Patterns of natural selection on size at metamorphosis in water frogs.
Strategies for optimal metamorphosis are key adaptations in organisms with complex life cycles, and the components of the larval growth environment causing variation in this trait are well studied empirically and theoretically. However, when relating these findings to a broader evolutionary or ecological context, usually the following assumptions are made: (1) size at metamorphosis positively relates to future fitness, and (2) the larval growth environment affects fitness mainly through its effect on timing of and size at metamorphosis. These assumptions remain poorly tested, because data on postmetamorphic fitness components are still rare. We created variation in timing of and size at metamorphosis by manipulating larval competition, nonlethal presence of predators, pond drying, and onset of larval development, and measured the consequences for subsequent terrestrial survival and growth in 1564 individually marked water frogs (Rana lessonae and R. esculenta), raised in enclosures in their natural environment. Individuals metamorphosing at a large size had an increased chance of survival during the following terrestrial stage (mean linear selection gradient: 0.09), grew faster and were larger at maturity than individuals metamorphosing at smaller sizes. Late metamorphosing individuals had a lower survival rate (mean linear selection gradient: -0.03) and grew more slowly than early metamorphosing ones. We found these patterns to be consistent over the three years of the study and the two species, and the results did not depend on the nature of the larval growth manipulation. Furthermore, individuals did not compensate for a small size at metamorphosis by enhancing their postmetamorphic growth. Thus, we found simple relationships between larval growth and postmetamorphic fitness components, and support for this frequently made assumption. Our results suggest postmetamorphic selection for fast larval growth and provide a quantitative estimate for the water frog example.


The effectiveness of daclatasvir based therapy in European patients with chronic hepatitis C and advanced liver disease.
There is limited evidence for the effectiveness of daclatasvir in patients whose hepatitis C threatens their life expectancy. The Named Patient Program in Europe included patients with advanced chronic hepatitis C, a life expectancy of less than 12 months and no other treatment options. A retrospective multi-country cohort of patients with chronic hepatitis C who received daclatasvir as part of the Named Patient Program in Austria, Denmark, Spain, Sweden, Switzerland and the United Kingdom. Treatment response was defined as a sustained virologic response (unquantifiable hepatitis C RNA) at 12 weeks post treatment. We summarised the characteristics of the patients in this cohort and estimated the rate of sustained virologic response for patients receiving daclatasvir and sofosbuvir with or without ribavirin using hierarchical Bayesian modelling. The 249 patients included had a median age of 56 years; most were male (78%), hepatitis C genotype 1 (75%), treatment experienced (65%) and with decompensated cirrhosis (59%). Many had had a liver transplant before receiving daclatasvir (40%). Of the 249 patients, 242 patients received daclatasvir and sofosbuvir and either reached 12 weeks post treatment or died during (n = 9) or after treatment (n = 4) or were lost to follow up during treatment (n = 1). The estimated rate of sustained virologic response at 12 weeks post treatment was 87% (95% credible interval 75 to 94%) for previously treated genotype 1 patients with decompensated cirrhosis. Daclatasvir with sofosbuvir is an effective treatment in clinical practice for hepatitis C genotype 1 patients with decompensated cirrhosis.


The Shipibo Ceremonial Use of Ayahuasca to Promote Well-Being: An Observational Study.
Promoting well-being is one of the main goals to improve health in the world. We examined the well-being and quality of life over the course of one year in a sample that participated in an Indigenous Shipibo healing program where traditional healers work in a series of ayahuasca ceremonies. We also explored the role of decentering as a mediator of psychological well-being. Participants who attended the program responded to an online survey that included a Psychological Well-Being Scale; Oxford Happiness Questionnaire; The World Health Organization Quality of Life Spirituality, Religiousness, and Personal Beliefs scale; the WHO Quality of Life-BREF scale; and Decentering scale. Baseline (T0) and postassessment (T1) were completed by 200 individuals. Of these, 101 completed the follow-up assessment at three months (T2), 91 at 6 months (T3), and 94 at 12 months follow-up (T4) after leaving the center. ANOVA test was performed in a representative subsample to control the passing of time two months before attending the program (T-1). Pearson's test was performed to examine the relationship between psychological well-being and decentering during the period of T0 and T1. A significant increase was observed in all the scales at all time points (p ≤ 0.01). The subgroup analysis performed in a representative subsample allowed us to infer that the significant differences in outcomes are due to the effect of their stay at the center and not the passing of time. We found a relationship between decentering and the improvement of psychological well-being (r = 0.57; p < 0.01). Our results suggest that the Indigenous Shipibo healing work with ayahuasca has value to improve long-term well-being and quality of life for Westerners.


Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3.
Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer's disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis (1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10, and TAU) at 5 different developmental stages (embryo [E15], 2, 4, 8, and 18 months), (2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant-based and single-gene-based (c-alpha test and sequence kernel association test (SKAT)) genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (log2FC > 1, adj. p-value < 0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ dense-core plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H, and p.H703Y) in our discovery and validation cohort, composed of 465 AD and mild cognitive impairment (MCI) Caucasian patients from the United Kingdom. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-value = 0.01). Adult-onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset AD, which warrants further investigation.


The role of cytology (Pap tests) and human papillomavirus testing in anal cancer screening.
To assess anal oncogenic human papillomavirus (HPV) and anal cytology as screening tests for detecting high-grade anal intraepithelial neoplasia (AIN 2+), as this is an immediate anal cancer precursor. Cross-sectional study of 401 HIV-positive men who have sex with men (MSM). The endpoint was histologically confirmed AIN 2+ obtained by high-resolution anoscopy. Cytology and biopsy specimens were assigned random numbers and independently assessed by two pathologists. We did concomitant anal cytology, anal HPV testing and HRA with directed biopsies without knowing the results of each intervention. The main outcome measures were the sensitivity, specificity, negative predictive value and positive predictive value of anal cytology and oncogenic HPV for the detection of AIN 2+. Cytology was abnormal in 67% of patients: high-grade squamous intraepithelial lesion, 12%; low-grade squamous intraepithelial lesion, 43% and atypical squamous cells of undetermined significance, 12%. Biopsies were abnormal in 68% of patients: AIN 2+, 25% and AIN 1, 43%. HPV was detected in 93% with multiple HPV types in 92% and oncogenic HPV types in 88%. Test performance characteristics for the detection of AIN 2+ using any abnormality on anal cytology were: sensitivity 84%, specificity 39%, negative predictive value 88% and positive predictive value 31%; using oncogenic HPV: sensitivity 100%, specificity 16%, negative predictive value 100% and positive predictive value 28%. Anal cytology and HPV detection have high sensitivity but low specificity for detecting AIN 2+. HIV-positive men who have sex with men have a high prevalence of AIN 2+ and require high-resolution anoscopy for optimal detection of high-grade anal dysplasia.


Alternate-Nostril Yoga Breathing Reduced Blood Pressure While Increasing Performance in a Vigilance Test.
BACKGROUND Reports suggest that vigilance or sustained attention increases sympathetic activity. A persistent increase in sympathetic activity can lead to an increase in blood pressure. Alternate-nostril yoga breathing has been shown to be useful to (i) improve attention and (ii) decrease the systolic and diastolic blood pressure. Earlier studies did not report simultaneous recordings of the blood pressure and performance in vigilance tests after alternate-nostril yoga breathing. With this background, the present study was planned to determine if 15 minutes of alternate nostril yoga breathing could improve the performance in a vigilance test without an increase in blood pressure. MATERIAL AND METHODS Fifteen healthy male volunteers participated in the study (group mean age ±SD, 22.4±2.4 years). Participants were assessed on 3 separate days in 3 different sessions. These were (i) alternate nostril yoga breathing, (ii) breath awareness, and (iii) sitting quietly as a control. Blood pressure and the digit vigilance test were simultaneously assessed before and after each session. RESULTS Systolic blood pressure (p<0.01), mean arterial blood pressure (p<0.05), and the time taken to complete the digit vigilance test (p<0.05) significantly decreased following alternate-nostril yoga breathing. The time taken to complete the digit vigilance test differed significantly between sessions (p<0.05). The time taken to complete the digit vigilance test was also significantly decreased after sitting quietly (p<0.01). CONCLUSIONS Alternate-nostril yoga breathing appears to improve performance in the digit vigilance test, along with a reduction in systolic blood pressure. This is suggestive of better vigilance without sympathetic activation.


Neural pathways in tactile object recognition.
To define further the brain regions involved in tactile object recognition using functional MRI (fMRI) techniques. The neural substrates involved in tactile object recognition (TOR) have not been elucidated. Studies of nonhuman primates and humans suggest that basic motor and somatosensory mechanisms are involved at a peripheral level; however, the mechanisms of higher order object recognition have not been determined. The authors investigated 11 normal volunteers utilizing fMRI techniques in an attempt to determine the neural pathways involved in TOR. Each individual performed a behavioral paradigm with the activated condition involving identification of objects by touch, with identification of rough/smooth as the control. Data suggest that in a majority of individuals, TOR involves the calcarine and extrastriatal cortex, inferior parietal lobule, inferior frontal gyrus, and superior frontal gyrus-polar region. TOR may utilize visual systems to access an internal object representation. The parietal cortices and inferior frontal regions may be involved in a concomitant lexical strategy of naming the object being examined. Frontal polar activation likely serves a role in visuospatial working memory or in recognizing unusual representations of objects. Overall, these findings suggest that TOR could involve a network of cortical regions subserving somatosensory, motor, visual, and, at times, lexical processing. The primary finding suggests that in this normal study population, the visual cortices may be involved in the topographic spatial processing of TOR.


