The pathological findings of breast cancer in patients surviving 25 years after radical mastectomy.
The authors report the findings in 107 women who are known to have survived 25 years from among a population of 746 consecutive patients who underwent radical mastectomy for breast carcinoma at the University of Chicago Hospitals and Clinics from 1929 to 1955. Of these patients, 103 had invasive carcinomas, two had intraductal carcinomas, and two had subareolar papillomatosis. Six patients had to be excluded because of inadequate pathologic material. The pathologic findings in 93 cases were compared with those in an equal number of control cases dying within a comparatively short period (median, 3.4 years; range 0.9-9.9 years) after radical mastectomy. These were matched for age, tumor size, and number of positive nodes. Only two of our patients suffered recurrences, and none died of her original tumor; however, 12 developed second primaries in the opposite breast, and four died from them. Compared with all patients who underwent radical mastectomy in this period, the 25-year survivors were younger (69 versus 43% were younger than age 50 years), had smaller tumors (39 versus 26% less than 2 cm in diameter), and a larger number (60 versus 39%) had negative nodes. Nonetheless, 12% of the survivors had tumors larger than 5 cm in diameter and 11% had four or more positive nodes. Histologically, 19% of the 25-year survivors had medullary, mucoid, infiltrating lobular, tubular or lipid rich carcinomas, whereas there was only one lobular and one apocrine carcinoma in the control group. Compared with controls, the survivors had a higher percentage of Grade I tumors and a lower incidence of lymphatic and vascular invasion in the breast. Only one 25-year survivor compared with 16 controls had blood vessel invasion. A surprising 63% of the 25-year survivors had lymphatic or vascular invasion within the tumor, or lymph node metastases compared with 82% of controls. While our studies confirm the importance of these well-known prognostic indicators, it also shows that some patients with pathologically unfavorable lesions, i.e., large tumors of high grade with extensive lymphatic invasion and many positive nodes, treated by radical mastectomy may survive for 25 years. However, we could not accurately predict, among the cases we studied, who would be expected to survive 25 years or who would die within four years.


MyrSINEs: a novel SINE family in the anteater genomes.
Recent rapid generation of genomic sequence data has allowed many researchers to perform comparative analyses in various mammalian species. However, characterization of transposable elements, such as short interspersed repetitive elements (SINEs), has not been reported for several mammalian groups. Because SINEs occupy a large portion of the mammalian genome, they are believed to have contributed to the constitution and diversification of the host genomes during evolution. In the present study, we characterized a novel SINE family in the anteater genomes and designated it the MyrSINE family. Typical SINEs consist of a tRNA-related, a tRNA-unrelated and an AT-rich (or poly-A) region. MyrSINEs have only tRNA-related and poly-A regions; they are included in a group called t-SINE. The tRNA-related regions of the MyrSINEs were found to be derived from tRNA(Gly). We demonstrate that the MyrSINE family can be classified into three subfamilies. Two of the MyrSINE subfamilies are distributed in the genomes of both giant anteater and tamandua, while the other is present only in the giant anteater. We discuss the evolutionary history of MyrSINEs and their relationship to the evolution of anteaters. We also speculate that the simple structure of t-SINEs may be a potential evolutionary source for the generation of the typical SINE structure.


Autoimmunizing mechanisms in thymoma and thymus.
Autoimmunizing mechanisms are very hard to study in humans, so we have focused on vital clues in thymomas and hyperplastic thymuses in myasthenia gravis (MG). According to our multi-step hypothesis: thymic epithelial cells (TEC) present epitopes from the isolated acetylcholine receptor (AChR) subunits they express, and autoimmunize helper T cells; subsequently, these evoke "early antibodies" that then attack rare thymic myoid cells expressing intact AChR; in the resulting germinal centers, autoantibodies diversify to recognize native AChR. We have studied: 1) thymomas, to identify autoimmunizing cell types, focusing on IFN-alpha, against which many patients have high titer autoantibodies, as in another highly informative autoimmune syndrome. Although IFN-alpha is much easier to label than the sparse and delicate AChR subunits, we have not yet located obviously autoimmunizing micro-environments; 2) hyperplastic MG thymuses, where we find (a) upregulation of complement receptors and regulators on hyperplastic TEC and deposition of activated C3b complement component on them, (b) absence of complement regulators from almost all myoid cells, indicating vulnerability to attack, and (c) deposition of C3b, and even of the terminal membrane attack complex, especially on the myoid cells close to the infiltrating germinal centers. The changes are very similar in over 50% of the so-called seronegative patients with generalized MG (SNMG) but without detectable autoantibodies against AChR or MuSK, consistently with other evidence that they belong to the spectrum of AChR-seropositive MG. Together, moreover, our findings implicate both myoid cells and TEC in autoimmunization, and thus strongly support our hypothesis.


Authentic Borna disease virus transcripts are spliced less efficiently than cDNA-derived viral RNAs.
Borna disease virus (BDV) is a non-segmented, negative-strand RNA virus that replicates and transcribes its genome in the nucleus of infected cells. It uses the cellular splicing machinery to generate a set of alternatively spliced mRNAs from the 2.8 and 7.1 kb primary transcripts, each harbouring two introns. To determine whether splicing of these transcripts is regulated by viral factors, the extent of splicing was studied in infected cells and COS-7 cells transiently transfected with plasmids encoding the 2.8 kb RNA of BDV. Unspliced RNA was found to be the most abundant RNA species in infected cells, whereas viral transcripts lacking both introns were only found in minute amounts. In sharp contrast, plasmid-derived 2.8 kb RNA was predominantly intron 1-spliced and double-spliced. Co-expression of the BDV proteins P, N and X did not influence splicing of plasmid-expressed 2.8 kb RNA. Furthermore, the splicing pattern did not change when the 2.8 kb RNA was expressed in BDV-infected cells. Based on these results we speculate that splicing of authentic BDV transcripts is tightly linked to transcription by the viral polymerase.


A molecular Einstein ring: imaging a starburst disk surrounding a quasi-stellar object.
Images of the molecular CO 2-1 line emission and the radio continuum emission from the redshift 4.12 gravitationally lensed quasi-stellar object (QSO) PSS J2322+1944 reveal an Einstein ring with a diameter of 1.5". These observations are modeled as a star-forming disk surrounding the QSO nucleus with a radius of 2 kiloparsecs. The implied massive star formation rate is 900 solar masses per year. At this rate, a substantial fraction of the stars in a large elliptical galaxy could form on a dynamical time scale of 108 years. The observation of active star formation in the host galaxy of a high-redshift QSO supports the hypothesis of coeval formation of supermassive black holes and stars in spheroidal galaxies.


A Skin Cancer Prevention Facial-Aging Mobile App for Secondary Schools in Brazil: Appearance-Focused Interventional Study.
The incidence of melanoma is increasing faster than any other major cancer both in Brazil and worldwide. Southeast Brazil has especially high incidences of melanoma, and early detection is low. Exposure to ultraviolet (UV) radiation is a primary risk factor for developing melanoma. Increasing attractiveness is a major motivation among adolescents for tanning. A medical student-delivered intervention that takes advantage of the broad availability of mobile phones and adolescents' interest in their appearance indicated effectiveness in a recent study from Germany. However, the effect in a high-UV index country with a high melanoma prevalence and the capability of medical students to implement such an intervention remain unknown. In this pilot study, our objective was to investigate the preliminary success and implementability of a photoaging intervention to prevent skin cancer in Brazilian adolescents. We implemented a free photoaging mobile phone app (Sunface) in 15 secondary school classes in southeast Brazil. Medical students "mirrored" the pupils' altered 3-dimensional (3D) selfies reacting to touch on tablets via a projector in front of their whole grade accompanied by a brief discussion of means of UV protection. An anonymous questionnaire capturing sociodemographic data and risk factors for melanoma measured the perceptions of the intervention on 5-point Likert scales among 356 pupils of both sexes (13-19 years old; median age 16 years) in grades 8 to 12 of 2 secondary schools in Brazil. We measured more than 90% agreement in both items that measured motivation to reduce UV exposure and only 5.6% disagreement: 322 (90.5%) agreed or strongly agreed that their 3D selfie motivated them to avoid using a tanning bed, and 321 (90.2%) that it motivated them to improve their sun protection; 20 pupils (5.6%) disagreed with both items. The perceived effect on motivation was higher in female pupils in both tanning bed avoidance (n=198, 92.6% agreement in females vs n=123, 87.2% agreement in males) and increased use of sun protection (n=197, 92.1% agreement in females vs n=123, 87.2% agreement in males) and independent of age or skin type. All medical students involved filled in a process evaluation revealing that they all perceived the intervention as effective and unproblematic, and that all pupils tried the app in their presence. The photoaging intervention was effective in changing behavioral predictors for UV protection in Brazilian adolescents. The predictors measured indicated an even higher prospective effectiveness in southeast Brazil than in Germany (>90% agreement in Brazil vs >60% agreement in Germany to both items that measured motivation to reduce UV exposure) in accordance with the theory of planned behavior. Medical students are capable of complete implementation. A randomized controlled trial measuring prospective effects in Brazil is planned as a result of this study.


Effects of toothbrush hardness on in vitro wear and roughness of composite resins.
To investigate and compare the effects of toothbrushes with different hardness on abrasion and surface roughness of composite resins. Toothbrushes (DENT. EX Slimhead II 33, Lion Dental Products Co. Ltd., Tokyo, Japan) marked as soft, medium and hard, were used to brush 10 beam-shaped specimens of each of three composites resins (Venus [VEN], Venus Diamond [VED] and Venus Pearl [VEP]; HeraeusKulzer) with standardized calcium carbonate slurry in a multistation testing machine (2N load, 60 Hz). After each of five cycles with 10k brushing strokes the wear depth and surface roughness of the specimens were determined. After completion of 50k strokes representative samples were inspected by SEM. Data were treated with ANOVA and regression analyses (p < 0.05). Abrasion of the composite resins increased linearly with increasing number of brushing cycles (r² > 0.9). Highest wear was recorded for VEN, lowest for VED. Hard brushes produced significantly higher wear on VEN and VEP, whereas no difference in wear by toothbrush type was detected for VED. Significantly highest surface roughness was found on VED specimens (Ra > 1.5 µm), the lowest one on VEN (Ra < 0.3 µm). VEN specimens showed increased numbers of pinhole defects when brushed with hard toothbrushes, surfaces of VEP were uniformly abraded without level differences between the prepolymerized fillers and the glass filler-loaded matrix, VED showed large glass fillers protruding over the main filler-loaded matrix portion under each condition. Abrasion and surface roughness of composite resins produced by toothbrushing with dentifrice depend mainly on the type of restorative resin. Hardness grades of toothbrushes have minor effects only on abrasion and surface roughness of composite resins. No relationship was found between abrasion and surface roughness. The grade of the toothbrush used has minor effect on wear, texture and roughness of the composite resin.


