Identification of an iridium-containing compound with a formal oxidation state of IX.
One of the most important classifications in chemistry and within the periodic table is the concept of formal oxidation states. The preparation and characterization of compounds containing elements with unusual oxidation states is of great interest to chemists. The highest experimentally known formal oxidation state of any chemical element is at present VIII, although higher oxidation states have been postulated. Compounds with oxidation state VIII include several xenon compounds (for example XeO4 and XeO3F2) and the well-characterized species RuO4 and OsO4 (refs 2-4). Iridium, which has nine valence electrons, is predicted to have the greatest chance of being oxidized beyond the VIII oxidation state. In recent matrix-isolation experiments, the IrO4 molecule was characterized as an isolated molecule in rare-gas matrices. The valence electron configuration of iridium in IrO4 is 5d(1), with a formal oxidation state of VIII. Removal of the remaining d electron from IrO4 would lead to the iridium tetroxide cation ([IrO4](+)), which was recently predicted to be stable and in which iridium is in a formal oxidation state of IX. There has been some speculation about the formation of [IrO4](+) species, but these experimental observations have not been structurally confirmed. Here we report the formation of [IrO4](+) and its identification by infrared photodissociation spectroscopy. Quantum-chemical calculations were carried out at the highest level of theory that is available today, and predict that the iridium tetroxide cation, with a Td-symmetrical structure and a d(0) electron configuration, is the most stable of all possible [IrO4](+) isomers.


Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites.
Vascular endothelial growth factors (VEGFs) regulate the development and growth of the blood and lymphatic vascular systems. Of the three VEGF receptors (VEGFR), VEGFR-1 and -2 are expressed on blood vessels; VEGFR-2 is found also on lymphatic vessels. VEGFR-3 is expressed mainly on lymphatic vessels but it is also up-regulated in tumor angiogenesis. Although VEGFR-3 is essential for proper lymphatic development, its signal transduction mechanisms are still incompletely understood. Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the VEGFR-3 carboxyl-terminal tail. These sites were used both in VEGFR-3 overexpressed in 293 cells and when the endogenous VEGFR-3 was activated in lymphatic endothelial cells. Interestingly, VEGF-C stimulation of lymphatic endothelial cells also induced the formation of VEGFR-3/VEGFR-2 heterodimers, in which VEGFR-3 was phosphorylated only at three of the five sites while the two most carboxyl-terminal tyrosine residues appeared not to be accessible for the VEGFR-2 kinase. Our data suggest that the carboxyl-terminal tail of VEGFR-3 provides important regulatory tyrosine phosphorylation sites with potential signal transduction capacity and that these sites are differentially used in ligand-induced homo- and heterodimeric receptor complexes.


Geographic location and phylogeny are the main determinants of the size of the geographical range in aquatic beetles.
Why some species are widespread while others are very restricted geographically is one of the most basic questions in biology, although it remains largely unanswered. This is particularly the case for groups of closely related species, which often display large differences in the size of the geographical range despite sharing many other factors due to their common phylogenetic inheritance. We used ten lineages of aquatic Coleoptera from the western Palearctic to test in a comparative framework a broad set of possible determinants of range size: species' age, differences in ecological tolerance, dispersal ability and geographic location. When all factors were combined in multiple regression models between 60-98% of the variance was explained by geographic location and phylogenetic signal. Maximum latitudinal and longitudinal limits were positively correlated with range size, with species at the most northern latitudes and eastern longitudes displaying the largest ranges. In lineages with lotic and lentic species, the lentic (better dispersers) display larger distributional ranges than the lotic species (worse dispersers). The size of the geographical range was also positively correlated with the extent of the biomes in which the species is found, but we did not find evidence of a clear relationship between range size and age of the species. Our findings show that range size of a species is shaped by an interplay of geographic and ecological factors, with a phylogenetic component affecting both of them. The understanding of the factors that determine the size and geographical location of the distributional range of species is fundamental to the study of the origin and assemblage of the current biota. Our results show that for this purpose the most relevant data may be the phylogenetic history of the species and its geographical location.


Dye sensitized photoelectrolysis cells.
To advance the progress of photoelectrolysis, various promising devices integrated with p- and n-type photocatalysts and dye sensitized photoelectrodes have been systematically studied. This review discusses, from theory to practice, an integration strategy for state-of-the-art dye sensitized solar cells (DSSCs) with potential p- and n-type photo-electrocatalysts or directly with dye sensitized photoanodes and cathodes for hydrogen and oxygen production through water splitting. Thorough insight into the theoretical approach which systematically drives the photoelectrolysis reaction directly or in a coupled mode, with diverse configurations of DSSCs and other photovoltaic (PV) cells, is crucial to understand the underlying fundamental concepts and elucidate trends in such reactions, and will serve as a guide to design new electrocatalysts and their integration with new PV devices, while simultaneously underlining major gaps that are required to address the challenges. Likewise, challenges, opportunities and frontiers in tandem and hybrid perovskite electrolysis processes are also discoursed in the present tutorial review. We illustrate our analysis by encompassing these integrated systems to photo-electrolysis, artificial photosynthesis such as CO2 conversion into value-added chemical reduction-products, where advancements in new catalysts and solution-processed inexpensive PV devices can certainly enrich the overall performance of the renewable production of solar fuels, including solar driven carbonaceous fuels.


Resting energy expenditure in cryptogenic fibrosing alveolitis.
A proportion of patients with chronic airflow limitation appear to have a raised resting energy expenditure (REE). This has been suggested as the reason for weight loss which may occur in these patients. A previous study found an increased REE in patients with interstitial lung disease of mixed aetiology. We were interested in studying REE in a more homogeneous group, with cryptogenic fibrosing alveolitis (CFA). Twenty patients with CFA were studied. They were compared with 18 controls matched for age, sex, weight and height. REE was measured by indirect calorimetry. Fat-free mass (FFM), was estimated by anthropometry. Patients had respiratory function tests performed, disability related to breathlessness was assessed by the activity section of the St George's Respiratory Questionnaire. Mean REE in the CFA group was not different from the control group: 5.20 (0.56) versus 5.12 (0.51) kj x h(-1) x kgFFM(-1). REE was elevated to greater than 110% of the value predicted by the Harris-Benedict equation in one CFA patient and in no control subjects. There was no correlation of REE with weight, pulmonary function tests, arterial oxygen saturation or activity score. The prevalence of a raised resting energy expenditure in cryptogenic fibrosing alveolitis patients with low transfer factor and relatively preserved vital capacity is low, and is less than that reported previously in a group of patients with interstitial lung disease of mixed aetiology.


Brown-Vialetto-Van Laere syndrome: two siblings with a new mutation and dramatic therapeutic effect of high-dose riboflavin.
Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare and severe neurometabolic disease. We present two siblings with BVVLS with a novel homozygous mutation in SLC52A3 (formerly C20orf54) gene. The first sibling was admitted with respiratory insufficiency and required mechanical ventilation. After administration of a high dose of riboflavin, all his clinical symptoms were resolved, which also strongly suggested the diagnosis of BVVLS. The second sibling was also found to have the same genetic mutation as her brother. Although she was symptom-free, riboflavin was initiated empirically. On follow-up, she developed no neurologic or metabolic problems with entirely normal growth and development. BVVLS should be considered in the differential diagnosis of unexplained neurologic symptoms such as polyneuropathy and respiratory insufficiency, as BVVLS and multiple acyl-CoA dehydrogenation defect have broadly overlapping symptoms. Furthermore, our cases once again suggest that with proper diagnosis and early high-dose riboflavin treatment, complete reversal of neurologic deficits in BVVLS is possible.