Sleep versus wake classification from heart rate variability using computational intelligence: consideration of rejection in classification models.
Reliability of classification performance is important for many biomedical applications. A classification model which considers reliability in the development of the model such that unreliable segments are rejected would be useful, particularly, in large biomedical data sets. This approach is demonstrated in the development of a technique to reliably determine sleep and wake using only the electrocardiogram (ECG) of infants. Typically, sleep state scoring is a time consuming task in which sleep states are manually derived from many physiological signals. The method was tested with simultaneous 8-h ECG and polysomnogram (PSG) determined sleep scores from 190 infants enrolled in the collaborative home infant monitoring evaluation (CHIME) study. Learning vector quantization (LVQ) neural network, multilayer perceptron (MLP) neural network, and support vector machines (SVMs) are tested as the classifiers. After systematic rejection of difficult to classify segments, the models can achieve 85%-87% correct classification while rejecting only 30% of the data. This corresponds to a Kappa statistic of 0.65-0.68. With rejection, accuracy improves by about 8% over a model without rejection. Additionally, the impact of the PSG scored indeterminate state epochs is analyzed. The advantages of a reliable sleep/wake classifier based only on ECG include high accuracy, simplicity of use, and low intrusiveness. Reliability of the classification can be built directly in the model, such that unreliable segments are rejected.


The 37/67 kDa laminin receptor (LR) inhibitor, NSC47924, affects 37/67 kDa LR cell surface localization and interaction with the cellular prion protein.
The 37/67 kDa laminin receptor (LR) is a non-integrin protein, which binds both laminin-1 of the extracellular matrix and prion proteins, that hold a central role in prion diseases. The 37/67 kDa LR has been identified as interactor for the prion protein (PrP(C)) and to be required for pathological PrP (PrP(Sc)) propagation in scrapie-infected neuronal cells, leading to the possibility that 37/67 kDa LR-PrP(C) interaction is related to the pathogenesis of prion diseases. A relationship between 37/67 kDa LR and PrP(C) in the presence of specific LR inhibitor compounds has not been investigated yet. We have characterized the trafficking of 37/67 kDa LR in both neuronal and non-neuronal cells, finding the receptor on the cell surface and nuclei, and identified the 67 kDa LR as the almost exclusive isoform interacting with PrP(C). Here, we show that the treatment with the 37/67 kDa LR inhibitor, NSC47924, affects both the direct 37/67 kDa LR-PrP(C) interaction in vitro and the formation of the immunocomplex in live cells, inducing a progressive internalization of 37/67 kDa LR and stabilization of PrP(C) on the cell surface. These data reveal NSC47924 as a useful tool to regulate PrP(C) and 37/67 kDa LR trafficking and degradation, representing a novel small molecule to be tested against prion diseases.


Osteoporosis is a neglected health priority in Arab World: a comparative bibliometric analysis.
Osteoporosis is an important health problem with serious consequences. Evaluation of osteoporosis scientific output from Arab countries has not been explored and there are few internationally published reports on research activity about osteoporosis. The main objectives of this study were to analyze the research output originating from Arab countries and 3 Middle Eastern non-Arab countries, particularly Israel, Turkey and Iran in the field of osteoporosis. Original scientific articles or reviews published from the 21 Arab countries, Israel, Turkey and Iran about "osteoporosis" were screened using the ISI Web of Science database. The time frame for the result was up to year 2012. The total number of original and review research articles published globally about osteoporosis was 43,571. The leading country in osteoporosis research was United States of America (14,734; 33.82%). Worldwide, Turkey ranked 16th while Israel and Iran ranked 24th and 31st respectively. Among Arab countries, Egypt and Kingdom of Saudi Arabia came on positions 41 and 45 respectively. A total of 426 documents about "osteoporosis" were published from Arab countries which represents 0.98% of the global research output. Research about osteoporosis from Arab countries was very low until 2002 and then increased steadily. The total number of citations for osteoporosis documents from the Arab world was 5551 with an average citation of 13.03 per document and an h- index of 35. Thirty (7.04%) documents published from Arab countries about osteoporosis were published in Saudi Medical Journal. Egypt, with a total publication of 117 (27.47%) ranked first among the Arab countries in research about osteoporosis while American University in Beirut was the most productive institution with a total of 47 (11.03%) documents. Compared with other non-Arab countries in the Middle East, the research productivity from the Arab countries was lesser than that from Turkey and Israel but higher than that from Iran. The present data showed low research productivity in osteoporosis field in Arab countries. Research output can be improved by investing in more international and national collaborative research projects in the field of osteoporosis.


Clustering of suicides in children and adolescents.
Suicide is one of the major causes of death in young people, in whom suicide can occur in clusters. In this Review, we have investigated definitions and epidemiology of such clusters, the factors associated with them, mechanisms by which they occur, and means of intervening and preventing them. Clustering of suicidal behaviour is more common in young people (<25 years) than adults. Suicide clusters can occur as a greater number of episodes than expected at a specific location, including in institutions (eg, schools, universities, psychiatric units, and youth offender units). They might also involve linked episodes spread out geographically. Locations exposed to clusters can be at risk for future clusters. Mechanisms involved in clusters include social transmission (particularly via person-to-person transmission and the media), perception that suicidal behaviour is widespread, susceptible young people being likely to socialise with others at risk of suicidal behaviour, and social cohesion contributing to the diffusion of ideas and attitudes. The internet and social media might have particularly important roles in spreading suicidal behaviour. The effect of suicide clusters on communities and institutions is usually profound. Experience of intervening in clusters has resulted in best practice guidance. This guidance includes preparation for occurrence of clusters in both community and institutional settings. Identification of clusters in the community requires real-time monitoring of suicidal behaviour. Effective intervention is more likely if a cluster response group is established than if no such group exists. The response should include bereavement support, provision of help for susceptible individuals, proactive engagement with media interest, and population-based approaches to support and prevention. Social media can provide a powerful means for disseminating information and reaching young people at risk.


Could the A2A11 human leucocyte antigen locus correlate with maximal aerobic power?
1. The power of the aerobic metabolic pathway correlates well with successful physical performance in endurance sports events. The ability to alter the pathway through training presents well-known limitations, and consequently a good genetic endowment is essential to participate in elite sporting activities. 2. In 32 subjects (16 healthy pairs of male twin sportsmen, 8 monozygotic and 8 dizygotic) zygosity was determined by means of the genetic analysis of human leucocyte antigen (HLA) system specificities at class I and II loci and other genetic variants. The subjects performed a progressive exercise test on a treadmill to ascertain the maximal oxygen uptake (VO2max), measured by an automatic breath-by-breath analyser. We have considered the relationship between the A, B and C loci of the HLA system and VO2max. 3. We found a high correlation between the presence of both HLA A2 and A11 and VO2max. In the A2A11 group (n = 6) we found a VO2max (mean +/- SD) equal to 71 +/- 4 ml min-1 kg-1. The group without this pair of alleles (n = 26) showed a much lower aerobic power (58 +/- 5 ml min-1 kg-1). Differences between the two groups were found to be largely significant (P < 0.001). It is noteworthy that in two pairs of dizygotic twins, the higher VO2max value corresponded to the twin with the A2A11 allele. 4. The very marked concordance between the presence of the A2A11 locus of the HLA system and the VO2max could be of great interest for the identification of outstanding performers.


Genes, language, cognition, and culture: towards productive inquiry.
The Queen Mary conference on "Integrating Genetic and Cultural Evolutionary Approaches to Language," and the papers in this special issue, clearly illustrate the excitement and potential of trans-disciplinary approaches to language as an evolved biological capacity (phylogeny) and an evolving cultural entity (glossogeny). Excepting the present author, the presenters/authors are mostly young rising stars in their respective fields, and include scientists with backgrounds in linguistics, animal communication, neuroscience, evolutionary biology, anthropology, and computer science. On display was a clear willingness to engage with different approaches and terminology and a commitment to shared standards of scientific rigor, empirically driven theory, and logical argument. Because the papers assembled here, together with the introduction, speak for themselves, I will focus in this "extro-duction" on some of the terminological and conceptual difficulties which threaten to block this exciting wave of scientific progress in understanding language evolution, in both senses of that term. In particular I will first argue against the regrettably widespread practice of opposing cultural and genetic explanations of human cognition as if they were dichotomous. Second, I will unpack the debate concerning "general-purpose" and "domain-specific" mechanisms, which masquerades as a debate about nativism but is nothing of the sort. I believe that framing discussions of language in these terms has generated more heat than light, and that a modern molecular understanding of genes, development, behavior, and evolution renders many of the assumptions underlying this debate invalid.


Low and high affinity cellular receptors for interleukin 2. Implications for the level of Tac antigen.
Interleukin 2 promotes proliferation of T cells by virtue of its interaction with a high-affinity cell surface receptor. This receptor is a 55,000 mol wt glycoprotein that is also recognized by the murine monoclonal antibody, anti-Tac. Quantitative binding studies with radiolabeled IL-2 and anti-Tac, however, initially indicated far more antibody binding sites per cell than IL-2 binding sites. Extension of the IL-2 binding analysis to concentrations several thousand-fold higher than that necessary for the T cell proliferative response demonstrated the existence of a class (or classes) of low-affinity IL-2 binding sites. Inclusion of the low-affinity IL-2 binding greatly reduced the quantitative discrepancy in the ligand binding assays. That the low-affinity binding, as well as the high-affinity interaction, was associated with the Tac molecule was indicated by the finding that the antibody could substantially or totally block the entire spectrum of IL-2 binding and by the finding that IL-2 could in turn block all radiolabeled anti-Tac binding. The low-affinity sites were found on activated T cells, several human and murine T cell lines and two examples of Tac-positive B cells. The physiological role of the low-affinity IL-2 binding sites and the molecular changes in the Tac protein that give rise to the affinity differences remain open to investigation.