Symmetrical arrangement of the heterologous regions of rabbit poxvirus and vaccinia virus DNA.
Cleavage sites for the restriction endonucleases EcoRI, KpnI and XhoI were mapped on rabbit poxvirus and vaccinia virus DNA. These physical maps were used to analyse the structural variations between the two DNAs. Two specific heterologous regions, symmetrically arranged at each end of the genomes, have been identified. Region 1, representing the exterior part of the terminal repetition, appears to contain unrelated sequences in each DNA and accounts for the difference in length of the two genomes. Region 2, separated from region 1 by a conserved part of the terminal repetition, is located at the transition from repeated to unique DNA sequences. Its overall length of about 4 megadaltons is well conserved and it contains individual DNA-specific as well as conserved restriction sites. The major central part of the genomes (over 100 megadaltons) contains very few, widely dispersed restriction site variations.


Hydrophobic interactions leading to a complex interplay between bioelectrocatalytic properties and multilayer meso-organization in layer-by-layer assemblies.
The present study explores the development of mesostructured bioelectrochemical interfaces with accurate compositional and topological control of the supramolecular architecture through the layer-by-layer assembly of ternary systems based on poly(allylamine) containing an osmium polypyridyl complex (OsPA), an anionic surfactant, sodium dodecyl sulfate (SDS) or sodium octodecyl sulfate (ODS), and glucose oxidase (GOx). We show that the introduction of the anionic surfactant allows a sensitive increase of the polyelectrolyte and the enzyme uptake at pH 7.0, enhancing its catalytic behavior in the presence of glucose as compared to the surfactant-free system (OsPA/GOx)n constructed at the same pH. Structural characterization of the multilayer films was performed by means of grazing-incidence small-angle X-ray scattering (GISAXS), which showed the formation of mesostructured domains within the composite assemblies. Experimental results indicate that the balance between ionic and hydrophobic interactions plays a leading role not only in the construction of the self-assembled system but also in the functional properties of the bioactive interface. The structure of the ternary multilayered films depends largely on the length of the alkyl chain of the surfactant. We show that surfactants incorporated into the film also play a role as chemical entities capable of tuning the hydrophobicity of the whole assembly. In this way, the deliberate introduction of short-range hydrophobic forces was exploited as an additional variable to manipulate the adsorption and coverage of protein during each assembly step. However, the integration of long-chain surfactants may lead to the formation of very well-organized interfacial architectures with poor electron transfer properties. This, in turn, leads to a complex trade-off between enzyme coverage and redox wiring that is governed by the meso-organization and the hydrophobic characteristics of the multilayer assembly.


Effects of vitamin A on growth and differentiation of human tracheobronchial epithelial cell cultures in serum-free medium.
Differentiating epithelial cell cultures from human tracheobronchial epithelium have been propagated in serum-free medium. The major objective of this study was to examine the trophic effects of vitamin A on cell multiplication and morphology of the tracheal cell cultures. The cellular responses were analyzed in terms of growth kinetics, morphological and ultrastructural alterations and secretion of glycoconjugates. Cell cultures in control medium exhibited characteristics of epithelial cells including microvilli on cell surfaces, desmosomes between cells, and numerous secretory vesicles in the cytoplasm. Vitamin A at 10(-6) M and 10(-7) M inhibited cell replication and enhanced the secretion of [3H]glucosamine-labeled glycoconjugates. Further, vitamin A increased the production of plasma membrane vesicles and acquisition by the cells of a highly secretory ultrastructure. This in vitro model of human epithelial cells will be important in the investigation of various aspects of growth and differentiation.


Dietary Emulsifiers Alter Composition and Activity of the Human Gut Microbiota in vitro, Irrespective of Chemical or Natural Emulsifier Origin.
The use of additives in food products has become an important public health concern. In recent reports, dietary emulsifiers have been shown to affect the gut microbiota, contributing to a pro-inflammatory phenotype and metabolic syndrome. So far, it is not yet known whether similar microbiome shifts are observable for a more diverse set of emulsifier types and to what extent these effects vary with the unique features of an individual's microbiome. To bridge this gap, we investigated the effect of five dietary emulsifiers on the fecal microbiota from 10 human individuals upon a 48 h exposure. Community structure was assessed with quantitative microbial profiling, functionality was evaluated by measuring fermentation metabolites, and pro-inflammatory properties were assessed with the phylogenetic prediction algorithm PICRUSt, together with a TLR5 reporter cell assay for flagellin. A comparison was made between two mainstream chemical emulsifiers (carboxymethylcellulose and P80), a natural extract (soy lecithin), and biotechnological emulsifiers (sophorolipids and rhamnolipids). While fecal microbiota responded in a donor-dependent manner to the different emulsifiers, profound differences between emulsifiers were observed. Rhamnolipids, sophorolipids, and soy lecithin eliminated 91 ± 0, 89 ± 1, and 87 ± 1% of the viable bacterial population after 48 h, yet they all selectively increased the proportional abundance of putative pathogens. Moreover, profound shifts in butyrate (-96 ± 6, -73 ± 24, and -34 ± 25%) and propionate (+13 ± 24, +88 ± 50, and +29 ± 16%) production were observed for these emulsifiers. Phylogenetic prediction indicated higher motility, which was, however, not confirmed by increased flagellin levels using the TLR5 reporter cell assay. We conclude that dietary emulsifiers can severely impact the gut microbiota, and this seems to be proportional to their emulsifying strength, rather than emulsifier type or origin. As biotechnological emulsifiers were especially more impactful than chemical emulsifiers, caution is warranted when considering them as more natural alternatives for clean label strategies.


Cancer chemotherapy during pregnancy. Consortium of cancer in pregnancy evidence.
I have an 8-weeks' pregnant patient who was diagnosed with stage III Hodgkin's disease last week. The oncologist suggests delaying chemotherapy until the second trimester. What are the effects of chemotherapy on a fetus after the first trimester? Where can I find reliable information on the subject? Available data suggest that exposure to chemotherapy during the first trimester of pregnancy is associated with increased risk of major malformations. Exposure during the second and third trimesters does not result in major malformations, but could have nonteratogenic effects, such as low birth weight. The brain develops throughout pregnancy, and it could be affected later in pregnancy.


Virtual Character Animation Based on Affordable Motion Capture and Reconfigurable Tangible Interfaces.
Software for computer animation is generally characterized by a steep learning curve, due to the entanglement of both sophisticated techniques and interaction methods required to control 3D geometries. This paper proposes a tool designed to support computer animation production processes by leveraging the affordances offered by articulated tangible user interfaces and motion capture retargeting solutions. To this aim, orientations of an instrumented prop are recorded together with animator's motion in the 3D space and used to quickly pose characters in the virtual environment. High-level functionalities of the animation software are made accessible via a speech interface, thus letting the user control the animation pipeline via voice commands while focusing on his or her hands and body motion. The proposed solution exploits both off-the-shelf hardware components (like the Lego Mindstorms EV3 bricks and the Microsoft Kinect, used for building the tangible device and tracking animator's skeleton) and free open-source software (like the Blender animation tool), thus representing an interesting solution also for beginners approaching the world of digital animation for the first time. Experimental results in different usage scenarios show the benefits offered by the designed interaction strategy with respect to a mouse & keyboard-based interface both for expert and non-expert users.


Upfront haploidentical transplant for acquired severe aplastic anemia: registry-based comparison with matched related transplant.
Haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT) is an alternative treatment method for severe aplastic anemia (SAA) patients lacking suitable identical donors and those who are refractory to immunosuppressive therapy (IST). The current study evaluated the feasibility of upfront haploidentical HSCT in SAA patients. We conducted a multicenter study based on a registry database. One hundred fifty-eight SAA patients who underwent upfront transplantation between June 2012 and September 2015 were enrolled. Eighty-nine patients had haploidentical donors (HIDs), and 69 had matched related donors (MRDs) for HSCT. The median times for myeloid engraftment in the HID and MRD cohorts were 12 (range, 9-20) and 11 (range, 8-19) days, with a cumulative incidence of 97.8 and 97.1% (P = 0.528), respectively. HID recipients had an increased cumulative incidence of grades II-IV acute graft-versus-host disease (aGVHD) (30.3 vs. 1.5%, P < 0.001), grades III-IV aGVHD (10.1 vs. 1.5%, P = 0.026), and chronic GVHD (cGVHD) (30.6 vs. 4.4%, P < 0.001) at 1 year but similar extensive cGVHD (3.4 vs. 0%, P = 0.426). The three-year estimated overall survival (OS) rates were 86.1 and 91.3% (P = 0.358), while the three-year estimated failure-free survival (FFS) rates were 85.0 and 89.8% (P = 0.413) in the HID and MRD cohorts, respectively. In multivariate analysis, survival outcome for the entire population was significantly adversely associated with increased transfusions and poor performance status pre-SCT. We did not observe differences in primary engraftment and survival outcomes by donor type. Haploidentical SCT as upfront therapy was an effective and safe option for SAA patients, with favorable outcomes in experienced centers.


Comparative Anatomy of the Ovine and Female Pelvis.
Pelvic organ prolapse affects half of vaginally parous women. Several animal models are used to study its pathophysiology and treatment. Sheep are interesting because they develop spontaneously prolapse with similar risk factors as women and can be used for vaginal surgery. This study describes ovine pelvis anatomy and compares it to women's pelvis to provide anatomical tools for translational researchers. MRI, pelvic dissections, and histology were used for detailed macro- and microscopic analysis of relevant anatomical structures in 6 nulliparous ewes. Although sheep are quadrupeds, the gross and microscopic anatomies are similar to the female pelvis. Principal differences are the shape and its orientation, the absence of the sacrospinous ligament and the internal obturator. The levator ani (except for the puborectalis) and the coccygeus muscle are present, yet the latter is more developed - coinciding with the tail. The dimensions and morphology of the ovine vagina is comparable. The retropubic and the rectovaginal space are accessible transvaginally. There is a wide expression of estrogen receptors with low or absent immunoreactivity in the urethral epithelium, bladder, anus and internal anal sphincter. The ovine pelvic floor has many anatomical and ultrastructural similarities to the female pelvic floor.


