Dot comparison stimuli are not all alike: the effect of different visual controls on ANS measurement.
The most common method of indexing Approximate Number System (ANS) acuity is to use a nonsymbolic dot comparison task. Currently there is no standard protocol for creating the dot array stimuli and it is unclear whether tasks that control for different visual cues, such as cumulative surface area and convex hull size, measure the same cognitive constructs. Here we investigated how the accuracy and reliability of magnitude judgements is influenced by visual controls through a comparison of performance on dot comparison trials created with two standard methods: the Panamath program and Gebuis & Reynvoet's script. Fifty-one adult participants completed blocks of trials employing images constructed using the two protocols twice to obtain a measure of immediate test-retest reliability. We found no significant correlation between participants' accuracy scores on trials created with the two protocols, suggesting that tasks employing these protocols may measure different cognitive constructs. Additionally, there were significant differences in the test-retest reliabilities for trials created with each protocol. Finally, strong congruency effects for convex hull size were found for both sets of protocol trials, which provides some clarification for conflicting results in the literature.


The effects of sediment-associated triorganotin compounds on the gills of the European flounder, Platichthys flesus (L.).
The effects of exposure to sediment-associated tri-n-butyltin chloride (TBT) and triphenyltin chloride (TPhT) were examined in the euryhaline European flounder, Platichthys flesus (L.). The effects were quantified by measuring the changes in sodium efflux, Na(+)/K(+)-ATPase activity and the numbers, areas and distribution of chloride cells in the gills of freshwater-adapted fish, following a rapid transfer to seawater. After transfer, the Na(+)/K(+)-ATPase activity and the sodium efflux significantly increased in both the TPhT and control groups but not in the TBT group. However, Na(+)/K(+)-ATPase activity and the sodium efflux in the TPhT group had returned to pre-salinity transfer levels by day 15 after the initial exposure to TPhT. Morphological changes in the numbers and areas of chloride cells, known to be associated with seawater adaptation, took place in the control group, i.e. there was a significant reduction in the number of lamellar chloride cells accompanied by an increase in the number of interlamellar chloride cells. There was a reduction in the numbers of lamellar chloride cells in the TBT-exposed group following transfer to seawater but the mean number was significantly higher than the control group by the end of the experiment. In the TPhT-exposed group, the reduction was not significantly different to that seen in the control group. By the end of the experiment, both organotin-exposed groups had significantly lower mean numbers of interlamellar chloride cells than the control group. Before transfer to seawater, the mean areas of lamellar and interlamellar chloride cells of all three groups were not significantly different. On transfer, the mean areas of lamellar chloride cells in the control group became significantly smaller than the mean areas of the organotin groups. There was no significant difference in the mean areas of interlamellar chloride cells in the control and TBT groups between the start and finish of the experiment but there was a significant increase in the mean area of TPhT-treated animals at the end of the experiment when compared to the control group. The results presented in this study lead to the conclusion that tri-n-butyltin chloride and triphenyltin chloride in sediments are capable of significantly disrupting both the physiological as well as morphological components of ionic regulatory functions of an estuarine fish, at concentrations currently found in estuarine sediments.


Cell-cell interactions promote mammary epithelial cell differentiation.
Mammary epithelium differentiates in a stromal milieu of adipocytes and fibroblasts. To investigate cell-cell interactions that may influence mammary epithelial cell differentiation, we developed a co-culture system of murine mammary epithelium and adipocytes and other fibroblasts. Insofar as caseins are specific molecular markers of mammary epithelial differentiation, rat anti-mouse casein monoclonal antibodies were raised against the three major mouse casein components to study this interaction. Mammary epithelium from mid-pregnant mice was plated on confluent irradiated monolayers of 3T3-L1 cells, a subclone of the Swiss 3T3 cell line that differentiates into adipocytes in monolayer culture and other cell monolayers (3T3-C2 cells, Swiss 3T3 cells, and human foreskin fibroblasts). Casein was synthesized by mammary epithelium only in the presence of co-cultured cells and the lactogenic hormone combination of insulin, hydrocortisone, and prolactin. Synthesis and accumulation of alpha-, beta-, and gamma-mouse casein within the epithelium was shown by immunohistochemical staining of cultured cells with anti-casein monoclonal antibodies, and the specificity of the immunohistochemical reaction was demonstrated using immunoblots. A competitive immunoassay was used to measure the amount of casein secreted into the culture medium. In a 24-h period, mammary epithelium co-cultured with 3T3-L1 cells secreted 12-20 micrograms beta-casein per culture dish. There was evidence of specificity in the cell-cell interaction that mediates hormone-dependent casein synthesis. Swiss 3T3 cells, newborn foreskin fibroblasts, substrate-attached material ("extracellular matrix"), and tissue culture plastic did not support casein synthesis, whereas monolayers of 3T3-L1 and 3T3-C2 cells, a subclone of Swiss 3T3 cells that does not undergo adipocyte differentiation, did. We conclude that interaction between mammary epithelium and other specific nonepithelial cells markedly influences the acquisition of hormone sensitivity of the epithelium and hormone-dependent differentiation.


Protothecosis in 17 Australian dogs and a review of the canine literature.
Systemic protothecosis was diagnosed in 17 Australian dogs between 1988 and 2005. There was a preponderance of young-adult (median 4 years), medium- to large-breed dogs. Females (12/17 cases) and Boxer dogs (7 cases, including 6 purebreds and one Boxer cross) were over-represented. Sixteen of 17 dogs died, with a median survival of four months. A disproportionate number of cases were from coastal Queensland. In most patients, first signs were referable to colitis (11/17 cases), which varied in severity, and was often present for many months before other symptoms developed. Subsequent to dissemination, signs were mostly ocular (12 cases) and/or neurologic (8 cases). Two dogs had signs due to bony lesions. Once dissemination was evident, death or euthanasia transpired quickly. Prototheca organisms had a tropism for the eye, central nervous system (CNS), bone, kidneys and myocardium, tissues with a good blood supply. Microscopic examination and culture of urine (5 cases), cerebrospinal fluid (CSF;1 case), rectal scrapings (4 cases), aspirates or biopsies of eyes (5 cases) and histology of colonic biopsies (6 cases) as well as skin and lymph nodes (2 cases) helped secure a diagnosis. Of the cases where culture was successful, P wickerhamii was isolated from two patients, while P zopfii was isolated from five. P zopfii infections had a more aggressive course. Treatment was not attempted in most cases. Combination therapy with amphotericin B and itraconazole proved effective in two cases, although in one of these treatment should have been for a longer duration. One surviving dog is currently still receiving itraconazole. Protothecosis should be considered in all dogs with refractory colitis, especially in female Boxers.


Dietary patterns at 6, 15 and 24 months of age are associated with IQ at 8 years of age.
Diet supplies the nutrients needed for the development of neural tissues that occurs over the first 2 years of life. Our aim was to examine associations between dietary patterns at 6, 15 and 24 months and intelligence quotient (IQ) scores at 8 years. Participants were enrolled in an observational birth cohort (ALSPAC study, n = 7,097). Dietary data was collected by questionnaire and patterns were extracted at each time using principal component analysis. IQ was measured using the Wechsler Intelligence Scale for Children at 8 years. Associations between dietary patterns and IQ were examined in regression analyses adjusted for potential confounding and by propensity score matching, with data imputation for missing values. At all ages, higher scores on a Discretionary pattern (characterized by biscuits, chocolate, sweets, soda, crisps) were associated with 1-2 point lower IQ. A Breastfeeding pattern at 6 months and Home-made contemporary patterns at 15 and 24 months (herbs, legumes, cheese, raw fruit and vegetables) were associated with 1-to-2 point higher IQ. A Home-made traditional pattern (meat, cooked vegetables, desserts) at 6 months was positively associated with higher IQ scores, but there was no association with similar patterns at 15 or 24 months. Negative associations were found with patterns characterized by Ready-prepared baby foods at 6 and 15 months and positive associations with a Ready-to-eat foods pattern at 24 months. Propensity score analyses were consistent with regression analyses. This study suggests that dietary patterns from 6 to 24 months may have a small but persistent effect on IQ at 8 years.


Diffusion of beta-lactam antibiotics into proteoliposomes reconstituted with outer membranes of isogenic imipenem-susceptible and -resistant strains of Enterobacter cloacae.
The influence of outer membrane (OM) permeability on carbapenem susceptibility was studied in strains of Enterobacter cloacae, a species in which carbapenem resistance depends upon the conjunction of overproduction of the chromosomal cephalosporinase and reduction of OM permeability. Relative trans-OM diffusion rates were measured using the liposome swelling assay. Proteoliposomes were reconstituted with OM from the members of an isogenic set of E. cloacae strains, selected in vivo or in vitro, which produced either porins F and D (wild-type), or F or D only, or neither. For all but one mutant, and compared with the wild-type strain, the respective increases in MICs and decreases in trans-OM diffusion of carbapenems were: nil and 13 to 18%; 4- to 32-fold and 33 to 50%; > or = 64-fold and > or = 90%. Our results suggest (i) that carbapenems (and other beta-lactam antibiotics) diffuse through porins F and D, but more rapidly through porin F, and (ii) that OM permeability is the critical factor in determining the level of MICs of carbapenems for cephalosporinase-overproducing strains of E. cloacae. The OM of one particular low-level carbapenem-resistant and porin F- and D-deficient mutant was at least five times more permeable to carbapenems than the similarly porin-deficient high-level resistant mutants. We infer from this observation the possible existence of an alternative carbapenem penetration pathway which could be associated with two as yet uncharacterized overproduced OM proteins of about 22 and 47 kDa.