Power, participation and their problems: A consideration of power dynamics in the use of participatory epidemiology for one health and zoonoses research.
The use of Participatory Epidemiology in veterinary research intends to include livestock keepers and other local stakeholders in research processes and the development of solutions to animal health problems, including potentially zoonotic diseases. It can also be an attempt to bring some of the methods and insights of social science into a discipline largely shaped by natural science methods and ways of seeing the world. The introduction of participatory methodologies to veterinary epidemiology and disease surveillance follows a wider movement in development thinking, questioning the top-down nature of much post-second world war development efforts directed from the Global North towards the Global South. In the best cases, participatory methods can help to empower the poor and marginalised to participate in and have some control over research and interventions which affect them. Compiled from experience in multi-disciplinary One Health projects, this paper briefly traces the rise of participatory epidemiology before examining some of the limitations observed in its implementation and steps that might be taken to alleviate the problems observed. The three areas in which the operationalisation of Participatory Epidemiology in veterinary and One Health research could be improved are identified as: broadening the focus of engagement with communities beyond quantitative data extraction; taking note of the wider power structures in which research takes place, and questioning who speaks for a community when participatory methods are used. In particular, the focus falls on how researchers from different disciplines, including veterinary medicine and the social sciences, can work together to ensure that participatory epidemiology is employed in such a way that it improves the quality of life of both people and animals around the world.


Growth and in-vitro metabolism of placental tissues of cows from day 100 to day 250 of gestation.
Weight of placental tissues of cows increased exponentially from Day 100 to Day 250 of gestation, but at much slower relative and absolute rates than fetal weight. In addition, growth rate of fetal placental tissues was less than that of maternal placental tissues. Concentrations of DNA, RNA and protein, however, increased in fetal placental but not in maternal placental tissues. Fetal placental tissues therefore exhibited hyperplasia, which probably contributes to increased functional capacity of the placenta during late gestation. The rate of O2 uptake in vitro was greatest for maternal placental tissues, suggesting that the maternal portion of the placenta accounts for most of the large rate of placental O2 utilization in vivo. Compared with other placental tissues, rate of secretion of macromolecules by intercaruncular endometrium was high, but decreased from Day 100 to 250, suggesting that uterine glandular secretory activity may decrease as gestation advances. Rate of secretion of macromolecules also was high for intercotyledonary tissues and increased with day of gestation, suggesting a role for secretory products of chorioallantois in gravid uterine function.


Study of magnesium bioavailability from ten organic and inorganic Mg salts in Mg-depleted rats using a stable isotope approach.
Literature data on the bioavailability of various Mg forms provide scarce information on the best Mg salt to be used in animal and human supplementation. This study aimed to investigate the bioavailability of different forms of Mg in rats using Mg stable isotopes. Eighty male Wistar rats aged 6 weeks were fed a semi-purified Mg-depleted diet for three weeks. The rats were then randomised into ten groups and received, for two more weeks, the same diet repleted with Mg (550 mg Mg/kg) as: oxide, chloride, sulphate, carbonate, acetate, pidolate, citrate, gluconate, lactate or aspartate. After 10 days of Mg-repleted diet, the rats received orally 1.8 mg of an enriched 26Mg. Faeces and urine were then collected for 4 consecutive days. Isotope ratios in faeces and urine were determined. The Mg absorption values obtained varied from 50% to 67%. Organic Mg salts were slightly more available than inorganic Mg salts. Mg gluconate exhibited the highest Mg bioavailability of the ten Mg salts studied. Urinary 26Mg excretion varied from 0.20 mg to 0.33 mg, and feeding with the organic pidolate, citrate, gluconate and aspartate salts resulted in higher urinary 26Mg excretion than with inorganic salts. Ultimately, 26Mg retention was higher in the rats receiving the organic salts such as gluconate, lactate and aspartate than in those receiving the inorganic salts. Taken together, these results indicate that 26Mg is sufficiently bioavailable from the ten different Mg salts studied in the present experiment, although Mg gluconate exhibited the highest bioavailability under these experimental conditions.


MHC class I-mediated antigen presentation and induction of CD8+ cytotoxic T-cell responses in autoimmune diabetes-prone NOD mice.
The common class I alleles (e.g., Kd and Db) within the H2g7 major histocompatibility complex (MHC) clearly contribute to autoimmune IDDM in NOD mice, but the mechanism by which this occurs has been controversial. One laboratory has reported that the peptide transporter encoded by the Tap1 gene within H2g7 is defective, and this contributes to IDDM by impairing MHC class I-mediated antigen presentation. If true, defective MHC class I-mediated antigen presentation should segregate with the H2g7 haplotype. NOD mice, related congenic stocks, and other control strains were used to test this hypothesis. H2g7-positive strains did not differ from those expressing other MHC haplotypes in ability to present MHC class I-restricted H3aa or H3ab minor histocompatibility (H) antigens to cytotoxic T-lymphocytes (CTL). The H2g7 haplotype was found to have a reduced capacity to mediate MHC class I-restricted presentation of the H47a minor H antigen. However, MHC class I-restricted presentation of H47a was found to be Tap independent. NOD mice and control strains also did not differ in ability to activate adenovirus-specific MHC class I restricted CTL. Thus, the H2g7 haplotype is not characterized by a Tap gene defect that only impairs the inductive phase of the immune response. In addition, MHC class I-restricted presentation of either minor H or adenoviral antigens was equivalent in male and female NOD mice. Therefore, while the class I alleles of the H2g7 haplotype exert diabetogenic functions in NOD mice, this is not elicited through a Tap gene defect. The absence of female-specific Tap gene defects also indicates this cannot account for the reduced male incidence of IDDM in some NOD mouse colonies.


Inhibition of neuronal nitric oxide synthase by 6-nitrocatecholamines, putative reaction products of nitric oxide with catecholamines under oxidative stress conditions.
6-Nitrodopamine and 6-nitronoradrenaline (6-nitronorepinephrine), putative products of the nitric oxide (NO)-dependent nitration of dopamine and noradrenaline, are reported to be reversible, competitive inhibitors of neuronal nitric oxide synthase (nNOS) with K(i) values of 45 and 52 microM respectively. The nitrocatecholamines inhibited H(2)O(2) production in the absence of L-arginine and tetrahydrobiopterin (BH(4)) (the IC(50) values for 6-nitrodopamine and 6-nitronoradrenaline were 85 and 55 microM respectively) but without affecting cytochrome c reduction. The apparent K(i) values for nitrocatecholamine inhibition of enzyme activation by BH(4) were 18 microM for 6-nitrodopamine and 40 microM for 6-nitronoradrenaline. Both nitrocatecholamines antagonized the dimerization of nNOS induced by BH(4) and by L-arginine, the effect being reversed by BH(4) (more than 10 microM) and L-arginine (e.g. 100 microM). Overall, these results suggest that nitrocatecholamines interfere with nNOS activity by binding to the enzyme in the proximity of the substrate and BH(4)-binding sites near the haem group.


Mapping the global research landscape and knowledge gaps on multimorbidity: a bibliometric study.
To summarize global research trends and activities on multimorbidity; then to assess the knowledge gaps and to identify implications for knowledge exchange between high income countries (HICs) and low- and middle- income countries (LMICs). A comprehensive search was conducted to identify research publications on multimorbidity in the Web of ScienceTM, as well as diabetes, depression, hypertension, and Chronic Obstructive Pulmonary Disease (COPD). The time frame for the search was from 1900 to June, 2016. Information (such as publication date, subject category, author, country of origin, title, abstract, and keywords) were extracted and the full texts were obtained for the co-citation analysis. Data were linked with the life expectancy at birth (years) and Gross National Income (GNI). Co-citation and hierarchal clustering analysis was used to map the trends and research networks with CiteSpace II (JAVA freeware, copyright Chaomei Chen, http://cluster.cis.drexel.edu/~cchen/citespace/). We identified 2864 relevant publications as at June 2016, with the first paper on this topic indexed in 1974 from Germany, but 80% were published after 2010. Further analysis yielded two knowledge gaps: (1) compared with single conditions (diabetes, hypertension, depression, and COPD), there is a mismatch between the high prevalence of multimorbidity and its research outputs (ratio of articles on multimorbidity vs other four single conditions is 1:13-150); (2) although a total of 76 countries have contributed to this research area, only 5% of research originated from LMICs where 73% of non-communicable disease (NCD) related deaths had occurred. Additional analysis showed the median year of first publication occurred 15 years later in the LMICs compared with HICs (2010 vs 1995); and longer life expectancy was associated with exponentially higher publication outputs (Pearson correlation coefficient r = 0.95) at the global level. The life expectancy at the median year (1994) of first publication was 66.1, with the gap between LMICs and HICs 7.9 (68.4 vs 76.3). This study confirms substantial knowledge gaps in the research agenda on multimorbidity, with input urgently needed to move us forward worldwide, especially for and in LMICs. There is the possibility that LMICs can learn from and collaborate with HICs in this area.


