with high symmetry, such as double-identical gap split ring resonators, possess dark eigenmodes. These dark eigenmodes are dominated by magnetic dipole and/or higher-order multi-poles such as electric quadrapoles. Consequently these dark modes interact very weakly with the surrounding environment, and can have very high quality factors (Q). In this work, we have studied, experimentally as well as theoretically, these dark eigenmodes in terahertz metamaterials. Theoretical investigations with the help of classical perturbation theory clearly indicate the existence of these dark modes in symmetric plasmonic metamaterials. However, these dark modes can be excited experimentally by breaking the symmetry within the constituting metamaterial resonators cell, resulting in high quality factor resonance mode. The symmetry broken metamaterials with such high quality factor can pave the way in realizing high sensitivity sensors, in addition to other applications.


Nonprimate hepaciviruses in domestic horses, United kingdom.
Although the origin of hepatitis C virus infections in humans remains undetermined, a close homolog of this virus, termed canine hepacivirus (CHV) and found in respiratory secretions of dogs, provides evidence for a wider distribution of hepaciviruses in mammals. We determined frequencies of active infection among dogs and other mammals in the United Kingdom. Samples from dogs (46 respiratory, 99 plasma, 45 autopsy samples) were CHV negative by PCR. Screening of 362 samples from cats, horses, donkeys, rodents, and pigs identified 3 (2%) positive samples from 142 horses. These samples were genetically divergent from CHV and nonprimate hepaciviruses that horses were infected with during 2012 in New York state, USA. Investigation of infected horses demonstrated nonprimate hepacivirus persistence, high viral loads in plasma (10(5)-10(7) RNA copies/mL), and liver function test results usually within reference ranges, although several values ranged from high normal to mildly elevated. Disease associations and host range of nonprimate hepaciviruses warrant further investigation.