Nutritional quality of foods served in contracted second level lodging homes.
The food served in contracted Second Level Lodging Homes (SLLH) in Hamilton-Wentworth was studied to assess compliance with current by-law standards, make recommendations about nutrition standards and identify educational needs. Dietitians collected food frequency data in 62 SLLH and recorded food served during one day. Only 44% of homes provided the minimum servings recommended by 1982 Canada's Food Guide. Recommended nutrient intakes for ten nutrients were met by 20% of homes. Provision of therapeutic diets was inconsistent. The study indicates the need for better nutritional standards and strategies to ensure SLLH residents access to sufficient, nutritious and personally acceptable food.


Nano-reservoir Bioadhesive Tablets Enhance Protein Drug Permeability Across the Small Intestine.
Most therapeutic proteins are classified as class III drugs according to the Biopharmaceutical Classification System means that the low permeability across the intestinal epithelium is the rate-limited step for their oral absorption. Cationic chitosan nanoparticles have been found to open the tight junctions between epithelial cells. On the other hand, bioadhesive delivery devices could prolong the gastrointestinal residence time. In the present study, we developed a novel nano-reservoir bioadhesive tablets that combining the advantages of cationic nanoparticles and bioadhesive delivery devices anticipated achieving effective transport of sufficient protein drugs across the intestinal epithelium. The nano-reservoir in bioadhesive tablets was composed of chitosan nanoparticles (CS-NPs) loading a model protein drug bovine serum albumin (BSA). The formula of bioadhesive tablets was optimized by using rotatable central composite design and response surface methodology. The nano-reservoir, BSA-loaded CS-NPs, had an average particle diameter of 312.5 ± 12.89 nm and zeta-potential value of 26.76 ± 3.56 mV. Carboxymethyl chitosan added to the formula significantly ameliorated the tight junction damage of the Caco-2 cell monolayer induced by CS-NPs, meanwhile maintained the high transport efficiency of BSA. Permeability study exhibited that these nano-reservoir bioadhesive tablets combining the advantages of cationic nanoparticles and bioadhesive tablets significantly enhanced BSA transport through rabbit small intestine in comparison with either conventional bioadhesive tablets or CS-NPs. Therefore, these nano-reservoir bioadhesive tablets provided a great potential dosage form design for the oral delivery of protein drugs.


Repeated use of GAL1 for gene disruption in Candida albicans.
A technique which has the potential to allow repeated use of the same selectable marker to create gene disruptions in Candida albicans has been developed. In this approach, originally described for Saccharomyces cerevisiae, the selectable marker is flanked by direct repeats. Mitotic recombination between these repeats leads to elimination of the selectable marker. A module in which the GALq1 gene is flanked by direct repeats of the bacterial CAT gene was constructed and used to disrupt one copy of the URA3 gene in a gal1 mutant. Gal- revertants were selected by plating on 2-deoxy-D-galactose (2DOG). The frequency of 2DOG-resistant colonies recovered was 20 times higher than that obtained with a similar construct not flanked by direct repeats. Of these, 20% had lost the GAL1 gene by recombination between the direct repeats. The GAL1 gene was used again to disrupt the remaining wild-type copy of the URA3 gene of one of these gal1 isolates, resulting in a stable ura3 mutant. This technique should be generally applicable to derive homozygous gene disruptions in this diploid organism.


Migratory flyway and geographical distance are barriers to the gene flow of influenza virus among North American birds.
Despite the importance of migratory birds in the ecology and evolution of avian influenza virus (AIV), there is a lack of information on the patterns of AIV spread at the intra-continental scale. We applied a variety of statistical phylogeographic techniques to a plethora of viral genome sequence data to determine the strength, pattern and determinants of gene flow in AIV sampled from wild birds in North America. These analyses revealed a clear isolation-by-distance of AIV among sampling localities. In addition, we show that phylogeographic models incorporating information on the avian flyway of sampling proved a better fit to the observed sequence data than those specifying homogeneous or random rates of gene flow among localities. In sum, these data strongly suggest that the intra-continental spread of AIV by migratory birds is subject to major ecological barriers, including spatial distance and avian flyway.


Prevalence of physical health problems among youth entering residential treatment.
To examine the prevalence of physical health problems among youth entering residential treatment. The sample included 1744 youth (mean age: 14.6 ± 1.8 years) entering a large residential treatment program between 2000 and 2010. Youth received an intake medical evaluation, including a review of available records, detailed medical history, and physical examination. Medical conditions present at the time of the evaluation were recorded by the examining physician and later coded by the research team. Only diagnoses recognized by the International Classification of Diseases, 10th Revision, were included in the analyses. To maintain the focus on physical health problems, behavioral and emotional disorders listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision were excluded. Obesity, acne, and allergies were also excluded. Approximately one-third (33.7%) of youth had a physical health diagnosis at the time of intake. Asthma was the most prevalent condition diagnosed (15.3% of the sample). Girls were significantly more likely to have a diagnosis than were boys (37.1% vs 31.5%). Age was not associated with diagnostic status. Rates of physical health conditions differed significantly by ethnicity: black (36.4%) and white (35.4%) youth had the highest rates, and Hispanic youth (23.2%) had the lowest. Youth who enter residential treatment have high rates of physical health conditions. These problems could complicate mental health treatment and should be considered in multidisciplinary treatment planning.


Testing for uniformity in multidimensional data.
Testing for uniformity in multidimensional data is important in exploratory pattern analysis, statistical pattern recognition, and image processing. The goal of this paper is to determine whether the data follow the uniform distribution over some compact convex set in K-dimensional space, called the sampling window. We first provide a simple, computationally efficient method for generating a uniformly distributed sample over a set which approximates the convex hul of the data. We then test for uniformity by comparing this generated sample to the data by using Friedman-Rafsky's minimal spanning tree (MST) based test. Experiments with both simulated and real data indicate that this MST-based test is useful in deciding if data are uniform.


Auxiliary subunits of AMPA receptors: The discovery of a forebrain-selective antagonist, LY3130481/CERC-611.
Drugs originate from the discovery of compounds, natural or synthetic, that bind to proteins (receptors, enzymes, transporters, etc.), the interaction of which modulates biological cascades that have potential therapeutic benefit. Rational strategies for identifying novel drug therapies are typically based on knowledge of the structure of the target proteins and the design of new chemical entities that modulate these proteins in a beneficial manner. The present review discusses a novel approach to drug discovery based on the identification and characterization of auxiliary proteins, the transmembrane AMPA receptor regulatory proteins (TARPs) that are associated with AMPA receptors. Utilizing these auxiliary proteins in compound screening led to the discovery of the TARP-dependent-AMPA forebrain selective receptor antagonist (TDAA), LY3130481/CERC-611 that is currently in clinical development for epilepsy.


Fermentation Biotechnology Applied to Cereal Industry By-Products: Nutritional and Functional Insights.
Cereals are one of the major food sources in human diet and a large quantity of by-products is generated throughout their processing chain. These by-products mostly consist of the germ and outer layers (bran), deriving from dry and wet milling of grains, brewers' spent grain originating from brewing industry, or others originating during bread-making and starch production. Cereal industry by-products are rich in nutrients, but still they end up as feed, fuel, substrates for biorefinery, or waste. The above uses, however, only provide a partial recycle. Although cereal processing industry side streams can potentially provide essential compounds for the diet, their use in food production is limited by their challenging technological properties. For this reason, the development of innovative biotechnologies is essential to upgrade these by-products, potentially leading to the design of novel and commercially competitive functional foods. Fermentation has been proven as a very feasible option to enhance the technological, sensory, and especially nutritional and functional features of the cereal industry by-products. Through the increase of minerals, phenolics and vitamins bioavailability, proteins digestibility, and the degradation of antinutritional compounds as phytic acid, fermentation can lead to improved nutritional quality of the matrix. In some cases, more compelling benefits have been discovered, such as the synthesis of bioactive compounds acting as antimicrobial, antitumoral, antioxidant agents. When used for baked-goods manufacturing, fermented cereal by-products have enhanced their nutritional profile. The key factor of a successful use of cereal by-products in food applications is the use of a proper bioprocessing technology, including fermentation with selected starters. In the journey toward a more efficient food chain, biotechnological approaches for the valorization of agricultural side streams can be considered a very valuable help.


Silica nanoparticle crystals and ordered coatings using lys-sil and a novel coating device.
Silica nanoparticles with a narrow particle size distribution and controlled diameters of 10-20 nm are synthesized via hydrolysis and hydrothermal aging of tetraethylorthosilicate in an aqueous L-lysine solution. Cryo-transmission electron microscopy (cryo-TEM) reveals that the silica nanoparticles assemble to form close-packed nanoparticle crystals over short length scales on carbon-coated grids. Evaporative drying of the same sols results in nanoparticle stability and remarkable long-range facile ordering of the silica nanoparticles over scales greater than 10 microm. Whereas small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) discount the possibility of a core (silica)-shell (lysine) structure, the possibility remains for lysine occlusion within the silica nanoparticles and concomitant hydrogen bonding effects driving self-assembly. Facile ordering of the silica nanoparticles into multilayer and monolayer coatings over square-centimeter areas by evaporation-induced self-assembly is demonstrated using a novel dip-coating device.


Chromosome Translocations as a Driver of Diversification in Mole Voles Ellobius (Rodentia, Mammalia).
The involvement of chromosome changes in the initial steps of speciation is controversial. Here we examine diversification trends within the mole voles Ellobius, a group of subterranean rodents. The first description of their chromosome variability was published almost 40 years ago. Studying the G-band structure of chromosomes in numerous individuals revealed subsequent homologous, step-by-step, Robertsonian translocations, which changed diploid numbers from 54 to 30. Here we used a molecular cytogenetic strategy which demonstrates that chromosomal translocations are not always homologous; consequently, karyotypes with the same diploid number can carry different combinations of metacentrics. We further showed that at least three chromosomal forms with 2n = 34 and distinct metacentrics inhabit the Pamir-Alay mountains. Each of these forms independently hybridized with E. tancrei, 2n = 54, forming separate hybrid zones. The chromosomal variations correlate slightly with geographic barriers. Additionally, we confirmed that the emergence of partial or monobrachial homology appeared to be a strong barrier for hybridization in nature, in contradistinction to experiments which we reported earlier. We discuss the possibility of whole arm reciprocal translocations for mole voles. Our findings suggest that chromosomal translocations lead to diversification and speciation.