Coverage of intermittent preventive treatment and insecticide-treated nets for the control of malaria during pregnancy in sub-Saharan Africa: a synthesis and meta-analysis of national survey data, 2009-11.
Pregnant women in malaria-endemic countries in sub-Saharan Africa are especially vulnerable to malaria. Recommended prevention strategies include intermittent preventive treatment with two doses of sulfadoxine-pyrimethamine and the use of insecticide-treated nets. However, progress with implementation has been slow and the Roll Back Malaria Partnership target of 80% coverage of both interventions by 2010 has not been met. We aimed to review the coverage of intermittent preventive treatment, insecticide-treated nets, and antenatal care for pregnant women in sub-Saharan Africa and to explore associations between coverage and individual and country-level factors, including the role of funding for malaria prevention. We used data from nationally representative household surveys from 2009-11 to estimate coverage of intermittent preventive treatment, use of insecticide-treated nets, and attendance at antenatal clinics by pregnant women in sub-Saharan Africa. Using demographic data for births and published data for malaria exposure, we also estimated the number of malaria-exposed births (livebirths and stillbirths combined) for 2010 by country. We used meta-regression analysis to investigate the factors associated with coverage of intermittent preventive treatment and use of insecticide-treated nets. Of the 21·4 million estimated malaria-exposed births across 27 countries in 2010, an estimated 4·6 million (21·5%, 95% CI 19·3-23·7) were born to mothers who received intermittent preventive treatment. Insecticide-treated nets were used during pregnancy for 10·5 million of 26·9 million births across 37 countries (38·8%, 34·6-43·0). Antenatal care was attended at least once by 16·3 of 20·8 million women in 2010 (78·3%, 75·2-81·4; n=26 countries) and at least twice by 14·7 of 19·6 million women (75·1%, 72·9-77·3; n=22 countries). For the countries with previous estimates for 2007, coverage of intermittent preventive treatment increased from 13·1% (11·9-14·3) to 21·2% (18·9-23·5; n=14 countries) and use of insecticide-treated nets increased from 17·9% (15·1-20·7) to 41·6% (37·2-46·0; n=24 countries) in 2010. A fall in coverage by more than 10% was seen in two of 24 countries for intermittent preventive treatment and in three of 30 countries for insecticide-treated nets. High disbursement of funds for malaria control and a long time interval since adoption of the relevant policy were associated with the highest coverage of intermittent preventive treatment. High disbursement of funds for malaria control and high total fertility rate were associated with the greatest use of insecticide-treated nets, whereas a high per-head gross domestic product (GDP) was associated with less use of nets than was a lower GDP. Coverage of intermittent preventive treatment showed greater inequity overall than use of insecticide-treated nets, with richer, educated, and urban women more likely to receive preventive treatment than their poorer, uneducated, rural counterparts. Although coverage of intermittent preventive treatment and use of insecticide-treated nets by pregnant women has increased in most countries, coverage remains far below international targets, despite fairly high rates of attendance at antenatal clinics. The effect of the implementation of WHO's 2012 policy update for intermittent preventive treatment, which aims to simplify the message and align preventive treatment with the focused antenatal care schedule, should be assessed to find out whether it leads to improvements in coverage. Bill & Melinda Gates Foundation.


Explicit all-atom modeling of realistically sized ligand-capped nanocrystals.
We present a study of an explicit all-atom representation of nanocrystals of experimentally relevant sizes (up to 6 nm), "capped" with alkyl chain ligands, in vacuum. We employ all-atom molecular dynamics simulation methods in concert with a well-tested intermolecular potential model, MM3 (molecular mechanics 3), for the studies presented here. These studies include determining the preferred conformation of an isolated single nanocrystal (NC), pairs of isolated NCs, and (presaging studies of superlattice arrays) unit cells of NC superlattices. We observe that very small NCs (3 nm) behave differently in a superlattice as compared to larger NCs (6 nm and above) due to the conformations adopted by the capping ligands on the NC surface. Short ligands adopt a uniform distribution of orientational preferences, including some that lie against the face of the nanocrystal. In contrast, longer ligands prefer to interdigitate. We also study the effect of changing ligand length and ligand coverage on the NCs on the preferred ligand configurations. Since explicit all-atom modeling constrains the maximum system size that can be studied, we discuss issues related to coarse-graining the representation of the ligands, including a comparison of two commonly used coarse-grained models. We find that care has to be exercised in the choice of coarse-grained model. The data provided by these realistically sized ligand-capped NCs, determined using explicit all-atom models, should serve as a reference standard for future models of coarse-graining ligands using united atom models, especially for self-assembly processes.


Morphology of influenza B/Lee/40 determined by cryo-electron microscopy.
Cryo-electron microscopy projection image analysis and tomography is used to describe the overall architecture of influenza B/Lee/40. Algebraic reconstruction techniques with utilization of volume elements (blobs) are employed to reconstruct tomograms of this pleomorphic virus and distinguish viral surface spikes. The purpose of this research is to examine the architecture of influenza type B virions by cryo-electron tomography and projection image analysis. The aims are to explore the degree of ribonucleoprotein disorder in irregular shaped virions; and to quantify the number and distribution of glycoprotein surface spikes (hemagglutinin and neuraminidase) on influenza B. Projection image analysis of virion morphology shows that the majority (∼83%) of virions are spherical with an average diameter of 134±19 nm. The aspherical virions are larger (average diameter = 155±47 nm), exhibit disruption of the ribonucleoproteins, and show a partial loss of surface protein spikes. A count of glycoprotein spikes indicates that a typical 130 nm diameter type B virion contains ∼460 surface spikes. Configuration of the ribonucleoproteins and surface glycoprotein spikes are visualized in tomogram reconstructions and EM densities visualize extensions of the spikes into the matrix. The importance of the viral matrix in organization of virus structure through interaction with the ribonucleoproteins and the anchoring of the glycoprotein spikes to the matrix is demonstrated.


Cannabidiol--antiepileptic drug comparisons and interactions in experimentally induced seizures in rats.
A comparison of the anticonvulsant and neurotoxic effects of cannabidiol (CBD), delta 9tetrahydrocannabinol, cannabinol and antiepileptic drugs (phenytoin, phenobarbital, carbamazepine, chlordiazepoxide, clonazepam, ethosuximide and trimethadione) was made in rats. Median effective potencies (ED 50 values) for maximal electroshock, audiogenic seizures and TD50 values for a rotor rod neurotoxicity test were calculated. Additionally, the interactive effects of CBD and the antiepileptic drugs against maximal electroshock and audiogenic seizures were studied. Each drug was given orally at peak effect time. CBD was an effective and relatively potent anticonvulsant in both maximal electroshock and audiogenic seizure tests. The anticonvulsant potency of phenytoin was significantly increased when combined with phenobarbital, CBD and phenobarbital plus CBD. Additionally, CBD reliably reduced the anticonvulsant potencies of chlordiazepoxide, clonazepam, trimethadione and ethosuximide. These data indicate that CBD is an effective anticonvulsant with a specificity more comparable to drugs clinically effective in major than minor seizures. Furthermore, it appears that CBD enhances the anticonvulsant effects of the former and reduces the effects of the latter types of antiepileptic drugs.


Ultra-narrow band perfect absorbers based on plasmonic analog of electromagnetically induced absorption.
A novel plasmonic metamaterial consisting of the solid (bar) and the inverse (slot) compound metallic nanostructure for electromagnetically induced absorption (EIA) is proposed in this paper, which is demonstrated to achieve an ultra-narrow absorption peak with the linewidth less than 8 nm and the absorptivity exceeding 97% at optical frequencies. This is attributed to the plasmonic EIA resonance arising from the efficient coupling between the magnetic response of the slot (dark mode) and the electric resonance of the bar (bright mode). To the best of our knowledge, this is the first time that the plasmonic EIA is used to realize the narrow-band perfect absorbers. The underlying physics are revealed by applying the two-coupled-oscillator model. The near-perfect-absorption resonance also causes an enhancement of about 50 times in H-field and about 130 times in E-field within the slots. Such absorber possesses potential for applications in filter, thermal emitter, surface enhanced Raman scattering, sensing and nonlinear optics.


A richly interactive exploratory data analysis and visualization tool using electronic medical records.
Electronic medical records (EMRs) contain vast amounts of data that is of great interest to physicians, clinical researchers, and medial policy makers. As the size, complexity, and accessibility of EMRs grow, the ability to extract meaningful information from them has become an increasingly important problem to solve. We develop a standardized data analysis process to support cohort study with a focus on a particular disease. We use an interactive divide-and-conquer approach to classify patients into relatively uniform within each group. It is a repetitive process enabling the user to divide the data into homogeneous subsets that can be visually examined, compared, and refined. The final visualization was driven by the transformed data, and user feedback direct to the corresponding operators which completed the repetitive process. The output results are shown in a Sankey diagram-style timeline, which is a particular kind of flow diagram for showing factors' states and transitions over time. This paper presented a visually rich, interactive web-based application, which could enable researchers to study any cohorts over time by using EMR data. The resulting visualizations help uncover hidden information in the data, compare differences between patient groups, determine critical factors that influence a particular disease, and help direct further analyses. We introduced and demonstrated this tool by using EMRs of 14,567 Chronic Kidney Disease (CKD) patients. We developed a visual mining system to support exploratory data analysis of multi-dimensional categorical EMR data. By using CKD as a model of disease, it was assembled by automated correlational analysis and human-curated visual evaluation. The visualization methods such as Sankey diagram can reveal useful knowledge about the particular disease cohort and the trajectories of the disease over time.