Interrater reliability and coding guide for nonpsychotic formal thought disorder.
Reliable and valid assessment of abnormal speech patterns may enable earlier recognition of nonpsychotic disorders through characteristic speech patterns. This study sought to establish interrater reliability using a standardized guide for scoring. A scoring guide defining 27 elements (e.g., inappropriate self-reference, simple loss of goal, circumstantiality) of disordered thought was developed. The seminal work of Andreasen's and Holzman's groups provided 12 elements, and 15 new elements were suggested by clinical literature. Audiotaped interviews with 12 psychiatric inpatients, adults of both sexes and various ages hospitalized for acute management of nonpsychotic psychiatric disorders, provided speech samples for observation of disordered thought by two independent raters. Using the guide's definitions and accompanying examples of elements of disordered thought, reliability in scoring was high (kappa of .85 for agreement on the presence of any abnormal speech element and kappa values from .66 to 1.00 for agreement on the presence of individual elements).


Naltrexone and buprenorphine combination in the treatment of opioid dependence.
Naltrexone treatment has demonstrated some advantages for special populations of heroin addicted individuals, but patients' compliance seems to be very poor, with a low adherence and low retention rate. Kappa-opioid system overdrive seems to contribute to opioid protracted abstinence syndrome, with dysphoria and psychosomatic symptoms during naltrexone treatment. The objective of this observational study was to determine the effectiveness of a functional k antagonist in improving naltrexone treatment outcome. A partial mu agonist/kappa antagonist (buprenorphine) and a mu antagonist (naltrexone) were combined during a 12 weeks protocol, theoretically leaving k antagonism as the major medication effect. Sixty patients were submitted to outpatient rapid detoxification utilizing buprenorphine and opioid antagonists. Starting on the fifth day, 30 patients (group A) received naltrexone alone. Alternatively, 30 patients (group B) received naltrexone (50mg oral dose) plus buprenorphine (4 mg sublingual) for the 12 weeks of the observational study. The endpoints of the study were: retention in treatment, negative urinalyses, changes in psychological symptoms (Symptom Checklist-90 Revised: SCL-90) and craving scores (visual analysis scale (VAS)). Thirty-four subjects (56.67%) completed the 12 weeks study. Twenty-one patients (35.0%) had all urine samples negative for opiates and cocaine. nine subjects (15.0%) had urine samples negative for cocaine and opiates for the last 4 weeks of the study. five subjects (8.3%) continued to use cocaine during the 12 weeks of the study. No significant change in pupillary diameter after buprenorphine administration was evidenced during clinical observations from baseline across the weekly measurements. Retention rates in group A (naltrexone) and group B (naltrexone + buprenorphine) at week 12 were respectively 40% (12 patients) and 73.33% (22 patients), with a significant difference in favour of group B (p= 0.018). Patients treated with naltrexone in combination with buprenorphine (B patients) showed a significantly lower rate of positive urines for morphine (4.45%) and cocaine metabolites (9.09%) than those treated with naltrexone alone (A) (25%, morphine; 33.33% cocaine) (p< 0.05; p< 0.05). Irritability, depression, tiredness, psychosomatic symptoms and craving scores decreased significantly less in Group A patients than in group B patients. The dysfunction of opioid system with kappa receptors hyper-activation provoked by heroin exposure, probably underlying dysphoric and psychosomatic symptoms during naltrexone treatment, seems to be counteracted, at least in part, by buprenorphine. The combination of buprenorphine and naltrexone may significantly improve the outcome of opioid antagonists treatment in terms of retention, negative urinalyses, and reduced dysphoria, mood symptoms and craving.


Foraging adaptation and the relationship between food-web complexity and stability.
Ecological theory suggests that complex food webs should not persist because of their inherent instability. "Real" ecosystems often support a large number of interacting species. A mathematical model shows that fluctuating short-term selection on trophic links, arising from a consumer's adaptive food choice, is a key to the long-term stability of complex communities. Without adaptive foragers, food-web complexity destabilizes community composition; whereas in their presence, complexity may enhance community persistence through facilitation of dynamical food-web reconstruction that buffers environmental fluctuations. The model predicts a linkage pattern consistent with field observations.


NADH autofluorescence, a new metabolic biomarker for cancer stem cells: Identification of Vitamin C and CAPE as natural products targeting "stemness".
Here, we assembled a broad molecular "tool-kit" to interrogate the role of metabolic heterogeneity in the propagation of cancer stem-like cells (CSCs). First, we subjected MCF7 cells to "metabolic fractionation" by flow cytometry, using fluorescent mitochondrial probes to detect PCG1α activity, as well ROS and hydrogen-peroxide (H2O2) production; NADH levels were also monitored by auto-fluorescence. Then, the various cell populations were functionally assessed for "stem cell activity", using the mammosphere assay (3D-spheroids). Our results indicate that a sub-population of MCF7 cells, with increased PGC1α activity, high mitochondrial ROS/H2O2 production and high NADH levels, all form mammospheres with a higher efficiency. Thus, it appears that mitochondrial oxidative stress and the anti-oxidant response both contribute to the promotion of mitochondrial biogenesis and oxidative metabolism in CSCs. Further validation was provided by using specific inhibitors to target metabolic processes (the NAD+ salvage pathway, glycolysis, mitochondrial protein synthesis and OXPHOS), significantly reducing CSC propagation. As a consequence, we have now identified a variety of clinically-approved drugs (stiripentol), natural products (caffeic acid phenyl ester (CAPE), ascorbic acid, silibinin) and experimental pharmaceuticals (actinonin, FK866, 2-DG), that can be used to effectively inhibit CSC activity. We discuss the use of CAPE (derived from honey-bee propolis) and Vitamin C, as potential natural therapeutic modalities. In this context, Vitamin C was ~10 times more potent than 2-DG for the targeting of CSCs. Similarly, stiripentol was between 50 to 100 times more potent than 2-DG.


