Genetic Diversity and Reassortment of Hantaan Virus Tripartite RNA Genomes in Nature, the Republic of Korea.
Hantaan virus (HTNV), a negative sense tripartite RNA virus of the Family Bunyaviridae, is the most prevalent hantavirus in the Republic of Korea (ROK). It is the causative agent of Hemorrhagic Fever with Renal Syndrome (HFRS) in humans and maintained in the striped field mouse, Apodemus agrarius, the primary zoonotic host. Clinical HFRS cases have been reported commonly in HFRS-endemic areas of Gyeonggi province. Recently, the death of a member of the ROK military from Gangwon province due to HFRS prompted an investigation of the epidemiology and distribution of hantaviruses in Gangwon and Gyeonggi provinces that border the demilitarized zone separating North and South Korea. To elucidate the geographic distribution and molecular diversity of HTNV, whole genome sequences of HTNV Large (L), Medium (M), and Small (S) segments were acquired from lung tissues of A. agrarius captured from 2003-2014. Consistent with the clinical incidence of HFRS established by the Korea Centers for Disease Control & Prevention (KCDC), the prevalence of HTNV in naturally infected mice in Gangwon province was lower than for Gyeonggi province. Whole genomic sequences of 34 HTNV strains were identified and a phylogenetic analysis showed geographic diversity of the virus in the limited areas. Reassortment analysis first suggested an occurrence of genetic exchange of HTNV genomes in nature, ROK. This study is the first report to demonstrate the molecular prevalence of HTNV in Gangwon province. Whole genome sequencing of HTNV showed well-supported geographic lineages and the molecular diversity in the northern region of ROK due to a natural reassortment of HTNV genomes. These observations contribute to a better understanding of the genetic diversity and molecular evolution of hantaviruses. Also, the full-length of HTNV tripartite genomes will provide a database for phylogeographic analysis of spatial and temporal outbreaks of hantavirus infection.


Phenotypic and genotypic stability of multiple lines of transgenic pigs expressing recombinant human protein C.
The genotypic and phenotypic stability of four lines of transgenic pigs expressing recombinant human protein C in milk was examined. Two lines were established with a construct consisting of a 2.6 kb mouse WAP promoter and a 9.4 kb human protein C genomic DNA. Two lines were established with another construct consisting of a 4.1 kb mouse WAP promoter and a 9.4 kb human protein C genomic DNA. Genotypic stability was measured by transgene copy number transmission. Outbred offspring having a single transgene integration locus were established from a founder having three independent, multicopy loci. Phenotypic stability over multiple lactations was defined by the combination of recombinant human protein C expression levels and the isoform signature of recombinant human protein C in western blots. Both cDNA and genomic human protein C transgenes gave similar ranges of expression levels of about 100-1800 micrograms ml-1. Within a given outbred lineage having a single loci for the cDNA transgene, the expression levels ranged between 100-400 micrograms ml-1. Western blots of reduced recombinant protein C revealed that single chain content was not dependent on expression level and was consistent within each transgenic line, but varied between transgenic lines. This suggests that native swine genetics may play a role in selection of production herds with optimal post-translational proteolytic processing capability. Although swine are not conventional dairy livestock, it is agreed that the short generation times, multiple offspring per litter, stable paternal transmission of the transgene, and milk production capabilities of swine offer distinct advantages over conventional dairy livestock for the establishment of a herd producing a therapeutic recombinant protein.


Ecological studies of ultraviolet B, vitamin D and cancer since 2000.
The purpose of this review is to summarize ecological studies of solar ultraviolet B (UVB), vitamin D and cancer since 2000. The journal literature is surveyed and summarized. The ecological approach has been the primary tool used during the past two decades to extend the applicability of the UVB-vitamin D-cancer theory to include at least 18 types of cancer. Many of these studies were conducted in the United States, which has the advantages of availability of reliable age-standardized cancer incidence and mortality rate data for geographic areas at various spatial resolutions, and an asymmetric solar UVB dose pattern, with higher UVB irradiance in the west and lower in the east, at any particular latitude. In addition, indices for other cancer risk-modifying factors are readily available including those for smoking, alcohol consumption, ethnic background, urban/rural residence, socioeconomic status, air pollution, and in limited fashion, diet. The ecological approach has also been used to identify latitudinal variations in cancer mortality rates in Australia, China, Japan, and Spain, and in multicountry studies. It has been used to investigate the relative roles of solar UVB and dietary factors on a global scale. The ecological approach has also been applied to cancer survival. Studies in Norway and England found that individuals diagnosed with cancer in summer or fall, when serum 25-hydroxyvitamin D levels are highest, had a milder clinical course and longer survival than those diagnosed in winter or spring. These findings provide strong evidence that vitamin D status plays an important role in controlling the outcome of cancer. Support for the UVB-vitamin D-cancer theory is now scientifically strong enough to warrant use of vitamin D in cancer prevention, and as a component of treatment. More research studies would help to explore whether there are benefits beyond the substantial effects that have been observed.


Tunable photoluminescence in a van der Waals heterojunction built from a MoS2 monolayer and a PTCDA organic semiconductor.
We report the photoluminescence (PL) characteristics of a van der Waals (vdW) heterojunction constructed by simply depositing an organic semiconductor of 3,4,9,10-perylene tetracarboxylic dianhydride (PTCDA) onto a two-dimensional MoS2 monolayer. The crystallinity of PTCDA on MoS2 is significantly improved due to the vdW epitaxial growth. We observe an enhanced PL intensity and PL peak shift of the MoS2/PTCDA heterojunction compared with the solo MoS2 and PTCDA layer. The synergistic PL characteristics are believed to originate from the hybridization interaction between the MoS2 and the PTCDA as evidenced by density functional theory calculations and Raman measurements. The hybridization interfacial interaction is found to be greatly influenced by the crystalline ordering of the PTCDA film on the 2D MoS2. Our study opens up a new avenue to tune the PL of vdW heterojunctions consisting of TMDs and organic semiconductors for optoelectronic applications.


Home Reading Environment and Brain Activation in Preschool Children Listening to Stories.
Parent-child reading is widely advocated to promote cognitive development, including in recommendations from the American Academy of Pediatrics to begin this practice at birth. Although parent-child reading has been shown in behavioral studies to improve oral language and print concepts, quantifiable effects on the brain have not been previously studied. Our study used blood oxygen level-dependent functional magnetic resonance imaging to examine the relationship between home reading environment and brain activity during a story listening task in a sample of preschool-age children. We hypothesized that while listening to stories, children with greater home reading exposure would exhibit higher activation of left-sided brain regions involved with semantic processing (extraction of meaning). Nineteen 3- to 5-year-old children were selected from a longitudinal study of normal brain development. All completed blood oxygen level-dependent functional magnetic resonance imaging using an age-appropriate story listening task, where narrative alternated with tones. We performed a series of whole-brain regression analyses applying composite, subscale, and individual reading-related items from the validated StimQ-P measure of home cognitive environment as explanatory variables for neural activation. Higher reading exposure (StimQ-P Reading subscale score) was positively correlated (P < .05, corrected) with neural activation in the left-sided parietal-temporal-occipital association cortex, a "hub" region supporting semantic language processing, controlling for household income. In preschool children listening to stories, greater home reading exposure is positively associated with activation of brain areas supporting mental imagery and narrative comprehension, controlling for household income. These neural biomarkers may help inform eco-bio-developmental models of emergent literacy.


Mechanical coupling between the hemithoraces in humans.
Unilateral airway occlusion permits measurement of single lung function. Since the results suggest that the occluded lung influences the mobility of the contralateral hemithorax, we wanted to test this hypothesis. In eight healthy subjects, we measured, using computed tomography, lung parenchymal area and inner rib cage parasagittal and transverse diameters at three different levels and at maximal inspiration and expiration. These measurements were made without and during balloon occlusion of one mainstem bronchus at residual volume (RV) and at total lung capacity (TLC). Unilateral occlusion at RV reduced the ipsilateral diameters in maximal inspiration, but the increase during inspiration was still 39-50% of that without occlusion. The inspiratory increase in contralateral diameters was reduced to 64-80% of the increase without occlusion. Occlusion at TLC reduced the expiratory decrease in ipsilateral diameters to 37-57% of that without occlusion. The expiratory decrease on the contralateral side was reduced to 56-70% of that without occlusion. Due to accompanying mediastinal shifts the parenchymal areas of the occluded lung barely changed. In contrast, the contralateral area was 86-97% of that without occlusion. We conclude that the movement of the two hemithoraces are, at least partially, interdependent. The occluded hemithorax prevents full expansion/compression of the nonoccluded contralateral side, whilst its own mobility appears to be increased by the presence of this nonoccluded side. Potential negative effects are outweighed by the physiological benefit of the coupling, as this mechanism could secure ventilation to a chest half without own movement.


Epidemiological and clinical studies of nutrition.
In this review, we briefly summarize some of the key developments in nutritional epidemiology and cancer over the past two decades with a focus on the strengths and limitations of study designs and dietary assessment methods. We present the evidence on dietary fat, meat, fiber, antioxidant nutrients, and calcium in relation to carcinogenesis from large cohort studies and randomized clinical trials (RCTs) and refer to the conclusions of the 2007 World Cancer Research Fund/American Institute for Cancer Research summary report. One prominent theme that emerged is the lack of concordance of results from RCTs and observational studies. There are multiple potential reasons for these discrepancies, including differences in study population, dose and timing of the exposure, adherence to an intervention, length of follow-up, and the primary endpoint. Therefore, null findings of RCTs do not necessarily indicate a lack of effect for the tested dietary factors on cancer risk, as some of these nutrients may have chemopreventive effects if given at the right time and in the right dose. It is likely that potential benefits from diet are due to a combination of food constituents rather than single components acting in isolation. Future efforts need to recognize the integrative nature of dietary exposures and attempt to study nutrients in the larger context of the foods and diets in which they are consumed.