Implicit cognition is impaired and dissociable in a head-injured group with executive deficits.
Implicit or non-conscious cognition is traditionally assumed to be robust to pathology but Gomez-Beldarrain et al. recently showed deficits on a single implicit task after head injury. Laboratory research suggests that implicit processes dissociate. This study therefore examined implicit cognition in 20 head-injured patients and age- and IQ-matched controls using a battery of four implicit cognition tasks: a serial reaction time task (SRT), mere exposure effect task, automatic stereotype activation and hidden co-variation detection. Patients were assessed on an extensive neuropsychological battery, and MRI scanned. Inclusion criteria included impairment on at least one measure of executive function. The patient group was impaired relative to the control group on all the implicit cognition tasks except automatic stereotype activation. Effect size analyses using the control mean and standard deviation for reference showed further dissociations across patients and across implicit tasks. Patients impaired on implicit tasks had more cognitive deficits overall than those unimpaired, and a larger dysexecutive self/other discrepancy (DEX) score suggesting greater behavioural problems. Performance on the SRT task correlated with a composite measure of executive function. Head injury thus produced heterogeneous impairments in the implicit acquisition of new information. Implicit activation of existing knowledge structures appeared intact. Impairments in implicit cognition and executive function may interact to produce dysfunctional behaviour after head injury. Future comparisons of implicit and explicit cognition should use several measures of each function, to ensure that they measure the latent variable of interest.


Nonlinear spectral management: linearization of the lossless fiber channel.
Using the integrable nonlinear Schrödinger equation (NLSE) as a channel model, we describe the application of nonlinear spectral management for effective mitigation of all nonlinear distortions induced by the fiber Kerr effect. Our approach is a modification and substantial development of the so-called "eigenvalue communication" idea first presented in A. Hasegawa, T. Nyu, J. Lightwave Technol. 11, 395 (1993). The key feature of the nonlinear Fourier transform (inverse scattering transform) method is that for the NLSE, any input signal can be decomposed into the so-called scattering data (nonlinear spectrum), which evolve in a trivial manner, similar to the evolution of Fourier components in linear equations. We consider here a practically important weakly nonlinear transmission regime and propose a general method of the effective encoding/modulation of the nonlinear spectrum: The machinery of our approach is based on the recursive Fourier-type integration of the input profile and, thus, can be considered for electronic or all-optical implementations. We also present a novel concept of nonlinear spectral pre-compensation, or in other terms, an effective nonlinear spectral pre-equalization. The proposed general technique is then illustrated through particular analytical results available for the transmission of a segment of the orthogonal frequency division multiplexing (OFDM) formatted pattern, and through WDM input based on Gaussian pulses. Finally, the robustness of the method against the amplifier spontaneous emission is demonstrated, and the general numerical complexity of the nonlinear spectrum usage is discussed.


What Do Providers Want from a Pain Screening Measure Used in Daily Practice?
We aimed to understand providers' experiences and preferences regarding several brief pain screening measures. We collected two waves of data for this analysis. Wave one: We conducted nine focus groups with multidisciplinary Department of Veterans Affairs (VA) providers. Wave two: To understand an emergent theme in wave one, we conducted 15 telephone interviews with prescribing providers where we used a semistructured guide comparing screening measures currently used in VA practices. Using content analysis of the wave two interviews, we evaluated providers' perceptions of important aspects of brief pain screening measures and reported emergent themes. Five emergent themes underlie providers' perceptions of the utility of brief pain screening measures: 1) item abstractness: how bounded and concrete a patient's interpretation of an individual item is; 2) item distinctness: belief in the patient's ability to differentiate between the meaning of various items in a pain measure; 3) item anchoring: presence of a description under each response option making the meaning explicit; 4) item look-back period: the period of time over which patients are asked to remember and comment on their pain; 5) parsimony: identifying the shortest and simplest approach possible to acquire desired information. Overly complex or adaptive screening tools may include information that is ultimately not used by providers. Conversely, overly simplistic pain screening tools may omit information that helps providers understand the impact of pain on patients' lives. As pain is nuanced, complex, and subjective, all screening measures exhibit some limitations. No single pain measure serves all chronic pain patients, and specific contexts or settings may warrant additional specific items.


Genomic and transcriptomic signals of thermal tolerance in heat-tolerant corals (Platygyra daedalea) of the Arabian/Persian Gulf.
Scleractinian corals occur in tropical regions near their upper thermal limits and are severely threatened by rising ocean temperatures. However, several recent studies have shown coral populations can harbour genetic variation in thermal tolerance. Here, we have extended these approaches to study heat tolerance of corals in the Persian/Arabian Gulf, where heat-tolerant local populations experience extreme summer temperatures (up to 36°C). To evaluate whether selection has depleted genetic variation in thermal tolerance, estimate potential future adaptive responses and understand the functional basis for these corals' unusual heat tolerance, we conducted controlled crosses in the Gulf coral Platygyra daedalea. Heat tolerance is highly heritable in this population (h 2 = 0.487-0.748), suggesting substantial potential for adaptive responses to selection for elevated temperatures. To identify genetic markers associated with this variation, we conducted genomewide SNP genotyping in parental corals and tested for relationships between paternal genotype and offspring thermal tolerance. Resulting multilocus SNP genotypes explained a large fraction of variation in thermal tolerance in these crosses (69%). To investigate the functional basis of these differences in thermal tolerance, we profiled transcriptional responses in tolerant and susceptible families, revealing substantial sire effects on transcriptional responses to thermal stress. We also studied sequence variation in these expressed sequences, identifying alleles and functional groups of differentially expressed genes associated with thermal tolerance. Our findings demonstrate that corals in this population harbour extensive genetic variation in thermal tolerance, and heat-tolerant phenotypes differ in both gene sequences and transcriptional stress responses from their susceptible counterparts.


Effect of hepatic cytochrome P450 (P450) oxidoreductase deficiency on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA adduct formation in P450 reductase conditional null mice.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), formed during the cooking of foods, induces colon cancer in rodents. PhIP is metabolically activated by cytochromes P450 (P450s). To evaluate the role of hepatic P450s in the bioactivation of PhIP, we used Reductase Conditional Null (RCN) mice, in which cytochrome P450 oxidoreductase (POR), the unique electron donor to P450s, can be specifically deleted in hepatocytes by pretreatment with 3-methylcholanthrene (3-MC), resulting in the loss of essentially all hepatic P450 function. RCN mice were treated orally with 50 mg/kg b.wt. PhIP daily for 5 days, with and without 3-MC pretreatment. PhIP-DNA adducts (i.e., N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [dG-C8-PhIP]), measured by liquid chromatography-tandem mass spectrometry, were highest in colon (1362 adducts/10(8) deoxynucleosides), whereas adduct levels in liver were ∼3.5-fold lower. Whereas no differences in PhIP-DNA adduct levels were found in livers with active POR versus inactivated POR, adduct levels were on average ∼2-fold lower in extrahepatic tissues of mice lacking hepatic POR. Hepatic microsomes from RCN mice with or without 3-MC pretreatment were also incubated with PhIP and DNA in vitro. PhIP-DNA adduct formation was ∼8-fold lower with hepatic microsomes from POR-inactivated mice than with those with active POR. Most of the hepatic microsomal activation of PhIP in vitro was attributable to CYP1A. Our results show that PhIP-DNA adduct formation in colon involves hepatic N-oxidation, circulation of activated metabolites via the bloodstream to extrahepatic tissues, and further activation, resulting in the formation of dG-C8-PhIP. Besides hepatic P450s, PhIP may be metabolically activated mainly by a non-P450 pathway in liver.


Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila.
Overexpression of sirtuins (NAD(+)-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila melanogaster. Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background. Here we re-examined the reported effects of sirtuin overexpression on ageing and found that standardization of genetic background and the use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila. In C. elegans, outcrossing of a line with high-level sir-2.1 overexpression abrogated the longevity increase, but did not abrogate sir-2.1 overexpression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low-copy-number sir-2.1 overexpression also abrogated longevity. A Drosophila strain with ubiquitous overexpression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported, but was not long-lived relative to the appropriate transgenic controls, and nor was a new line with stronger overexpression of dSir2. These findings underscore the importance of controlling for genetic background and for the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life-extending effect of dietary restriction on ageing in Drosophila has also been reported to be dSir2 dependent. We found that dietary restriction increased fly lifespan independently of dSir2. Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects of sirtuins on lifespan in C. elegans and Drosophila.


Olfactory neuroblastoma.
Few neoplasms are unique to the sinonasal tract, but sinonasal undifferentiated carcinoma and olfactory neuroblastoma are malignant tumors which require unique management. Due to the rarity of these tumors, practicing pathologists are not always aware of their distinctive clinical, radiographic, histologic, immunohistochemical, and molecular features. These cases are frequently submitted for consultation, further suggesting the diagnostic difficulties inherent to these tumors. Specifically, olfactory neuroblastoma is a neoplasm that can histologically mimic many tumors within the sinonasal tract, making recognition of this tumor important, as the management frequently requires a bicranial-facial surgical approach, a trephination procedure which can be quite technically difficult and challenging to achieve a good result. The management is therefore quite unique in comparison to other sinonasal tract malignancies, setting it apart diagnostically and managerially from other lesions.


Variations in radiation exposures of adults and children in the UK.
Members of the UK population receive radiation doses from a number of sources including cosmic radiation, from uranium, thorium and their decay products, particularly radon, and from medical sources. On average, members of the UK population receive an effective dose of about 200 mSv over their lifetime. This results in a risk of fatal cancer of about 1%. However, the radiation dose is not the same to all individuals. Some components give doses that vary systematically from one region to another. Doses may also vary greatly from one individual to another. The rate at which the dose is accumulated may vary as the individual ages. Different organs and tissues do not necessarily receive the same dose. This paper discusses these factors and attempts to quantify them. Cosmic rays deliver doses which vary little across the body or between individuals. Terrestrial gamma rays also deliver more or less uniform whole-body doses, but the difference between individuals can be greater. Radionuclides in food deliver doses which vary both across the body and between individuals. These variations are even more marked in the case of doses from radon and from medical exposures.