Evaluating professionalism in medical undergraduates using selected response questions: findings from an item response modelling study.
Professionalism is a difficult construct to define in medical students but aspects of this concept may be important in predicting the risk of postgraduate misconduct. For this reason attempts are being made to evaluate medical students' professionalism. This study investigated the psychometric properties of Selected Response Questions (SRQs) relating to the theme of professional conduct and ethics comparing them with two sets of control items: those testing pure knowledge of anatomy, and; items evaluating the ability to integrate and apply knowledge ("skills"). The performance of students on the SRQs was also compared with two external measures estimating aspects of professionalism in students; peer ratings of professionalism and their Conscientiousness Index, an objective measure of behaviours at medical school. Item Response Theory (IRT) was used to analyse both question and student performance for SRQs relating to knowledge of professionalism, pure anatomy and skills. The relative difficulties, discrimination and 'guessabilities' of each theme of question were compared with each other using Analysis of Variance (ANOVA). Student performance on each topic was compared with the measures of conscientiousness and professionalism using parametric and non-parametric tests as appropriate. A post-hoc analysis of power for the IRT modelling was conducted using a Monte Carlo simulation. Professionalism items were less difficult compared to the anatomy and skills SRQs, poorer at discriminating between candidates and more erratically answered when compared to anatomy questions. Moreover professionalism item performance was uncorrelated with the standardised Conscientiousness Index scores (rho = 0.009, p = 0.90). In contrast there were modest but significant correlations between standardised Conscientiousness Index scores and performance at anatomy items (rho = 0.20, p = 0.006) though not skills (rho = .11, p = .1). Likewise, students with high peer ratings for professionalism had superior performance on anatomy SRQs but not professionalism themed questions. A trend of borderline significance (p = .07) was observed for performance on skills SRQs and professionalism nomination status. SRQs related to professionalism are likely to have relatively poor psychometric properties and lack associations with other constructs associated with undergraduate professional behaviour. The findings suggest that such questions should not be included in undergraduate examinations and may raise issues with the introduction of Situational Judgement Tests into Foundation Years selection.


The genetic landscape of a cell.
A genome-scale genetic interaction map was constructed by examining 5.4 million gene-gene pairs for synthetic genetic interactions, generating quantitative genetic interaction profiles for approximately 75% of all genes in the budding yeast, Saccharomyces cerevisiae. A network based on genetic interaction profiles reveals a functional map of the cell in which genes of similar biological processes cluster together in coherent subsets, and highly correlated profiles delineate specific pathways to define gene function. The global network identifies functional cross-connections between all bioprocesses, mapping a cellular wiring diagram of pleiotropy. Genetic interaction degree correlated with a number of different gene attributes, which may be informative about genetic network hubs in other organisms. We also demonstrate that extensive and unbiased mapping of the genetic landscape provides a key for interpretation of chemical-genetic interactions and drug target identification.


Functional exercise capacity, physical activity, and respiratory and peripheral muscle strength in pulmonary hypertension according to disease severity.
[Purpose] This study investigated functional capacity, physical activity, and respiratory and peripheral muscle strength in different functional classes of pulmonary arterial hypertension (PAH) compared with healthy subjects. [Subjects and Methods] This study included 31 patients with class II (n = 16) or class III (n = 15) PAH, classified according to the World Health Organization. Fifteen healthy subjects served as controls. Functional capacity was assessed using the 6-minute walk test (6MWT). Physical activity was determined using the International Physical Activity Questionnaire Short Form (IPAQ-SF). Respiratory muscle strength was measured using a mouth pressure device. Peripheral muscle strength was evaluated using a dynamometer. [Results] The 3 groups had similar demographic variables (p > 0.05). There were significant differences in 6MWT distance, maximal inspiratory pressure, and IPAQ categorical classification between the 3 groups (p < 0.05). Maximal expiratory pressure; total IPAQ score; and knee extensor, shoulder abductor, and hand grip strength were significantly lower in PAH patients (classes II and III) than in healthy subjects (p < 0.05). [Conclusion] As PAH progresses, respiratory muscle strength, functional exercise capacity, and physical activity decrease. Functional class should be taken into consideration when planning rehabilitation programs for this patient group.


Novel rescue procedure for inferior vena cava reconstruction in living-donor liver transplantation using a vascular graft recovered 25 h after donors' circulatory death and systematic review.
Liver transplantation is a lifesaving treatment for patients suffering from end-stage liver disease. Rarely, acute congestion of the inferior vena cava (IVC) is being encountered because of tumor compression. MELD allocation does not reflect severity of this condition because of lack of organ failure. Herein, a patient is being presented undergoing urgent living-donor liver transplantation (LDLT) with IVC reconstruction for a fast-growing hepatic epithelioid hemangioendothelioma (HEH). IVC reconstruction using a venous graft recovered from a 25-h after circulatory-death prior transplantation became necessary to compensate severe venous congestion. Additionally, a systematic review of the literature searching MEDLINE/PubMed was performed. Protocol and eligibility criteria were specified in advance and registered at the PROSPERO registry (CRD42013004827). Published literature of IVC reconstruction in LDLT was selected. Two reports describing IVC reconstruction with cryopreserved IVC grafts and one IVC reconstruction using a deceased after-circulatory-death-donor IVC graft were included. Follow-up was at 12 and 13 months, respectively. Regarding the graft recovery in the setting of living-related donation, this graft remained patent during the nine-month follow-up period. This is the first report on the use of a venous graft from a circulatory-death-donor, not eligible for whole organ recovery. We demonstrate in this study the feasibility of using a size and blood-group-compatible IVC graft from a cold-stored donor, which can solve the problem of urgent IVC reconstruction in patients undergoing LDLT.


Universal flux-fluctuation law in small systems.
The relation between flux and fluctuation is fundamental to complex physical systems that support and transport flows. A recently obtained law predicts monotonous enhancement of fluctuation as the average flux is increased, which in principle is valid but only for large systems. For realistic complex systems of small sizes, this law breaks down when both the average flux and fluctuation become large. Here we demonstrate the failure of this law in small systems using real data and model complex networked systems, derive analytically a modified flux-fluctuation law, and validate it through computations of a large number of complex networked systems. Our law is more general in that its predictions agree with numerics and it reduces naturally to the previous law in the limit of large system size, leading to new insights into the flow dynamics in small-size complex systems with significant implications for the statistical and scaling behaviors of small systems, a topic of great recent interest.


Emerging themes in food security: environmental justice, extended families and the multiple roles of grandmothers.
Pre- and perinatal nutritional status defines the development of adult metabolism and energy balance in humans. Young children in poor households are disproportionately more vulnerable to food insecurity given the cumulative impact of chronic stress on susceptibility to chronic diseases as an adult. Qualitative studies focusing on the experience of food insecurity in Latin America are scarce. In Argentina, although socioeconomic indicators improved in the aftermath of the 2001ecomomic crisis, the disadvantaged provinces in the north continue to bear the burden of historical inequities. The study was conducted among Primary Health Care patients in the city of San Salvador de Jujuy, Argentina. It analyzes environmental and household level stressors through the narratives of mothers with young children living with food insecurity, from the perspectives of eco-developmental conceptual frameworks. We conducted 11 semi-structured interviews with mothers of children < 1 to 6 years of age who participated in maternal-child health programs in Primary Health Care clinics and lived in food insecure households. Interviews focused on the environmental context and the resources and processes for obtaining and preparing daily meals. The Eco-bio-developmental (EBD) framework and the vulnerability-assets approach, provided a basis for conceptualizing the significance of findings. Our results indicated the need to understand pathways in the association of stressors, vulnerability and ill health, as well as the mitigating role of social relationships. For example, understanding the link between the stress of being exposed to environmental contaminants and the capacity to overcome food insecurity, or developing strategies to integrate the support provided by kinship networks like extended families into food security programs. The results also indicate the importance of developing support mechanisms for vulnerable family members like grandmothers in food insecure households who play instrumental roles as providers and caretakers of younger relatives. The empirical evidence generated by this study may inform community based strategies and public health policies to address food insecurity in vulnerable population groups who face health effects from multiple stressors.