Interaction of mouse splenocytes and macrophages with bacterial strains in vitro: the effect of age in the immune response.
Probiotics influence the immune system, both at the local and systemic level. Recent findings suggest the relation between microbiota and the immune system alters with age. Our objective was to address direct effects of six bacterial strains on immune cells from young and aged mice: Lactobacillus plantarum WCFS1, Lactobacillus casei BL23, Lactococcus lactis MG1363, Bifidobacterium breve ATCC15700, Bifidobacterium infantis ATCC15697, and Akkermansia muciniphila ATCC BAA-835. We used splenocytes and naïve or interferon-γ-stimulated bone marrow-derived macrophages (BMDM) as responder populations. All tested bacterial strains induced phenotypic and cytokine responses in splenocytes and BMDM. Based on magnitude of the cellular inflammatory response and cytokine profiles, two subgroups of bacteria were identified, i.e. L. plantarum and L. casei versus B. breve, B. infantis, and A. muciniphila. The latter group of bacteria induced high levels of cytokines produced under inflammatory conditions, including tumour necrosis factor (TNF), interleukin (IL)-6 and IL-10. Responses to L. lactis showed features of both subgroups. In addition, we compared responses by splenocytes and BMDM derived from young mice to those of aged mice, and found that splenocytes and BMDM derived from aged mice had an increased IL-10 production and dysregulated IL-6 and TNF production compared to young immune cells. Overall, our study shows differential inflammatory responses to distinct bacterial strains, and profound age-dependent effects. These findings, moreover, support the view that immune environment importantly influences bacterial immune effects.


Cardioprotection in ischemia/reperfusion injury: spotlight on sphingosine-1-phosphate and bradykinin signalling.
Complex signal-transduction cascades are known to be involved in regulating cardiomyocyte function, death and survival during acute cardiac ischemia-reperfusion process, but detailed survival signalling pathways are not clear. This review presents and discusses the recent findings bearing upon the evidence on the cardioprotective effect of sphingosine-1-phosphate (S1P) and bradykinin in acute cardiac ischemia-reperfusion and underlying signalling mechanisms, particularly, through activation of P21 activated kinase.


Effects of Coffee and Its Components on the Gastrointestinal Tract and the Brain-Gut Axis.
Coffee is one of the most popular beverages consumed worldwide. Roasted coffee is a complex mixture of thousands of bioactive compounds, and some of them have numerous potential health-promoting properties that have been extensively studied in the cardiovascular and central nervous systems, with relatively much less attention given to other body systems, such as the gastrointestinal tract and its particular connection with the brain, known as the brain-gut axis. This narrative review provides an overview of the effect of coffee brew; its by-products; and its components on the gastrointestinal mucosa (mainly involved in permeability, secretion, and proliferation), the neural and non-neural components of the gut wall responsible for its motor function, and the brain-gut axis. Despite in vitro, in vivo, and epidemiological studies having shown that coffee may exert multiple effects on the digestive tract, including antioxidant, anti-inflammatory, and antiproliferative effects on the mucosa, and pro-motility effects on the external muscle layers, much is still surprisingly unknown. Further studies are needed to understand the mechanisms of action of certain health-promoting properties of coffee on the gastrointestinal tract and to transfer this knowledge to the industry to develop functional foods to improve the gastrointestinal and brain-gut axis health.


Conflicts of Interest in GM Bt Crop Efficacy and Durability Studies.
Public confidence in genetically modified (GM) crop studies is tenuous at best in many countries, including those of the European Union in particular. A lack of information about the effects of ties between academic research and industry might stretch this confidence to the breaking point. We therefore performed an analysis on a large set of research articles (n = 672) focusing on the efficacy or durability of GM Bt crops and ties between the researchers carrying out these studies and the GM crop industry. We found that ties between researchers and the GM crop industry were common, with 40% of the articles considered displaying conflicts of interest (COI). In particular, we found that, compared to the absence of COI, the presence of a COI was associated with a 50% higher frequency of outcomes favorable to the interests of the GM crop company. Using our large dataset, we were able to propose possible direct and indirect mechanisms behind this statistical association. They might notably include changes of authorship or funding statements after the results of a study have been obtained and a choice in the topics studied driven by industrial priorities.


Elevated Dnmt3a activity promotes polyposis in Apc(Min) mice by relaxing extracellular restraints on Wnt signaling.
Aberrant DNA methylation is a common early event in neoplasia, but it is unclear how this relates to dysregulation of DNA (cytosine-5) methyltransferases (Dnmts). Here we use knock-in transgenic mice to investigate the consequences of intestinal epithelium-specific overexpression of de novo Dnmt3a. A novel gene targeting strategy, based on the intestinal epithelium-specific, uniform expression of the A33 glycoprotein, is employed to restrict Dnmt3a overexpression in homozygous A33(Dnmt3a) mutant mice. A33(Dnmt3a) mice infrequently develop spontaneous intestinal polyps. However, when genetically challenged, tumor multiplicity in A33(Dnmt3a);Apc(Min) compound mice is 3-fold higher than in Apc(Min) mice. Although we observe a requirement for spontaneous loss of heterozygosity of the adenomatous polyposis coli (Apc) gene to trigger tumorigenesis in Apc(Min) mice, lesions in A33(Dnmt3a);Apc(Min) mice frequently retain the wild-type Apc allele. However, epithelia from normal mucosa and polyps of A33(Dnmt3a);Apc(Min) mice show hypermethylation-mediated transcriptional silencing of the Wnt antagonists Sfrp5, and to a lesser extent, Sfrp1 and increased nuclear beta-catenin alongside activation of the Wnt-target gene Axin2/Conductin. Conversely, enforced Sfrp5 expression suppresses canonical Wnt-signaling more effectively in wild-type than in Apc(Min) cells. Aberrant activation of the canonical Wnt pathway, either by mono-allelic Apc loss or transcriptional silencing of Sfrp5 is largely insufficient to promote polyposis, but epistatic interactions between these genetic and epigenetic events enables initiation and promotion of disease. This mechanism is likely to play a role in human colorectal cancer, because we also show that elevated DNMT3A expression coincides with repressed SFRP5 and enhanced AXIN2/CONDUCTIN expression in paired patient biopsies.


Radial spoke protein 9 is necessary for axoneme assembly in Plasmodium but not in trypanosomatid parasites.
Flagella are important for eukaryote cell motility, including in sperm, and are vital for life cycle progression of many unicellular eukaryotic pathogens. The '9+2' axoneme in most motile flagella comprises nine outer doublet and two central-pair singlet microtubules. T-shaped radial spokes protrude from the outer doublets towards the central pair and are necessary for effective beating. We asked whether there were radial spoke adaptations associated with parasite lineage-specific properties in apicomplexans and trypanosomatids. Following an orthologue search for experimentally uncharacterised radial spoke proteins (RSPs), we identified and analysed RSP9. Trypanosoma brucei and Leishmania mexicana have an extensive RSP complement, including two divergent RSP9 orthologues, necessary for flagellar beating and swimming. Detailed structural analysis showed that neither orthologue is needed for axoneme assembly in Leishmania. In contrast, Plasmodium has a reduced set of RSPs including a single RSP9 orthologue, deletion of which in Plasmodium berghei leads to failure of axoneme formation, failed male gamete release, greatly reduced fertilisation and inefficient life cycle progression in the mosquito. This indicates contrasting selection pressures on axoneme complexity, likely linked to the different mode of assembly of trypanosomatid versus Plasmodium flagella.


Infrequent existence of simian virus 40 large T antigen DNA in malignant mesothelioma in Japan.
Malignant mesothelioma is the most common primary pleural neoplasm. Association of simian virus 40 (SV40) with malignant mesothelioma has been reported, suggesting that SV40 plays an important role in the origin of a subset of these tumors. However, significant geographic variation is present as to how often this association occurs. As no study concerning SV40 in malignant mesothelioma has been reported from Japan, we examined the frequency of SV40 infection in Japanese malignant mesothelioma cases. In pleural malignant mesothelioma tissue from 35 patients in Japan, we sought the presence of SV40 large T antigen DNA using real-time polymerase chain reaction (PCR), as well as expression of the viral protein using immunohistological methods. Real-time PCR demonstrated that two of 35 mesotheliomas contained DNA sequences encoding portions of SV40 large T antigen. None of the 35 malignant mesothelioma specimens showed immunoreactivity for SV40 large T antigen. SV40 infection does not appear to have a major role in the development of malignant mesothelioma in Japan.


En route intraosseous access performed in the combat setting.
To describe and compare vascular access practices used by en route care providers during medical evacuation (MEDEVAC). This was a retrospective cohort study. Medical records of US military personnel injured in combat and transported by MEDEVAC teams were queried. The subjects were transported by military en route care providers, in the combat theater during Operation Enduring Freedom (OEF) between January 2011 and March 2014. The authors reviewed 1,267 MEDEVAC records of US casualties and included 832 subjects that had vascular access attempts. The outcome measures for this study were vascular access success rates, including intravenous (IV) and intraosseous (IO) attempts. Subjects were grouped by type of vascular access: None, peripheral intravenous (PIV), IO, and PIV + IO (combination of PIV and IO) and by vascular access (PIV or IO) success (No versus Yes). Survival rate, in-flight events, ventilator, intensive care and in hospital days, and 30-day outcomes were compared among groups. The authors used chisquare or Fisher's exact tests to evaluate categorical variables. Analysis of variance (ANOVA) or Kruskal-Wallis tests were used for continuous variables. Vascular access was attempted in 832 (66 percent) of the 1,267 subjects transported by MEDEVAC during this study period. The majority (n = 758) of the access attempts were PIV of which 93 percent (706/758) were successful. In 74 subjects, IO was the only access attempted with an 85 percent (n = 63) success rate. The overall success rate with IO placement was 88 percent. Intraosseous access has been used successfully in the combat setting and accounts for approximately 12 percent of vascular access in the MEDEVAC population the authors studied.


Evaluation of a modified self-report measure of social adjustment.
A self-report Social Adjustment Scale (SAS-M) for use in British populations was devised by modifying the original North American version, its usefulness was evaluated among 331 women drawn from two local populations. In a group of mothers of one year old babies (n = 130), high levels of agreement were found between the subjects' self-ratings on the SAS-M and (i) a psychiatrist's ratings of their social adjustment made at interview; (ii) ratings of the subjects' social adjustment made by their husbands on the SAS-M; (iii) measures of concurrent mental state. In a group of women undergoing elective sterilization (n = 201), the SAS-M was found to be sensitive to changes in mental state over time. Possible application of the SAS-M in psychiatric research, particularly when an interview is not feasible, are discussed.