Added fructose: a principal driver of type 2 diabetes mellitus and its consequences.
Data from animal experiments and human studies implicate added sugars (eg, sucrose and high-fructose corn syrup) in the development of diabetes mellitus and related metabolic derangements that raise cardiovascular (CV) risk. Added fructose in particular (eg, as a constituent of added sucrose or as the main component of high-fructose sweeteners) may pose the greatest problem for incident diabetes, diabetes-related metabolic abnormalities, and CV risk. Conversely, whole foods that contain fructose (eg, fruits and vegetables) pose no problem for health and are likely protective against diabetes and adverse CV outcomes. Several dietary guidelines appropriately recommend consuming whole foods over foods with added sugars, but some (eg, recommendations from the American Diabetes Association) do not recommend restricting fructose-containing added sugars to any specific level. Other guidelines (such as from the Institute of Medicine) allow up to 25% of calories as fructose-containing added sugars. Intake of added fructose at such high levels would undoubtedly worsen rates of diabetes and its complications. There is no need for added fructose or any added sugars in the diet; reducing intake to 5% of total calories (the level now suggested by the World Health Organization) has been shown to improve glucose tolerance in humans and decrease the prevalence of diabetes and the metabolic derangements that often precede and accompany it. Reducing the intake of added sugars could translate to reduced diabetes-related morbidity and premature mortality for populations.


Enamel reduction techniques in orthodontics: a literature review.
Artificial abrasion of interproximal surfaces has been described for almost seventy years as orthodontic intervention for achievement and maintenance of ideal treatment outcome. A variety of terms and approaches have been introduced throughout this period implying a growing clinicians' interest. Nevertheless, the widespread recognition of enamel stripping technique was initiated by the advent of bonded orthodontic attachments and a 2-article series of Sheridan in the 80's. Since then, experimental and clinical research has been focused on the investigation of instrumentation efficacy and potential iatrogenic sequelae related to interproximal stripping. This review discusses the evolution, technical aspects and trends of enamel reduction procedures as documented in the literature.


A randomized control trial of the effect of yoga on verbal aggressiveness in normal healthy volunteers.
To study the effect of yoga on verbal aggressiveness in normal healthy adults. Of the 1228 persons who attended introductory lectures, 226 subjects of both sexes who satisfied the inclusion and exclusion criteria and who consented to participate in the study were randomly allocated into two groups. These 226 subjects were between the ages of 17 and 62 years and 173/226 completed the eight weeks of intervention. The Yoga (Y) group practised an integrated yoga module that included asanas, pranayama, meditation, notional correction, and devotional sessions. The control group practised mild to moderate physical exercises (PE). Both groups had supervised practices (by trained experts) for one hour daily, six days a week for eight weeks. Verbal Aggressiveness was assessed before and after eight weeks using the self-administered Verbal Aggressive Scale. The baseline score of the two groups did not differ significantly (P = 0.66). There was a significant decrease in verbal aggressiveness in the yoga group (P = 0.01 paired samples t-test) with a nonsignificant increase in the PE group. ANCOVA using pre- values as covariates showed a significant difference between the groups (P = 0.013). RMANOVA for interaction between the sexes or age groups in change scores were not significant. This study has demonstrated that an eight week intervention of an integrated yoga module decreased verbal aggressiveness in the yoga group (in males and those below 25 years of age), with a nonsignificant increase in the PE group.


Hypoxia downregulates p53 but induces apoptosis and enhances expression of BAD in cultures of human syncytiotrophoblasts.
Hypoxia is commonly assigned a role in the placental dysfunction characteristic of preeclampsia and intrauterine growth restriction. We previously showed that hypoxia upregulates p53 and enhances apoptosis in primary cultures of human cytotrophoblasts. Here we tested the hypothesis that hypoxia also induces apoptosis in syncytiotrophoblasts by upregulation of p53. Primary cultures of human cytotrophoblasts that had differentiated into syncytiotrophoblasts by 52 h were exposed for ≤24 h to 20% or <1% oxygen in the presence or absence of staurosporine or the p53 modulators nutlin-3, pifithrin-α, and pifithrin-μ. Proteins were detected by Western blot analysis or immunofluorescence. Compared with 20% oxygen, exposure of syncytiotrophoblasts to <1% oxygen upregulated hypoxia-inducible factor (HIF)-1α and rapidly downregulated p53. Activity of p53 in hypoxic syncytiotrophoblasts was reduced by the higher expression of the negative p53 regulator MDMX and by the reduction of phosphorylation of p53 at Ser(392), which reduces p53 activity. Conversely, staurosporine, a kinase inhibitor, and nutlin-3, a drug that enhances p53 expression, both raised p53 levels and increased the rate of apoptosis in syncytiotrophoblasts compared with vehicle controls. Immunofluorescence staining showed p53 immunolocalized to both cytoplasm and nuclei of nutlin-3-exposed syncytiotrophoblasts. The hypoxia-induced apoptosis in syncytiotrophoblasts correlated with enhanced expression of the proapoptotic BAD and a reduced level of antiapoptotic BAD phosphorylated on Ser(112). We surmise that cell death induced by extreme hypoxia in syncytiotrophoblasts follows a non-p53-dependent pathway, unlike that of a nonhypoxic stimulus and unlike hypoxic cytotrophoblasts. We speculate that downregulation of p53 activity in response to hypoxia reduces or eliminates the apoptosis transduced by the p53 pathway in syncytiotrophoblasts, thereby limiting cell death and maintaining the integrity of this critical villous component.


Genome of Methylobacillus flagellatus, molecular basis for obligate methylotrophy, and polyphyletic origin of methylotrophy.
Along with methane, methanol and methylated amines represent important biogenic atmospheric constituents; thus, not only methanotrophs but also nonmethanotrophic methylotrophs play a significant role in global carbon cycling. The complete genome of a model obligate methanol and methylamine utilizer, Methylobacillus flagellatus (strain KT) was sequenced. The genome is represented by a single circular chromosome of approximately 3 Mbp, potentially encoding a total of 2,766 proteins. Based on genome analysis as well as the results from previous genetic and mutational analyses, methylotrophy is enabled by methanol and methylamine dehydrogenases and their specific electron transport chain components, the tetrahydromethanopterin-linked formaldehyde oxidation pathway and the assimilatory and dissimilatory ribulose monophosphate cycles, and by a formate dehydrogenase. Some of the methylotrophy genes are present in more than one (identical or nonidentical) copy. The obligate dependence on single-carbon compounds appears to be due to the incomplete tricarboxylic acid cycle, as no genes potentially encoding alpha-ketoglutarate, malate, or succinate dehydrogenases are identifiable. The genome of M. flagellatus was compared in terms of methylotrophy functions to the previously sequenced genomes of three methylotrophs, Methylobacterium extorquens (an alphaproteobacterium, 7 Mbp), Methylibium petroleiphilum (a betaproteobacterium, 4 Mbp), and Methylococcus capsulatus (a gammaproteobacterium, 3.3 Mbp). Strikingly, metabolically and/or phylogenetically, the methylotrophy functions in M. flagellatus were more similar to those in M. capsulatus and M. extorquens than to the ones in the more closely related M. petroleiphilum species, providing the first genomic evidence for the polyphyletic origin of methylotrophy in Betaproteobacteria.


How do we perceive the pain of others? A window into the neural processes involved in empathy.
To what extent do we share feelings with others? Neuroimaging investigations of the neural mechanisms involved in the perception of pain in others may cast light on one basic component of human empathy, the interpersonal sharing of affect. In this fMRI study, participants were shown a series of still photographs of hands and feet in situations that are likely to cause pain, and a matched set of control photographs without any painful events. They were asked to assess on-line the level of pain experienced by the person in the photographs. The results demonstrated that perceiving and assessing painful situations in others was associated with significant bilateral changes in activity in several regions notably, the anterior cingulate, the anterior insula, the cerebellum, and to a lesser extent the thalamus. These regions are known to play a significant role in pain processing. Finally, the activity in the anterior cingulate was strongly correlated with the participants' ratings of the others' pain, suggesting that the activity of this brain region is modulated according to subjects' reactivity to the pain of others. Our findings suggest that there is a partial cerebral commonality between perceiving pain in another individual and experiencing it oneself. This study adds to our understanding of the neurological mechanisms implicated in intersubjectivity and human empathy.


Global standards and local knowledge building: upgrading small producers in developing countries.
Local knowledge building is a crucial factor for upgrading small producers and improving their market competitiveness and livelihoods. The rise of global standards affecting food safety and environmental sustainability in agriculture sparks debates on the impact on smallholders in developing countries. This article presents a perspective on the links of international standards to knowledge and institution building for developing the capabilities of small producers. Interacting with global practices, indigenous private and public actors create local institutions to develop capabilities for product and process innovations that contribute to economic development and enhance food security. Local innovation depends on collective strategic efforts through increasing networks among small producers and other organizations, including firms, nongovernmental organizations, and government, that foster knowledge circulation and bring diverse resources and support to build local capabilities.


Neocortex expansion is linked to size variations in gene families with chemotaxis, cell-cell signalling and immune response functions in mammals.
Increased brain size is thought to have played an important role in the evolution of mammals and is a highly variable trait across lineages. Variations in brain size are closely linked to corresponding variations in the size of the neocortex, a distinct mammalian evolutionary innovation. The genomic features that explain and/or accompany variations in the relative size of the neocortex remain unknown. By comparing the genomes of 28 mammalian species, we show that neocortical expansion relative to the rest of the brain is associated with variations in gene family size (GFS) of gene families that are significantly enriched in biological functions associated with chemotaxis, cell-cell signalling and immune response. Importantly, we find that previously reported GFS variations associated with increased brain size are largely accounted for by the stronger link between neocortex expansion and variations in the size of gene families. Moreover, genes within these families are more prominently expressed in the human neocortex during early compared with adult development. These results suggest that changes in GFS underlie morphological adaptations during brain evolution in mammalian lineages.


BIM, PUMA, and the achilles' heel of oncogene addiction.
Cancer cells undergo extensive genetic and epigenetic rewiring to support the malignant phenotype, and yet cell survival and proliferation often remain dependent on one or a limited number of driver mutations. This is the concept of oncogene addiction, the elucidation of which has led to substantial progress in therapeutic interventions. However, because resistance mechanisms often emerge, explicating the pathways that connect therapeutic oncogene inactivation to the cell death machinery is critical to exploiting additional synthetic lethal opportunities.