Biomarkers of lymphatic function and disease: state of the art and future directions.
Substantial advances have accrued over the last decade in the identification of the processes that contribute to lymphatic vascular development in health and disease. Identification of distinct regulatory milestones, from a variety of genetic models, has led to a stepwise chronology of lymphatic development. Several molecular species have been identified as important tissue biomarkers of lymphatic development and function. At present, vascular endothelial growth-factor receptor (VEGFR)-3/VEGF-C/VEGF-D signaling has proven useful in the identification of clinical lymphatic metastatic potential and the assessment of cancer prognosis. Similar biomarkers, to be utilized as surrogates for the assessment of inherited and acquired diseases of the lymphatic circulation, are actively sought, and will represent a signal advance in biomedical investigation.


(In)accuracy of blood pressure measurement in 14 Italian hospitals.
The diagnosis and control of hypertension depend on accurate measurement of blood pressure (BP). The literature on the accuracy of BP recording by health professionals is, however, limited, and no study directly interviewed patients in the hospital setting. This multicenter cross-sectional study aimed at evaluating the compliance to current recommendations on BP measurement by health professionals directly from patients and to investigate potential predictors of higher quality in BP recording. A trained nurse interviewed a random sample of adult patients hospitalized for an ordinary admission (except in the emergency room) lasting more than one night, without mental disorder, who had their BP routinely measured by the hospital personnel less than 3 h before. The questionnaire contained 15 items on the main procedures that are common to current guidelines. Fourteen public hospitals from seven regions of Italy participated, and 1334 questionnaires were collected. Nine of the recommended practices were followed in the majority (>70%) of BP recordings, whereas some others were infrequent or rare: in 98.6, 82.2 and 81.1% of the participants, respectively, the arm circumference was never recorded, BP was measured only once, and BP was never recorded in both arms. Overall, 10 or more recommended procedures were followed during 33.4% recordings. At multivariate analysis, physicians were less likely than nurses to provide a more accurate BP measurement. The operator's compliance to some recommendations in BP measurement is unacceptably low. This survey provides detailed indications for medical directors on the procedures and settings to prioritize in educational programs, which are definitely needed.


Pancreatic Cancer Heterogeneity Can Be Explained Beyond the Genome.
Pancreatic ductal adenocarcinoma (PDAC) remains a major health problem because it induces almost systematic mortality. Carcinogenesis begins with genetic aberrations which trigger epigenetic modifications. While genetic mutations initiate tumorigenesis, they are unable to explain the vast heterogeneity observed among PDAC patients. Instead, epigenetic changes drive transcriptomic alterations that can regulate the malignant phenotype. The contribution of factors from the environment and tumor microenvironment defines different epigenetic landscapes that outline two clinical subtypes: basal, with the worst prognosis, and classical. The epigenetic nature of PDAC, as a reversible phenomenon, encouraged several studies to test epidrugs. However, these drugs lack specificity and although there are epigenetic patterns shared by all PDAC tumors, there are others that are specific to each subtype. Molecular characterization of the epigenetic mechanisms underlying PDAC heterogeneity could be an invaluable tool to predict personalized therapies, stratify patients and search for novel therapies with more specific phenotype-based targets. Novel therapeutic strategies using current anticancer compounds or existing drugs used in other pathologies, alone or in combination, could be used to kill tumor cells or convert aggressive tumors into a more benign phenotype.


Correlated responses to neonicotinoid insecticides in clones of the peach-potato aphid, Myzus persicae (Hemiptera: Aphididae).
Although there are still no confirmed reports of strong resistance to neonicotinoid insecticides in aphids, the peach-potato aphid (Myzus persicae Sulzer) shows variation in response, with some clones exhibiting up to tenfold resistance to imidacloprid. Five clones varying in response to imidacloprid were tested with four other neonicotinoid molecules to investigate the extent of cross-resistance. All four compounds-thiamethoxam, thiacloprid, clothianidin and dinotefuran-were cross-resisted, with ED(50) values ranked in the same order as for imidacloprid. Resistance factors ranged up to 11 for imidacloprid, 18 for thiamethoxam, 13 for thiacloprid, 100 for clothianidin and 6 for dinotefuran. This variation in response does not appear to be sufficient to compromise the field performance of neonicotinoids aimed at controlling aphids. However, it highlights the need for careful vigilance and stewardship in all M. persicae populations, and a need to consider neonicotinoids as a single cross-resisted group for management purposes.


Knowledge of pharmacists and parents towards antibiotic use in pediatrics: a cross-sectional study in Lebanon.
to assess the knowledge of both parents and community pharmacists regarding antibiotics use and resistance in pediatrics in Lebanon. A cross-sectional study was conducted between June and August 2017 in community pharmacies. A pre-established questionnaire targeting knowledge of parents and pharmacists regarding antibiotics use/misuse was carried out. An index of knowledge was computed to assess factors associated with good knowledge on antibiotics use/misuse. The study showed that 28.7% of pharmacists did not know which factors may contribute to antimicrobial resistance. Concerning the misuse of antibiotics, pharmacists blamed at first parents (90.1%), at second level physicians (72.8%), and third themselves (59.4%). Furthermore, pharmacists believed that the socioeconomic problems of the country (86.1%), the level of resistance to the molecule of choice (80.8%), the lack of consultation time (71.2%) and the lack of national guidelines/recommendations (66.3%) might be additional factors contributing to antimicrobial resistance. In case of acute otitis media, the majority of pharmacists chose the correct treatment, dose and duration according to international guidelines; this was in contrast to the results obtained in case of pharyngitis. Female pharmacists had a significantly higher knowledge score compared to their male counterparts (ORa=2.51). Half of parents (42.6%) declared that antibiotics act against both viruses and bacteria, 55.9% still believe that the presence of fever requires the administration of antibiotics, 50% didn't know the consequences of antibiotics misuse, 58.4% said that it is okay to give their child antibiotics without a physician's advice or based on a pharmacist's recommendation, and 66.7% trusted the pharmacist in the antibiotic prescription. Parents with a university level of education or a master's degree had significantly better knowledge compared to illiterate ones (ORa=9.04 and ORa=16.46, respectively). Based on the results obtained, it would be necessary to implement educational campaigns in order to increase awareness on antibiotics misuse and resistance in pediatrics.


The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling.
Vascular endothelial (VE)-cadherin transfers intracellular signals contributing to vascular hemostasis. Signaling through VE-cadherin requires association and activity of different intracellular partners. Yes-associated protein (YAP)/TAZ transcriptional cofactors are important regulators of cell growth and organ size. We show that EPS8, a signaling adapter regulating actin dynamics, is a novel partner of VE-cadherin and is able to modulate YAP activity. By biochemical and imaging approaches, we demonstrate that EPS8 associates with the VE-cadherin complex of remodeling junctions promoting YAP translocation to the nucleus and transcriptional activation. Conversely, in stabilized junctions, 14-3-3-YAP associates with the VE-cadherin complex, whereas Eps8 is excluded. Junctional association of YAP inhibits nuclear translocation and inactivates its transcriptional activity both in vitro and in vivo in Eps8-null mice. The absence of Eps8 also increases vascular permeability in vivo, but did not induce other major vascular defects. Collectively, we identified novel components of the adherens junction complex, and we introduce a novel molecular mechanism through which the VE-cadherin complex controls YAP transcriptional activity.