Stratification constrains future heat and carbon uptake in the Southern Ocean between 30°S and 55°S.
The Southern Ocean between 30°S and 55°S is a major sink of excess heat and anthropogenic carbon, but model projections of these sinks remain highly uncertain. Reducing such uncertainties is required to effectively guide the development of climate mitigation policies for meeting the ambitious climate targets of the Paris Agreement. Here, we show that the large spread in the projections of future excess heat uptake efficiency and cumulative anthropogenic carbon uptake in this region are strongly linked to the models' contemporary stratification. This relationship is robust across two generations of Earth system models and is used to reduce the uncertainty of future estimates of the cumulative anthropogenic carbon uptake by up to 53% and the excess heat uptake efficiency by 28%. Our results highlight that, for this region, an improved representation of stratification in Earth system models is key to constrain future carbon budgets and climate change projections.


Redirecting valvular myofibroblasts into dormant fibroblasts through light-mediated reduction in substrate modulus.
Fibroblasts residing in connective tissues throughout the body are responsible for extracellular matrix (ECM) homeostasis and repair. In response to tissue damage, they activate to become myofibroblasts, which have organized contractile cytoskeletons and produce a myriad of proteins for ECM remodeling. However, persistence of myofibroblasts can lead to fibrosis with excessive collagen deposition and tissue stiffening. Thus, understanding which signals regulate de-activation of myofibroblasts during normal tissue repair is critical. Substrate modulus has recently been shown to regulate fibrogenic properties, proliferation and apoptosis of fibroblasts isolated from different organs. However, few studies track the cellular responses of fibroblasts to dynamic changes in the microenvironmental modulus. Here, we utilized a light-responsive hydrogel system to probe the fate of valvular myofibroblasts when the Young's modulus of the substrate was reduced from ~32 kPa, mimicking pre-calcified diseased tissue, to ~7 kPa, mimicking healthy cardiac valve fibrosa. After softening the substrata, valvular myofibroblasts de-activated with decreases in α-smooth muscle actin (α-SMA) stress fibers and proliferation, indicating a dormant fibroblast state. Gene signatures of myofibroblasts (including α-SMA and connective tissue growth factor (CTGF)) were significantly down-regulated to fibroblast levels within 6 hours of in situ substrate elasticity reduction while a general fibroblast gene vimentin was not changed. Additionally, the de-activated fibroblasts were in a reversible state and could be re-activated to enter cell cycle by growth stimulation and to express fibrogenic genes, such as CTGF, collagen 1A1 and fibronectin 1, in response to TGF-β1. Our data suggest that lowering substrate modulus can serve as a cue to down-regulate the valvular myofibroblast phenotype resulting in a predominantly quiescent fibroblast population. These results provide insight in designing hydrogel substrates with physiologically relevant stiffness to dynamically redirect cell fate in vitro.


Weekly Teriparatide Versus Bisphosphonate for Bone Union During 6 Months After Multi-Level Lumbar Interbody Fusion for Osteoporotic Patients: A Multicenter, Prospective, Randomized Study.
Multicenter, prospective randomized study. Evaluate the impact of weekly teriparatide (WT) and bone contact (BC) status of grafted bone in patients recovering from multilevel lumbar interbody fusion (M-LIF). WT has been reported to significantly improve bone fusion following posterior or transforaminal interbody fusion in osteoporosis patients. Patients older than 50 years and osteoporotic were recruited. We defined the fusion of two or more consecutive intervertebral levels as M-LIF. All patients were instrumented with pedicle, iliac, or S-2 alar iliac screws after transplanting cages and autogenous bone between vertebral bodies. After surgical indication for M-LIF, the subjects were randomly allocated to receive either subcutaneous WT from 1 week to 6 months postoperatively (WT arm, N = 50) or a bisphosphonate (BP; BP arm, N = 54). Blinded radiological evaluations were performed using computed tomography (CT). Evaluation of bone fusion was performed at the intervertebral disc located at the bottom of the fixed range. The degree of bone fusion was calculated as a score from 2 to 6 points, with 2 defined as complete fusion. Bone fusion rate was also compared at 6 months postoperatively based on BC status of the grafted bone on CT immediately after surgery. Mean bone fusion score at 6 months postoperatively was 3.9 points in the WT group and 4.2 points in the BP group. The bone fusion rate at 6 months postoperatively tended to be higher in the WT group (46.8% vs. 32.7% in the BP group). The 6-month postoperative fusion rate of immediately postoperative of BC+ patients was significantly higher than that of BC- patients (47.4% vs. 9.5%). In M-LIF, there were no significant differences in bone fusion score between WT- and BP-treated patients. In contrast, BC status immediately postoperatively had a major impact on 6-month bone fusion. 1.


The extracellular signal-regulated kinase pathway phosphorylates AML1, an acute myeloid leukemia gene product, and potentially regulates its transactivation ability.
AML1 (also called PEBP2alphaB, CBFA2, or CBFalpha2) is one of the most frequently disrupted genes in chromosome abnormalities seen in human leukemias. It has been reported that AML1 plays several pivotal roles in myeloid hematopoietic differentiation and other biological phenomena, probably through the transcriptional regulation of various relevant genes. Here, we investigated the mechanism of regulation of AML1 functions through signal transduction pathways. The results showed that AML1 is phosphorylated in vivo on two serine residues within the proline-, serine-, and threonine-rich region, with dependence on the activation of extracellular signal-regulated kinase (ERK) and with interleukin-3 stimulation in a hematopoietic cell line. These in vivo phosphorylation sites of AML1 were phosphorylated directly in vitro by ERK. Although differences between wild-type AML1 and phosphorylation site mutants in DNA-binding affinity were not observed, we have shown that ERK-dependent phosphorylation potentiates the transactivation ability of AML1. Furthermore the phosphorylation site mutations reduced the transforming capacity of AML1 in fibroblast cells. These data indicate that AML1 functions are potentially regulated by ERK, which is activated by cytokine and growth factor stimuli. This study provides some important clues for clarifying unidentified facets of the regulatory mechanism of AML1 function.


Chromium diffusion and reduction in soil aggregates.
The distribution of metal contaminants such as chromium in soils can be strongly localized by transport limitations and redox gradients within soil aggregates. Measurements of Cr(VI) diffusion and reduction to Cr(III) were obtained in soil columns representing transects into soil aggregates in order to quantify influences of organic carbon (OC) and redox potentials on Cr transport distances and microbial community composition. Shifts in characteristic redox potentials, and the extent of Cr(VI) reduction to Cr(III) were related to OC availability. Depth profiles of Cr(VI, III) obtained with micro X-ray absorption near edge structure (micro-XANES) spectroscopy reflected interdependent effects of diffusion and spatially dependent redox potentials on reduction kinetics and microbial community composition. Shallow diffusion depths (2-10 mm) and very sharply terminated diffusion fronts in columns amended with OC (80 and 800 ppm) reflected rapid increases in Cr reduction kinetics over very short (mm) distances. These results suggest that Cr contamination in soils can be restricted to the outsides of soil aggregates due to localized transport and rapid reduction and that bulk sample characterization is inadequate for understanding the controlling biogeochemical processes.


Household water treatment and the millennium development goals: keeping the focus on health.
Waterborne diseases such as diarrhea are a major killer in low-income settings, particularly of young children. For those without access to safe drinking water, household water treatment, such as boiling, chlorinating, and filtering water in the home, when combined with safe storage (HWTS) can significantly improve water quality and prevent disease, thereby contributing to the child survival and other health priorities encompassed within the Millennium Development Goals (MDGs). There is uncertainly, however, about whether HWTS should count toward the MDG water target, which promotes "sustainable access to safe drinking water". This paper reviews the relevant research and concludes that it should not. Although HWTS can significantly improve water quality, it does not improve water quantity and access-key aspects of the MDG water target that are essential for optimal improvements in health and development. A policy that excludes HWTS from the MDG water target will discourage governments from diverting scarce public resources from comprehensive and long-term improvements in water supplies. At the same time, the health-oriented MDGs provide a sufficient case for scaling up effective and appropriate HWTS among target populations. Moreover, a health-based strategy for HWTS will help ensure that promotion of the intervention is driven by measurable improvements in outcomes rather than inputs, thus encouraging advances in both hardware and programmatic delivery that will make HWTS more effective, appropriate, and accessible to vulnerable populations.


Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events.
An increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews. This increase was significant in trials that did not randomise participants to an inhaled corticosteroid, but less certain in the smaller numbers of participants in trials that included an inhaled corticosteroid in the randomised treatment regimen. We set out to compare the risks of mortality and non-fatal serious adverse events in trials which have randomised patients with chronic asthma to regular formoterol versus regular salmeterol, when each are used with an inhaled corticosteroid as part of the randomised treatment. Trials were identified using the Cochrane Airways Group Specialised Register of trials. Manufacturers' web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol were also checked. The date of the most recent search was July 2009. Controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid), and were of at least 12 weeks duration. Two authors independently selected trials for inclusion in the review and extracted outcome data. Unpublished data on mortality and serious adverse events were sought from the sponsors and authors. Eight studies met the eligibility criteria of the review recruiting 6,163 adults and adolescents. There were seven studies (involving 5,935 adults and adolescents) comparing formoterol and budesonide to salmeterol and fluticasone. All but one study administered the products as a combined inhaler, and most used formoterol 50 mcg and budesonide 400 mcg twice daily versus salmeterol 50 mcg and fluticasone 250 mcg twice daily. There were two deaths overall (one on each combination) and neither were thought to be related to asthma.There was no significant difference between treatment groups for non-fatal serious adverse events, either all-cause (Peto OR 1.14; 95% CI 0.82 to 1.59, I(2) = 26%) or asthma-related (Peto OR 0.69; 95% CI 0.37 to 1.26, I(2) = 33%). Over 23 weeks the rates for all-cause serious adverse events were 2.6% on formoterol and budesonide and 2.3% on salmeterol and fluticasone, and for asthma-related serious adverse events, 0.6% and 0.8% respectively.There was one study (228 adults) comparing formoterol and beclomethasone to salmeterol and fluticasone, but there were no deaths or hospital admissions.No studies were found in children. The seven identified studies in adults did not show any significant difference in safety between formoterol and budesonide in comparison with salmeterol and fluticasone. Asthma-related serious adverse events were rare, and there were no reported asthma-related deaths. There was a single small study comparing formoterol and beclomethasone to salmeterol and fluticasone in adults, but no serious adverse events occurred in this study. No studies were found in children.Overall there is insufficient evidence to decide whether regular formoterol and budesonide or beclomethasone have equivalent or different safety profiles from salmeterol and fluticasone.


Replacement of successful fixed implant prostheses using duplication techniques.
Replication of desirable design features of an existing implant prosthesis is often appropriate in the construction of a replacement that produces the same spatial relationship to the supporting dental implants. An adaptation of a laboratory copy technique used in conventional complete denture prosthodontics is described. A silicone putty mold that enables the creation of the corresponding fit surface, polished surface, and arch form is used for making a transitional or a definitive complete or partial fixed implant prosthesis. Variations using a basic replication technique are appropriate in clinical practice for refabricating a prosthesis of a preferred design. The procedure is suitable for both acrylic resin-metal or metal ceramic restorations.


Crystal structure of HslUV complexed with a vinyl sulfone inhibitor: corroboration of a proposed mechanism of allosteric activation of HslV by HslU.
On the basis of the structure of a HslUV complex, a mechanism of allosteric activation of the HslV protease, wherein binding of the HslU chaperone propagates a conformational change to the active site cleft of the protease, has been proposed. Here, the 3.1 A X-ray crystallographic structure of Haemophilus influenzae HslUV complexed with a vinyl sulfone inhibitor is described. The inhibitor, which reacts to form a covalent linkage to Thr1 of HslV, binds in an "antiparallel beta" manner, with hydrogen-bond interactions between the peptide backbone of the protease and that of the inhibitor, and with two leucinyl side chains of the inhibitor binding in the S1 and S3 specificity pockets of the protease. Comparison of the structure of the HslUV-inhibitor complex with that of HslV without inhibitor and in the absence of HslU reveals that backbone interactions would correctly position a substrate for cleavage in the HslUV complex, but not in the HslV protease alone, corroborating the proposed mechanism of allosteric activation. This activation mechanism differs from that of the eukaryotic proteasome, for which binding of activators opens a gated channel that controls access of substrates to the protease, but does not perturb the active site environment.


Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation.
Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined.


Evaluation of antagonists of the discriminative stimulus and response rate effects of phencyclidine.
The present studies examined whether a variety of drugs representative of diverse pharmacological classes were able to antagonize either the discriminative stimulus or response rate suppressing effects of phencyclidine (PCP). Rats were trained to lever press according to fixed-ratio 32 reinforcement schedules for food pellet delivery and to discriminate PCP from saline vehicle during daily (Monday-Friday) experimental sessions. Drugs combined with PCP to test for antagonism included an alpha-1 (prazosin) and an alpha-2 (yohimbine) adrenergic antagonist, the adenosine receptor agonist, I-phenylisopropyl adenosine, the gamma-aminobutyric acid agonist, imidazole acetic acid, the dopaminergic antagonist, haloperidol, the acylating agent of the PCP receptor, metaphit, and the dopaminergic drugs (+)- and (-)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine. All test drugs except metaphit were tested in rats trained to discriminate 2.5 mg/kg of PCP from saline. (+)- and (-)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine were additionally tested in rats trained to discriminate 1.0 mg/kg of PCP from saline. Metaphit was only tested in rats which had been trained to discriminate a 1.0-mg/kg PCP dose. None of the test drugs systematically reduced PCP level selection to vehicle levels. Yohimbine and prazosin, however, but not the other test drugs, partially reversed the response rate reducing effects of PCP. Evidence that alpha adrenergic antagonists have some PCP antagonistic effects were confirmed for the response rate effects of PCP, indicating a possible role of adrenergic mediation of these effects.


Effects of intrauterine growth retardation on mortality and morbidity in infants and young children.
This review aims to quantify the risks of mortality and morbidity associated with intrauterine growth retardation (IUGR). Twenty-nine data sets with birth-weight-specific mortalities are examined to determine whether consistent patterns of risk emerge when data from different populations are compared. Measures of mortality risk are also made with birth weight as a dichotomous variable. Twelve data sets are presented. From the data available, it is estimated that for term infants weighing 2000-2499 g at birth, the risk of neonatal death is 4 times higher than for infants weighing 2500-2999 g, and 10 times higher than for infants weighing 3000-3499 g. The risk of postneonatal death in term infants weighing 2000-2499 g is estimated to be 2 times higher than for infants 2500-2999 g, and 4 times that of infants weighing 3000-3499 g. Estimates of risk for IUGR infants are less consistent than for preterm infants. This could be due to methodological differences, particularly smaller sample sizes in the studies in developing countries, or may reflect real variation in risk. The latter may be associated with the heterogeneity of IUGR across populations, or to varying risks depending, for example, on which infections predominate or infant age at peak prevalence. IUGR is most prevalent in developing countries and the review therefore focuses on morbidity from diarrhoeal and respiratory infections. Data from nine studies are presented. There is an increased risk of diarrhoea in term infants < 2500 g and an increased risk of pneumonia. The risks of morbidity and mortality appear to differ depending on whether infants are wasted or stunted at birth. Stunted infants of low birth weight have higher neonatal mortality than wasted newborns, but this could be due to inclusion of infants with congenital anomalies who are often stunted. Wasted infants are more prone than stunted infants to neonatal morbidity. No comparative postneonatal data were located.


Employing biomarkers of healthy ageing for leveraging genetic studies into human longevity.
Genetic studies have thus far identified a limited number of loci associated with human longevity by applying age at death or survival up to advanced ages as phenotype. As an alternative approach, one could first try to identify biomarkers of healthy ageing and the genetic variants associated with these traits and subsequently determine the association of these variants with human longevity. In the present study, we used this approach by testing whether the 35 baseline serum parameters measured in the Leiden Longevity Study (LLS) meet the proposed criteria for a biomarker of healthy ageing. The LLS consists of 421 families with long-lived siblings of European descent, who were recruited together with their offspring and the spouses of the offspring (controls). To test the four criteria for a biomarker of healthy ageing in the LLS, we determined the association of the serum parameters with chronological age, familial longevity, general practitioner-reported general health, and mortality. Out of the 35 serum parameters, we identified glucose, insulin, and triglycerides as biomarkers of healthy ageing, meeting all four criteria in the LLS. We subsequently showed that the genetic variants previously associated with these parameters are significantly enriched in the largest genome-wide association study for human longevity. In conclusion, we showed that biomarkers of healthy ageing can be used to leverage genetic studies into human longevity. We identified several genetic variants influencing the variation in glucose, insulin and triglycerides that contribute to human longevity.


WHO Needs High FIO2?
World Health Organization and the United States Center for Disease Control have recently recommended the use of 0.8 FIO2 in all adult surgical patients undergoing general anaesthesia, to prevent surgical site infections. This recommendation has arisen several discussions: As a matter of fact, there are numerous studies with different results about the effect of FIO2 on surgical site infection. Moreover, the clinical effects of FIO2 are not limited to infection control. We asked some prominent authors about their comments regarding the recent recommendations.


Cardiorespiratory synchrony in turtles.
Many reptiles, particularly diving species, display characteristic cardiovascular changes associated with lung ventilation (cardiorespiratory synchrony). Previous studies on freshwater turtles show that heart rate and pulmonary blood flow rate (Qpul) increase two- to fourfold during ventilation compared with breath-holding, and some studies report concomitant decreases in systemic blood flow rate (Qsys). The primary aim of this study was to provide a detailed description of cardiorespiratory synchrony in free-diving and fully recovered turtles (Trachemys scripta). During breath-holds lasting longer than 5 min, Qpul averaged 15 ml min-1 kg-1 and increased more than threefold to a maximum value of 50 ml min-1 kg-1 during ventilation. Qsys also increased during ventilation compared with during breath-holds lasting longer than 5 min (from 44 to 73 ml min-1 kg-1 during ventilation). Neither Qpul nor Qsys was affected by the number of breaths in the ventilatory periods. Changes in Qpul and Qsys were accomplished entirely through a significant increase in heart rate during ventilation, while total stroke volume (systemic+pulmonary) remained constant. Irrespective of the ventilatory state, Qsys exceeded Qpul by 20-30 ml min-1 kg-1. Nevertheless, because Qpul increased relatively more than Qsys during ventilation, Qpul/Qsys increased from 0.29 during apnoea to 0.80 during lung ventilation. This study confirms cardiorespiratory synchrony in the turtle Trachemys scripta but, in contrast to earlier studies, a net right-to-left cardiac shunt prevailed regardless of ventilatory state.