Genera in Bionectriaceae, Hypocreaceae, and Nectriaceae (Hypocreales) proposed for acceptance or rejection.
With the recent changes concerning pleomorphic fungi in the new International Code of Nomenclature for algae, fungi, and plants (ICN), it is necessary to propose the acceptance or protection of sexual morph-typified or asexual morph-typified generic names that do not have priority, or to propose the rejection or suppression of competing names. In addition, sexual morph-typified generic names, where widely used, must be proposed for rejection or suppression in favour of asexual morph-typified names that have priority, or the latter must be proposed for conservation or protection. Some pragmatic criteria used for deciding the acceptance or rejection of generic names include: the number of name changes required when one generic name is used over another, the clarity of the generic concept, their relative frequencies of use in the scientific literature, and a vote of interested mycologists. Here, twelve widely used generic names in three families of Hypocreales are proposed for acceptance, either by conservation or protection, despite their lack of priority of publication, or because they are widely used asexual morph-typified names. Each pair of generic names is evaluated, with a recommendation as to the generic name to be used, and safeguarded, either through conservation or protection. Four generic names typified by a species with a sexual morph as type that are younger than competing generic names typified by a species with an asexual morph type, are proposed for use. Eight older generic names typified by species with an asexual morph as type are proposed for use over younger competing generic names typified by a species with a sexual morph as type. Within Bionectriaceae, Clonostachys is recommended over Bionectria; in Hypocreaceae, Hypomyces is recommended over Cladobotryum, Sphaerostilbella over Gliocladium, and Trichoderma over Hypocrea; and in Nectriaceae, Actinostilbe is recommended over Lanatonectria, Cylindrocladiella over Nectricladiella, Fusarium over Gibberella, Gliocephalotrichum over Leuconectria, Gliocladiopsis over Glionectria, Nalanthamala over Rubrinectria, Nectria over Tubercularia, and Neonectria over Cylindrocarpon.


No Evidence That Nitrogen Limitation Influences the Elemental Composition of Isopod Transcriptomes and Proteomes.
The field of stoichiogenomics aims at understanding the influence of nutrient limitations on the elemental composition of the genome, transcriptome, and proteome. The 20 amino acids and the 4 nt differ in the number of nutrients they contain, such as nitrogen (N). Thus, N limitation shall theoretically select for changes in the composition of proteins or RNAs through preferential use of N-poor amino acids or nucleotides, which will decrease the N-budget of an organism. While these N-saving mechanisms have been evidenced in microorganisms, they remain controversial in multicellular eukaryotes. In this study, we used 13 surface and subterranean isopod species pairs that face strongly contrasted N limitations, either in terms of quantity or quality. We combined in situ nutrient quantification and transcriptome sequencing to test if N limitation selected for N-savings through changes in the expression and composition of the transcriptome and proteome. No evidence of N-savings was found in the total N-budget of transcriptomes or proteomes or in the average protein N-cost. Nevertheless, subterranean species evolving in N-depleted habitats displayed lower N-usage at their third codon positions. To test if this convergent compositional change was driven by natural selection, we developed a method to detect the strand-asymmetric signature that stoichiogenomic selection should leave in the substitution pattern. No such signature was evidenced, indicating that the observed stoichiogenomic-like patterns were attributable to nonadaptive processes. The absence of stoichiogenomic signal despite strong N limitation within a powerful phylogenetic framework casts doubt on the existence of stoichiogenomic mechanisms in metazoans.


IGHV1-69-encoded antibodies expressed in chronic lymphocytic leukemia react with malondialdehyde-acetaldehyde adduct, an immunodominant oxidation-specific epitope.
The immunoglobulins expressed by chronic lymphocytic leukemia (CLL) B cells are highly restricted, suggesting they are selected for binding either self or foreign antigen. Of the immunoglobulin heavy-chain variable (IGHV) genes expressed in CLL, IGHV1-69 is the most common, and often is expressed with little or no somatic mutation, and restricted IGHD and IGHJ gene usage. We found that antibodies encoded by one particular IGHV1-69 subset, designated CLL69C, with the HCDR3 encoded by the IGHD3-3 gene in reading frame 2 and IGHJ6, specifically bound to oxidation-specific epitopes (OSE), which are products of enhanced lipid peroxidation and a major target of innate natural antibodies. Specifically, CLL69C bound immunodominant OSE adducts termed MAA (malondialdehyde-acetaldehyde-adducts), which are found on apoptotic cells, inflammatory tissues, and atherosclerotic lesions. It also reacted specifically with MAA-specific peptide mimotopes. Light chain shuffling indicated that non-stochastically paired L chain of IGLV3-9 contributes to the antigen binding of CLL69C. A nearly identical CLL69C Ig heavy chain was identified from an MAA-enriched umbilical cord phage displayed Fab library, and a derived Fab with the same HCDR3 rearrangement displayed identical MAA-binding properties. These data support the concept that OSE (MAA-epitopes), which are ubiquitous products of inflammation, may play a role in clonal selection and expansion of CLL B cells.


Associations between toddlers' and parents' BMI, in relation to family socio-demography: a cross-sectional study.
It is well established that the pregnancy and the first years of life are important for future childhood health and body weight. Even though current evidence suggests that both parents are important for childhood health, the influence that parents' BMI and socio-demography has on toddlers' BMI has so far received little attention. This study aimed to increase our knowledge on the association between toddlers' and parents' BMI, in relation to family socio-demography. Further, the aim was to investigate the interaction between the mothers' and fathers' BMI in relation to their child's BMI. A total of 697 children with a median age of 18 months (range 16-24 months) participated in the study along with their mothers (n = 697) and fathers (n = 674). As regards representability, our parental sample had a lower proportion of immigrants and the parents were more gainfully employed compared to parents in the rest of Sweden (when the child was 18 months old). The parents completed a questionnaire on parental and child health. Data on parental weight, height, and socio-demographics were recorded along with the child's weight and height measured at an ordinary child health care visit. We used the thresholds for children's BMI that were recommended for surveillance by the Royal College of Paediatrics and Child Health in 2012 based on the WHO reference population. Among the toddlers, 33 % had a BMI above the WHO 85(th) percentile and 14 % had a BMI above the WHO 95(th) percentile. The probability of a toddler having a BMI above the WHO 95(th) percentile was significantly increased if either the mother or father was overweight (BMI ≥ 25 kg/m(2)). Furthermore, we found a positive synergistic effect between the mother and father being overweight and their child having a BMI above the WHO 85(th) percentile. No associations were found between the toddlers' BMI and the family's socio-demographics, but there were associations between the parents' BMI and the family's socio-demographics. High BMI is common even in toddlers in this population. The risk increases if one parent is overweight, and it increases even more if both parents are overweight. The results in this study confirm the importance of considering familial risk factors when examining child health and BMI at ordinary child health care visits already at an early age.


Council of Europe Resolution CM/Res(2016)2: a major contribution to patient safety from reconstituted injectable medicines?
This article focuses on the reconstitution of parenteral medicines and the work that has been carried out at the European level to improve patient safety. Reconstitution may occur in a clinical area, for example, ward, theatre and so on, or within pharmacy. The quality of reconstituted medicines should ideally be the same, regardless of where reconstitution takes place. However, in practice, risks are greater when reconstitution is carried out in clinical areas. Although ideally all reconstitutions should be carried out within pharmacy aseptic units, capacity is generally not available to allow this, so a risk assessment approach must be taken to enable the healthcare establishment to decide which products must be reconstituted in pharmacy and which, with appropriate safeguards, can be reconstituted in clinical areas. Although guidance on reconstitution has been established in some countries, this is not the case across much of Europe. The Committee of Experts on Quality and Safety Standards in Pharmaceutical Practices and Pharmaceutical Care (Council of Europe) (hereafter: Committee of Experts) has undertaken work to develop quality and safety standards for reconstitution in the different locations within healthcare establishments, taking a risk-based approach. In June 2016, the Committee of Ministers of the Council of Europe adopted Resolution CM/Res(2016)2 on good reconstitution practices in healthcare establishments for medicinal products for parenteral use. Drafted by the Committee of Experts, the Resolution recommends implementation measures for best practices for the reconstitution of injectable medicines for administration to patients. This article summarises the rationale behind the Resolution, its drafting process and main chapters. There is no justification for patient safety with respect to reconstituted medicines to be variable across the Member States of the Council of Europe. Implementation of Resolution CM/Res(2016)2 will enable risk reduction in healthcare establishments and is a major contribution to patient safety from injectable medicines at the international level.


Computer-aided design for metabolic engineering.
The development and application of biotechnology-based strategies has had a great socio-economical impact and is likely to play a crucial role in the foundation of more sustainable and efficient industrial processes. Within biotechnology, metabolic engineering aims at the directed improvement of cellular properties, often with the goal of synthesizing a target chemical compound. The use of computer-aided design (CAD) tools, along with the continuously emerging advanced genetic engineering techniques have allowed metabolic engineering to broaden and streamline the process of heterologous compound-production. In this work, we review the CAD tools available for metabolic engineering with an emphasis, on retrosynthesis methodologies. Recent advances in genetic engineering strategies for pathway implementation and optimization are also reviewed as well as a range of bionalytical tools to validate in silico predictions. A case study applying retrosynthesis is presented as an experimental verification of the output from Retropath, the first complete automated computational pipeline applicable to metabolic engineering. Applying this CAD pipeline, together with genetic reassembly and optimization of culture conditions led to improved production of the plant flavonoid pinocembrin. Coupling CAD tools with advanced genetic engineering strategies and bioprocess optimization is crucial for enhanced product yields and will be of great value for the development of non-natural products through sustainable biotechnological processes.