Allicin protects auditory hair cells and spiral ganglion neurons from cisplatin - Induced apoptosis.
Cisplatin is a broad-spectrum anticancer drug that is commonly used in the clinic. Ototoxicity is one of the major side effects of this drug, which caused irreversible sensorineural hearing loss. Allicin, the main biologically active compound derived from garlic, has been shown to exert various anti-apoptotic and anti-oxidative activities in vitro and in vivo studies. We took advantage of C57 mice intraperitoneally injected with cisplatin alone or with cisplatin and allicin combined, to investigate whether allicin plays a protective role in vivo against cisplatin ototoxicity. The result showed that C57 mice in cisplatin group exhibited increased shift in auditory brainstem response, whereas the auditory fuction of mice in allicin + cisplatin group was protected in most frequencies, which was accordance with observed damages of outer hair cells (OHCs) and spiral ganglion neurons (SGNs) in the cochlea. Allicin markedly protected SGN mitochondria from damage and releasing cytochrome c, and significantly reduced pro-apoptosis factor expressions activated by cisplatin, including Bax, cleaved-caspase-9, cleaved-caspase-3and p53. Furthermore, allicin reduced the level of Malondialdehyde (MDA), but increased the level of superoxide dismutase (SOD). All data suggested that allicin could prevent hearing loss induced by cisplatin effectively, of which allicin protected SGNs from apoptosis via mitochondrial pathway while protected OHCs and supporting cells (SCs) from apoptosis through p53 pathway.


Tuberculosis in complex emergencies.
This paper describes the key factors and remaining challenges for tuberculosis (TB) control programmes in complex emergencies. A complex emergency is "a humanitarian crisis in a country, region or society where there is total or considerable breakdown of authority resulting from internal or external conflict and which requires an international response that goes beyond the mandate or capacity of any single agency and/or the ongoing United Nations country programme." Some 200 million people are believed to live in countries affected by complex emergencies; almost all of these are developing countries that also bear the main burden of TB. The effects of complex emergencies impact on TB control programmes, interfering with the goals of identifying and curing TB patients and possibly leading to the emergence of MDR-TB. There are many detailed descriptions of aid interventions during complex emergencies; yet TB control programmes are absent from most of these reports. If TB is neglected, it may quickly result in increased morbidity and mortality, as was demonstrated in Bosnia and Herzegovina and in Somalia. TB is a major disease in complex emergencies and requires an appropriate public health response. While there is no manual to cover complex emergencies, the interagency manual for TB control in refugee and displaced populations provides valuable guidance. These programmes contribute to the body of evidence needed to compile such a manual, and should ensure that the experiences of TB control in complex emergencies lead to the establishment of evidence-based programmes.


Infection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production.
Oral infection of C57BL/6J mice with Toxoplasma gondii results in a marked bacterial dysbiosis and the development of severe pathology in the distal small intestine that is dependent on CD4+ T cells and interferon gamma (IFN-γ). This dysbiosis and bacterial translocation contribute to the development of ileal pathology, but the factors that support the bloom of bacterial pathobionts are unclear. The use of microbial community profiling and shotgun metagenomics revealed that Toxoplasma infection induces a dysbiosis dominated by Enterobacteriaceae and an increased potential for nitrate respiration. In vivo experiments using bacterial metabolic mutants revealed that during this infection, host-derived nitrate supports the expansion of Enterobacteriaceae in the ileum via nitrate respiration. Additional experiments with infected mice indicate that the IFN-γ/STAT1/iNOS axis, while essential for parasite control, also supplies a pool of nitrate that serves as a source for anaerobic respiration and supports overgrowth of Enterobacteriaceae Together, these data reveal a trade-off in intestinal immunity after oral infection of C57BL/6J mice with T. gondii, in which inducible nitric oxide synthase (iNOS) is required for parasite control, while this host enzyme is responsible for specific modification of the composition of the microbiome that contributes to pathology.IMPORTANCEToxoplasma gondii is a protozoan parasite and a leading cause of foodborne illness. Infection is initiated when the parasite invades the intestinal epithelium, and in many host species, this leads to intense inflammation and a dramatic disruption of the normal microbial ecosystem that resides in the healthy gut (the so-called microbiome). One characteristic change in the microbiome during infection with Toxoplasma-as well as numerous other pathogens-is the overgrowth of Escherichia coli or similar bacteria and a breakdown of commensal containment leading to seeding of peripheral organs with gut bacteria and subsequent sepsis. Our findings provide one clear explanation for how this process is regulated, thereby improving our understanding of the relationship between parasite infection, inflammation, and disease. Furthermore, our results could serve as the basis for the development of novel therapeutics to reduce the potential for harmful bacteria to bloom in the gut during infection.


Association between maternal education and infant diarrhea in different household and community environments of Cebu, Philippines.
Maternal education is one of the strongest determinants of infant survival in developing countries, however, questions remain regarding the extent to which its effects vary as a function of contextual variables. In this study, a multi-level interactive model is used to assess whether the protective effect of maternal education on the risk of infant diarrhea is modified by three aspects of the mother's familial and community environment: household assets, community economic resources and the availability of mothers' clubs. 2484 study participants were interviewed in 1984 as part of the Cebu Longitudinal Infant Health and Nutrition Study. The findings suggest that the protective effect of maternal education on infant diarrhea varies according to the socio-economic environment in which the mother lives: maternal education protects against infant diarrhea in the more economically and socially advantaged communities but has no effect in the more disadvantaged communities. The results also indicate that the protective effect of maternal education is smaller in the wealthier households. These data suggest that improvement in maternal education level, alone, may not always have the expected beneficial effects on infant health. Corollary measures to improve access of mothers and children to basic community resources and efforts to help mothers be more effective in their various social roles may be necessary preconditions for higher levels of maternal education to result in improved infant health.


Hormonal activation of let-7-C microRNAs via EcR is required for adult Drosophila melanogaster morphology and function.
Steroid hormones and their nuclear receptors drive developmental transitions in diverse organisms, including mammals. In this study, we show that the Drosophila steroid hormone 20-hydroxyecdysone (20E) and its nuclear receptor directly activate transcription of the evolutionarily conserved let-7-complex (let-7-C) locus, which encodes the co-transcribed microRNAs miR-100, let-7 and miR-125. These small RNAs post-transcriptionally regulate the expression of target genes, and are required for the remodeling of the Drosophila neuromusculature during the larval-to-adult transition. Deletion of three 20E responsive elements located in the let-7-C locus results in reduced levels of let-7-C microRNAs, leading to neuromuscular and behavioral defects in adults. Given the evolutionary conservation of let-7-C microRNA sequences and temporal expression profiles, these findings indicate that steroid hormone-coupled control of let-7-C microRNAs is part of an ancestral pathway controlling the transition from larval-to-reproductive animal forms.


Everyday Life Theories of Emotions in Conflicts From Bali, the Spanish Basque Country, and the German Ruhr Area.
This article presents findings from a cross-cultural study on emotions in conflicts in Bali, the Spanish Basque Country, and the German Ruhr Area. The study had two aims: (1) to investigate the ways in which individuals make sense of how emotions, their expressions, and interaction conflicts are interrelated and (2) to compare the findings from the three regions. A particular interest was to explore and compare everyday life emotion theories. Ten semistructured interviews were conducted in each region. This method was triangulated with cross-cultural narrative interpretations and the task of relating emotion words to conflicts. The data were subjected to qualitative content analysis. The results show that partly different emotions were related to conflicts in the three datasets and that similar emotions may differ in antecedents, conceptual foundation, and behavioral consequences. Emotions similar to anger were commonly related to conflicts. In Bali, this emotion was mainly expressed through silence and rather hypocognated. The respective emotions received a deeper conceptual analysis and also served as conflict models in the other regions. Emotions similar to pride were related to the prolongation of conflicts in the Basque Country, considered causes of conflicts in the Ruhr Area, but were not related to conflicts in Bali. All three datasets show that the main indicators used to ascribe emotions to others are not facial expressions but subtle nuances and omissions of typical behavior and conventionalized signs. In the Basque Country, the emotions respeto and confianza form a continuum for the codification of interpersonal distance that produces different levels of expressiveness. These emotions act as a culture-specific socioemotional means of emotion regulation. The Balinese emotion lek has a similar function, as it neutralizes emotions similar to anger at their onset, acting as a substitute for deliberate forms of emotion regulation. All three datasets indicate that a hydraulic model is employed to conceptualize emotions, although the suppression of expressions is not pathologized in Bali but considered rather difficult to achieve. The communicative imaginaries of how emotions are experienced were surprisingly similar, with the exception that in Bali emotions are situated in the liver and described with a gustatory nomenclature.


Reduced response to Epstein-Barr virus antigens by T-cells in systemic lupus erythematosus patients.
Epstein-Barr virus (EBV) has for long been associated with systemic lupus erythematosus (SLE). In this study, we investigated the levels of latent and lytic antigen EBV-specific T-cells and antibodies in SLE patients. T cells were analyzed by flow cytometry and antibodies were analyzed by enzyme-linked immunosorbent assay. SLE patients showed a significantly reduced number of activated (CD69) T-cells upon ex vivo stimulation with EBV nuclear antigen (EBNA) 1 or EBV early antigen diffuse (EBV-EA/D) in whole blood samples compared with healthy controls. Also, a reduced number of T-cells from SLE patients were found to produce interferon-γ upon stimulation with these antigens. Importantly, responses to a superantigen were normal in SLE patients. Compared with healthy controls, SLE patients had fewer EBV-specific T-cells but higher titres of antibodies against EBV. Furthermore, an inverse correlation was revealed between the number of lytic antigen EBV-specific T-cells and disease activity of the SLE patients, with high-activity SLE patients having fewer T-cells than low-activity SLE patients. These results indicate a limited or a defective EBV-specific T-cell response in SLE patients, which may suggest poor control of EBV infection in SLE with an immune reaction shift towards a humoral response in an attempt to control viral reactivation. A role for decreased control of EBV as a contributing agent in the development or exacerbation of SLE is proposed.