Nonreciprocal optical diffraction by a single layer of gyromagnetic cylinders.
We study the diffraction of optical waves by a single layer of gyromagnetic cylinders. We show that a nonvanishing rotating dipole momentum is excited in a single gyromagnetic cylinder because of the classic analog of the Zeeman effect on photonic angular momentum states (PAMSs). Consequently, different collective dipole modes are excited in a gyromagnetic cylinder array at opposite incident angles. Nonreciprocal optical diffraction effects can be observed, where the transmission and reflection coefficients depend on the sign of the incident angle. A novel phenomenon of nonreciprocal negative directional transmission is demonstrated and numerically analyzed. This work highlights the potential of PAMSs in manipulating the propagation of optical waves for various applications.


Review of online educational resources for medical physicists.
Medical physicists are often involved in the didactic training of graduate students, residents (both physics and physicians), and technologists. As part of continuing medical education, we are also involved in maintenance of certification projects to assist in the education of our peers. As such, it is imperative that we remain current concerning available educational resources. Medical physics journals offer book reviews, allowing us an opportunity to learn about newly published books in the field. A similar means of communication is not currently available for online educational resources. This information is conveyed through informal means. This review presents a summary of online resources available to the medical physics community that may be useful for educational purposes.


Dissecting dietary melanoidins: formation mechanisms, gut interactions and functional properties.
Dietary melanoidins are late stage Maillard reaction products (MRPs), browning colorants and predominantly high molecular weight (HMW) chemicals. They originate through polycondensation reactions of reducing sugars and proteins or amino acids upon thermal processing. Their presence in several daily food and beverages (i.e. coffee, beer, honey, bakery products, chocolate, grilled meat) contribute to food sensory characters (i.e. color, aroma, and flavor). Additionally, melanoidins exhibit many biological attributes (i.e. antioxidant, anti-obesity, antibacterial activity and impact on gut microbiota as prebiotics). However, dissecting melanoidins specific biological and functional characteristics in relation to their metabolism and gut interaction with link to their chemical structures has yet to be reported in literature. For a better understanding of melanoidins benefits and flavor properties in processed foods, this review represents a state of the art comprehensive insight of its formation mechanism and chemistry in relation to their functionalities and health effects. Further, a compile of the factors affecting melanoidins production to optimize for the best flavor attributes while minimizing hazardous compounds is presented. This study presents the first analysis of melanoidins gut interaction in context to its different action mechanisms.


Productivity of crossbred dairy cows suckling their calves for 12 or 24 weeks post calving.
An experiment on restricted suckling of crossbred dairy cows was conducted at the Livestock Research Centre, Tanga in northeast Tanzania. Thirty-six Bos taurus (Holstein Friesian and Jersey) x Bos indicus (East African Zebu) cows were allocated alternately as they calved to suckling their calves for either 12 or 24 weeks after calving. Cows grazed improved pastures and were offered 4 kg concentrate daily. Milking occurred twice daily by hand; calves were allowed to suck residual milk for 30 min following each milking. Calves were also allowed access to grazing and were offered a maximum of 1 kg concentrate daily to 24 weeks of age. Weaning age had no significant effect on lactation milk yield for human consumption, the mean (SE) yield being 1806 (102.0) L and 1705 (129.1) L for 12- and 24-week weaning, respectively. Cows from the two treatments suffered similar losses of live weight and body condition score during lactation and neither group had returned to the original body condition score 40 weeks following calving. Post-partum anoestrous intervals were prolonged. Although not significant, cows suckling calves to 24 weeks had a mean interval to first oestrus extended by 38 days compared with cows suckling calves to 12 weeks. The mean (SE) daily live weight gains of the calves to 52 weeks were 263 (14.1) g/day and 230 (18.1) g/day for calves weaned at 12 and 24 weeks, respectively, such that 12-month weights were 119 (5.6) kg and 110 (7.3) kg, respectively. Twelve-week-weaned calves consumed more concentrate (p<0.05) from 13 to 24 weeks than did 24-week weaned calves. Calculation of residual milk consumption removed by calves from birth to 12 weeks indicated that it accounted for 28%) of total yield. No benefits in cow and calf performance and welfare were found to justify prolonging the suckling period to 24 weeks.


SNARE proteins: one to fuse and three to keep the nascent fusion pore open.
Neurotransmitters are released through nascent fusion pores, which ordinarily dilate after bilayer fusion, preventing consistent biochemical studies. We used lipid bilayer nanodiscs as fusion partners; their rigid protein framework prevents dilation and reveals properties of the fusion pore induced by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor). We found that although only one SNARE per nanodisc is required for maximum rates of bilayer fusion, efficient release of content on the physiologically relevant time scale of synaptic transmission apparently requires three or more SNARE complexes (SNAREpins) and the native transmembrane domain of vesicle-associated membrane protein 2 (VAMP2). We suggest that several SNAREpins simultaneously zippering their SNARE transmembrane helices within the freshly fused bilayers provide a radial force that prevents the nascent pore from resealing during synchronous neurotransmitter release.


Analysis of the UK recommendations on obesity based on a proposed implementation framework.
There is considerable expertise in the obesity field in identifying, appraising, and synthesising evidence to develop guidelines and recommendations for policy and practice. The recommendations, while based on evidence, are not formulated in a way that readily leads to implementation. This paper analyses the recent UK recommendations on obesity using a proposed implementation framework. Two bibliographic databases (Medline and Embase) and various health related and government websites were systematically searched for obesity recommendations published between 1996 and 2007. All the documents published on recommendations for either prevention or treatment of obesity in the UK were assessed. A proposed implementation framework was developed for the purpose of this review. All the UK recommendations were critically appraised and results summarised according to the criteria used within the framework. Cross-country applicability of the proposed framework was assessed using the Swedish policy recommendations on obesity. Most recommendations on obesity while demonstrating their basis in evidence, fail to meet the implementation standards. They tend to be non-specific in identifying who is responsible for implementation and monitoring, and often no timescale is indicated. The costs of implementation are rarely estimated and those responsible for such funding are not specified. There are some notable exemptions to the general pattern emanating from more operational and locally based groups. The Swedish policy details 79 proposals with responsibility clearly identified and costs are presented for 20 of them. This policy satisfied most of the framework criteria but failed to give details on evaluation, monitoring and the timeframe for implementation. Public health has developed skills in appraising evidence and formulating recommendations based on appropriate evidence but these are often not implemented. Different skills are required to translate these recommendations into actions. Public health clearly needs to develop the implementation skills to a level comparable to the ability to synthesise evidence.


Genomic classification of serous ovarian cancer with adjacent borderline differentiates RAS pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver.
Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies. We reviewed >1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling. We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC. Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents.


Metabolomic profiling reveals salivary hypotaurine as a potential early detection marker for medication-related osteonecrosis of the jaw.
Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse event of bone-modifying agents used to prevent bone complications in cancer patients with bone metastasis. Currently, early treatment is the only way to prevent further progression, as the pathogenesis of MRONJ has not yet been elucidated, and a standard treatment has not been established. The aim of this study was to identify a marker for early detection marker of MRONJ by exploring substances in saliva specific to MRONJ at an early stage. We collected salivary samples from 17 patients with MRONJ and conducted metabolomic analyses using capillary electrophoresis mass spectrometry for non-targeted analysis of hydrophilic metabolites. In the screening cohort, we compared the saliva of patients with stage ≥1 advanced MRONJ (n = 9) with that of controls without MRONJ before chemotherapy (n = 9). The top 5 most elevated salivary metabolites were histamine, 3-(4-hydroxyphenyl)propionate, malonate, carnosine, and hypotaurine. In the validation cohort, we analyzed additional patients with stage ≥1 advanced MRONJ (n = 8) and controls without MRONJ after chemotherapy (n = 9), confirming a significant 2.28-fold elevation in the salivary concentration of hypotaurine. These results revealed elevated salivary hypotaurine concentration as a potential marker for the early detection of MRONJ.


Improved cognitive performance in human volunteers following administration of guarana (Paullinia cupana) extract: comparison and interaction with Panax ginseng.
Extracts from the plant guarana (Paullinia cupana) feature as putatively stimulating ingredients in a number of foods, drinks and dietary/herbal supplements. To date, little research in humans has examined the potential psychoactive effects of these extracts. Extracts of Panax ginseng, which are often sold in combination with guarana, contain similar potentially active components, and have been shown to modulate cognitive performance. In this double-blind, counterbalanced, placebo-controlled study, the cognitive and mood effects of separate single doses of: 75 mg of a dried ethanolic extract of guarana (approx 12% caffeine), 200 mg of Panax ginseng (G115), and their combination (75 mg/200 mg), were assessed in 28 healthy young (18-24) participants. On each day of the study (separated by a 7-day washout), cognitive performance and subjective mood were assessed pre-dose and at 1, 2.5, 4 and 6 h post-dose using the Cognitive Drug Research computerised assessment battery, Serial subtraction tasks and Bond-Lader mood scales. In comparison to placebo, all three treatments resulted in improved task performance throughout the day. In the case of guarana, improvements were seen across 'attention' tasks (but with some evidence of reduced accuracy), and on a sentence verification task. While also increasing the speed of attention task performance, both ginseng and the ginseng/guarana combination also enhanced the speed of memory task performance, with little evidence of modulated accuracy. Guarana and the combination, and to a lesser extent ginseng, also led to significant improvements in serial subtraction task performance. These results provide the first demonstration in humans of the psychoactive effects of guarana, and confirmation of the psychoactive properties of ginseng. Given the low caffeine content (9 mg) of this dose of guarana extract, the effects are unlikely to be attributable to its caffeine content.