Ambulatory blood pressure and metabolic abnormalities in hypertensive subjects with inappropriately high left ventricular mass.
Appropriateness of left ventricular (LV) mass to cardiac workload can be evaluated by the ratio of observed LV mass to the value predicted for an individual's gender, height(2.7), and stroke work at rest (%PLVM). It is unclear which pathophysiological factors are associated with inappropriately high LV mass in hypertensive subjects. Adequate LV mass was defined by the 90% confidence interval (73% to 128%) of the distribution of %PLVM in 393 normal-weight normotensive subjects. In 185 hypertensive subjects (aged 56+/-11 years; 60% male, 29% black), according to %PLVM, 164 (88%) had adequate LV mass, 16 (9%) had inappropriately high LV mass (%PLVM >128%), and 5 (3%) had %PLVM <73% (low LV mass). Age, gender, smoking habit, proportion of never-treated subjects, total cholesterol, triglycerides, and creatinine levels did not differ significantly between subjects with adequate and inappropriately high LV mass. Body mass index, fasting glucose, and proportion of black subjects were higher (all P<0.05), while HDL cholesterol was lower (P<0.05) in subjects with inappropriately high LV mass. Blood pressure at the echocardiogram was comparable between subjects with adequate and inappropriately high LV mass, but the latter group had higher ambulatory blood pressure (P<0.01). Subjects with inappropriately high LV mass also had higher aortic root dimension and LV relative wall thickness and relatively lower LV systolic performance than those with adequate LV mass (all P<0.001). Larger aortic root diameter and lower systolic function were also found in hypertensive subjects with inappropriate LV hypertrophy compared with those with adequate LV hypertrophy. In an exploratory case-control study that compared subjects with low %PLVM with age-matched counterparts with adequate LV mass, low %PLVM was associated with lower body mass index, more favorable metabolic profile, and higher LV myocardial contractility. Higher body mass index, larger aortic root, and black race were independent correlates of increased %PLVM. Thus, in arterial hypertension, levels of LV mass inappropriately high for gender, cardiac workload, and height(2.7) are associated with higher body mass index, higher ambulatory blood pressure, larger aortic root diameters, and relatively low myocardial contractility.


Inferring antenatal care visit timing in low- and middle-income countries: Methods to inform potential maternal vaccine coverage.
The timing of antenatal care (ANC) visits directly affect health intervention coverage and impact, especially for those interventions requiring strict gestational age windows for administration, such as maternal respiratory syncytial virus (RSV) vaccine. Existing nationally representative population-based surveys do not record the timing of ANC visits beyond the first, limiting the availability of reliable data around timing of subsequent ANC visits in most low- and middle-income countries (LMICs). Here, we describe a model that estimates the timing of ANC visits by gestational age using publicly available multi-country survey data. We used the Demographic and Health Surveys (DHS) data from 69 LMICs. We used several factors to estimate the timing of subsequent ANC visits by gestation age: the timing of the first ANC visit (ANC1) in a given pregnancy, derived from the DHS; the country's reported average ANC coverage at each ANC visit (ANC1 through the fourth ANC visit [ANC4]); and the World Health Organization's guidance on recommended ANC visit. We then used the timing of ANC visit by gestation age to predict the coverage of a potential maternal RSV vaccine administered at 24-36 weeks of gestation. We calculated the maternal immunization coverage by summing the number of eligible women vaccinated at any ANC visit divided by the total number of pregnant women. We find, in general, countries with higher ANC1 coverage were predicted to have higher vaccination coverage. In 82% of countries, the modeled vaccine coverage is less than ANC4 coverage. The methods illustrated in this paper have implications on the precision of estimating impact and programmatic feasibility of time-critical interventions, especially for pregnant women. The methods can be easily adapted to vaccine demand forecasts models, vaccine impact assessments, and cost-effectiveness analyses and can be adapted to other maternal interventions that have administration timing restrictions.


Expression of p27(Kip1) and bcl-2, cigarette smoking, and colorectal cancer risk.
Although a positive association between cigarette smoking and colorectal adenoma development is consistently found, the association with colorectal cancer remains controversial. We evaluated the potential roles of p27(Kip1) and bcl-2 protein expressions in conjunction with cigarette smoking exposure and colorectal cancer risk in a hospital-based case-control study. A total of 163 colorectal cancer patients from Roswell Park Cancer Institute and Buffalo General Hospital and 326 healthy controls responded to a standardized questionnaire on colorectal cancer risk factors including detailed information on their history of cigarette smoking; 110 of the patients' tumours were available for immunohistochemical analysis of p27(Kip1) and bcl-2 protein overexpression. An avidin-biotin immunoperoxidase procedure was used to determine expression after incubation with mouse monoclonal p27(Kip1) and mouse monoclonal bcl-2 antibodies, respectively. A statistically significant trend for total pack-years of smoking was found when p27(Kip1) positive cases were compared with p27(Kip1) negative cases (trend test, p = 0.007). Although a weak inverse association was observed with smoking exposure among p27(Kip1) negative tumour cases in comparison to controls, a significant dose-response association was seen with p27(Kip1) positive tumours. The relative risk of developing a p27(Kip1) positive tumour was estimated to be 1.17 (95% CI 0.54-2.54) for those with less than 20 pack-years, 1.95 (95 % CI 0.95-3.97) for those with 20-39 pack-years, and 2.25 (95% CI 1.14-4.45) for those with greater than 39 pack-years of smoking exposure (trend test, p = 0.009) when compared with controls. When cases with bcl-2 expression were compared with cases without bcl-2 expression, suggestion of a trend was also observed with pack-years smoked (trend test, p = 0.09). In our study of 110 patients with sporadic colorectal cancer and 326 controls, we observed differences in associations between cigarette smoking and expressions in p27(Kip1) and bcl-2. Our data suggest that bcl-2 overexpression (or a bcl-2 dependent pathway) is associated with cigarette smoking in the development of colorectal cancer, whereas a loss of p27(Kip1) expression is not. These associations indicate that there is aetiological heterogeneity in colorectal cancer development, and that they can indirectly allude to where these changes in protein expression occur in the adenoma-carcinoma sequence (i.e. early versus late events).


Thermal decomposition, chemical composition, in vitro digestibility and gas production and in situ degradability of oilseed residues from the biofuel industry.
Thermal analysis could rapidly and easily predict nutritional value of ruminant feeds. The hypothesis is that crambe meal (CM) has a quality similar to that of soybean meal (SM), and the objective of this study was to determine the nutritional characteristics of CM and compare them to those of SM. CM had greater concentrations of phytic acid (26.3 vs. 16.0 g/kg) and phenol compounds (615 vs. 393 mg gallic acid (GAE)/kg) than SM. In vitro dry matter (DM) digestibility was lower for CM than SM (752 vs. 975 g/kg DM). Cumulative in vitro gas production at 48 h of incubation (14.1 vs. 19.4 mL/100 mg substrate DM), and energy release (4.5 vs. 5.7 kJ/g substrate DM) were lower for CM than SM. CM had a higher concentration of low digestible fiber, hence degradability of DM was lower and the proportion of indigestible fraction was greater for CM than SM. High concentrations of indigestible compounds were likely responsible for lower gas production of CM compared to SM. These results suggest CM quality is lower than that of SM and that thermal analysis is a useful tool to precisely determine the nutritive value of oilseed residues.


Evaluation of a pilot volunteer feeding assistance program: influences on the dietary intakes of elderly hospitalised patients and lessons learnt.
Malnutrition is a serious concern in hospitals and is known to be associated with increased complications for patients, increased hospital costs and length of stay. Trained volunteers that assist 'at risk' and malnourished patients at lunch meals have been shown to effectively increase nutritional intake in a suburban hospital in Sydney. The pilot study reported here aimed to evaluate and share learnings from a similar, newly implemented program, comparing energy and macronutrient intakes on days with no volunteer assistance, to days with volunteers. Dietary intakes were determined by visual estimation of meal trays before and after meals, for two days without volunteers, and two days with volunteer assistance at lunch. Macronutrient and energy intakes were compared and data such as weight, height, diet type and medical history were obtained from medical records. Questionnaires were completed by nurses and volunteers in regards to their views and experiences with the program. Hospital based. Eight patients (83±4.5 years) participated in the study. When volunteers were present at lunch, the average macronutrient and energy intakes increased, though not statistically significantly. The mean increases were 316 kJ (p=0.175) for energy, 3.1 g (p=0.468) for protein, 1.4 g (p=0.418) for fat and 11.6 g (p=0.084) for carbohydrates. Non-significant increases in macronutrients were also noted for the average daily intakes. Although not statistically significant, energy and macronutrient intakes increased when volunteers were present. The implementation of a volunteer feeding assistance program is one strategy to assist dietary intakes but requires a ready team of volunteers, training, acceptance and significant time to develop.


Neuroprotective effect of carvedilol and melatonin on 3-nitropropionic acid-induced neurotoxicity in neuroblastoma.
In neurodegenerative diseases, progressive oxidative stress is a major event that precedes neuronal death. Oxidative stress is characterized by an imbalance between oxidants and antioxidants. This imbalance induced oxidative molecular and cell damage, reducing cellular viability. 3-Nitropropionic acid (3NP) causes oxidative stress and other molecular and cellular changes similar to those observed in neurons of patients with Huntington's disease. Since carvedilol and melatonin act as free-radical scavengers, this study examined the effect of carvedilol (10(-5) M) and melatonin (10(-5) M) on oxidative and cell damage induced by 3NP in N1E-115 neuroblastoma cells. Carvedilol and melatonin prevented the increases in lipid peroxidation and total LDH activity, as well as the depletion of reduced glutathione (GSH) and the reduction of antioxidative enzymes activities in N1E-115 cells incubated with 100 mM 3NP. All these carvedilol and melatonin effects were more intense when the drugs were added before rather than after inducing the damage by 3NP. These results also provided evidence supporting the hypothesis that carvedilol and melatonin can be useful for treating neurodegenerative diseases, such as Huntington's disease.