Multiple Score Comparison: a network meta-analysis approach to comparison and external validation of prognostic scores.
Prediction models and prognostic scores have been increasingly popular in both clinical practice and clinical research settings, for example to aid in risk-based decision making or control for confounding. In many medical fields, a large number of prognostic scores are available, but practitioners may find it difficult to choose between them due to lack of external validation as well as lack of comparisons between them. Borrowing methodology from network meta-analysis, we describe an approach to Multiple Score Comparison meta-analysis (MSC) which permits concurrent external validation and comparisons of prognostic scores using individual patient data (IPD) arising from a large-scale international collaboration. We describe the challenges in adapting network meta-analysis to the MSC setting, for instance the need to explicitly include correlations between the scores on a cohort level, and how to deal with many multi-score studies. We propose first using IPD to make cohort-level aggregate discrimination or calibration scores, comparing all to a common comparator. Then, standard network meta-analysis techniques can be applied, taking care to consider correlation structures in cohorts with multiple scores. Transitivity, consistency and heterogeneity are also examined. We provide a clinical application, comparing prognostic scores for 3-year mortality in patients with chronic obstructive pulmonary disease using data from a large-scale collaborative initiative. We focus on the discriminative properties of the prognostic scores. Our results show clear differences in performance, with ADO and eBODE showing higher discrimination with respect to mortality than other considered scores. The assumptions of transitivity and local and global consistency were not violated. Heterogeneity was small. We applied a network meta-analytic methodology to externally validate and concurrently compare the prognostic properties of clinical scores. Our large-scale external validation indicates that the scores with the best discriminative properties to predict 3 year mortality in patients with COPD are ADO and eBODE.


Hyperbaric oxygen protects against myocardial reperfusion injury via the inhibition of inflammation and the modulation of autophagy.
Our previous study demonstrated that hyperbaric oxygen (HBO) preconditioning protected against myocardial ischemia reperfusion injury (MIRI) and improved myocardial infarction. However, HBO's effect on MIRI-induced inflammation and autophagy remains unclear. In this study, we investigate the potential impact and underlying mechanism of HBO preconditioning on an MIRI-induced inflammatory response and autophagy using a ligation of the left anterior descending (LAD) coronary artery rat model. Our results showed that HBO restored myocardial enzyme levels and decreased the apoptosis of cardiomyocytes, which were induced by MIRI. Moreover, HBO significantly suppressed MIRI-induced inflammatory cytokines. This effect was associated with the inhibition of the TLR4-nuclear factor kappa-B (NF-κB) pathway. Interestingly, lower expression levels of microtubule-associated protein 1 light chain 3B (LC3B) and Beclin-1 were observed in the HBO-treatment group. Furthermore, we observed that HBO reduced excessive autophagy by activating the mammalian target of the rapamycin (mTOR) pathway, as evidenced by higher expression levels of threonine protein kinase (Akt) and phosphorylated-mTOR. In conclusion, HBO protected cardiomocytes during MIRI by attenuating inflammation and autophagy. Our results provide a new mechanistic insight into the cardioprotective role of HBO against MIRI.


Compositional control of pore geometry in multivariate metal-organic frameworks: an experimental and computational study.
A new approach is reported for tailoring the pore geometry in five series of multivariate metal–organic frameworks (MOFs) based on the structure [Zn2(bdc)2(dabco)] (bdc = 1,4-benzenedicarboxylate, dabco = 1,8-diazabicyclooctane), DMOF-1. A doping procedure has been adopted to form series of MOFs containing varying linker ratios. The series under investigation are [Zn2(bdc)(2-x)(bdc-Br)x(dabco)]·nDMF 1 (bdc-Br = 2-bromo-1,4-benzenedicarboxylate), [Zn2(bdc)(2-x)(bdc-I)x(dabco)]·nDMF 2 (bdc-I = 2-iodo-1,4-benzenedicarboxylate), [Zn2(bdc)(2-x)(bdc-NO2)x(dabco)]·nDMF 3 (bdc-NO2 = 2-nitro-1,4-benzenedicarboxylate), [Zn2(bdc)(2-x)(bdc-NH2)x(dabco)]·nDMF 4 (bdc-NH2 = 2-amino-1,4-benzenedicarboxylate) and [Zn2(bdc-Br)(2-x)(bdc-I)x(dabco)]·nDMF 5. Series 1-3 demonstrate a functionality-dependent pore geometry transition from the square, open pores of DMOF-1 to rhomboidal, narrow pores with increasing proportion of the 2-substituted bdc linker, with the rhomboidal-pore MOFs also showing a temperature-dependent phase change. In contrast, all members of series 4 and 5 have uniform pore geometries. In series 4 this is a square pore topology, whilst series 5 exhibits the rhomboidal pore form. Computational analyses reveal that the pore size and shape in systems 1 and 2 is altered through non-covalent interactions between the organic linkers within the framework, and that this can be controlled by the ligand functionality and ratio. This approach affords the potential to tailor pore geometry and shape within MOFs through judicious choice of ligand ratios.


Charge reduction of oligonucleotide anions via gas-phase electron transfer to xenon cations.
Multiply-charged anions derived from electrospray (ES) ionization of the oligonucleotide 5'-d(GTCTTAGCGCTAAGAC)-3' have been subjected to electron transfer reactions with ionized xenon in a quadrupole ion trap and found to undergo minimal fragmentation. This observation stands in contrast with electron transfer to rare gases from anions of smaller oligonucleotides which have been shown to undergo extensive fragmentation. The present results are attributed to longer anion lifetimes for the larger oligonucleotide anions (following highly exothermic electron transfer) which then allow for collisional cooling by the helium bath gas. Reduction to singly charged anions with minimal fragmentation is noted, indicating that xenon cations can be considered as a reagent for simplifying ES mass spectra of moderately sized oligonucleotides. The relative merits of the use of xenon cations in the quadropole ion trap for this purpose is discussed.


Post-partum involution of the canine uterus - gross anatomical and histological features.
We aimed to study the normal puerperium in the bitch. Ovariohysterectomy was performed in nine bitches, each at a different day after normal whelping; their genital tract was subject to gross anatomical examination, as well as to histological examination and electron microscopy scanning. Corpora albicans were evenly distributed in the left and right ovaries and placental sites were evenly distributed among left and right uterine horns. Placental sites were initially of dark green to grey colour, later becoming dark brown; their length and height progressively decreased. Height of the myometrium and diameter of the uterine glands progressively decreased. Trophoblast-like cells were consistently observed at the placental sites and on the surface of the interplacental areas, at all time points where hysterectomy had been performed. It is suggested that involution of the canine genital tract can last up to 3 months and is slow. Continuous (up to D84 post-partum) presence of prominent placental sites should be considered a normal feature of canine uterine post-partum involution.


The value of staging laparoscopy in gastric cancer.
Treatment options for patients with gastric cancer (GC) are based on tumor staging and resectability. Although only surgery provides improved survival, resection is contraindicated and should be avoided in the presence of intra-abdominal disease stage M1 (liver, peritoneal, or non-local lymph node metastases). Thus, a detailed and precise evaluation is imperative for optimal treatment. Staging laparoscopy (SL) constitutes a major tool in the accurate diagnosis of several types of cancers, including GC. SL presents several critical advantages: it can diagnose intra-abdominal disease; serve as a complement to other imaging studies; allow for biopsies; facilitate intraoperative ultrasound evaluations; allow for sampling of peritoneal fluid for cytological examination; and serve as an option for the administration of intraperitoneal chemotherapy. Although considered and advocated as a very useful asset in the pre-treatment cancer-staging arsenal, the wider application of SL has been long debated. The purpose of our study was to evaluate the contribution of laparoscopy to GC staging.


Macular choroidal blood flow velocity decreases with regression of acute central serous chorioretinopathy.
To quantitatively evaluate the time course of macular choroidal blood flow velocity in acute central serous chorioretinopathy (CSC). This retrospective observational case series included 21 eyes of 20 patients (17 men, 3 women; mean age, 53.0 years) with treatment-naïve acute CSC. Laser speckle flowgraphy was performed to calculate macular mean blur rate (MBR), an indicator of relative blood flow velocity at the first visit, 3 and 6 months thereafter. Changes in average MBR values were compared with visual improvement at 6 months. Subretinal fluid completely resolved in all eyes within 6 months, while best-corrected visual acuity (BCVA) significantly improved at 6 months compared to the initial BCVA. During the follow-up period, the average MBR significantly decreased to 92.8% and 82.3% at 3 and 6 months, respectively, against baseline (100%). Importantly, there was a negative correlation between the BCVA recovery and the MBR decrease, showing the possible association of MBR increase with poor visual prognosis. Multiple regression analysis demonstrated no significant correlation between MBR and ocular perfusion pressure. These results indicate that macular choroidal blood flow velocity decreases concurrently with regression of CSC, suggesting a validity of choroidal blood flow elevation in the pathogenesis of acute CSC.


Effects of keratinocyte growth factor on the proliferation and radiation survival of human squamous cell carcinoma cell lines in vitro and in vivo.
Keratinocyte growth factor (KGF) has potent mitogenic activity on normal epithelial cells and has been found to enhance intestinal crypt cell survival in irradiated mice and to prevent radiation and chemotherapy-induced mucositis in animal models. The purpose of the study reported here is to investigate the effect of recombinant human KGF on the proliferation and survival of human squamous carcinoma cell lines following irradiation. The level of KGF receptor (KGFR) mRNA in normal Balb/Mk cell line and human head and neck squamous carcinoma cell lines was assessed using a RNase protection assay. The clonogenic assay and MTT assay were used to study the proliferative effects of KGF on human tumor cell lines and Balb/MK cell line in vitro. Effects of KGF on in vivo tumor growth and radiosensitivity were studied in three KGFR-positive human squamous cell carcinoma xenografts (FaDu, Detroit 562 and A431) in nude mice, and a murine KGFR-negative melanoma tumor (B16) in Balb/c mice. Seven of 10 tumor cell lines studied expressed KGFR mRNA. None of these tumor cell lines showed enhanced proliferation when exposed to KGF for 2 days or less. Prolonged exposure to KGF for 7 days or longer resulted in low level stimulation of proliferation in both clonogenic and MTT assays in four of seven KGFR-positive cell lines. Two KGFR-negative cell lines also had a low proliferative response to KGF in a clonogenic assay, but not in the MTT assay. Normal keratinocyte Balb/MK cells, which expressed a moderate level of KGFR mRNA, had a strongly proliferative response to KGF. Its KGF enhancement ratio (KER) of plating efficiency was 24-70 times higher than that of the tumor cells studied (p < 0.001). The KGF-stimulated tumor cell growth was almost completely inhibited by heparin or epidermal growth factor (EGF). There were no significant differences (p > 0.05) in the survival of any of tumor cell lines in the presence or absence of KGF (100 ng/ml) irradiated with doses of 0-15 Gy, and no significant differences (p > 0.05) between the radiobiological parameters D0, Dq, and n number from the SHMT model, alpha, beta, and alpha/beta ratio from the LQ model and SF2 for radiation survival curves for cell lines irradiated in the presence or absence of KGF. Three KGFR-positive human squamous cell carcinoma xenografts in nude mice, and a murine KGFR-negative melanoma tumor in Balb/c mice treated with 1.0 mg/kg of KGF for 3 days grew at the same rate as in untreated mice. The recombinant human KGF resulted in little or no stimulation of the proliferation of human head and neck squamous tumor cell lines and did not affect the radiosensitivity of these cell lines in vitro and in vivo. Therefore, KGF may be of clinical value in preventing radiation-induced mucositis and may have the potential to increase the therapeutic index of radiotherapy for treatment of cancers.