Control of rat natural killer cell-mediated allorecognition by a major histocompatibility complex region encoding nonclassical class I antigens.
The ability of natural killer (NK) cells to eliminate normal allogeneic hemic cells is well established in several species including mice, rats, and humans. The controlling elements for NK susceptibility in these species map to the major histocompatibility complex (MHC), but in contrast to findings in mice and humans, the mode of inheritance is not always recessive in rats. This finding is not easily explained by the missing self and hemopoietic histocompatibility (Hh) models for NK recognition, and has led to the idea that certain alloantigens may trigger NK cell reactivity. In our in vitro system for assessing rat NK alloreactivity, we have employed target and inhibitor cells from a large panel of MHC congenic, intra-MHC recombinant and MHC mutant rat strains, as well as appropriate F1 hybrids between them, and we show the following: (a) The nonclassical class I (RT1.C) region was most important in determining the susceptibility of target cells to alloreactive NK cells in vitro. Lymphocyte susceptibility to lysis in vivo also mapped to the C region, which supports the concept that the in vivo and in vitro alloreactivity assays reflect the same recognition process. (b) Four different RT1-controlled NK allospecificities (represented by the u, l, a, and n haplotypes) could be discerned when we used polyclonal NK cells from the PVG (RT1c) strain as effector cells. Three of the target specificities recognized were controlled mainly by the RT1.C region. (c) The expression of RT1.C region-controlled parental strain NK allodeterminants could be demonstrated in F1 hybrids heterozygous for the C region alone and were therefore inherited nonrecessively. (d) Loss of an RT1.C region-controlled NK allospecificity could be shown with the MHC mutant LEW.1LM1 rat strain characterized by a genomic deletion of about 100 kb of the C region. Taken together, these observations have demonstrated a major importance of the nonclassical class I region, i.e., RT1.C, in controlling rat NK allorecognition, and have thereby assigned a hitherto undescribed immunological property to this region. Furthermore, some of the present data are consistent with the existence of polymorphic NK-triggering alloantigens that are coded for by the RT1.C region.


Prevalence of staphylococcal enterotoxins, toxin genes and genetic-relatedness of foodborne Staphylococcus aureus strains isolated in the Marmara Region of Turkey.
Staphylococcus aureus is a major foodborne pathogen and it has the ability to produce a number of extracellular toxins. We analyzed 1070 food samples obtained from retail markets and dairy farms in the Marmara Region of Turkey for the presence of S. aureus. Out of 147 isolates, 92 (62.6%) were enterotoxigenic. PCR was used to investigate the presence of staphylococcal enterotoxin genes (sea, seb, sec, sed, see, seg, seh, sei, sej, sek, sel, sem, sen, seo, sep, seq and seu), exfoliative toxin genes (eta and etb) and the toxic-shock syndrome toxin gene (tst). The PCR results showed that 53.3% of the isolates contained staphylococcal enterotoxin-like (SEl) toxin genes (seg, seh, sei, sej, sek, sel, sem, sen, seo, sep, seq and seu) which were more frequent than classical enterotoxin genes (sea to see). Furthermore, seo, sei, sem, seg, seu and sec were found in 37.0, 32.7, 30.4, 29.3, 29.3 and 27.2% of the isolates, respectively. The tst gene was detected and confirmed by DNA sequencing in 9 isolates. The presence of eta and etb were not found in the isolates. Enterotoxigenic capabilities of isolates with SEA-SEE were investigated by ELISA. Enterotoxigenic S. aureus isolates produced one to three enterotoxins, with the most frequently produced types being enterotoxin A and C. There was a correlation of 72.1% between production of a specific toxin and the presence of the respective genes. PFGE analysis was used to identify genetic-relatedness of enterotoxigenic S. aureus isolates and the results revealed that 13 groups of isolates from different or the same origin that contained the same genes showed 100% homology with indistinguishable band patterns. The other enterotoxigenic isolates showed related band patterns with 72-86% homology in sea-, 61-90% homology in sec-, 80-96% homology in seh-, and 69-96% homology in sep-positive isolates. To our knowledge, this is the first study to examine enterotoxins and related gene contents of S. aureus food isolates in the Marmara Region of Turkey.


Progressive Care of Obese Patients.
Obese patients have complex needs that complicate their care during hospitalization. These patients often have comorbid conditions, including hypertension, heart failure, obstructive sleep apnea, pressure ulcers, and difficulty with mobility. Obese patients may be well served in the progressive care setting because they may require more intensive nursing care than can be delivered in a general care unit. Progressive care nurses have core competencies that enable them to safely and effectively care for obese patients. A plan of care with interdisciplinary collaboration illustrates the integrative care for obese progressive care patients. (Critical Care Nurse 2016; 36[4]:58-63).


Suprarenal fixation of endovascular aortic stent grafts: assessment of medium-term to long-term renal function by analysis of juxtarenal stent morphology.
The effect of suprarenal stent fixation during endovascular aortic aneurysm repair (EVAR) on renal function remains unclear. A unique validated three-dimensional intraluminal imaging technique was used to analyze the effect of suprarenal stent position relative to renal artery orifices. Also analyzed was its medium-term to long-term effects on renal function. The study cohort comprised 29 of 34 consecutive patients who underwent EVAR with the Zenith endograft system from September 1999 to March 2002 at a single institution. The precise locations of the uncovered suprarenal stent struts were assessed by a virtual endoscopic imaging technique. Anatomic and quantitative categorization of patients was made according to the configuration of uncovered stent struts across the renal artery ostia (RAO). The anatomic subgroups were defined as struts located centrally or peripherally across both RAO. The quantitative subgroups were defined as RAO crossed by multiple struts, a solitary strut, or no struts. The subgroups were compared for their renal function, as assessed by temporal measurements of serum creatinine concentration and creatinine clearance, and renal parenchymal perfusion defects, as assessed using contrast-enhanced computed tomography (CT). Mean follow-up was 52.7 months. Separate subgroup analysis for both anatomic and quantitative configurations did not demonstrate any significant difference in renal function between the different strut permutations (P > .05). Follow-up imaging confirmed one case of renal infarction secondary to an occluded accessory renal artery, although this patient had normal serum creatinine levels. RAO coverage by suprarenal uncovered stents does not appear to have a significant effect on renal function as evaluated by creatinine measurements in patients with normal preoperative renal function.


Psychological and neuroendocrine measures related to functional immune changes in anticipation of HIV-1 serostatus notification.
Our previous work indicated that gay males ultimately found to be seronegative showed impaired lymphocyte proliferative responses to phytohemagglutinin (PHA) and pokeweed mitogen (PWM) upon entering a study in which they would be notified of their human immunodeficiency virus-Type 1 (HIV-1) antibody status. To examine the degree to which alterations in various neuroendocrine and psychological markers might be related to this phenomenon we measured plasma cortisol, beta-endorphin, denial coping strategies, intrusive thoughts related to AIDS risk, and several affective distress markers in 46 HIV-1 seronegative subjects at each of the timepoints previously studied. Results indicated that cortisol levels were elevated at study entry and decreased across the subsequent five-week period--mirroring the changes in mitogen responsivity across these timepoints. Analyses of individual differences showed that higher baseline cortisol and lower denial coping scores predicted lower PHA values at baseline. Persisting intrusive thoughts about risk of HIV-1 infectivity (after seronegativity notification) were consistently associated with higher plasma cortisol levels. Finally, beta-endorphin levels did not change significantly across the 10-week observation period, were not associated with psychological variables, and were inconsistently associated with immune functioning.


Evolutionary origin and functional divergence of totipotent cell homeobox genes in eutherian mammals.
A central goal of evolutionary biology is to link genomic change to phenotypic evolution. The origin of new transcription factors is a special case of genomic evolution since it brings opportunities for novel regulatory interactions and potentially the emergence of new biological properties. We demonstrate that a group of four homeobox gene families (Argfx, Leutx, Dprx, Tprx), plus a gene newly described here (Pargfx), arose by tandem gene duplication from the retinal-expressed Crx gene, followed by asymmetric sequence evolution. We show these genes arose as part of repeated gene gain and loss events on a dynamic chromosomal region in the stem lineage of placental mammals, on the forerunner of human chromosome 19. The human orthologues of these genes are expressed specifically in early embryo totipotent cells, peaking from 8-cell to morula, prior to cell fate restrictions; cow orthologues have similar expression. To examine biological roles, we used ectopic gene expression in cultured human cells followed by high-throughput RNA-seq and uncovered extensive transcriptional remodelling driven by three of the genes. Comparison to transcriptional profiles of early human embryos suggest roles in activating and repressing a set of developmentally-important genes that spike at 8-cell to morula, rather than a general role in genome activation. We conclude that a dynamic chromosome region spawned a set of evolutionarily new homeobox genes, the ETCHbox genes, specifically in eutherian mammals. After these genes diverged from the parental Crx gene, we argue they were recruited for roles in the preimplantation embryo including activation of genes at the 8-cell stage and repression after morula. We propose these new homeobox gene roles permitted fine-tuning of cell fate decisions necessary for specification and function of embryonic and extra-embryonic tissues utilised in mammalian development and pregnancy.