Ric c 1 and Ric c 3, the allergenic 2S albumin storage proteins of Ricinus communis: complete primary structures and phylogenetic relationships.
The 2S albumin storage protein of Ricinus communis consists of the two heterodimeric proteins Ric c 1 and Ric c 3 each of which is composed of a small and a large subunit linked together by disulphide bridges. The complete primary structures of both heterodimeric proteins were determined by enzymatic degradation and automated Edman degradation. The sequences of all four chains correspond to the known cDNA sequence of the gene of a presumed precursor molecule and to the previously determined partial sequences for Ric c 1 and Ric c 3. In addition, few differences in amino acid positions were found which seem to be related to different varieties of R. communis. Sequence comparisons with 2S albumin from other plant genera revealed high degrees of homology and support the view of a common genetic origin of this protein family. Ric c 1 and Ric c 3 which have 11,212 and 12,032 daltons, respectively, share a similar molecular size, biological function and allergenicity with the 2S albumins from Brassica juncea (Braj 1E) and Sinapis alba L (Sin a 1). Ric c 1 and Ric c 3 may be classified as isoallergens if, additionally, the high degree of similarity in the position of polar residues is taken into account.


Oleic acid-derived oleoylethanolamide: A nutritional science perspective.
The fatty acid ethanolamide oleoylethanolamide (OEA) is an endogenous lipid mediator derived from the monounsaturated fatty acid, oleic acid. OEA is synthesized from membrane glycerophospholipids and is a high-affinity agonist of the nuclear transcription factor peroxisome proliferator-activated receptor α (PPAR-α). Dietary intake of oleic acid elevates circulating levels of OEA in humans by increasing substrate availability for OEA biosynthesis. Numerous clinical studies demonstrate a beneficial relationship between high-oleic acid diets and body composition, with emerging evidence to suggest OEA may mediate this response through modulation of lipid metabolism and energy intake. OEA exposure has been shown to stimulate fatty acid uptake, lipolysis, and β-oxidation, and also promote food intake control. Future research on high-oleic acid diets and body composition is warranted to confirm these outcomes and elucidate the underlying mechanisms by which oleic acid exerts its biological effects. These findings have significant practical implications, as the oleic acid-derived OEA molecule may be a promising therapeutic agent for weight management and obesity treatment.


Supratentorial primitive neuroectodermal tumors of the central nervous system in adults: molecular and histopathologic analysis of 12 cases.
Advances in understanding the molecular basis of primitive neuroectodermal tumors of the central nervous system (CNS-PNET) biology are critical to improve patient outcome. Recently, new data on their molecular features have been reported, suggesting that supratentorial PNET (s-PNET) in adult patients may represent a specific tumor entity among CNS-PNETs. In this study, we analyzed the clinicopathologic and molecular features of 12 cases of s-PNET in adult patients. The follow-up analysis showed that these tumors have an aggressive clinical behavior. At the histopathologic level, they resembled their pediatric counterpart, showing a variable spectrum of neuronal differentiation. These cases did not show astrocytic differentiation; therefore, they did not qualify for the differential diagnosis of glioblastoma variants. The tumors were also screened for mutation of TP53, IDH1, IDH2, and β-catenin, using single strand conformation polymorphism-based and sequencing assays, and were analyzed for c-myc/N-myc gene copy numbers with a quantitative polymerase chain reaction-based method. The strand conformation polymorphism-based mutational analysis showed that 5 tumors harbored TP53 mutations. In 2 cases, a mutation at codon 132 of the IDH1 gene was also found. No mutations of the β-catenin or IDH2 genes were identified. No cases presented c-myc or N-myc amplifications. Only 1 case presented overexpression of epidermal growth factor receptor. In conclusion, our data show a high incidence of TP53 mutations in this group of tumors and show, in comparison with pediatric s-PNET, the absence of amplification of the c-myc/N-myc genes, indicating that s-PNET in adult patients may represent a specific subset of tumors among CNS-PNETs.


Topical metronidazole therapy for rosacea.
Forty patients with rosacea were treated topically with 0.75% metronidazole gel in a randomized split-face double-blind paired-comparison trial. With twice-daily applications, 36.7, 48.5, and 65.1 mean percent reductions in total papules and pustules were noted over baseline at 3, 6, and 9 weeks, respectively, on the side of the face receiving metronidazole therapy. Therapy with vehicle alone produced a maximum mean percent reduction of 14.9 at nine weeks. Erythema also responded but was less improved by the end of nine weeks of therapy. A mild increase in telangiectasia was noted on both actively treated and placebo-treated sides. The gel was locally well tolerated. Only two of 40 patients failed to complete the trial, both because of flares of rosacea (one at two days, and one at five weeks). No systemic symptoms were noted, and no consistent abnormalities were found in the results of laboratory studies (hematology, chemistry, and urinalysis). Topical metronidazole gel therapy appears to be a safe and efficacious therapy in the treatment of moderate to severe rosacea.


Rapid detection and quantification of bisulfite reductase genes in oil field samples using real-time PCR.
Sulfate-reducing bacteria (SRB) pose a serious problem to offshore oil industries by producing sulfide, which is highly reactive, corrosive and toxic. The dissimilatory sulfite reductase (dsr) gene encodes for enzyme dissimilatory sulfite reductase and catalyzes the conversion of sulfite to sulfide. Because this gene is required by all sulfate reducers, it is a potential candidate as a functional marker. Denaturing gradient gel electrophoresis fingerprints revealed the presence of considerable genetic diversity in the DNA extracts achieved from production water collected from various oil fields. A quantitative PCR (qPCR) assay was developed for rapid and accurate detection of dsrB in oil field samples. A standard curve was prepared based on a plasmid containing the appropriate dsrB fragment from Desulfomicrobium norvegicum. The quantification range of this assay was six orders of magnitude, from 4.5 x 10(7) to 4.5 x 10(2) copies per reaction. The assay was not influenced by the presence of foreign DNA. This assay was tested against several DNA samples isolated from formation water samples collected from geographically diverse locations of India. The results indicate that this qPCR approach can provide valuable information related to the abundance of the bisulfite reductase gene in harsh environmental samples.


[Mechanisms of spontaneous relaxation of smooth muscle (guinea pig taenia coli) depolarized in a hyperkalemic medium].
Experiments were performed on isolated strips of guinea pig taenia coli by the double sucrose-gap method. The artificial node was depolarized with potassium solution (from 120 to 167.7 mM KCl). When the bathing solution contained 0.4 mM Ca and the temperature was equal to 25 degrees C then potassium contracture was followed by fast relaxation. The muscular tone changed slightly during rectangular pulse of hyperpolarizing current, after switching off the current muscle generated a transient contractile response. The amplitude of such off-responses increased in some range with increasing in strength and duration of conditioning current. Treatment of muscle with compound D-600 resulted in a reduction of muscular tone and elimination of off-responses. The addition of Na ions to potassium solution (substitution of 47.7 mM KCl with the same quantity of NaCl) reduced muscular tone and enhanced the relaxation after off-responses. In sodium-free potassium solution each off-response was followed by increasing muscular tone but when the bathing solution contained Na ions this increase of the tone was not observed. The data obtained strongly suggest that the spontaneous relaxation of smooth muscle which was contracted in K-solution resulted from: 1) inactivation of calcium channels of surface membrane, 2) sequastration of Ca ions by intracellular storange sites, 3) extrusion of Ca in extracellular space (in part by means of Na-Ca exchange diffusion).


A powerful and flexible multilocus association test for quantitative traits.
Association mapping of complex traits typically employs tagSNP genotype data to identify a trait locus within a region of interest. However, considerable debate exists regarding the most powerful strategy for utilizing such tagSNP data for inference. A popular approach tests each tagSNP within the region individually, but such tests could lose power as a result of incomplete linkage disequilibrium between the genotyped tagSNP and the trait locus. Alternatively, one can jointly test all tagSNPs simultaneously within the region (by using genotypes or haplotypes), but such multivariate tests have large degrees of freedom that can also compromise power. Here, we consider a semiparametric model for quantitative-trait mapping that uses genetic information from multiple tagSNPs simultaneously in analysis but produces a test statistic with reduced degrees of freedom compared to existing multivariate approaches. We fit this model by using a dimension-reducing technique called least-squares kernel machines, which we show is identical to analysis using a specific linear mixed model (which we can fit by using standard software packages like SAS and R). Using simulated SNP data based on real data from the International HapMap Project, we demonstrate that our approach often has superior performance for association mapping of quantitative traits compared to the popular approach of single-tagSNP testing. Our approach is also flexible, because it allows easy modeling of covariates and, if interest exists, high-dimensional interactions among tagSNPs and environmental predictors.


Structural Mechanism of ω-Currents in a Mutated Kv7.2 Voltage Sensor Domain from Molecular Dynamics Simulations.
Activation of voltage-gated ion channels is regulated by conformational changes of the voltage sensor domains (VSDs), four water- and ion-impermeable modules peripheral to the central, permeable pore domain. Anomalous currents, defined as ω-currents, have been recorded in response to mutations of residues on the VSD S4 helix and associated with ion fluxes through the VSDs. In humans, gene defects in the potassium channel Kv7.2 result in a broad range of epileptic disorders, from benign neonatal seizures to severe epileptic encephalopathies. Experimental evidence suggests that the R207Q mutation in S4, associated with peripheral nerve hyperexcitability, induces ω-currents at depolarized potentials, but the fine structural details are still elusive. In this work, we use atom-detailed molecular dynamics simulations and a refined model structure of the Kv7.2 VSD in the active conformation in a membrane/water environment to study the effect of R207Q and four additional mutations of proven clinical importance. Our results demonstrate that the R207Q mutant shows the most pronounced increase of hydration in the internal VSD cavity, a feature favoring the occurrence of ω-currents. Free energy and kinetics calculations of sodium permeation through the native and mutated VSD indicate as more favorable the formation of a cationic current in the latter. Overall, our simulations establish a mechanistic linkage between genetic variations and their physiological outcome, by providing a computational description that includes both thermodynamic and kinetic features of ion permeation associated with ω-currents.