The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis.
The nuclear factor of activated T cells (NFAT) family of transcription factors controls calcium signaling in T lymphocytes. In this study, we have identified a crucial regulatory role of the transcription factor NFATc2 in T cell-dependent experimental colitis. Similar to ulcerative colitis in humans, the expression of NFATc2 was up-regulated in oxazolone-induced chronic intestinal inflammation. Furthermore, NFATc2 deficiency suppressed colitis induced by oxazolone administration. This finding was associated with enhanced T cell apoptosis in the lamina propria and strikingly reduced production of IL-6, -13, and -17 by mucosal T lymphocytes. Further studies using knockout mice showed that IL-6, rather than IL-23 and -17, are essential for oxazolone colitis induction. Administration of hyper-IL-6 blocked the protective effects of NFATc2 deficiency in experimental colitis, suggesting that IL-6 signal transduction plays a major pathogenic role in vivo. Finally, adoptive transfer of IL-6 and wild-type T cells demonstrated that oxazolone colitis is critically dependent on IL-6 production by T cells. Collectively, these results define a unique regulatory role for NFATc2 in colitis by controlling mucosal T cell activation in an IL-6-dependent manner. NFATc2 in T cells thus emerges as a potentially new therapeutic target for inflammatory bowel diseases.


Good Intentions in Universal Design: A Global Challenge for Higher Education.
It is not often that a high-level edict requires higher education centres to promote universal design through their programmes; however the recent United Nations Beijing Declaration and Action Plan (UNESCAP 2017) expressly states that, "academic institutions should provide training programmes on universal design for policymakers, building inspectors and contractors, as well as integrating universal design and accessibility into curricula related to architecture, urban planning, transport, civil engineering and other relevant academic branches". This is particularly timely in the Asia-Pacific region, where economies continue to show massive expansion of their built environments. This imperative to future-proof any development therefore is vital, especially considering the growing percentile of older people with their needs for safe and accessible living. Achieving these ends clearly implies a need both to educate professionals and to enact appropriate codes and standards, which in turn require the training of personnel to carry them out. Anticipating this need, Goal 3 of the United Nations Incheon Strategy (UNESCAP 2012) optimistically calls for "civil society involvement in conducting accessibility audits, creating guidelines and advocacy work to promote universal design" and "to enhance mechanisms for tracking its progress". While such good intentions are admirable, they will require radical steps to be achieved. The paper describes examples, including those from the writers' own experiences, outlining a range of practical methods which academics and teachers involved in inculcating universal design principles in both European and Asian centres, through their teaching, training and technology transfer, can positively support continued cooperation towards a more inclusive World for everyone.


CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion.
RhoA, Rac1 and Cdc42, the best-characterized members of the Rho family of small GTPases, are critical regulators of many cellular activities. Cdc42 GTPase-activating protein (CdGAP) is a serine- and proline-rich RhoGAP protein showing GAP activity against both Cdc42 and Rac1 but not RhoA. CdGAP is phosphorylated downstream of the MEK-ERK (extracellular signal-regulated kinase) pathway in response to serum and is required for normal cell spreading and polarized lamellipodia formation. In this study, we found that CdGAP protein and mRNA levels are highly increased in mammary tumor explants expressing an activated Neu/ErbB-2 (Neu-NT) receptor. In response to transforming growth factor-β (TGFβ) stimulation, Neu-NT-expressing mammary tumor explants demonstrate a clear induction in cell motility and invasion. We show that downregulation of CdGAP expression by small interfering RNA abrogates the ability of TGFβ to induce cell motility and invasion of Neu-NT-expressing mammary tumor explants. However, it has no effect on TGFβ-mediated cell adhesion on type 1 collagen and fibronectin. Interestingly, protein expression of E-Cadherin is highly increased in Neu-NT-expressing mammary tumor explants depleted of CdGAP. In addition, complete loss of E-Cadherin expression is not observed in CdGAP-depleted cells during TGFβ-mediated epithelial to mesenchymal transition. Downregulation of the CdGAP expression also decreases cell proliferation of Neu-NT-expressing mammary tumor explants independently of TGFβ. Rescue analysis using re-expression of various CdGAP deletion-mutant proteins revealed that the proline-rich domain (PRD) but not the GAP domain of CdGAP is essential to mediate TGFβ-induced cell motility and invasion. Finally, we found that TGFβ induces the expression and phosphorylation of CdGAP in mammary epithelial NMuMG cells. Taken together, these studies identify CdGAP as a novel molecular target in TGFβ signaling and implicate CdGAP as an essential component in the synergistic interaction between TGFβ and Neu/ErbB-2 signaling pathways in breast cancer cells.


Sodium fluoride reveals multiple pathways for regulation of surface expression of the C3b/C4b receptor (CR1) on human polymorphonuclear leukocytes.
We have examined the effects of NaF on C3b receptor (CR1) expression and function in human polymorphonuclear leukocytes (PMN). Plasma membrane expression of CR1 was determined with a monoclonal antibody (3D9); CR1 function was assessed with erythrocytes bearing C3b (EC3b) or C3b oligomers prepared with avidin and biotin. NaF inhibited in a dose-dependent manner CR1-mediated phagocytosis and NaF inhibited f-met-leu-phe or phorbol dibutyrate-induced increases in CR1 expression, with 50% inhibition at 5 mM NaF. Increased plasma membrane expression of CR3 induced by f-met-leu-phe also was inhibited by NaF. However, increased CR1 and CR3 expression due to incubation at 37 degrees C were unaffected by 10 mM NaF. Incubation of PMN with 10 mM NaF depleted 80% of intracellular adenosine triphosphate (ATP) after 10 min. However, inhibition of CR1 function was unrelated to ATP level, inasmuch as normal increases in CR1 expression and in phagocytosis occurred 20 min after removal of NaF, whereas ATP levels remained below 25% of normal. Strikingly, internalization of soluble oligomeric C3b ligands was unaffected by 10 mM NaF, which completely inhibited phorbol dibutyrate-induced CR1 internalization and EC3b phagocytosis. We conclude that there are two different mechanisms for increasing plasma membrane expression of CR1, one of which is inhibitable by NaF. Moreover, there are two distinct pathways of CR1 internalization which can also be distinguished by their sensitivity to NaF.