Four-year evaluation of a resin composite including nanofillers in posterior cavities.
The aim of this prospective study was to evaluate the clinical performance of the restorative material Ceram.X in combination with an experimental one-bottle etch-and-rinse adhesive (K-0127). A single operator placed two Class I or II restorations in molars of 43 patients. One molar was restored with Ceram.X/K-0127 (Dentsply DeTrey), the other one with Tetric Ceram/Syntac Classic (Ivoclar Vivadent). At baseline, after one, two, and four years the restorations were evaluated by a second dentist using modified Ryge's criteria. After four years, 27 patients were examined. In one patient, both restorations (Class II) had to be removed for root canal treatment due to pulpitis. Another Class II Ceram.X restoration (3.8%; 4.3% [1 of 23] of Class II restorations) showed score C with regard to wear/anatomical form. Thus, the cumulative failure rate was 7.4% in the Ceram.X group (8.3% of Class II restorations [2 of 24]) and 3.7% in the Tetric Ceram group (4.2% of Class II restorations [1 of 24]). Furthermore, three restorations (11.5%) in each group showed score B for anatomical form and marginal integrity. Slight marginal discoloration (score B) was found at five Ceram.X restorations (19.2%) and four Tetric Ceram restorations (15.4%). Two restorations (7.7%) in each group showed slight changes in color stability (score B). No sensitivity, recurrent caries, or changes in surface texture were recorded after four years. No statistically significant differences were found between the two restorative materials (p > 0.05). After four years of clinical service, 92.6% of Ceram.X/K-0127 and 96.3% of Tetric Ceram/Syntac Classic restorations performed clinically well.


Virological response is associated with decline in hemoglobin concentration during pegylated interferon and ribavirin therapy in hepatitis C virus genotype 1.
Anemia may increase the likelihood of achieving a sustained virological response (SVR) during pegylated interferon and ribavirin treatment of hepatitis C virus (HCV) infection. To determine whether hemoglobin decline is associated with SVR, we retrospectively evaluated the CHARIOT study of 871 treatment-naïve HCV genotype 1 patients. Anemia (serum hemoglobin <100 g/L) occurred in 137 (16%) patients, of whom only 14 (10%) received erythropoietin. Hemoglobin decline >30g/L from baseline occurred in 76% of patients overall, including 526 patients who did not become anemic. Virological responses were higher in anemic patients compared with those who did not develop anemia (end of treatment, 80% versus 65%, P = 0.003; SVR, 61% versus 50%, P = 0.02); these differences remained significant when patients receiving erythropoietin were excluded from analysis. SVR was also higher in patients with hemoglobin decline >30 g/L compared with patients without a similar decline. In multiple logistic regression analyses with treatment group and baseline characteristics, the odds ratio for SVR was 1.97 (95% confidence interval, 1.08-3.62) for anemia and 2.17 (95% confidence interval, 1.31-3.62) for hemoglobin decline >30 g/L. Patients who first developed a hemoglobin decline >30 g/L during weeks 5-12 and 13-48 were more likely to achieve SVR than those who first developed such changes in weeks 0-4 or who never experienced them. Patients with HCV genotype 1 infection who develop anemia or experience a hemoglobin decline >30 g/L during weeks 5-48 of therapy achieve higher virological responses to pegylated interferon and ribavirin therapy that are unrelated to erythropoietin use.


Targeting group I p21-activated kinases to control malignant peripheral nerve sheath tumor growth and metastasis.
Malignant peripheral nerve sheath tumors (MPNSTs) are devastating sarcomas for which no effective medical therapies are available. Over 50% of MPSNTs are associated with mutations in NF1 tumor suppressor gene, resulting in activation of Ras and its effectors, including the Raf/Mek/Erk and PI3K/Akt/mTORC1 signaling cascades, and also the WNT/β-catenin pathway. As Group I p21-activated kinases (Group I Paks, PAK1/2/3) have been shown to modulate Ras-driven oncogenesis, we asked if these enzymes might regulate signaling in MPNSTs. In this study we found a strong positive correlation between the activity of PAK1/2/3 and the stage of human MPNSTs. We determined that reducing Group I Pak activity diminished MPNST cell proliferation and motility, and that these effects were not accompanied by significant blockade of the Raf/Mek/Erk pathway, but rather by reductions in Akt and β-catenin activity. Using the small molecule PAK1/2/3 inhibitor Frax1036 and the MEK1/2 inhibitor PD0325901, we showed that the combination of these two agents synergistically inhibited MPNST cell growth in vitro and dramatically decreased local and metastatic MPNST growth in animal models. Taken together, these data provide new insights into MPNST signaling deregulation and suggest that co-targeting of PAK1/2/3 and MEK1/2 may be effective in the treatment of patients with MPNSTs.


The calcium-dependent protein kinase 3 of toxoplasma influences basal calcium levels and functions beyond egress as revealed by quantitative phosphoproteome analysis.
Calcium-dependent protein kinases (CDPKs) are conserved in plants and apicomplexan parasites. In Toxoplasma gondii, TgCDPK3 regulates parasite egress from the host cell in the presence of a calcium-ionophore. The targets and the pathways that the kinase controls, however, are not known. To identify pathways regulated by TgCDPK3, we measured relative phosphorylation site usage in wild type and TgCDPK3 mutant and knock-out parasites by quantitative mass-spectrometry using stable isotope-labeling with amino acids in cell culture (SILAC). This revealed known and novel phosphorylation events on proteins predicted to play a role in host-cell egress, but also a novel function of TgCDPK3 as an upstream regulator of other calcium-dependent signaling pathways, as we also identified proteins that are differentially phosphorylated prior to egress, including proteins important for ion-homeostasis and metabolism. This observation is supported by the observation that basal calcium levels are increased in parasites where TgCDPK3 has been inactivated. Most of the differential phosphorylation observed in CDPK3 mutants is rescued by complementation of the mutants with a wild type copy of TgCDPK3. Lastly, the TgCDPK3 mutants showed hyperphosphorylation of two targets of a related calcium-dependent kinase (TgCDPK1), as well as TgCDPK1 itself, indicating that this latter kinase appears to play a role downstream of TgCDPK3 function. Overexpression of TgCDPK1 partially rescues the egress phenotype of the TgCDPK3 mutants, reinforcing this conclusion. These results show that TgCDPK3 plays a pivotal role in regulating tachyzoite functions including, but not limited to, egress.


Patients' engagement with "Sweet Talk" - a text messaging support system for young people with diabetes.
Guidelines for optimizing type 1 diabetes in young people advocate intensive insulin therapy coupled with personal support from the health care team. "Sweet Talk" is a novel intervention designed to support patients between clinic visits using text messages sent to a mobile phone. Scheduled messages are tailored to patient profiles and diabetes self-management goals, and generic messages include topical "newsletters" and anonymized tips from other participants. The system also allows patients to submit data and questions to the diabetes care team. The aim was to explore how patients with type 1 diabetes interact with the Sweet Talk system in order to understand its utility to this user group. Subjects were 64 young people with diabetes who were participating in the intervention arms of a randomized controlled trial. All text messages submitted to Sweet Talk during a 12-month period were recorded. Messaging patterns and content were analyzed using mixed quantitative and qualitative methods. Patients submitted 1180 messages during the observation period (mean 18.4, median 6). Messaging frequency ranged widely between participants (0-240) with a subset of 5 high users contributing 52% of the total. Patients' clinical and sociodemographic characteristics were not associated with total messaging frequency, although girls sent significantly more messages unrelated to diabetes than did boys (P = .002). The content of patients' messages fell into 8 main categories: blood glucose readings, diabetes questions, diabetes information, personal health administration, social messages, technical messages, message errors, and message responses. Unprompted submission of blood glucose values was the most frequent incoming message type (35% of total). Responses to requests for personal experiences and tips generated 40% of all the incoming messages, while topical news items also generated good responses. Patients also used the service to ask questions, submit information about their self-management, and order supplies. No patients nominated supporters to receive text messages about their self-management goals. Another option that was not used was the birthday reminder service. Automated, scheduled text messaging successfully engaged young people with diabetes. While the system was primarily designed to provide "push" support to patients, submission of clinical data and queries illustrates that it was seen as a trusted medium for communicating with care providers. Responses to the newsletters and submission of personal experiences and tips for circulation to other participants also illustrate the potential value of such interventions for establishing a sense of community. Although participants submitted relatively few messages, positive responses to the system suggest that most derived passive support from reading the messages. The Sweet Talk system could be readily adapted to suit other chronic disease models and age groups, and the results of this study may help to inform the design of future text message support interventions.


Double-outlet right ventricle revisited.
Double-outlet right ventricle is a form of ventriculoarterial connection. The definition formulated by the International Society for Nomenclature of Paediatric and Congenital Heart Disease is based on hearts with both arterial trunks supported in their greater part by a morphologically right ventricle. Bilateral infundibula and ventricular septal defects are highly debated criteria. This study examines the anatomic controversies surrounding double-outlet right ventricle. We show that hearts with double-outlet right ventricle can have atrioventricular-to-arterial valvular continuity. We emphasize the difference between the interventricular communication and the zone of deficient ventricular septation. The hearts examined were from the University of Florida in Gainesville; Johns Hopkins All Children's Hospital, St Petersburg, Fla; and Lurie Children's Hospital, Chicago, Ill. Each specimen had at least 75% of both arterial roots supported by the morphologically right ventricle, with a total of 100 hearts examined. The morphologic method was used to assess anatomic features, including arterial-atrioventricular valvular continuity, subarterial infundibular musculature, and the location of the hole between the ventricles. Most hearts had fibrous continuity between one of the arterial valves and an atrioventricular valve, with bilateral infundibula in 23%, and intact ventricular septum in 5%. Bilateral infundibula are not a defining feature of double-outlet right ventricle, representing only 23% of the specimens in our sample. The interventricular communication can have a posteroinferior muscular rim or extend to become perimembranous (58%). Double-outlet right ventricle can exist with an intact ventricular septum.


From Inuit to implementation: omega-3 fatty acids come of age.
During the past 25 years, the cardiovascular effects of marine omega-3 (omega-3) fatty acids have been the subject of increasing investigation. In the late 1970s, epidemiological studies revealed that Greenland Inuits had substantially reduced rates of acute myocardial infarction compared with Western control subjects. These observations generated more than 4,500 studies to explore this and other effects of omega-3 fatty acids on human metabolism and health. From epidemiology to cell culture and animal studies to randomized controlled trials, the cardioprotective effects of omega-3 fatty acids are becoming recognized. These fatty acids, when incorporated into the diet at levels of about 1 g/d, seem to be able to stabilize myocardial membranes electrically, resulting in reduced susceptibility to ventricular dysrhythmias, thereby reducing the risk of sudden death. The recent GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico)-Prevention study of 11,324 patients showed a 45% decrease in risk of sudden cardiac death and a 20% reduction in all-cause mortality in the group taking 850 mg/d of omega-3 fatty acids. These fatty acids have potent anti-inflammatory effects and may also be antiatherogenic. Higher doses of omega-3 fatty acids can lower elevated serum triglyceride levels; 3 to 5 g/ d can reduce triglyceride levels by 30% to 50%, minimizing the risk of both coronary heart disease and acute pancreatitis. This review summarizes the emerging evidence of the use of omega-3 fatty acids in the prevention of coronary heart disease.