A Global Perspective on Phosphorus Management Decision Support in Agriculture: Lessons Learned and Future Directions.
The evolution of phosphorus (P) management decision support tools (DSTs) and systems (DSS), in support of food and environmental security has been most strongly affected in developed regions by national strategies (i) to optimize levels of plant available P in agricultural soils, and (ii) to mitigate P runoff to water bodies. In the United States, Western Europe, and New Zealand, combinations of regulatory and voluntary strategies, sometimes backed by economic incentives, have often been driven by reactive legislation to protect water bodies. Farmer-specific DSSs, either based on modeling of P transfer source and transport mechanisms, or when coupled with farm-specific information or local knowledge, have typically guided best practices, education, and implementation, yet applying DSSs in data poor catchments and/or where user adoption is poor hampers the effectiveness of these systems. Recent developments focused on integrated digital mapping of hydrologically sensitive areas and critical source areas, sometimes using real-time data and weather forecasting, have rapidly advanced runoff modeling and education. Advances in technology related to monitoring, imaging, sensors, remote sensing, and analytical instrumentation will facilitate the development of DSSs that can predict heterogeneity over wider geographical areas. However, significant challenges remain in developing DSSs that incorporate "big data" in a format that is acceptable to users, and that adequately accounts for catchment variability, farming systems, and farmer behavior. Future efforts will undoubtedly focus on improving efficiency and conserving phosphate rock reserves in the face of future scarcity or prohibitive cost. Most importantly, the principles reviewed here are critical for sustainable agriculture.


Molecular Genetic Influences on Normative and Problematic Alcohol Use in a Population-Based Sample of College Students.
Background: Genetic factors impact alcohol use behaviors and these factors may become increasingly evident during emerging adulthood. Examination of the effects of individual variants as well as aggregate genetic variation can clarify mechanisms underlying risk. Methods: We conducted genome-wide association studies (GWAS) in an ethnically diverse sample of college students for three quantitative outcomes including typical monthly alcohol consumption, alcohol problems, and maximum number of drinks in 24 h. Heritability based on common genetic variants (h2SNP) was assessed. We also evaluated whether risk variants in aggregate were associated with alcohol use outcomes in an independent sample of young adults. Results: Two genome-wide significant markers were observed: rs11201929 in GRID1 for maximum drinks in 24 h, with supportive evidence across all ancestry groups; and rs73317305 in SAMD12 (alcohol problems), tested only in the African ancestry group. The h2SNP estimate was 0.19 (SE = 0.11) for consumption, and was non-significant for other outcomes. Genome-wide polygenic scores were significantly associated with alcohol outcomes in an independent sample. Conclusions: These results robustly identify genetic risk for alcohol use outcomes at the variant level and in aggregate. We confirm prior evidence that genetic variation in GRID1 impacts alcohol use, and identify novel loci of interest for multiple alcohol outcomes in emerging adults. These findings indicate that genetic variation influencing normative and problematic alcohol use is, to some extent, convergent across ancestry groups. Studying college populations represents a promising avenue by which to obtain large, diverse samples for gene identification.


Genome‑wide analysis and prediction of functional long noncoding RNAs in osteoblast differentiation under simulated microgravity.
Long noncoding RNAs (lncRNAs) have been regarded as important regulators in numerous biological processes during cell development. However, the holistic lncRNA expression pattern and potential functions during osteoblast differentiation under simulated microgravity remain unknown. In the present study, a high throughput microarray assay was performed to detect lncRNA and mRNA expression profiles during MC3TC‑E1 pre‑osteoblast cell osteo‑differentiation under simulated microgravity. The expression of 857 lncRNAs and 2,264 mRNAs was signi-ficantly altered when MC3T3‑E1 cells were exposed to simulated microgravity. A relatively consistent distribution pattern on the chromosome and a co‑expression network were observed between the differentially‑expressed lncRNAs and mRNAs. Genomic context analysis further identified 132 differentially‑expressed lncRNAs and nearby coding gene pairs. Subsequently, 3 lncRNAs were screened out for their possible function in osteoblast differentiation, based on their co‑expression association and potential cis‑acting regulatory pattern with the deregulated mRNAs. The present study aimed to provide a comprehensive understanding of and a foundation for future studies into lncRNA function in mechanical signal‑mediated osteoblast differentiation.


Clinical Mimics: An Emergency Medicine-Focused Review of Syncope Mimics.
Syncope is an event that causes a transient loss of consciousness (LOC) secondary to global cerebral hypoperfusion. The transient nature of the event can make diagnosis in the emergency department (ED) difficult, as symptoms have often resolved by time of initial presentation. The symptoms and presentation of syncope are similar to many other conditions, which can lead to difficulty in establishing a diagnosis in the ED. This review evaluates patients presenting with a history concerning for possible syncope, mimics of syncope, and approach to managing syncope mimics. Syncope is caused by transient LOC secondary to global cerebral hypoperfusion. Many conditions can present similarly to syncope, making diagnosis in the ED difficult. Some of the most emergent conditions include seizures, stroke, metabolic disorders, and head trauma. Other nonemergent conditions include cataplexy, pseudosyncope, or deconditioning. Many laboratory studies and imaging can be nondiagnostic during ED evaluation. For patients presenting with apparent syncope, immediate treatment should focus on identifying and treating life-threatening conditions. History and physical examination can help guide further diagnostic evaluation and management. Patients with apparent syncope should be evaluated for potential immediate life-threatening conditions. A thorough history and physical examination can aid in distinguishing syncope from common mimics and help identify and subsequently treat life-threatening conditions.


[The level of anxiety and depression in the early puerperium - preliminary communication].
Childbirth is both joyful and stressful life event. This stressful life event results in different emotions occurring with different strength among new mothers, one of them is postpartum depression. However, postnatal depression received the predominance of research attention in recent years, and several authors have pointed attention to the importance of distinguishing between postpartum depression and postpartum anxiety. The primary purpose of the presented research was to assess the level of anxiety and depression among women who were hospitalised after delivery. The second purpose was to determine if some additional factors influence the level of anxiety and depression. The study was conducted on the sample of 46 women who had delivered infants in the Gynecology - Obstetrics Clinical Hospital UM in Poznań, Poland in 2010. Method. Polish adaptations of standard questionnaires were used to measure variables such as anxiety (STAI), depression (BDI), styles of coping (CISS) and temperament (PTS). Additional data were collected using a questionnaire developed by the authors. Statistical analysis assessed the level and frequency of anxiety (as a state and as a trait) and depression and associations between these factors as well as associations with additional variables (including: mode of delivery, styles of coping with stress and temperament). The score in BDI in mothers after delivery was associated positively with emotion - oriented style of coping and anxiety as a state and as a trait and negatively with strength of inhibition processes. Anxiety as a trait was positively related to c-section.


Enhanced amygdala kindling after electrical stimulation of the ventral tegmental area: implications for fear and anxiety.
Electrical kindling refers to the seizure-generating properties of brain stimulation. In addition to producing epilepsy, the reorganization of forebrain neurocircuitry associated with kindling contributes to psychiatric disturbances involving fear and anxiety. The amygdala is a limbic structure that kindles readily and regulates the complex neurocircuitry underlying emotional responding. Dopamine-containing ventral tegmental area (VTA) neurons, known to be activated by threatening environmental stimuli, are an important component of the amygdala-based fear network. Using amygdala kindling as an indicator of sensitization development, we report here that repeated low-current, high-frequency stimulation of the VTA provoked afterdischarge in the central amygdala and enhanced kindling rate. By establishing a fundamental link between VTA activation and neural excitability in the central amygdala, the present results are consistent with the possibility of a common process underlying epileptogenisis and the fear motivational consequences of amygdala and VTA kindling. Considering the established role of the VTA and the amygdala in emotional responding, such a sensitization mechanism might mediate exaggerated fearfulness.


Impaired Maturation of Cognitive Control in Adolescents Who Develop Major Depressive Disorder.
This study examined whether development of two forms of cognitive control (proactive and reactive) between early and midadolescence was associated with the onset of major depressive disorder (MDD) during the same period and if it prospectively predicted MDD onset between mid- and late adolescence. Adolescents (N = 165) completed 3 waves of assessments, at 12 (T1), 16 (T2), and 18 (T3) years of age. Diagnostic interviews were conducted at each time point to identify three groups of adolescents: "early MDD," those who developed MDD between early (T1) and mid- (T2) adolescence (n = 23); "late MDD," those who developed MDD between mid- (T2) and late (T3) adolescence (n = 20); and "controls," those who did not develop MDD (n = 122). A modified Stroop task was completed at T1 and T2 to examine development of proactive and reactive cognitive control. Adolescents with early MDD exhibited significant declines in reactive control, as well as a trend level decline for proactive control, during this period compared to controls. No significant differences in reactive or proactive control were identified in adolescents with late MDD compared to controls, but they did exhibit significant improvements in proactive control compared to those with early MDD. These findings suggest that normative maturation of reactive, and possibly proactive, cognitive control abilities are impaired in adolescents who develop MDD between early and midadolescence. This has implications for understanding the mechanisms underlying certain forms of behavioral dysregulation that are commonly seen in MDD.


Peripheral Edema: Evaluation and Management in Primary Care.
Edema is a common clinical sign that may indicate numerous pathologies. As a sequela of imbalanced capillary hemodynamics, edema is an accumulation of fluid in the interstitial compartment. The chronicity and laterality of the edema guide evaluation. Medications (e.g., antihypertensives, anti-inflammatory drugs, hormones) can contribute to edema. Evaluation should begin with obtaining a basic metabolic panel, liver function tests, thyroid function testing, brain natriuretic peptide levels, and a urine protein/creatinine ratio. Validated decision rules, such as the Wells and STOP-Bang (snoring, tired, observed, pressure, body mass index, age, neck size, gender) criteria, can guide decision-making regarding the possibility of venous thromboembolic disease and obstructive sleep apnea, respectively. Acute unilateral lower-extremity edema warrants immediate evaluation for deep venous thrombosis with a d-dimer test or compression ultrasonography. For patients with chronic bilateral lower-extremity edema, duplex ultrasonography with reflux can help diagnose chronic venous insufficiency. Patients with pulmonary edema or elevated brain natriuretic peptide levels should undergo echocardiography to assess for heart failure. Lymphedema is often a clinical diagnosis; lymphoscintigraphy can be performed if the diagnosis is unclear. Treatment of edema is specific to the etiology. Diuretics are effective but should be used only for systemic causes of edema. Ruscus extract and horse chestnut seed demonstrate moderate-quality evidence to improve edema from chronic venous insufficiency. Compression therapy is effective for most causes of edema.