The Measurement of Sexual Selection Using Bateman's Principles: An Experimental Test in the Sex-Role-Reversed Pipefish Syngnathus typhle.
Angus J. Bateman's classic study of sexual selection in Drosophila melanogaster has had a major influence on the development of sexual selection theory. In some ways, Bateman's study has served a catalytic role by stimulating debate on sex roles, sexual conflict and other topics in sexual selection. However, there is still considerable disagreement regarding whether or not "Bateman's principles" are helpful in the study of sexual selection. Here, we test the idea that Bateman's principles provide the basis for a useful method to quantify and compare mating systems. In this study, we focus on the sex-role-reversed pipefish Syngnathus typhle as a model system to study the measurement of sexual selection. We set up artificial breeding assemblages of pipefish in the laboratory and used microsatellite markers to resolve parentage. Three different sex-ratio treatments (female-biased, even and male-biased) were used to manipulate the expected intensity of sexual selection. Measures of the mating system based on Bateman's principles were calculated and compared to the expected changes in the intensity of sexual selection. We also compare the results of this study to the results of a similar study of Bateman's principles in the rough-skinned newt, a species with conventional sex roles. The results of this experiment show that measures of the mating system based on Bateman's principles do accurately capture the relative intensities of sexual selection in the different treatments and species. Thus, widespread use of Bateman's principles to quantify mating systems in nature would facilitate comparative studies of sexual selection and mating system evolution.


Insights into the nitric oxide reductase mechanism of flavodiiron proteins from a flavin-free enzyme.
Flavodiiron proteins (FDPs) catalyze reductive scavenging of dioxygen and nitric oxide in air-sensitive microorganisms. FDPs contain a distinctive non-heme diiron/flavin mononucleotide (FMN) active site. Alternative mechanisms for the nitric oxide reductase (NOR) activity consisting of either protonation of a diiron-bridging hyponitrite or "super-reduction" of a diferrous-dinitrosyl by the proximal FMNH(2) in the rate-determining step have been proposed. To test these alternative mechanisms, we examined a deflavinated FDP (deflavo-FDP) from Thermotoga maritima. The deflavo-FDP retains an intact diiron site but does not exhibit multiturnover NOR or O(2) reductase (O(2)R) activity. Reactions of the reduced (diferrous) deflavo-FDP with nitric oxide were examined by UV-vis absorption, EPR, resonance Raman, and FTIR spectroscopies. Anaerobic addition of nitric oxide up to one NO per diferrous deflavo-FDP results in formation of a diiron-mononitrosyl complex characterized by a broad S = (1)/(2 )EPR signal arising from antiferromagnetic coupling of an S = (3)/(2) {FeNO}(7) with an S = 2 Fe(II). Further addition of NO results in two reaction pathways, one of which produces N(2)O and the diferric site and the other of which produces a stable diiron-dinitrosyl complex. Both NO-treated and as-isolated deflavo-FDPs regain full NOR and O(2)R activities upon simple addition of FMN. The production of N(2)O upon addition of NO to the mononitrosyl deflavo-FDP supports the hyponitrite mechanism, but the concomitant formation of a stable diiron-dinitrosyl complex in the deflavo-FDP is consistent with a super-reduction pathway in the flavinated enzyme. We conclude that a diiron-mononitrosyl complex is an intermediate in the NOR catalytic cycle of FDPs.


Gargling for oral hygiene and the development of fever in childhood: a population study in Japan.
Fever is one of the most common symptoms among children and is usually caused by respiratory infections. Although Japanese health authorities have long recommended gargling to prevent respiratory infections, its effectiveness among children is not clear. The children in this observational study were enrolled from 145 nursery schools in Fukuoka City, Japan. Children in the exposure group were instructed to gargle at least once a day. The endpoints of this study were incidence of fever during the daytime and incidence of sickness absence. Differences among gargling agents for each endpoint were also analyzed. A total of 19,595 children aged 2 to 6 years were observed for 20 days (391,900 person-days). In multivariate logistic regression, the overall odds ratio (OR) for fever onset in the gargling group was significantly lower (OR = 0.68). In age-stratified analysis, ORs were significantly lower at age 2 (OR = 0.67), 4 (OR = 0.46), and 5 (OR = 0.41) years. Regarding sickness absence, the overall OR was 0.92 (not significant) in the gargling group. In age-stratified analysis, ORs were significantly lower at age 4 (OR = 0.68), 5 (OR = 0.59), and 6 (OR = 0.63) years. In subgroup analysis, significantly lower ORs for fever onset were observed for children who gargled with green tea (OR = 0.32), functional water (OR = 0.46), or tap water (OR = 0.70). However, the ORs were not significant for sickness absence. Gargling might be effective in preventing febrile diseases in children.


A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons.
Neurogenin1 (Ngn1), Neurogenin2 (Ngn2), and Mash1 encode bHLH transcription factors with neuronal determination functions. In the telencephalon, the Ngns and Mash1 are expressed at high levels in complementary dorsal and ventral domains, respectively. We found that Ngn function is required to maintain these two separate expression domains, as Mash1 expression is up-regulated in the dorsal telencephalon of Ngn mutant embryos. We have taken advantage of the replacement of the Ngns by Mash1 in dorsal progenitors to address the role of the neural determination genes in neuronal-type specification in the telencephalon. In Ngn2 single and Ngn1; Ngn2 double mutants, a population of early born cortical neurons lose expression of dorsal-specific markers and ectopically express a subset of ventral telencephalic-specific markers. Analysis of Mash1; Ngn2 double mutant embryos and of embryos carrying a Ngn2 to Mash1 replacement mutation demonstrated that ectopic expression of Mash1 is required and sufficient to confer these ventral characteristics to cortical neurons. Our results indicate that in addition to acting as neuronal determinants, Mash1 and Ngns play a role in the specification of dorsal-ventral neuronal identity, directly linking pathways of neurogenesis and regional patterning in the forebrain.


BMI and uterine size: is there any relationship?
To evaluate the influence of BMI on the prevalence of fibroids and uterine weight. Uterine pathology specimens of all the women who underwent hysterectomy for benign indications from 1995 to 2002 were studied. Patient characteristics such as age, race, body mass index (BMI), and parity were collected by chart review. The data were statistically analyzed using a 1-way analysis of variance and regression analysis. Uterine weight and fibroids were the dependent variables and BMI, age, and parity were the independent variables. The correlation between BMI and the presence/number of fibroids and their size was also studied. Among the 873 patients who underwent hysterectomy for benign indications, 47.1% were obese and these women had the highest mean uterine weight of 349.53 g. Overall, BMI had a significant correlation with the uterine size (P<0.0001). For every 1-point increase in BMI, uterine weight increased by 7.56 g. BMI positively correlated with uterine size both in the women with fibroids (P=0.038) and in those without fibroids (P=0.016). After controlling for fibroids, every 1-point increase in BMI resulted in an increase of 4.56 g in uterine weight (P<0.0001). In addition, there was a significant correlation between BMI and the presence of fibroids (P<0.0001), but not with the size of fibroids (P=0.11). A significant correlation was found between BMI and uterine weight in all the women, independent of age and parity. For every 1-point increase in BMI, there was a 7.56 g increase in uterine weight. This association needs to be further assessed in healthy women without uterine pathology.