Active music classes in infancy enhance musical, communicative and social development.
Previous studies suggest that musical training in children can positively affect various aspects of development. However, it remains unknown as to how early in development musical experience can have an effect, the nature of any such effects, and whether different types of music experience affect development differently. We found that random assignment to 6 months of active participatory musical experience beginning at 6 months of age accelerates acquisition of culture-specific knowledge of Western tonality in comparison to a similar amount of passive exposure to music. Furthermore, infants assigned to the active musical experience showed superior development of prelinguistic communicative gestures and social behaviour compared to infants assigned to the passive musical experience. These results indicate that (1) infants can engage in meaningful musical training when appropriate pedagogical approaches are used, (2) active musical participation in infancy enhances culture-specific musical acquisition, and (3) active musical participation in infancy impacts social and communication development.


Metabolic adaptations to methionine restriction that benefit health and lifespan in rodents.
Restriction of dietary methionine by 80% slows the progression of aged-related diseases and prolongs lifespan in rodents. A salient feature of the methionine restriction phenotype is the significant reduction of adipose tissue mass, which is associated with improvement of insulin sensitivity. These beneficial effects of MR involve a host of metabolic adaptations leading to increased mitochondrial biogenesis and function, elevated energy expenditure, changes of lipid and carbohydrate homeostasis, and decreased oxidative damage and inflammation. This review summarizes observations from MR studies and provides insight about potential mediators of tissue-specific responses associated with MR's favorable metabolic effects that contribute to health and lifespan extension.


Violence against women during the Liberian civil conflict.
Civilians were often the casualties of fighting during the recent Liberian civil conflict. Liberian health care workers played a crucial role in documenting violence against women by soldiers and fighters during the war. To document women's experiences of violence, including rape and sexual coercion, from a soldier or fighter during 5 years of the Liberian civil war from 1989 through 1994. Interview and survey. High schools, markets, displaced persons camps, and urban communities in Monrovia, Liberia, in 1994. A random sample of 205 women and girls between the ages of 15 and 70 years (88% participation rate). One hundred (49%) of 205 participants reported experiencing at least 1 act of physical or sexual violence by a soldier or fighter. Survey participants reported being beaten, tied up, or detained in a room under armed guard (17%); strip-searched 1 or more times (32%); and raped, subjected to attempted rape, or sexually coerced (15%). Women who were accused of belonging to a particular ethnic group or fighting faction or who were forced to cook for a soldier or fighter were at increased risk for physical and sexual violence. Of the 106 women and girls accused of belonging to an ethnic group or faction, 65 (61%) reported that they were beaten, locked up, strip-searched, or subjected to attempted rape, compared with 27 (27%) of the 99 women who were not accused (P< or =.02, .07, .001, and .06, respectively). Women and girls who were forced to cook for a soldier or fighter were more likely to report experiencing rape, attempted rape, or sexual coercion than those who were not forced to cook (55% vs 10%; P< or =.001, .06, and .001, respectively). Young women (those younger than 25 years) were more likely than women 25 years or older to report experiencing attempted rape and sexual coercion (18% vs 4%, P=.02 and .04, respectively). This collaborative research allowed Liberian women to document wartime violence against women in their own communities and to develop a unique program to address violence against women in Liberia.


topIb, a phylogenetic hallmark gene of Thaumarchaeota encodes a functional eukaryote-like topoisomerase IB.
Type IB DNA topoisomerases can eliminate torsional stresses produced during replication and transcription. These enzymes are found in all eukaryotes and a short version is present in some bacteria and viruses. Among prokaryotes, the long eukaryotic version is only observed in archaea of the phylum Thaumarchaeota. However, the activities and the roles of these topoisomerases have remained an open question. Here, we demonstrate that all available thaumarchaeal genomes contain a topoisomerase IB gene that defines a monophyletic group closely related to the eukaryotic enzymes. We show that the topIB gene is expressed in the model thaumarchaeon Nitrososphaera viennensis and we purified the recombinant enzyme from the uncultivated thaumarchaeon Candidatus Caldiarchaeum subterraneum. This enzyme is active in vitro at high temperature, making it the first thermophilic topoisomerase IB characterized so far. We have compared this archaeal type IB enzyme to its human mitochondrial and nuclear counterparts. The archaeal enzyme relaxes both negatively and positively supercoiled DNA like the eukaryotic enzymes. However, its pattern of DNA cleavage specificity is different and it is resistant to camptothecins (CPTs) and non-CPT Top1 inhibitors, LMP744 and lamellarin D. This newly described thermostable topoisomerases IB should be a promising new model for evolutionary, mechanistic and structural studies.


Low tube voltage CT for improved detection of pancreatic cancer: detection threshold for small, simulated lesions.
Pancreatic ductal adenocarcinoma is associated with dismal prognosis. The detection of small pancreatic tumors which are still resectable is still a challenging problem.The aim of this study was to investigate the effect of decreasing the tube voltage from 120 to 80 kV on the detection of pancreatic tumors. Three scanning protocols was used; one using the standard tube voltage (120 kV) and current (160 mA) and two using 80 kV but with different tube currents (500 and 675 mA) to achieve equivalent dose (15 mGy) and noise (15 HU) as that of the standard protocol.Tumors were simulated into collected CT phantom images. The attenuation in normal parenchyma at 120 kV was set at 130 HU, as measured previously in clinical examinations, and the tumor attenuation was assumed to differ 20 HU and was set at 110HU. By scanning and measuring of iodine solution with different concentrations the corresponding tumor and parenchyma attenuation at 80 kV was found to be 185 and 219 HU, respectively.To objectively evaluate the differences between the three protocols, a multi-reader multi-case receiver operating characteristic study was conducted, using three readers and 100 cases, each containing 0-3 lesions. The highest reader averaged figure-of-merit (FOM) was achieved for 80 kV and 675 mA (FOM=0,850), and the lowest for 120 kV (FOM=0,709). There was a significant difference between the three protocols (p<0,0001), when making an analysis of variance (ANOVA). Post-hoc analysis (students t-test) shows that there was a significant difference between 120 and 80 kV, but not between the two levels of tube currents at 80 kV. We conclude that when decreasing the tube voltage there is a significant improvement in tumor conspicuity.


Regulation of thalamocortical axon branching by BDNF and synaptic vesicle cycling.
During development, axons form branches in response to extracellular molecules. Little is known about the underlying molecular mechanisms. Here, we investigate how neurotrophin-induced axon branching is related to synaptic vesicle cycling for thalamocortical axons. The exogenous application of brain-derived neurotrophic factor (BDNF) markedly increased axon branching in thalamocortical co-cultures, while removal of endogenous BDNF reduced branching. Over-expression of a C-terminal fragment of AP180 that inhibits clathrin-mediated endocytosis affected the laminar distribution and the number of branch points. A dominant-negative synaptotagmin mutant that selectively targets synaptic vesicle cycling, strongly suppressed axon branching. Moreover, axons expressing the mutant synaptotagmin were resistant to the branch-promoting effect of BDNF. These results suggest that synaptic vesicle cycling might regulate BDNF induced branching during the development of the axonal arbor.


International consensus (ICON) on assessment of oropharyngeal dysphagia.
To present international recommendations regarding the proper evaluation of oropharyngeal dysphagia (OD), both objectively and subjectively (self-evaluation). Following a thorough review of the literature, 5 experts in the field from 4 different continents answered separately a questionnaire regarding the work-up of OD. Individual answers were presented and discussed during the world ENT conference that was held in Paris in June 2017. This article will present the recommendations issued from that meeting. For the initial objective assessment of OD, it is recommended to perform either a functional endoscopic evaluation of swallowing (FEES) or a videofluoroscopic swallowing study (VFSS). FEES is the more popular investigation given its increased ease of use and accessibility. When evaluating for the presence of aspiration during the objective evaluation of OD, it is recommended to perform either a FEES or a VFSS. In this case, FEES is the favored investigation given its likely increased sensitivity. In order to highlight the presence of oropharyngeal food residue following the deglutition process, it is recommended to perform either a FEES or a VFSS; FEES likely being the more sensitive investigation while VFSS allows a better quantification of the amount of pharyngeal residue. Is it also recommended to objectify the quality of the deglutition process by means of a score during the objective evaluation of OD. Finally, it is recommended to utilize a self-evaluation questionnaire during research studies exploring the deglutition process.