Expression of vitreous cytokines in proliferative vitreoretinopathy: a prospective study.
Proliferative vitreoretinopathy (PVR) is a major cause of failure of retinal detachment surgery. It is believed to be a wound-healing process in the retina. Many of the cellular functions are influenced by cytokines and growth factors such as interleukins (ILs). The present study was conducted to investigate the presence of transforming growth factor-beta 2 (TGF-beta2), basic fibroblast growth factor (bFGF), IL-1beta, IL-6, and protein in the vitreous of patients with retinal detachment and to determine the value of these mediators in predicting the future development of PVR. A prospective study was conducted in 140 consecutive patients with rhegmatogenous retinal detachment in whom vitrectomy was considered necessary. Vitreous samples were analyzed for the presence of TGF-beta2, bFGF, IL-1beta, IL-6, and protein. Patients were then followed up for 3 months for the development of postoperative PVR. The mean levels of TGF-beta2, bFGF, IL-1beta, and protein in the vitreous were significantly higher (P < 0.05) in patients with preoperative PVR compared with those without. The mean levels of TGF-beta2, bFGF, IL-6, and protein in the vitreous were significantly higher (P < 0.05) in patients who had postoperative PVR compared with those who did not. Multivariate logistic regression analysis showed IL-6 and protein to be significant (P < 0.05), independent, predictive risk factors for the development of PVR. The various cytokines may play a role in the pathobiology of PVR. High vitreous levels of IL-6 and protein were identified as significant risk factors for PVR. A model was developed to predict the probability of development of postoperative PVR in these patients, and it may be used to indicate intravitreal pharmacologic treatment for those at risk.


Multiparametric assessment of renal physiology in healthy volunteers using noninvasive magnetic resonance imaging.
Noninvasive methods of magnetic resonance imaging (MRI) can quantify parameters of kidney function. The main purpose of this study was to determine baseline values of such parameters in healthy volunteers. In 28 healthy volunteers (15 women and 13 men), arterial spin labeling to estimate regional renal perfusion, blood oxygen level-dependent transverse relaxation rate (R2*) to estimate oxygenation, and apparent diffusion coefficient (ADC), true diffusion (D), and longitudinal relaxation time (T1) to estimate tissue properties were determined bilaterally in the cortex and outer and inner medulla. Additionally, phase-contrast MRI was applied in the renal arteries to quantify total renal blood flow. The results demonstrated profound gradients of perfusion, ADC, and D with highest values in the kidney cortex and a decrease towards the inner medulla. R2* and T1 were lowest in kidney cortex and increased towards the inner medulla. Total renal blood flow correlated with body surface area, body mass index, and renal volume. Similar patterns in all investigated parameters were observed in women and men. In conclusion, noninvasive MRI provides useful tools to evaluate intrarenal differences in blood flow, perfusion, diffusion, oxygenation, and structural properties of the kidney tissue. As such, this experimental approach has the potential to advance our present understanding regarding normal physiology and the pathological processes associated with acute and chronic kidney disease.


Comparison of Experts and Residents Performing a Complex Procedure in a Temporal Bone Surgery Simulator.
To investigate the use of automated metrics from a virtual reality (VR) temporal bone surgery simulator to determine how the performance of experts and trainees differs when performing a complex otological procedure (mastoidectomy with posterior tympanotomy and cochleostomy). Cohort study. Using the University of Melbourne VR temporal bone surgery simulator, seven ENT consultants and seven ENT residents performed two trials of the surgical approach to cochlear implantation on a virtual temporal bone. Simulator recordings were used to calculate a range of automated metrics for each stage of the procedure, capturing efficiency, technique characteristics, drilled bone regions, and damage to vital anatomical structures. Results confirm that experts drilled more efficiently than residents. Experts generally used larger burrs and applied higher forces, resulting in faster material removal. However, they exercised more caution when drilling close to anatomical structures. Residents opened the temporal bone more widely, but neglected important steps in obtaining a clear view toward the round window, such as thinning the external ear canal wall and skeletonizing the medial aspect of the facial nerve. Residents used higher magnification and reoriented the temporal bone more often than experts. VR simulation provides metrics that allow the objective analysis of surgical technique, and identification of differences between the performance of surgical residents and their senior colleagues. The performance of residents could be improved with more guidance regarding how much force they should apply, what burr size they should use, how they should orient the bone, and for cochlear implant surgery guidance regarding anatomical regions requiring particular attention, to visualize the round window.


Results of surgical treatment of tibial plafond fractures.
To clarify which factors influence the final result of surgical management of plafond or pilon fractures, 66 patients with 67 pilon fractures treated at the Orthopaedic Department of the University of Athens between 1978 and 1993 were reviewed. There were eight (11.95%) Type I, 33 (49.25%) Type II, and 26 (38.8%) Type III fractures according to the Ruedi-Allgower classification. Eleven (16.4%) were open injuries. Fifty of the 67 fractures were treated by internal fixation following the AO principles, whereas minimal osteosynthesis was performed in nine cases, and the remaining eight cases were managed by external fixation. The final outcome of the treatment was evaluated after 2 to 17 years followup (mean, 8.1 years) and was based on the subjective, objective, and radiographic results of each case, using the method of Burwell and Charnley. The findings indicate that three parameters significantly influenced the outcome of plafond fracture management. Specifically, the results of surgical management were affected by the clinical type of the fracture, the quality of reduction achieved at surgery, and the specific surgical procedure by which the fracture was managed.


Toward a Molecular Understanding of the Mechanism of Cryopreservation by Polyampholytes: Cell Membrane Interactions and Hydrophobicity.
Cryopreservation enables long-term preservation of cells at ultralow temperatures. Current cryoprotective agents (CPAs) have several limitations, making it imperative to develop CPAs with advanced properties. Previously, we developed a novel synthetic polyampholyte-based CPA, copolymer of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and methacrylic acid(MAA) (poly(MAA-DMAEMA)), which showed excellent efficiency and biocompatibility. Introduction of hydrophobicity increased its efficiency significantly. Herein, we investigated the activity of other polyampholytes. We prepared two zwitterionic polymers, poly(sulfobetaine) (SPB) and poly(carboxymethyl betaine) (CMB), and compared their efficiency with poly(MAA-DMAEMA). Poly-SPB showed only intermediate property and poly-CMB showed no cryoprotective property. These data suggested that the polymer structure strongly influences cryoprotection, providing an impetus to elucidate the molecular mechanism of cryopreservation. We investigated the mechanism by studying the interaction of polymers with cell membrane, which allowed us to identify the interactions responsible for imparting different properties. Results unambiguously demonstrated that polyampholytes cryopreserve cells by strongly interacting with cell membrane, with hydrophobicity increasing the affinity for membrane interaction, which enables it to protect the membrane from various freezing-induced damages. Additionally, cryoprotective polymers, especially their hydrophobic derivatives, inhibit the recrystallization of ice, thus averting cell death. Hence, our results provide an important insight into the complex mechanism of cryopreservation, which might facilitate the rational design of polymeric CPAs with improved efficiency.


Tubuloglomerular feedback activity in virgin and 12-day-pregnant rats.
Tubuloglomerular feedback activity was evaluated by micropuncture and microperfusion techniques in virgin and 12-day-pregnant Munich-Wistar rats. Plasma volume increases in pregnancy, which could suppress feedback activity, thus contributing to the rise in glomerular filtration rate observed in normal midterm pregnancy. Late proximal tubules were microperfused at 0, 10, 20, and 40 nl/min and the resulting filtration rate in the same nephron was evaluated. Nephron filtration rate (SNGFR) in proximal and distal tubules of other nephrons was also measured to assess the degree of activation of the tubuloglomerular feedback system and the relation of the spontaneous (normal) late proximal flow rate and SNGFR (distal tubule collections). SNGFR decreased significantly (from the 0 nl/min perfusion value) when late proximal tubules were perfused at 20 and 40 nl/min in both virgin and 12-day-pregnant rats. Tubuloglomerular feedback activity was not suppressed in pregnancy, but the relationship between SNGFR and late proximal tubule perfusion rate was reset for a higher value for SNGFR. The difference between proximal and distal SNGFR suggests that the feedback system was more activated in the virgin than in the pregnant rat. Thus, in spite of the known increases in plasma volume that occur in pregnancy, the kidney does not sense this volume expansion as a stimulus to suppress feedback activity.


Immunoadjuvant efficacy of N-carboxymethyl chitosan for vaccination via dendritic cell activation.
To induce humoral- and cell-mediated immune responses in protein-based vaccinations, immunoadjuvants are needed. In this study, we investigated the immunoadjuvant effect of N-carboxymethyl chitosan (N-CMCh) on the vaccination system through dendritic cell activation. The results showed that N-CMCh nanoparticle enhanced the secretion of cytokines (interleukin [IL]-6, IL-12p70, and tumor necrosis factor-α) and antigen uptake in bone marrow-derived dendritic cells. This activated antigen-specific Th1 cell responses, including IL-2 and interferon-gamma production and proliferation. In addition, N-CMCh delayed the dissemination of ovalbumin (OVA) from an injection site in female C57BL/6 mice. As a result, in the subcutaneous vaccination, OVA-N-CMCh nanoparticles enhanced both humoral and cell-mediated vaccine responses.


Biofilm and the role of the ica operon and aap in Staphylococcus epidermidis isolates causing neurosurgical meningitis.
Fifty-five Staphylococcus epidermidis isolates, classified as contaminants or causing device-related meningitis, from external ventricular drain (EVD) and non-EVD cerebrospinal fluid specimens were characterized. Thirty-three of 42 (78.6%) meningitis isolates were PCR-positive for ica and aap, known determinants of polysaccharide- and protein-mediated biofilm production, whereas five of 13 (38.5%) contaminants were ica- and aap-negative; 71.4% of meningitis isolates and 84.6% of contaminants produced biofilm. ica+aap+ meningitis isolates produced more biofilm than ica+aap- isolates (p 0.0020). ica+aap- isolates did not produce more biofilm than ica-aap+ isolates (p 0.4368). Apparently, ica and aap are associated with biofilm production in S. epidermidis device-related meningitis isolates.