[Changes in factors associated with the nutrition transition in Mexico].
To describe the demographic and socioeconomic changes, food availability and food expense in Mexico during 1980-2000. From official statistics (Population Census, FAO Food Balance Sheets, Family Income and Expense National Survey and Economic Census) we estimated the evolution of population distribution according to locality size, occupational structure, woman participation in the wage-earning labor force, minimum wage, availability of food establishments and expense in food. The percentage of the population that lives in urban areas has increased, they are employed in the tertiary sector, womens participation in the labor market has increased but real minimum wages have decreased. Vegetables, oleaginous, oils, fish and seafood availability have decreased whereas animal fat, vegetables, fruits, softdrinks, meats and egg availability have increased. The number of inexpensive restaurants (cocinas económicas and fondas) has also increased. Food expenses have decreased while amount of money spent in food consumed away from home has increased. In Mexico, the growth in urban areas and the tertiary job sector shows a parallel growth in the availability of high fat and protein food, a greater diet variety and more opportunities to consume food not prepared in the home. On the other hand, the sale of equipment and places designed for recreational physical activity have increased. By reducing employment in the primary sector it is foreseeable that labor intensive physical activity will become less important overtime.


Descemet stripping and automated endothelial keratoplasty (DSAEK) versus non-Descemet stripping and automated endothelial keratoplasty (nDSAEK) for bullous keratopathy.
To investigate the long-term results of Descemet stripping and automated endothelial keratoplasty (DSAEK) versus non-Descemet stripping and automated endothelial keratoplasty (nDSAEK) for non-Fuchs bullous keratopathy. Retrospective comparative study. Twenty-nine eyes of 28 patients who underwent DSAEK and 60 eyes of 56 patients who underwent nDSAEK for bullous keratopathy were retrospectively analyzed in a clinical case-control study. All the operations were done using precut donor buttons prepared by overseas eye banks. The recipient Descemet membrane was stripped in DSAEK, whilst it was left intact in nDSAEK. Donor buttons were inserted through a 4.2-mm corneal incision using the pull-through technique. Air was injected into the anterior chamber at the end of the operation. We investigated the visual acuity, refraction, endothelial cell density, and complications. The average best spectacle-corrected visual acuity (BSCVA) was significantly improved at all time points measured after surgery in both the DSAEK and the nDSAEK groups, and no significant differences were found between the 2 groups after surgery. No significant differences in spherical equivalent were found between the groups before and after surgery. The endothelial cell density gradually decreased after the operation in both groups; however, no significant difference between the 2 groups was found at any of the time points measured. DSAEK and nDSAEK provided excellent refractive and reasonable visual outcomes in our long-term observation.


Pipeline for uncoilable or failed aneurysms: 3-year follow-up results.
OBJECTIVE The long-term effectiveness of endovascular treatment of large and giant wide-neck aneurysms using traditional endovascular techniques has been disappointing, with high recanalization and re-treatment rates. Flow diversion with the Pipeline Embolization Device (PED) has been recently used as a stand-alone therapy for complex aneurysms, showing significant improvement in effectiveness while demonstrating a similar safety profile to stent-supported coil treatment. However, relatively little is known about its long-term safety and effectiveness. Here the authors report on the 3-year safety and effectiveness of flow diversion with the PED in a prospective cohort of patients with large and giant internal carotid artery aneurysms enrolled in the Pipeline for Uncoilable or Failed Aneurysms (PUFS) trial. METHODS The PUFS trial is a prospective study of 107 patients with 109 aneurysms treated with the PED. Primary effectiveness and safety end points were demonstrated based on independently monitored 180-day clinical and angiographic data. Patients were enrolled in a long-term follow-up protocol including 1-, 3-, and 5-year clinical and imaging follow-up. In this paper, the authors report the midstudy (3-year) effectiveness and safety data. RESULTS At 3 years posttreatment, 74 subjects with 76 aneurysms underwent catheter angiography as required per protocol. Overall, complete angiographic aneurysm occlusion was observed in 71 of these 76 aneurysms (93.4% cure rate). Five aneurysms were re-treated, using either coils or additional PEDs, for failure to occlude, and 3 of these 5 were cured by the 3-year follow-up. Angiographic cure with one or two treatments of Pipeline embolization alone was therefore achieved in 92.1%. No recanalization of a previously completely occluded aneurysm was noted on the 3-year angiograms. There were 3 (2.6%) delayed device- or aneurysm-related serious adverse events, none of which led to permanent neurological sequelae. No major or minor late-onset hemorrhagic or ischemic cerebrovascular events or neurological deaths were observed in the 6-month through 3-year posttreatment period. Among 103 surviving patients, 85 underwent functional outcome assessment in which modified Rankin Scale scores of 0-1 were demonstrated in 80 subjects. CONCLUSIONS Pipeline embolization is safe and effective in the treatment of complex large and giant aneurysms of the intracranial internal carotid artery. Unlike more traditional endovascular treatments, flow diversion results in progressive vascular remodeling that leads to complete aneurysm obliteration over longer-term follow-up without delayed aneurysm recanalization and/or growth. Clinical trial registration no.: NCT00777088 (clinicaltrials.gov).


Reduced responses to selection after species range expansion.
Species range expansion reduces genetic variation at the margins of a species range and should thus compromise the adaptive potential of its marginal populations. Remarkably, this prediction has not previously been tested. Here, we show that populations of the plant Mercurialis annua, which expanded its range into Spain and Portugal from North Africa after the Pleistocene glaciation, respond to selection on a key life-history trait less well than populations from the species' historical refugium. Our results provide direct evidence of a decline in adaptive potential across the geographic range of a species after a shift in its distribution. Predicting evolutionary responses to environmental change will thus need to account for the genetic heterogeneity of species and the spatial dynamics of their geographic distributions.


Structural brain imaging of attention-deficit/hyperactivity disorder.
Many investigators have hypothesized that attention-deficit/hyperactivity disorder (ADHD) involves structural and functional brain abnormalities in frontal-striatal circuitry. Although our review suggests that there is substantial support for this hypothesis, a growing literature demonstrates widespread abnormalities affecting other cortical regions and the cerebellum. Because there is only one report studying adults with ADHD, this summary is based on children. A key limitation of the literature is that most of the studies until recently have been underpowered, using samples of fewer than 20 subjects per group. Nevertheless, these studies are largely consistent with the most comprehensive and definitive study (Castellanos et al 2002). Moreover, studies differ in the degree to which they address the influence of medications, comorbidities, or gender, and most have not addressed potentially important sources of heterogeneity such as family history of ADHD, subtype, or perinatal complications. Despite these limitations, a relatively consistent picture has emerged. The most replicated alterations in ADHD in childhood include significantly smaller volumes in the dorsolateral prefrontal cortex, caudate, pallidum, corpus callosum, and cerebellum. These results suggest that the brain is altered in a more widespread manner than has been previously hypothesized. Developmental studies are needed to address the evolution of this brain disorder into adulthood.


Inter-dinucleotide distances in the human genome: an analysis of the whole-genome and protein-coding distributions.
We study the inter-dinucleotide distance distributions in the human genome, both in the whole-genome and protein-coding regions. The inter-dinucleotide distance is defined as the distance to the next occurrence of the same dinucleotide. We consider the 16 sequences of inter-dinucleotide distances and two reading frames. Our results show a period-3 oscillation in the protein-coding inter-dinucleotide distance distributions that is absent from the whole-genome distributions. We also compare the distance distribution of each dinucleotide to a reference distribution, that of a random sequence generated with the same dinucleotide abundances, revealing the CG dinucleotide as the one with the highest cumulative relative error for the first 60 distances. Moreover, the distance distribution of each dinucleotide is compared to the distance distribution of all other dinucleotides using the Kullback-Leibler divergence. We find that the distance distribution of a dinucleotide and that of its reversed complement are very similar, hence, the divergence between them is very small. This is an interesting finding that may give evidence of a stronger parity rule than Chargaff's second parity rule.