A neural signature of food semantics is associated with body-mass index.
Visual recognition of objects may rely on different features depending on the category to which they belong. Recognizing natural objects, such as fruits and plants, weighs more on their perceptual attributes, whereas recognizing man-made objects, such as tools or vehicles, weighs more upon the functions and actions they enable. Edible objects are perceptually rich but also prepared for specific functions, therefore it is unclear how perceptual and functional attributes affect their recognition. Two event-related potentials experiments investigated: (i) whether food categorization in the brain is differentially modulated by sensory and functional attributes, depending on whether the food is natural or transformed; (ii) whether these processes are modulated by participants' body mass index. In experiment 1, healthy normal-weight participants were presented with a sentence (prime) and a photograph of a food. Primes described either a sensory feature ('It tastes sweet') or a functional feature ('It is suitable for a wedding party') of the food, while photographs depicted either a natural (e.g., cherry) or a transformed food (e.g., pizza). Prime-feature pairs were either congruent or incongruent. This design aimed at modulating N400-like components elicited by semantic processing. In experiment 1, N400-like amplitude was significantly larger for transformed food than for natural food with sensory primes, and vice versa with functional primes. In experiment 2, underweight and obese women performed the same semantic task. We found that, while the N400-like component in obese participants was modulated by sensory-functional primes only for transformed food, the same modulation was found in underweight participants only for natural food. These findings suggest that the level of food transformation interacts with participants' body mass index in modulating food perception and the underlying brain processing.


First Report of Sour Rot of California Peaches and Nectarines Caused by Yeasts.
In early July 2001, samples of nectarine and peach fruit were brought from orchards in northern Tulare County or from packinghouses to our laboratory for diagnosis of an unusual decay. When the decay lesions originated close to the stylar end, leaking juice streamed from it. When the decay lesion was on the stem end of the fruit and touched the packing box, it developed a decay consisting of a ring of 0.5 to 2.0 cm (inner diameter) and 1.0 to 3.0 cm (outer diameter). The leaking juice dissolved the cuticle, epidermis, and some of the flesh, creating distinct furrows in the tissue. Samples with similar decay lesions were examined in 2001, 2002, and 2003. In each year, isolations from these fruit consistently yielded two or three different yeasts that were identified as Geotrichum candidum Link, Issatchenkia scutulata (Phaff et al.) Kurtzman et al., and Kloeckera apiculata (Reess emend. Klocker) Janke. All three yeasts were isolated from most of the samples, although sometimes, different combinations of two of the yeasts recovered. To complete Koch's postulates, each yeast was single spored and cultured on acidified potato dextrose agar at 25°C to prepare a dense (108) cell suspension. Eight, mature, 'Elegant Lady' peach fruit were surface disinfested in 0.1% sodium hypochlorite for 3 min, allowed to dry, and wounded once with a sterile nail (3 × 5 mm) on the fruit cheek. A 50-µl drop of the cell suspension was placed in each wound, and the peaches were incubated in containers with >95% relative humidity at 27°C. Fruit inoculated similarly with a 50-µl drop of sterile water served as controls. In 2001, two containers containing eight fruit each were used for each yeast, and lesions started developing within 1 week after inoculation. The diameter of the decay lesion was measured after 10 days of incubation of the fruit. The diameter of decay lesions ranged from 21 to 68 mm for G. candidum, 30 to 55 mm for I. scutulata, and 9 to 39 mm for K. apiculata inoculations. The inoculation experiment was repeated with two containers of eight 'Red Glo' nectarine fruit per treatment yeast, under the same conditions as described above. Organisms recovered from the decay lesions were the same yeasts used for inoculating the peaches or nectarines. All three yeasts caused similar decay lesions in peaches, and the leaking effect was reproduced in both types of fruit. Symptoms were similar to those observed on fruit samples brought to our laboratory. Control fruit did not develop the characteristic decay lesions, although brown rot caused by Monilinia fructicola developed on a few of the control fruit. We concluded that each isolated yeast had the capacity to cause sour rot decay on stone fruit. From samples and reports, the disease has been found on 'Red Glo', 'Ruby Diamond', 'Zee Grand', 'Spring Bright', and 'Honey Blaze' nectarines and 'Elegant Lady' and 'Fire Red' peaches. G. candidum was isolated from peaches and other fruit in California and incited rot of 'Paloro' peach in 1960 (2) and caused postharvest sour rot of peaches originating from Georgia, Pennsylvania, New Jersey, and North Carolina (1). However, to our knowledge, this is the first report of G. candidum, I. scutulata, or K. apiculata causing sour rot of commercial peaches and nectarines in the field and postharvest situations in California. References: (1) C. L. Burton and W. R. Wright. Plant Dis. Rep. 53:580, 1969. (2) E. E. Butler. Phytopathology 50:665, 1960.


Ganglion cell-inner plexiform layer thickness of high definition optical coherence tomography in perimetric and preperimetric glaucoma.
We determined the diagnostic performance of ganglion cell-inner plexiform layer (GCIPL) parameters of high definition optical coherence tomography (HD-OCT) in perimetric and preperimetric glaucoma, and compared it to optic nerve head (ONH) and peripapillary retinal nerve fiber layer (RNFL) parameters. In a cross-sectional study, 53 eyes of normal subjects and 83 eyes of glaucoma patients (62 perimetric and 21 preperimetric) from the Longitudinal Glaucoma Evaluation Study (LOGES) underwent HD-OCT imaging with Optic Disc and Macular Cube protocols. Diagnostic abilities of GCIPL, ONH, and RNFL parameters were determined using area under receiver operating characteristic curves (AUC) and likelihood ratios (LR). The AUCs of GCIPL parameters to diagnose perimetric glaucoma ranged from 0.84 to 0.90. The same of ONH and RNFL parameters ranged from 0.88 to 0.97 and 0.56 to 0.94, respectively. The AUCs of GCIPL, ONH, and RNFL parameters to diagnose preperimetric glaucoma ranged from 0.55 to 0.63, 0.77 to 0.92, and 0.39 to 0.80, respectively. For diagnosing preperimetric glaucoma, AUCs of all GCIPL parameters were significantly lower (P < 0.05) than those of the global ONH (vertical cup-to-disc ratio [CDR]; AUC, 0.92) and RNFL (average RNFL; AUC, 0.79) parameters. Outside normal limits category of GCIPL parameters also were associated with significantly smaller effects on the posttest probability of perimetric and preperimetric glaucoma. The diagnostic ability of GCIPL parameters was similar to that of ONH and peripapillary RNFL parameters in perimetric glaucoma. However, in preperimetric glaucoma, the diagnostic ability of GCIPL parameters was significantly lower than that of ONH and RNFL parameters.


Searching the undetected mtDNA variants in forensic MPS data.
The efficiency of MPS in forensic mtDNA analysis has been thoroughly proven, although a reliable and well established data evaluation still remains a critical point. Numerous bioinformatics tools have been developed, but most of them require specific operating systems and high costs, while free open-source programs with user-friendly interfaces are few. In this study, 43 full mtGenomes were sequenced using the Ion Personal Genome Machine™ (PGM™) System and analyzed utilizing the plug-in Variant Caller (TVC) of the Ion Torrent Software Suite and the mtDNA-Server (mDS), a free web-based mitochondrial analysis tool for MPS data. The outcomes of these two different analysis tools were compared to variants noted after manual inspection of the aligned reads performed using Integrative Genomics Viewer (IGV). The comparison highlighted the presence of thirty-nine discordant variant calls, which were resolved by Sanger sequencing that confirmed the presence of all variants, except for 7 deletions. The combined adoption of IGV and Sanger type sequencing confirmatory steps, in addition of TVC and mDS analysis, resulted in a more accurate variants assignment with the detection of 32 additional true polymorphisms, which were noted in the final dataset. Regarding the heteroplasmy issue, out of a total of thirty heteroplasmic variants, twenty-eight were detected by the TVC, while the mDS detected twenty-two. Overall, none of the used bioinformatics tools were the perfect choice and a secondary analysis with an expert's opinion in complete mtGenome MPS data evaluation is still required in forensic genetic analysis.


Validation of a modified model of TNBS-induced colitis in rats. How to induce a chemical colitis in rats.
There is no standard practice in the induction of colitis by 2,4,6-trinitrobenzene sulfonic (TNBS) acid. Usually, the repeated administration of TNBS is preferred, because it will result in a local Th1 response that has the characteristics of Crohn`s disease. A total of 30 rats were randomized into two groups, consisting of a saline control group of ten rats and a TNBS groups of 20 rats. After the animals were anesthetized, 0.5 ml of either 0.9% saline (controls) or TNBS 50 mg/kg dissolved in 50% ethanol were instilled into the colon through a rubber catheter. The experiment was repeated weekly for four weeks, then, the rats were killed at day 40, and the distal colon removed. At day 40, the bowel wall was basically normal in the control group. In the TNBS group, the bowel lumen became narrow with thickened wall, and the mucosal surface presented adherent membrane with brown black, linear ulcers, proliferous lymphocyte tissue, inflammatory granulomas and submucosal neutrophil infiltration. The median score of the severity of the colonic damage was 0 in the control group, and 4,75 (range 4-5) in the TNBS group; the mean weight of the rats was 180+35 g in the TNBS group, while it was 215+25 in the control group. The presented experiment is a cost-effective and safe method to induce Crohn-like colonic damage using a lower dose of TNBS, thus avoiding the risk of a massive loss of rats. This model is rather suitable for the assessment of the effects of potential therapeutic agents. (www.actabiomedica.it).