Quantitative proteomics reveals a dynamic association of proteins to detergent-resistant membranes upon elicitor signaling in tobacco.
A large body of evidence from the past decade supports the existence, in membrane from animal and yeast cells, of functional microdomains playing important roles in protein sorting, signal transduction, or infection by pathogens. In plants, as previously observed for animal microdomains, detergent-resistant fractions, enriched in sphingolipids and sterols, were isolated from plasma membrane. A characterization of their proteic content revealed their enrichment in proteins involved in signaling and response to biotic and abiotic stress and cell trafficking suggesting that these domains were likely to be involved in such physiological processes. In the present study, we used (14)N/(15)N metabolic labeling to compare, using a global quantitative proteomics approach, the content of tobacco detergent-resistant membranes extracted from cells treated or not with cryptogein, an elicitor of defense reaction. To analyze the data, we developed a software allowing an automatic quantification of the proteins identified. The results obtained indicate that, although the association to detergent-resistant membranes of most proteins remained unchanged upon cryptogein treatment, five proteins had their relative abundance modified. Four proteins related to cell trafficking (four dynamins) were less abundant in the detergent-resistant membrane fraction after cryptogein treatment, whereas one signaling protein (a 14-3-3 protein) was enriched. This analysis indicates that plant microdomains could, like their animal counterpart, play a role in the early signaling process underlying the setup of defense reaction. Furthermore proteins identified as differentially associated to tobacco detergent-resistant membranes after cryptogein challenge are involved in signaling and vesicular trafficking as already observed in similar studies performed in animal cells upon biological stimuli. This suggests that the ways by which the dynamic association of proteins to microdomains could participate in the regulation of the signaling process may be conserved between plant and animals.


Depression and suicide risk prediction models using blood-derived multi-omics data.
More than 300 million people worldwide experience depression; annually, ~800,000 people die by suicide. Unfortunately, conventional interview-based diagnosis is insufficient to accurately predict a psychiatric status. We developed machine learning models to predict depression and suicide risk using blood methylome and transcriptome data from 56 suicide attempters (SAs), 39 patients with major depressive disorder (MDD), and 87 healthy controls. Our random forest classifiers showed accuracies of 92.6% in distinguishing SAs from MDD patients, 87.3% in distinguishing MDD patients from controls, and 86.7% in distinguishing SAs from controls. We also developed regression models for predicting psychiatric scales with R2 values of 0.961 and 0.943 for Hamilton Rating Scale for Depression-17 and Scale for Suicide Ideation, respectively. Multi-omics data were used to construct psychiatric status prediction models for improved mental health treatment.


A method to label cigarette smoke with 99mTc.
A method is described to label with 99mTc the particulate matter in the smoke from commercially obtained cigarettes. A solution of technetium heptasulfide is applied to the paper wrapper of the tobacco rod and then dried. Smoke from a cigarette treated in this way contains measurable amounts of 99mTc in the particulate phase. In contrast, no measurable radioactivity is found in the non-particulate (gaseous) phase of smoke. This method yields a gamma-emitting cigarette smoke which will permit future observation of particulate intake, deposition and clearance in experimental animals and man.


Endovascular therapy for acute ischemic stroke with distal medium vessel occlusion: a systematic review and meta-analysis.
Endovascular therapy (EVT) for distal medium vessel occlusions (DMVOs) is a potential frontier of acute ischemic stroke (AIS) treatment, but its efficacy against best medical therapy (BMT) remains unknown. We performed a systematic review and meta-analysis evaluating the efficacy and safety of EVT versus BMT in primary DMVO. We systematically searched PubMed, Cochrane Library and Embase, from inception to August 14, 2022, for studies comparing EVT with BMT in DMVO-AIS. We adopted the Distal Thrombectomy Summit Group's definition of DMVO. Efficacy outcomes were functional independence (90-day modified Rankin Scale (mRS) 0-2) and excellent functional outcomes (90-day mRS 0-1). Safety outcomes were symptomatic intracranial hemorrhage (sICH) and 90-day mortality. Fourteen observational and two randomized-controlled studies were included, with 1202 patients receiving EVT and 1267 receiving BMT. After trim-and-fill correction, EVT achieved significantly better odds of functional independence than BMT (adjusted OR 1.61, 95% CI 1.06 to 2.43). There were no significant differences in overall excellent functional outcomes (OR 1.23, 95% CI 0.88 to 1.71), sICH (OR 1.44, 95% CI 0.78 to 2.66), and mortality (OR 1.03, 95% CI 0.73 to 1.45). Stratified by EVT method, mechanical thrombectomy±intra-arterial thrombolysis achieved more excellent functional outcomes than BMT (OR 1.59, 95% CI 1.13 to 2.23). In mild strokes (National Institutes of Health Stroke Scale score <6), EVT caused significantly more sICH (OR 6.30, 95% CI 1.55 to 25.64). EVT shows promising efficacy benefit over BMT for primary DMVO-AIS. Further randomized controlled trials are necessary to evaluate the efficacy and safety of EVT in DMVO-AIS.


The Endophytic Bacteria Bacillus velezensis Lle-9, Isolated from Lilium leucanthum, Harbors Antifungal Activity and Plant Growth-Promoting Effects.
Bacillus velezensis is an important plant growth-promoting rhizobacterium with immense potential in agriculture development. In the present study, Bacillus velezensis Lle-9 was isolated from the bulbs of Lilium leucanthum. The isolated strain showed antifungal activities against plant pathogens like Botryosphaeria dothidea, Fusarium oxysporum, Botrytis cinerea and Fusarium fujikuroi. The highest percentage of growth inhibition i.e., 68.56±2.35% was observed against Fusarium oxysporum followed by 63.12 ± 2.83%, 61.67 ± 3.39% and 55.82 ± 2.76% against Botrytis cinerea, Botryosphaeria dothidea, and Fusarium fujikuroi, respectively. The ethyl acetate fraction revealed a number of bioactive compounds and several were identified as antimicrobial agents such as diketopiperazines, cyclo-peptides, linear peptides, latrunculin A, 5α-hydroxy-6-ketocholesterol, (R)-S-lactoylglutathione, triamterene, rubiadin, moxifloxacin, 9-hydroxy-5Z,7E,11Z,14Zeicosatetraenoic acid, D-erythro-C18-Sphingosine, citrinin, and 2- arachidonoyllysophosphatidylcholine. The presence of these antimicrobial compounds in the bacterial culture might have contributed to the antifungal activities of the isolated B. velezensis Lle- 9. The strain showed plant growth-promoting traits such as production of organic acids, ACC deaminase, indole-3-acetic acid (IAA), siderophores, and nitrogen fixation and phosphate solubilization. IAA production was accelerated with application of exogenous tryptophan concentrations in the medium. Further, the lily plants upon inoculation with Lle-9 exhibited improved vegetative growth, more flowering shoots and longer roots than control plants under greenhouse condition. The isolated B. velezensis strain Lle-9 possessed broad-spectrum antifungal activities and multiple plant growth-promoting traits and thus may play an important role in promoting sustainable agriculture. This strain could be developed and applied in field experiments in order to promote plant growth and control disease pathogens.


Mouth-Level Nicotine Intake Estimates from Discarded Filter Butts to Examine Compensatory Smoking in Low Nicotine Cigarettes.
A mandated reduction in the nicotine content of cigarettes could reduce smoking rate and prevalence. However, one concern is that smokers may compensate by increasing the intensity with which they smoke each cigarette to obtain more nicotine. This study assessed whether smokers engage in compensatory smoking by estimating the mouth-level nicotine intake of low nicotine cigarettes smoked during a clinical trial. Smokers were randomly assigned to receive cigarettes with one of five nicotine contents for 6 weeks. An additional group received a cigarette with the lowest nicotine content, but an increased tar yield. The obtained mouth-level nicotine intake from discarded cigarette butts for a subset of participants (51-70/group) was estimated using solanesol as described previously. A compensation index was calculated for each group to estimate the proportion of nicotine per cigarette recovered through changes in smoking intensity. There was no significant increase in smoking intensity for any of the reduced nicotine cigarettes as measured by the compensation index (an estimated 0.4% of the nicotine lost was recovered in the lowest nicotine group; 95% confidence interval, -0.1 to 1.2). There was a significant decrease in smoking intensity for very low nicotine content cigarettes with increased tar yield. Reductions in nicotine content did not result in compensatory changes in how intensively participants smoked research cigarettes. Combined with data from clinical trials showing a reduction in cigarettes smoked per day, these data suggest that a reduction in nicotine content is unlikely to result in increased smoke exposure.


Incorporation of [125I]-5-iodo-2-thiouracil in cultured hamster, rabbit, and human melanoma cells.
The incorporation of [2-14C]-2-thiouracil and a series of [125I]-5-iodo-2-thiouracils ([125I]ISUra(s)) into cultured Greene hamster melanoma cells was determined in order to establish their properties as false precursors in the melanin-biosynthetic pathway. The cold trichloroacetic acid-precipitable incorporation of [2-14C]-2-thiouracil as well as [125I]ISUra into melanoma cells after a 24- to 48-hr labeling period proved to be completely tyrosinase dependent (more than 99.5% inhibition could be achieved by 0.5 mM phenylthiourea). [125I]ISUra incorporation was 3-fold higher than was [2-14C]-2-thiouracil incorporation and was enhanced by 1 mM theophylline treatment. [125I]ISUra incorporation into hamster, rabbit, and human melanoma cells showed a linear relationship with cell melanin content. Methylation of the sulfur completely prevented the incorporation, while propylation but not methylation at position 6 resulted in lower incorporation. [125I]ISUra proved to be a marker for melanogenesis and may be useful in studies on the differentiation of cultured melanoma cells.


[Clinical results of four hundred and twenty-four cases with chest trauma].
In this retrospective study, we aimed to emphasize that thoracentesis is a fast and safe method to evaluate indication for thoracotomy in patients with thoracic trauma who have preshock or shock findings, without losing time by other examinations such as X - ray studies. File records of 424 patients who were admitted to Thoracic Surgery Deparments of Adiyaman State Hospital and Medical School of Yuzuncu Yil University between December 1994 and March 2002, were investigated. There were 371(87,5%) male and 53 (12,5%) female patients, aged 5 to 89 (mean, 38,35). Most of the patients (n:382, 90%) were recovered by tube drainage and conservative management. There were 30 (7.1%) cases who underwent thoracotomy or median sternotomy. Nine patients underwent thoracotomy after being diagnosed by only thoracentesis without X - ray and 8 (89,9%) of them survived. The overall mortality was 2,8% (12 cases). Diagnostic thoracentesis has to be one of the indications for emergency thoracotomy after prompt systemic physical examination in the approach to thoracic trauma patient.