Maternal dietary antigen avoidance during pregnancy or lactation, or both, for preventing or treating atopic disease in the child.
Some breastfed infants with atopic eczema benefit from elimination of cow milk, egg, or other antigens from their mother's diet. Maternal dietary antigens are also known to cross the placenta. To assess the effects of prescribing an antigen avoidance diet during pregnancy or lactation, or both, on maternal and infant nutrition and on the prevention or treatment of atopic disease in the child. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2006) and contacted researchers in the field. All randomized or quasi-randomized comparisons of maternal dietary antigen avoidance prescribed to pregnant or lactating women. We excluded trials of multimodal interventions that included manipulation of the infant's diet other than breast milk or of nondietary aspects of the infant's environment. We extracted data from published reports, supplemented by additional information received from the trialists we contacted. The evidence from four trials, involving 334 participants, does not suggest a protective effect of maternal dietary antigen avoidance during pregnancy on the incidence of atopic eczema during the first 18 months of life. Data on allergic rhinitis or conjunctivitis, or both, and urticaria are limited to a single trial each and are insufficient to draw meaningful inferences. Longer-term atopic outcomes have not been reported. The restricted diet during pregnancy was associated with a slightly but statistically significantly lower mean gestational weight gain, a nonsignificantly higher risk of preterm birth, and a nonsignificant reduction in mean birthweight.The evidence from one trial, involving 26 participants, did not observe a significant protective effect of maternal antigen avoidance during lactation on the incidence of atopic eczema during the first 18 months.One crossover trial involving 17 lactating mothers of infants with established atopic eczema found that maternal dietary antigen avoidance was associated with a nonsignificant reduction in eczema severity. Prescription of an antigen avoidance diet to a high-risk woman during pregnancy is unlikely to reduce substantially her child's risk of atopic diseases, and such a diet may adversely affect maternal or fetal nutrition, or both. Prescription of an antigen avoidance diet to a high-risk woman during lactation may reduce her child's risk of developing atopic eczema, but better trials are needed. Dietary antigen avoidance by lactating mothers of infants with atopic eczema may reduce the severity of the eczema, but larger trials are needed.


Gene-asbestos interaction in malignant pleural mesothelioma susceptibility.
Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, on average less than 10% of subjects highly exposed to asbestos develop MPM, suggesting the possible involvement of other risk factors. To identify the genetic factors that may modulate the risk of MPM, we conducted a gene-environment interaction analysis including asbestos exposure and 15 single nucleotide polymorphisms (SNPs) previously identified through a genome-wide association study on Italian subjects. In the present study, we assessed gene-asbestos interaction on MPM risk using relative excess risk due to interaction and synergy index for additive interaction and V index for multiplicative interaction. Generalized multifactor dimensionality reduction (GMDR) analyses were also performed. Positive deviation from additivity was found for six SNPs (rs1508805, rs2501618, rs4701085, rs4290865, rs10519201, rs763271), and four of them (rs1508805, rs2501618, rs4701085, rs10519201) deviated also from multiplicative models. However, after Bonferroni correction, deviation from multiplicative model was still significant for rs1508805 and rs4701085 only. GMDR analysis showed a strong MPM risk due to asbestos exposure and suggested a possible synergistic effect between asbestos exposure and rs1508805, rs2501618 and rs5756444. Our results suggested that gene-asbestos interaction may play an additional role on MPM susceptibility, given that asbestos exposure appears as the main risk factor.


Impacts of chronic kidney disease and diabetes on cardiovascular mortality in a general Japanese population: A 20-year follow-up of the NIPPON DATA90 study.
Background Studies have shown significant associations of chronic kidney disease (CKD) and diabetes mellitus (DM) with cardiovascular disease (CVD) mortality. The impact on the general population is an important public health issue. However, the population attributable fraction (PAF) of CVD because of CKD and/or DM in a general population is uncertain. Methods We followed 7229 participants (age: ≥30 years) with no history of CVD in a Japanese community. We divided participants into four categories according to CKD and/or DM and calculated hazard ratios (HRs) of CVD mortality for each category using a Cox proportional hazards model adjusted for age, dyslipidemia, smoking and alcohol consumption. In addition, PAFs of CVD were estimated among populations with CKD and/or DM. Results During 20-year follow-up, 488 participants died. HRs for CVD were 1.63 [95% confidence interval (CI): 1.16-2.30] with DM only, 1.42 (95% CI: 1.08-1.86) with CKD only and 2.37 (95% CI: 1.40-4.01) with CKD + DM. In men, the corresponding HRs for CVD were 1.88 (95% CI: 1.19-2.97), 1.71 (95% CI: 1.15-2.56) and 3.26 (95% CI: 1.69-6.30), respectively; the corresponding PAFs of CVD were 4.1%, 5.1% and 2.9%, respectively. PAFs for CVD among women were lower than those in men, 1.6% for DM only, 2.0% for CKD only and 0.7% for CKD + DM. Conclusions PAFs of CVD mortality due to CKD and/or DM were not so high in past 20 years; however, they might increase in the future because of recent increase in prevalence of these in Japanese population.


Oleanolic acid ethanol monosolvate.
CRYSTALS OF THE TITLE COMPOUND (SYSTEMATIC NAME: 3β-hy-droxy-olean-12-en-28-oic acid ethanol monosolvate), C(30)H(48)O(3)·C(2)H(5)OH, were obtained from unsuccessful co-crystallization trials. The asymmetric unit contains two symmetry-independent oleanolic acid mol-ecules, as well as two ethanol solvent mol-ecules. Inter-molecular O-H⋯O hydrogen bonds stabilize the crystal packing. In the oleanolic acid mol-ecules, ring C has a slightly distorted envelope conformation, while rings A, B, D and E adopt chair conformations and rings D and E are cis-fused. Both independent ethanol mol-ecules are orientationally disordered [occupancy ratios of 0.742 (8):0.258 (8) and 0.632 (12):0.368 (12).


Community and health system intervention to reduce disrespect and abuse during childbirth in Tanga Region, Tanzania: A comparative before-and-after study.
Abusive treatment of women during childbirth has been documented in low-resource countries and is a deterrent to facility utilization for delivery. Evidence for interventions to address women's poor experience is scant. We assessed a participatory community and health system intervention to reduce the prevalence of disrespect and abuse during childbirth in Tanzania. We used a comparative before-and-after evaluation design to test the combined intervention to reduce disrespect and abuse. Two hospitals in Tanga Region, Tanzania were included in the study, 1 randomly assigned to receive the intervention. Women who delivered at the study facilities were eligible to participate and were recruited upon discharge. Surveys were conducted at baseline (December 2011 through May 2012) and after the intervention (March through September 2015). The intervention consisted of a client service charter and a facility-based, quality-improvement process aimed to redefine norms and practices for respectful maternity care. The primary outcome was any self-reported experiences of disrespect and abuse during childbirth. We used multivariable logistic regression to estimate a difference-in-difference model. At baseline, 2,085 women at the 2 study hospitals who had been discharged from the maternity ward after delivery were invited to participate in the survey. Of these, 1,388 (66.57%) agreed to participate. At endline, 1,680 women participated in the survey (72.29% of those approached). The intervention was associated with a 66% reduced odds of a woman experiencing disrespect and abuse during childbirth (odds ratio [OR]: 0.34, 95% CI: 0.21-0.58, p < 0.0001). The biggest reductions were for physical abuse (OR: 0.22, 95% CI: 0.05-0.97, p = 0.045) and neglect (OR: 0.36, 95% CI: 0.19-0.71, p = 0.003). The study involved only 2 hospitals in Tanzania and is thus a proof-of-concept study. Future, larger-scale research should be undertaken to evaluate the applicability of this approach to other settings. After implementation of the combined intervention, the likelihood of women's reports of disrespectful treatment during childbirth was substantially reduced. These results were observed nearly 1 year after the end of the project's facilitation of implementation, indicating the potential for sustainability. The results indicate that a participatory community and health system intervention designed to tackle disrespect and abuse by changing the norms and standards of care is a potential strategy to improve the treatment of women during childbirth at health facilities. The trial is registered on the ISRCTN Registry, ISRCTN 48258486. ISRCTN Registry, ISRCTN 48258486.


Brief relationship therapy for alcoholism: a randomized clinical trial examining clinical efficacy and cost-effectiveness.
The purpose of this study was to examine the clinical efficacy and cost effectiveness of brief relationship therapy (BRT), a shortened version of standard behavioral couples therapy (S-BCT), with alcoholic male patients (N = 100) and their nonsubstance-abusing female partners. Participants were randomly assigned to 1 of 4 treatment conditions: (a) BRT, (b) S-BCT, (c) individual-based treatment (IBT), or (d) psychoeducational attention control treatment (PACT). Equivalency testing revealed that, compared with those assigned to S-BCT, participants who were randomly assigned to BRT had equivalent posttreatment and 12-month follow-up heavy drinking outcomes. Moreover, at 12-month follow-up, heavy drinking and dyadic adjustment outcomes for patients who received BRT were superior to those of patients who received IBT or PACT. BRT was significantly more cost effective than the S-BCT, IBT, or PACT.


Entrainment of the mouse circadian clock: Effects of stress, exercise, and nutrition.
The circadian clock system in mammals plays a fundamental role in maintaining homeostasis. Entrainment is an important characteristic of the internal clock, by which appropriate timing is maintained according to external daily stimuli, such as light, stress, exercise, and/or food. Disorganized entrainment or a misaligned clock time, such as jet lag, increases health disturbances. The central clock in the suprachiasmatic nuclei, located in the hypothalamus, receives information about arousal stimuli, such as physical stress or exercise, and changes the clock time by modifying neural activity or the expression of circadian clock genes. Although feeding stimuli cannot entrain the central clock in a normal light-dark cycle, the central clock can partially detect the metabolic status. Local clocks in the peripheral tissues, including liver and kidney, have a strong direct response to the external stimuli of stress, exercise, and/or food that is independent of the central clock. The mechanism underlying entrainment by stress/exercise is mediated by glucocorticoids, sympathetic nerves, oxidative stress, hypoxia, pH, cytokines, and temperature. Food/nutrition-induced entrainment is mediated by fasting-induced hormonal or metabolic changes and re-feeding-induced insulin or oxyntomodulin secretion. Chrono-nutrition is a clinical application based on chronobiology research. Future studies are required to elucidate the effects of eating and nutrient composition on the human circadian clock. Here, we focus on the central and peripheral clocks mostly in rodents' studies and review the findings of recent investigations of the effects of stress, exercise, and food on the entrainment system.