The effects of indoor air pollution from solid fuel use on cognitive function among middle-aged and older population in China.
Growing evidence has linked outdoor air pollution exposure with higher risk of cognitive impairments. However, the role of indoor air pollution in cognitive decline is not well elaborated. By using nationally representative longitudinal data, this study aimed to explore the effects of indoor air pollution from solid fuel use on cognitive function among middle-aged and older individuals in China. Data were obtained from 2011 to 2015 waves of CHARLS (China Health and Retirement Longitudinal Study). Scores from the Telephone Interview of Cognitive Status and figure drawing/word recall tests were used to measure cognitive function in 39,482 individuals. Exposure to indoor air pollution was measured as use of solid fuel for cooking. Solid fuel was defined as coal, biomass charcoal, wood, and straw; clean fuel was defined as liquefied gas, natural gas, and electricity. Linear mixed effect models were applied to examine the effect of indoor air pollution from solid fuel use on cognitive function. Participants had an average global cognitive function of 9.67 (SD = 4.13). Solid fuel users made up 49.71% of participants, but this proportion was much greater among those living in rural areas (64.22%). Compared with clean fuel users, solid fuel users had worse cognitive function. On average, solid fuel users had a 0.81 (95%CI: -0.89, -0.73) lower global cognition score, 0.63 (95%CI: -0.69, -0.57) lower mental health score, and 0.16 (95%CI: -0.22, -0.14) lower episodic memory score. These effects were stronger among participants who are female, aged 65 years old and above, have education level of primary school and below, or have cardiovascular diseases. These results provide evidence for the role of indoor air pollution in neurobehavioral disorders in China. Promotion of practices like expanded use of clean fuel and improved stoves in households may be crucial to significantly reduce indoor air pollution and protect mental health.


Towards an ontology for data quality in integrated chronic disease management: a realist review of the literature.
Effective use of routine data to support integrated chronic disease management (CDM) and population health is dependent on underlying data quality (DQ) and, for cross system use of data, semantic interoperability. An ontological approach to DQ is a potential solution but research in this area is limited and fragmented. Identify mechanisms, including ontologies, to manage DQ in integrated CDM and whether improved DQ will better measure health outcomes. A realist review of English language studies (January 2001-March 2011) which addressed data quality, used ontology-based approaches and is relevant to CDM. We screened 245 papers, excluded 26 duplicates, 135 on abstract review and 31 on full-text review; leaving 61 papers for critical appraisal. Of the 33 papers that examined ontologies in chronic disease management, 13 defined data quality and 15 used ontologies for DQ. Most saw DQ as a multidimensional construct, the most used dimensions being completeness, accuracy, correctness, consistency and timeliness. The majority of studies reported tool design and development (80%), implementation (23%), and descriptive evaluations (15%). Ontological approaches were used to address semantic interoperability, decision support, flexibility of information management and integration/linkage, and complexity of information models. DQ lacks a consensus conceptual framework and definition. DQ and ontological research is relatively immature with little rigorous evaluation studies published. Ontology-based applications could support automated processes to address DQ and semantic interoperability in repositories of routinely collected data to deliver integrated CDM. We advocate moving to ontology-based design of information systems to enable more reliable use of routine data to measure health mechanisms and impacts.


Fluoride tissue distribution: short-term kinetics.
The short-term distribution kinetics of 18F, with and without added carrier, were studied in 12 soft tissues and femur following intravenous administration in rats. The animals were killed in groups of four at 5, 10, 15, 20, 30, and 60 min after the dose. A tissue was judged to be kinetically homogeneous with plasma if an early and constant tissue water-to-plasma (T/P) 18F concentration ratio was established. In the carrier-free study, liver, heart, skin, fat, and kidney met this criterion. In the presence of carrier, four other tissues were added to this group. Brain, resting skeletal muscle, spleen, and femur did not achieve constant T/P values. The addition of carrier resulted in significantly lower T/P ratios in nine tissues. This was especially marked in femur. It is concluded that 1) none of the soft tissues studied strongly binds 18F; 2) most of these tissues are kinetically homogeneous with plasma; and 3) the presence of carrier fluoride can significantly influence the kinetic behavior and distribution of 18F. Finally, based on the current and previously reported 18F T/P ratios, and on reported intracellular-extracellular pH gradients, it is hypothesized that fluoride distribution in several soft tissues is determined by the diffusion equilibrium of HF, that is, by the magnitude of the transmembrane pH gradient.


Poor mobilizer: a retrospective study on proven and predicted incidence according to GITMO criteria.
The Italian Group for Bone Marrow Transplantation (Gruppo Italiano Trapianto di Midollo Osseo, GITMO) recently formalized criteria for a shared definition of poor mobilizer in order to facilitate randomized clinical trials and study comparison focusing on the efficacy of current mobilizing regimens. The availability of a standardized tool for poor mobilizer definition suggested us to retrospectively test GITMO criteria feasibility and applicability. Therefore we analyzed medical and laboratory records of adult patients affected by myeloma (MM) or lymphoma undergoing mobilization for autologous peripheral blood HSC collection from January 2010 to June 2011, at Servizio di Emotrasfusione, Istituto di Ematologia, Università Cattolica Del Sacro Cuore, Roma, UOC SIMT AO S. Camillo Forlanini Roma and SIMT Fondazione Policlinico Tor Vergata Roma. We collected data about 227 patients (134 male, 93 female) affected by MM (31.3%) NHL (58.6%) e HD (10.1%). Thirty-nine patients, 21 male and 18 female met proven poor mobilizer criteria definition resulting in a incidence of 17.2% (12.7% in MM, 21.8% in NHL and 4.3% in HD). Eleven patients, seven affected by lymphoma and four affected by myeloma, were defined predicted PM according to major criteria. Eight patients, seven affected by lymphoma and one affected by myeloma, were define predicted PM according to minor criteria. Sixteen out of 39 patients defined as poor mobilizer either according to major or minor criteria underwent collection procedures and eight (20.5%) achieved a cell dose ⩾2×10(6)/kg CD34(+) cells. GITMO criteria application was easy and resulted in poor mobilizer incidence comparable to current literature. Definitions of proven poor mobilizer and predicted poor mobilizer according to major criteria were very effective while minor criteria were less predictive. These results came from a retrospective analysis and therefore should be validated in future prospective trial. On the other hand these data could be an early overall view of the foreseeable future of peripheral blood stem cell collection. In conclusion we believe that these criteria will be able to better characterize poor mobilizer phenomenon and, consequently, to identify patients taking advantage from new mobilizing agents.


Perioperative hypothermia (33 degrees C) does not increase the occurrence of cardiovascular events in patients undergoing cerebral aneurysm surgery: findings from the Intraoperative Hypothermia for Aneurysm Surgery Trial.
Perioperative hypothermia has been reported to increase the occurrence of cardiovascular complications. By increasing the activity of sympathetic nervous system, perioperative hypothermia also has the potential to increase cardiac injury and dysfunction associated with subarachnoid hemorrhage. The Intraoperative Hypothermia for Aneurysm Surgery Trial randomized patients undergoing cerebral aneurysm surgery to intraoperative hypothermia (n = 499, 33.3 degrees +/- 0.8 degrees C) or normothermia (n = 501, 36.7 degrees +/- 0.5 degrees C). Cardiovascular events (hypotension, arrhythmias, vasopressor use, myocardial infarction, and others) were prospectively followed until 3-month follow-up and were compared in hypothermic and normothermic patients. A subset of 62 patients (hypothermia, n = 33; normothermia, n = 29) also had preoperative and postoperative (within 24 h) measurement of cardiac troponin-I and echocardiography to explore the association between perioperative hypothermia and subarachnoid hemorrhage-associated myocardial injury and left ventricular function. There was no difference between hypothermic and normothermic patients in the occurrence of any single cardiovascular event or in composite cardiovascular events. There was no difference in mortality (6%) between groups, and there was only a single primary cardiovascular death (normothermia). There was no difference between hypothermic and normothermic patients in postoperative versus preoperative left ventricular regional wall motion or ejection fraction. Compared with preoperative values, hypothermic patients had no postoperative increase in cardiac troponin-I (median change 0.00 microg/l), whereas normothermic patients had a small postoperative increase (median change + 0.01 microg/l, P = 0.038). In patients undergoing cerebral aneurysm surgery, perioperative hypothermia was not associated with an increased occurrence of cardiovascular events.


Rapid, accurate, and comparative differentiation of clinically and industrially relevant microorganisms via multiple vibrational spectroscopic fingerprinting.
Despite the fact that various microorganisms (e.g., bacteria, fungi, viruses, etc.) have been linked with infectious diseases, their crucial role towards sustaining life on Earth is undeniable. The huge biodiversity, combined with the wide range of biochemical capabilities of these organisms, have always been the driving force behind their large number of current, and, as of yet, undiscovered future applications. The presence of such diversity could be said to expedite the need for the development of rapid, accurate and sensitive techniques which allow for the detection, differentiation, identification and classification of such organisms. In this study, we employed Fourier transform infrared (FT-IR), Raman, and surface enhanced Raman scattering (SERS) spectroscopies, as molecular whole-organism fingerprinting techniques, combined with multivariate statistical analysis approaches for the classification of a range of industrial, environmental or clinically relevant bacteria (P. aeruginosa, P. putida, E. coli, E. faecium, S. lividans, B. subtilis, B. cereus) and yeast (S. cerevisiae). Principal components-discriminant function analysis (PC-DFA) scores plots of the spectral data collected from all three techniques allowed for the clear differentiation of all the samples down to sub-species level. The partial least squares-discriminant analysis (PLS-DA) models generated using the SERS spectral data displayed lower accuracy (74.9%) when compared to those obtained from conventional Raman (97.8%) and FT-IR (96.2%) analyses. In addition, whilst background fluorescence was detected in Raman spectra for S. cerevisiae, this fluorescence was quenched when applying SERS to the same species, and conversely SERS appeared to introduce strong fluorescence when analysing P. putida. It is also worth noting that FT-IR analysis provided spectral data of high quality and reproducibility for the whole sample set, suggesting its applicability to a wider range of samples, and perhaps the most suitable for the analysis of mixed cultures in future studies. Furthermore, our results suggest that while each of these spectroscopic approaches may favour different organisms (sample types), when combined, they would provide complementary and more in-depth knowledge (structural and/or metabolic state) of biological systems. To the best of our knowledge, this is the first time that such a comparative and combined spectroscopic study (using FT-IR, Raman and SERS) has been carried out on microbial samples.