Peripartum management of hypertension: a position paper of the ESC Council on Hypertension and the European Society of Hypertension.
Hypertensive disorders are the most common medical complications in the peripartum period associated with a substantial increase in morbidity and mortality. Hypertension in the peripartum period may be due to the continuation of pre-existing or gestational hypertension, de novo development of pre-eclampsia or it may be also induced by some drugs used for analgesia or suppression of postpartum haemorrhage. Women with severe hypertension and hypertensive emergencies are at high risk of life-threatening complications, therefore, despite the lack of evidence-based data, based on expert opinion, antihypertensive treatment is recommended. Labetalol intravenously and methyldopa orally are then the two most frequently used drugs. Short-acting oral nifedipine is suggested to be used only if other drugs or iv access are not available. Induction of labour is associated with improved maternal outcome and should be advised for women with gestational hypertension or mild pre-eclampsia at 37 weeks' gestation. This position paper provides the first interdisciplinary approach to the management of hypertension in the peripartum period based on the best available evidence and expert consensus.


AuGd integrated nanoprobes for optical/MRI/CT triple-modal in vivo tumor imaging.
Multi-modal imaging agents are desirable for tumor diagnosis because they can provide more information on the tumor than single-modal imaging agents. However, most reported multi-modal imaging agents are dual-modal agents rather than tri-modal agents; therefore, detailed information on the tumor may still be insufficient when such imaging agents are used. To ameliorate this issue, we synthesized a tri-modal imaging agent, composed of gold cluster and gadolinium oxide integrated nanoparticles (denoted as AuGds) using bovine serum albumin (BSA) as the template via a bio-mineralization method. The AuGds exhibit red fluorescence at ∼660 nm for optical imaging, strong X-ray absorption (around 700 HU) for CT imaging, and a high r1 value (∼12.39 mM-1 s-1) for MR imaging. After being chemically modified with folic acid (FA), the AuGds can specifically target folate receptors on KB tumor cells, and permit in vivo optical, MR, and CT imaging of xenografted tumors. By comparing these three imaging modalities, very clear structural and anatomical information on the in vivo tumor can be obtained. The AuGds show good biocompatibility, quick renal clearance, and do not induce normal tissue toxicity in vivo.


Exploring the associations between long-term care and mortality rates among stroke patients.
Information on types of long-term care received by stroke patients after hospital discharge is essential for the formulation of long-term care resource development policy. Comparisons of outcomes resulting from different types of long-term care can provide important considerations in the selection of long- term care services. The purpose of this study is to describe the patterns of long-term care received, and to explore if associations exist between long-term care services and mortality status among stroke patients after hospital discharge. Using a longitudinal quasi-experimental study design, this study collected information on the type of long-term care received at 1, 3, and 6 months after discharge for 714 patients. At one month after discharge, 4.5 % had died, and 22.1 % had regained all functions in activities of daily living and instrumental activities of daily living. The percentage of patients receiving institutional care, home or community-based care, and family care only were 10.4 % , 22.4 % , and 40.7 % respectively. The respective percentages at 3 months after discharge were 11.2 % , 18.7 % , and 38.0 % , and, at 6 months after discharge, 10.3 % , 19.4 % , and 30.9 % . After adjusting for age, sex, previous incidence of stroke, and physical functions, the odds of dying within 6 months after discharge for stroke patients receiving home or community-based care was significantly lower than those in institutions ( OR = 0.39; 95 % CI = 0.15 to 0.97 ). It is not clear why a lower mortality rate was observed among patients receiving home or community-based services. Differences in quality of care and quality of life among users of different types of long-term care services should be investigated. More research is needed to assess the causes of the disparity in mortality rates among users of different types of long-term care services.


The disfluent discourse: Effects of filled pauses on recall.
We investigated the mechanisms by which fillers, such as uh and um, affect memory for discourse. Participants listened to and attempted to recall recorded passages adapted from Alice's Adventures in Wonderland. The type and location of interruptions were manipulated through digital splicing. In Experiment 1, we tested a processing time account of fillers' effects. While fillers facilitated recall, coughs matched in duration to the fillers impaired recall, suggesting that fillers' benefits cannot be attributed to adding processing time. In Experiment 2, fillers' locations were manipulated based on norming data to be either predictive or non-predictive of upcoming material. Fillers facilitated recall in both cases, inconsistent with an account in which listeners predict upcoming material using past experience with the distribution of fillers. Instead, these results suggest an attentional orienting account in which fillers direct attention to the speech stream but do not always result in specific predictions about upcoming material.


Prematurity, Birth Weight, and Socioeconomic Status Are Linked to Atypical Diurnal Hypothalamic-Pituitary-Adrenal Axis Activity in Young Adults.
In a prospective, case-controlled longitudinal design, 180 preterm and fullterm infants who had been enrolled at birth participated in a comprehensive assessment battery at age 23. Of these, 149 young adults, 34 formerly full-term and 115 formerly preterm (22 healthy preterm, 48 with medical complications, 21 with neurological complications, and 24 small for gestational age) donated five saliva samples from a single day that were assayed for cortisol to assess diurnal variation of the hypothalamic-pituitary-adrenal (HPA) axis. Analyses were conducted to determine whether prematurity category, birth weight, and socioeconomic status were associated with differences in HPA axis function. Pre- and perinatal circumstances associated with prematurity influenced the activity of this environmentally sensitive physiological system. Results are consistent with the theory of Developmental Origins of Health and Disease and highlight a possible mechanism for the link between prematurity and health disparities later in life.


Knowledge, attitudes and practices on adolescent vaccination among adolescents, parents and teachers in Africa: A systematic review.
Vaccines are the most successful and cost-effective public health interventions available to avert vaccine-preventable diseases and deaths. Despite global progress in adolescent health, many adolescents in Africa still get sick and die from vaccine-preventable diseases due to lack of vaccination. Adolescents, parents and teachers are key players in the development and implementation of adolescent vaccination policies. Optimal knowledge, attitudes and practices towards adolescent vaccination among these key players may improve vaccine uptake among adolescents. We conducted a qualitative and quantitative systematic review on knowledge, attitudes and practices of adolescent vaccination among adolescents, parents and teachers in Africa. We searched PubMed, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, WHOLIS, Africa Wide and CINAHL for eligible quantitative and qualitative primary studies with no time limits. We also checked reference lists of included studies for eligible studies and searched grey literature. Two authors independently screened the search outputs, selected studies and extracted data; resolving discrepancies by consensus and discussion. Qualitative data were analysed using thematic analyses where applicable, while analyses from quantitative studies used different methods based on the type of outcomes. We included 18 cross-sectional studies in this review. The included studies were conducted in 10 out of the 54 countries in Africa. The 18 studies focused on a wide range of adolescent vaccines. Thirteen studies evaluated vaccines against Human Papilloma Virus, while each of the remaining 5 studies, evaluated vaccines against rabies, HIV, tetanus toxoid, tuberculosis and adolescent vaccines in general. Among the key players, we found low to moderate levels of knowledge about adolescent vaccination. Positive attitudes and practices towards adolescent vaccination, especially against Human Papilloma Virus were reported. Despite the low knowledge, our results showed high levels of acceptability to adolescent vaccination among adolescents, parents and teachers. It was evident in our review that all key demographics (parents, adolescents and teachers) were receptive towards adolescent vaccines. We propose relevant policy makers in Africa to consider continuous education programs such as those aimed to inform the parents, adolescents and teachers on adolescent vaccination.


Overall survival benefit associated with adjuvant radiotherapy in WHO grade II meningioma.
Adjuvant radiotherapy (RT) after surgical resection of World Health Organization (WHO) grade II meningioma, also known as atypical meningioma (AM), is a topic of controversy. The purpose of this study is to compare overall survival (OS) with or without adjuvant RT after subtotal resection (STR) or gross total resection (GTR) in AM patients diagnosed according to the 2007 WHO classification. The National Cancer Database was used to identify 2515 patients who were diagnosed with AM between 2009 and 2012 and underwent STR or GTR with or without adjuvant RT. Propensity score matching was first applied to balance covariates including age, year of diagnosis, sex, race, histology, and tumor size in STR or GTR cohorts stratified by adjuvant RT status. Multivariate regression according to the Cox proportional hazards model and Kaplan-Meier survival plots with log-rank test were then used to evaluate OS difference associated with adjuvant RT. GTR is associated with improved OS compared with STR. In the subgroup analysis, adjuvant RT in patients who underwent STR demonstrated significant association with improved OS compared with no adjuvant RT (adjusted hazard ratio [AHR] 0.590, P = .045); however, adjuvant RT is not associated with improved OS in patients who underwent GTR (AHR 1.093, P = .737). Despite the lack of consensus on whether adjuvant RT reduces recurrence after surgical resection of AM, our study observed significantly improved OS with adjuvant RT compared with no adjuvant RT after STR.


The ADP/ATP translocase drives mitophagy independent of nucleotide exchange.
Mitochondrial homeostasis depends on mitophagy, the programmed degradation of mitochondria. Only a few proteins are known to participate in mitophagy. Here we develop a multidimensional CRISPR-Cas9 genetic screen, using multiple mitophagy reporter systems and pro-mitophagy triggers, and identify numerous components of parkin-dependent mitophagy1. Unexpectedly, we find that the adenine nucleotide translocator (ANT) complex is required for mitophagy in several cell types. Whereas pharmacological inhibition of ANT-mediated ADP/ATP exchange promotes mitophagy, genetic ablation of ANT paradoxically suppresses mitophagy. Notably, ANT promotes mitophagy independently of its nucleotide translocase catalytic activity. Instead, the ANT complex is required for inhibition of the presequence translocase TIM23, which leads to stabilization of PINK1, in response to bioenergetic collapse. ANT modulates TIM23 indirectly via interaction with TIM44, which regulates peptide import through TIM232. Mice that lack ANT1 show blunted mitophagy and consequent profound accumulation of aberrant mitochondria. Disease-causing human mutations in ANT1 abrogate binding to TIM44 and TIM23 and inhibit mitophagy. Together, our findings show that ANT is an essential and fundamental mediator of mitophagy in health and disease.