Cognition in an ever-changing world: climatic variability is associated with brain size in Neotropical parrots.
Research on the conditions favoring the evolution of complex cognition and its underlying neural structures has increasingly stressed the role of environmental variability. These studies suggest that the ability to learn, behave flexibly and innovate would be favored under unpredictable variations in the availability of resources, as it would enable organisms to adjust to novel conditions. Despite the growing number of studies based on the idea that larger-brained organisms would be better prepared to cope with environmental challenges, direct testing of the association between brain size and environmental variability per se remains scant. Here we focus on Neotropical parrots as our model group and test the hypothesis that if relatively larger brains were favored in climatically variable environments, larger-brained species should currently tolerate a higher degree of environmental uncertainty. Although we show that there are also other factors underlying the dynamics of brain size variation in this group, our results support the hypothesis that proportionally larger-brained species are more tolerant to climatic variability, both on a temporal and spatial scale. Additionally, they suggest that the differences in relative brain size among Neotropical parrots represent multiple, recent events in the evolutionary history of the group, and are particularly tied to an increased dependence on more open and climatically unstable habitats. As this is the first study to present evidence of the link between brain size and climatic variability in birds, our findings provide a step towards understanding the potential benefits underlying variation in brain size and the maintenance of highly enlarged brains in this and other groups.


Considering just noticeable difference in assessments of physical accommodation for product design.
Configuring products or environments for the size of their human users requires the consideration of several characteristics of the target user population, including body dimensions (anthropometry) and preferred interaction. Users are both adaptable and imperfect observers, which often makes it difficult for them to distinguish between candidate designs. This insensitivity is described by a concept called 'just noticeable difference', or JND. This paper presents an implementation of JND modelling and demonstrates how its use in the sizing of products or environments for target user populations can improve expected performance. Two facets of this problem are explored: (1) how experimental measures of JND for dimensional optimisation tasks may be obtained, and (2) how measures of JND may be included in models of user-device interaction for both adjustable and discretely sized products and the assumptions required. A case study demonstrating the collection and modelling of JND for a simple univariate problem is also presented. Practitioner Summary: Since people are adaptable and imperfect observers, there exists a 'just noticeable difference' that can be considered when designing products and environments. When JND is modelled for a target population, less variability in design dimensions due to physical user requirements may be necessary. This paper considers JND in quantitative simulations of population accommodation.


Rewiring of transcriptional regulatory networks: hierarchy, rather than connectivity, better reflects the importance of regulators.
Network connectivity has been related to essentiality: Highly connected proteins (hubs) are more important for cell growth and survival. Although this is intuitively reasonable, another way to assess the role of a regulator is to assign it to a level within a "chain-of-command" hierarchy. Here, we analyzed the effects of network rewiring events on transcriptional regulatory hierarchies in two species. First, we superimposed the phenotypic effects of tampering with specific genes and their regulatory connections directly onto the hierarchies. To study second-order effects, which involved changes in the level of regulators within the hierarchy upon deletions or insertions of other regulators or connections, we reconstructed modified hierarchies. We found that rewiring events that affected upper levels had a more marked effect on cell proliferation rate and survival than did those involving lower levels. Moreover, we showed that the hierarchical level and type of change better reflected the phenotypic effect of rewiring than did the number of changes. We also investigated other features connected to the importance of upper-level regulators: In particular, relative to lower-level regulators, upper-level regulators exhibited a greater range of expression values across species, had fewer functionally redundant copies, and had a shorter half-life. Overall, our analysis shows that broadly constructed hierarchies may better reflect the importance of regulators for cell growth than classifications based on the number of connections (hubbiness).


Detecting and Classifying Human Touches in a Social Robot Through Acoustic Sensing and Machine Learning.
An important aspect in Human-Robot Interaction is responding to different kinds of touch stimuli. To date, several technologies have been explored to determine how a touch is perceived by a social robot, usually placing a large number of sensors throughout the robot's shell. In this work, we introduce a novel approach, where the audio acquired from contact microphones located in the robot's shell is processed using machine learning techniques to distinguish between different types of touches. The system is able to determine when the robot is touched (touch detection), and to ascertain the kind of touch performed among a set of possibilities: stroke, tap, slap, and tickle (touch classification). This proposal is cost-effective since just a few microphones are able to cover the whole robot's shell since a single microphone is enough to cover each solid part of the robot. Besides, it is easy to install and configure as it just requires a contact surface to attach the microphone to the robot's shell and plug it into the robot's computer. Results show the high accuracy scores in touch gesture recognition. The testing phase revealed that Logistic Model Trees achieved the best performance, with an F-score of 0.81. The dataset was built with information from 25 participants performing a total of 1981 touch gestures.


Solution-processed PbS quantum dot infrared photodetectors and photovoltaics.
In contrast to traditional semiconductors, conjugated polymers provide ease of processing, low cost, physical flexibility and large area coverage. These active optoelectronic materials produce and harvest light efficiently in the visible spectrum. The same functions are required in the infrared for telecommunications (1,300-1,600 nm), thermal imaging (1,500 nm and beyond), biological imaging (transparent tissue windows at 800 nm and 1,100 nm), thermal photovoltaics (>1,900 nm), and solar cells (800-2,000 nm). Photoconductive polymer devices have yet to demonstrate sensitivity beyond approximately 800 nm (refs 2,3). Sensitizing conjugated polymers with infrared-active nanocrystal quantum dots provides a spectrally tunable means of accessing the infrared while maintaining the advantageous properties of polymers. Here we use such a nanocomposite approach in which PbS nanocrystals tuned by the quantum size effect sensitize the conjugated polymer poly[2-methoxy-5-(2'-ethylhexyloxy-p-phenylenevinylene)] (MEH-PPV) into the infrared. We achieve, in a solution-processed device and with sensitivity far beyond 800 nm, harvesting of infrared-photogenerated carriers and the demonstration of an infrared photovoltaic effect. We also make use of the wavelength tunability afforded by the nanocrystals to show photocurrent spectra tailored to three different regions of the infrared spectrum.


Can public health reconcile profits and pandemics? An analysis of attitudes to commercial sector engagement in health policy and research.
Public health's terms of engagement with unhealthy commodity industries (alcohol, tobacco and ultra-processed food and drinks) have become increasingly contested in policy and research. We sought to identify approaches that could attract consensus support within and across policy domains. Using snowball sampling, we undertook an online survey of 335 health researchers, advocates and policymakers, in 40 countries, assessing responses to stated principles, claims and recommendations for engaging with unhealthy commodity industries in relation to key policy and research initiatives. Most respondents identified a fundamental conflict between industry interests and public health objectives for all three industries, with agreement greatest in relation to tobacco and weakest for food. This pattern was replicated across diverse questions regarding potential forms of engagement, including in rejecting voluntarism and partnership approaches to health policy. While awareness of tobacco industry tactics to influence policy and research was higher than for alcohol and food, most respondents rejected the view that the influence of the latter was less significant for public health. Proposals that health and research organisations should divest their funds attracted less support with respect to food, while restricting publication of industry-funded research in academic journals was the issue that most divided opinion. Respondents reported most difficulty in answering questions about the food industry. The strong consensus around restricting interactions with the tobacco industry supports increased implementation of the WHO Framework Convention on Tobacco Control's conflict of interest provisions. There is strong support for the extension of such practices to the alcohol industry, challenging current norms. More mixed responses indicate a need for greater clarity in defining the food industry, and for research analyzing links, similarities and differences across different types of unhealthy commodity producers. Partnership approaches to addressing non-communicable diseases seem incapable of attracting widespread support across public health, challenging practice in many contexts.


Study on suitability of KOD DNA polymerase for enzymatic production of artificial nucleic acids using base/sugar modified nucleoside triphosphates.
Recently, KOD and its related DNA polymerases have been used for preparing various modified nucleic acids, including not only base-modified nucleic acids, but also sugar-modified ones, such as bridged/locked nucleic acid (BNA/LNA) which would be promising candidates for nucleic acid drugs. However, thus far, reasons for the effectiveness of KOD DNA polymerase for such purposes have not been clearly elucidated. Therefore, using mutated KOD DNA polymerases, we studied here their catalytic properties upon enzymatic incorporation of nucleotide analogues with base/sugar modifications. Experimental data indicate that their characteristic kinetic properties enabled incorporation of various modified nucleotides. Among those KOD mutants, one achieved efficient successive incorporation of bridged nucleotides with a 2'-ONHCH₂CH₂-4' linkage. In this study, the characteristic kinetic properties of KOD DNA polymerase for modified nucleoside triphosphates were shown, and the effectiveness of genetic engineering in improvement of the enzyme for modified nucleotide polymerization has been demonstrated.


Redirected infection of directly biotinylated recombinant adenovirus vectors through cell surface receptors and antigens.
The inability of adenovirus to infect primitive hematopoietic cells presents an obstacle to the use of adenovirus vectors for gene transfer to these cell types. Therefore, expanding the tropism of adenovirus vectors to unique cell surface antigens would be an important development for gene therapy protocols. In this study, we sought to redirect infection of adenovirus vectors to primitive human hematopoietic cells that universally express the c-Kit receptor on their cell surface. To accomplish this, a vector was constructed by covalently linking biotin molecules to recombinant adenovirus, followed by addition of the biotinylated ligand for the c-Kit receptor, stem cell factor (SCF), through an avidin bridge. Gene transfer was directed specifically to c-Kit-positive hematopoietic cell lines, resulting in up to a 2,440-fold increase in luciferase expression with frequencies equivalent to recombinant virus infection of permissive cells. Substitution of biotinylated antibodies directed against c-Kit, CD34 (binds L-selectin), and CD44 (hyaluronate receptor) receptors for biotinylated SCF resulted in 50-, 8-, and 260-fold increases in reporter gene expression, respectively, demonstrating that infection also could be redirected through antibody-antigen interactions and through antigens other than growth factor receptors. The versatility of this vector was demonstrated further by infection of primary T cells with vectors targeted with antibodies to CD44 (resting and activated T cells) and biotinylated IL-2 (activated T cells only). Taken together, directly biotinylated adenovirus vectors represent a versatile and efficient method for redirection of virus infection to specific cells.


Bayesian Markov models consistently outperform PWMs at predicting motifs in nucleotide sequences.
Position weight matrices (PWMs) are the standard model for DNA and RNA regulatory motifs. In PWMs nucleotide probabilities are independent of nucleotides at other positions. Models that account for dependencies need many parameters and are prone to overfitting. We have developed a Bayesian approach for motif discovery using Markov models in which conditional probabilities of order k - 1 act as priors for those of order k This Bayesian Markov model (BaMM) training automatically adapts model complexity to the amount of available data. We also derive an EM algorithm for de-novo discovery of enriched motifs. For transcription factor binding, BaMMs achieve significantly (P = 1/16) higher cross-validated partial AUC than PWMs in 97% of 446 ChIP-seq ENCODE datasets and improve performance by 36% on average. BaMMs also learn complex multipartite motifs, improving predictions of transcription start sites, polyadenylation sites, bacterial pause sites, and RNA binding sites by 26-101%. BaMMs never performed worse than PWMs. These robust improvements argue in favour of generally replacing PWMs by BaMMs.


A rare case of leiomyosarcoma originating from the left round ligament of the uterus.
Uterine leiomyosarcomas (LMS) are rare malignancies with a poor prognosis. The incidence is reported to be 3-7/100.000 per year. Preoperative and intraoperative differentiation between LMS and large leiomyoma is always challenging. Therefore, LMS are often diagnosed during postoperative histologic evaluation of hysterectomy or myomectomy specimens. LMS of the round ligament of the uterus which can represent as an inguinal or pelvic mass is extremely rare. To our knowledge, there is only one case report of LMS arising from the round ligament available in the literature. Herein, we aimed to present the second case of LMS originating from the left round ligament of the uterus in a premenopausal woman initially misdiagnosed as an ovarian tumor.


Immunization With the CSF-470 Vaccine Plus BCG and rhGM-CSF Induced in a Cutaneous Melanoma Patient a TCRβ Repertoire Found at Vaccination Site and Tumor Infiltrating Lymphocytes That Persisted in Blood.
The CSF-470 cellular vaccine plus BCG and rhGM-CSF increased distant metastases-free survival in cutaneous melanoma patients stages IIB-IIC-III relative to medium dose IFN-α2b (CASVAC-0401 study). Patient-045 developed a mature vaccination site (VAC-SITE) and a regional cutaneous metastasis (C-MTS), which were excised during the protocol, remaining disease-free 36 months from vaccination start. CDR3-TCRβ repertoire sequencing in PBMC and tissue samples, along with skin-DTH score and IFN-γ ELISPOT assay, were performed to analyze the T-cell immune response dynamics throughout the immunization protocol. Histopathological analysis of the VAC-SITE revealed a highly-inflamed granulomatous structure encircled by CD11c+ nested-clusters, brisk CD8+ and scarce FOXP3+, lymphocytes with numerous Langhans multinucleated-giant-cells and macrophages. A large tumor-regression area fulfilled the C-MTS with brisk lymphocyte infiltration, mainly composed of CD8+PD1+ T-cells, CD20+ B-cells, and scarce FOXP3+ cells. Increasing DTH score and IFN-γ ELISPOT assay signal against the CSF-470 vaccine-lysate was evidenced throughout immunization. TCRβ repertoire analysis revealed for the first time the presence of common clonotypes between a VAC-SITE and a C-MTS; most of them persisted in blood by the end of the immunization protocol. In vitro boost with vaccine-lysate revealed the expansion of persistent clones that infiltrated the VAC-SITE and/or the C-MTS; other persistent clones expanded in the patient's blood as well. We propose that expansion of such persistent clonotypes might derive from two different although complementary mechanisms: the proliferation of specific clones as well as the expansion of redundant clones, which increased the number of nucleotide rearrangements per clonotype, suggesting a functional antigenic selection. In this patient, immunization with the CSF-470 vaccine plus BCG and rhGM-CSF induced a T-cell repertoire at the VAC-SITE that was able to infiltrate an emerging C-MTS, which resulted in the expansion of a T-cell repertoire that persisted in blood by the end of the 2-year treatment.


Effect of supplemental vitamin E for the prevention and treatment of cardiovascular disease.
To evaluate and synthesize the evidence on the effect of supplements of vitamin E on the prevention and treatment of cardiovascular disease. Systematic review of placebo-controlled randomized controlled trials; meta-analysis where justified. Eighty-four eligible trials were identified. For the outcomes of all-cause mortality, cardiovascular mortality, fatal or nonfatal myocardial infarction, and blood lipids, neither supplements of vitamin E alone nor vitamin E given with other agents yielded a statistically significant beneficial or adverse pooled relative risk (for example, pooled relative risk of vitamin E alone = 0.96 [95% confidence interval (CI), 0.84 to 1.10]; 0.97 [95% CI, 0.80 to 1.90]; and 0.72 [95% CI, 0.51 to 1.02] for all-cause mortality, cardiovascular mortality, and nonfatal myocardial infarction, respectively. There is good evidence that vitamin E supplementation does not beneficially or adversely affect cardiovascular outcomes.


Coarse-Super-Resolution-Fine Network (CoSF-Net): A Unified End-to-End Neural Network for 4D-MRI with Simultaneous Motion Estimation and Super-Resolution.
Four-dimensional magnetic resonance imaging (4D-MRI) is an emerging technique for tumor motion management in image-guided radiation therapy (IGRT). However, current 4D-MRI suffers from low spatial resolution and strong motion artifacts owing to the long acquisition time and patients' respiratory variations. If not managed properly, these limitations can adversely affect treatment planning and delivery in IGRT. In this study, we developed a novel deep learning framework called the coarse-super-resolution-fine network (CoSF-Net) to achieve simultaneous motion estimation and super-resolution within a unified model. We designed CoSF-Net by fully excavating the inherent properties of 4D-MRI, with consideration of limited and imperfectly matched training datasets. We conducted extensive experiments on multiple real patient datasets to assess the feasibility and robustness of the developed network. Compared with existing networks and three state-of-the-art conventional algorithms, CoSF-Net not only accurately estimated the deformable vector fields between the respiratory phases of 4D-MRI but also simultaneously improved the spatial resolution of 4D-MRI, enhancing anatomical features and producing 4D-MR images with high spatiotemporal resolution.


Effectiveness and safety of transcranial laser therapy for acute ischemic stroke.
We hypothesized that transcranial laser therapy (TLT) can use near-infrared laser technology to treat acute ischemic stroke. The NeuroThera Effectiveness and Safety Trial-2 (NEST-2) tested the safety and efficacy of TLT in acute ischemic stroke. This double-blind, randomized study compared TLT treatment to sham control. Patients receiving tissue plasminogen activator and patients with evidence of hemorrhagic infarct were excluded. The primary efficacy end point was a favorable 90-day score of 0 to 2 assessed by the modified Rankin Scale. Other 90-day end points included the overall shift in modified Rankin Scale and assessments of change in the National Institutes of Health Stroke Scale score. We randomized 660 patients: 331 received TLT and 327 received sham; 120 (36.3%) in the TLT group achieved favorable outcome versus 101 (30.9%), in the sham group (P=0.094), odds ratio 1.38 (95% CI, 0.95 to 2.00). Comparable results were seen for the other outcome measures. Although no prespecified test achieved significance, a post hoc analysis of patients with a baseline National Institutes of Health Stroke Scale score of <16 showed a favorable outcome at 90 days on the primary end point (P<0.044). Mortality rates and serious adverse events did not differ between groups with 17.5% and 17.4% mortality, 37.8% and 41.8% serious adverse events for TLT and sham, respectively. TLT within 24 hours from stroke onset demonstrated safety but did not meet formal statistical significance for efficacy. However, all predefined analyses showed a favorable trend, consistent with the previous clinical trial (NEST-1). Both studies indicate that mortality and adverse event rates were not adversely affected by TLT. A definitive trial with refined baseline National Institutes of Health Stroke Scale exclusion criteria is planned.


Imaging-based quantification of hepatic fat: methods and clinical applications.
Fatty liver disease comprises a spectrum of conditions (simple hepatic steatosis, steatohepatitis with inflammatory changes, and end-stage liver disease with fibrosis and cirrhosis). Hepatic steatosis is often associated with diabetes and obesity and may be secondary to alcohol and drug use, toxins, viral infections, and metabolic diseases. Detection and quantification of liver fat have many clinical applications, and early recognition is crucial to institute appropriate management and prevent progression. Histopathologic analysis is the reference standard to detect and quantify fat in the liver, but results are vulnerable to sampling error. Moreover, it can cause morbidity and complications and cannot be repeated often enough to monitor treatment response. Imaging can be repeated regularly and allows assessment of the entire liver, thus avoiding sampling error. Selection of appropriate imaging methods demands understanding of their advantages and limitations and the suitable clinical setting. Ultrasonography is effective for detecting moderate or severe fatty infiltration but is limited by lack of interobserver reliability and intraobserver reproducibility. Computed tomography allows quantitative and qualitative evaluation and is generally highly accurate and reliable; however, the results may be confounded by hepatic parenchymal changes due to cirrhosis or depositional diseases. Magnetic resonance (MR) imaging with appropriate sequences (eg, chemical shift techniques) has similarly high sensitivity, and MR spectroscopy provides unique advantages for some applications. However, both are expensive and too complex to be used to monitor steatosis.


Postural configuration affects the perception of earth-based space during pitch tilt.
This study investigates the relative contribution of body parts in the elaboration of a whole-body egocentric attraction phenomenon previously observed during earth-based judgments. This was addressed through a particular earth-based task requiring estimating the possibility of passing under a projected line, imagining a forward horizontal displacement. Different postural configurations were tested, involving whole-body tilt, trunk tilt alone or head tilt alone. Two legs positions relative to the trunk were manipulated. Results showed systematic deviations of the subjective "passability" toward the tilt, linearly related to the tilt magnitude. For each postural configuration, the egocentric influence appeared to be highly dependent on the position of trunk and head axes, whereas the legs position appeared not relevant. When compared to the whole-body tilt condition, tilting the trunk alone consistently reduced the amount of the deviation toward the tilt, whereas tilting the head alone consistently increased it. Our results suggest that several specific effects from multiple body parts can account for the global deviation of the estimates observed during whole-body tilt. Most importantly, we support that the relative contribution of the body segments could mainly depend on a reweighting process, probably based on the reliability of sensory information available for a particular postural set.