MicroRNAs in acute leukemia: from biological players to clinical contributors.
MicroRNAs (miRNAs) are involved in the management of hematopoiesis. As a consequence, miRNA dysregulation causes disruption of the hematopoietic system and leukemia may arise. We here comprehensively discuss miRNAs found discriminative for cytogenetic and molecular subtypes of acute leukemia. These miRNAs are either known miRNAs involved in leukemogenesis with proven tumor suppressor or oncogenic activities or are newly identified by high-throughput sequencing with yet unknown function. Furthermore, forces are outlined that drive aberrant miRNA function, which include genetic abnormalities (for example, deletions, translocations and mutations) and epigenetic aberrations (for example, aberrant DNA methylation or histone modifications). Interestingly, leukemia-silenced miRNAs can be re-expressed upon treatment with de-methylating agents. Targeting miRNA expression may serve a therapeutical role, albeit at present this way of targeted therapy is in its infancy. However, emerging knowledge about the biology of miRNAs in leukemia may result into a role for these miRNAs in the diagnosis and treatment of acute leukemia.


DDM-PGE(2)-mediated cytoprotection in renal epithelial cells by a thromboxane A(2) receptor coupled to NF-kappaB.
The present studies were conducted to determine the pharmacological nature of a cytoprotective 11-deoxy-16,16-dimethyl-PGE(2) (DDM-PGE(2)) receptor in LLC-PK(1) cells. DDM-PGE(2)-mediated cytoprotection against 2,3,5-(trisglutathion-S-yl)hydroquinone (TGHQ)-mediated cytotoxicity can be reproduced using thromboxane A(2) (TXA(2)) receptor (TP) agonists (U46619 and IBOP), and the cytoprotective response to DDM-PGE(2) and TP agonists is inhibited by TP antagonists (SQ-29,548 and ISAP). Western blot analysis using an antipeptide antibody against the human platelet TP receptor (55 kDa) identified a particulate associated 54-kDa protein. DDM-PGE(2)-mediated 12-O-tetradecanoyl phorbol-13-acetate (TPA) responsive element (TRE) binding activity is not inhibited by cyclooxygenase inhibitors (aspirin and indomethacin) or a TXA(2) synthase inhibitor (sulfasalazine), suggesting that the biological response to DDM-PGE(2) is not dependent on de novo TXA(2) biosynthesis. Peak DDM-PGE(2)- and U46619-mediated TRE binding activity and nuclear factor-kappaB (NF-kappaB) binding activity are inhibited by SQ-29,548. The full cytoprotective response to DDM-PGE(2) requires an 8-h pulse with agonist. DDM-PGE(2)-mediated TRE and NF-kappaB binding activity remain elevated in the presence of agonist and rapidly decay following agonist washout, suggesting a direct correlation between DDM-PGE(2)-mediated cytoprotection and persistent DNA binding activities. TPA, a protein kinase C activator, induces cytoprotection and a persistent increase of NF-kappaB binding activity. DDM-PGE(2)-mediated cytoprotection and NF-kappaB binding activity but not TRE binding activity are inhibited by sulfasalazine. We conclude that the DDM-PGE(2) receptor is a TP receptor and that the cytoprotective response may be mediated in part by NF-kappaB.


How can agricultural interventions contribute in improving nutrition health and achieving the MDGs in least-developed countries?
There are strong conceptual linkages between agricultural development and nutrition improvements which may be categorized into three main pathways: the development, own-production and market pathways. Evidence on the efficacy of these pathways is mixed with some strong, some negative and some weak impacts. These findings reflect both the importance of agriculture for nutrition and the conditionality of that importance on contextual factors. They are also the result of insufficient high-quality empirical research investigating these linkages. The most effective 'pathways' and interventions linking agricultural change to improved nutritional outcomes change with economic growth and development, with declining importance of the development and own-production pathways and increasing importance of the market pathway. Substantial challenges in operationalizing agricultural-nutrition linkages need to be overcome to better exploit potential opportunities.


Prostaglandin control of renal circulation in the unanesthetized dog and baboon.
Effects of indomethacin and meclofenamate, inhibitors of prostaglandin synthesis, were evaluated in the regulation of renal blood flow in conscious and anesthetized dogs and in tranquilized baboons, instrumented with arterial pressure catheters and renal blood flow probes. Indomethacin, 10 mg/kg, did not alter renal blood flow or resistance significantly in the conscious dog. In the anesthetized dog, however, indomethacin caused a reduction in renal blood flow (25 +/- 3% of control) and an elevation of renal vascular resistance (45 +/- 8% of control). Meclofenamate, 4 mg/kg, reduced renal flow (12 +/- 2%) and increased renal vascular resistance 15 +/- 4% in conscious dogs. In conscious dogs and tranquilized primates, indomethacin and meclofenamate reduced the reactive hyperemia in the renal bed after 15 s occlusion from a control of 36 +/- 5 ml to 6 +/- 2 ml, and after 45 s occlusion from a control of 98 +/- 9 ml to 17 +/- 5 ml. Methoxamine (10-50 mug/kg per min) and angiotensin II (0.03-0.12 mug/kg per min), infused in graded doses, induced significantly greater renal vasoconstriction in conscious dogs in the presence of indomethacin. Thus, in the conscious animal, prostaglandins appear to play only a minor role in the control of the renal circulation at rest, but are of greater importance in mediating the renal responses to reactive hyperemia and to vasoconstriction.


Probing dielectric interfaces on the nanoscale with elastic scattering patterns of single gold nanorods.
We study spatially isolated, individual gold nanorods placed at a planar interface between two dielectric media using confocal interference scattering microscopy in combination with higher order laser modes. Approaching refractive index matching conditions, we observe that the elastic scattering patterns of individual nanorods exhibit an exponential increase of both the scattering intensity and the signal-to-background ratio. In case refractive index matching conditions are fullfilled, the data acquisition rates are maximized and suitable for in-vivo biological measurements. In all cases, the characteristic two-lobe shape of the scattering patterns of single nanorods remains unchanged while the sign of the image contrast is a direct consequence of the refractive index variation occurring at the interface.


Characterizing Amyloid-Positive Individuals With Normal Tau PET Levels After 5 Years: An ADNI Study.
Individuals with biomarker evidence of β-amyloid (Aβ) deposition are increasingly being enrolled in clinical treatment trials but there is a need to identify markers to predict which of these individuals will also develop tau deposition. We aimed to determine whether Aβ-positive individuals can remain tau-negative for at least 5 years and identify characteristics that could distinguish between these individuals and those who develop high tau within this period. Tau PET positivity was defined using a Gaussian mixture model with log-transformed standard uptake value ratio values from 7 temporal and medial parietal regions using all participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with flortaucipir PET. Tau PET scans were classified as normal if the posterior probability of elevated tau was less than 1%. Aβ PET positivity was defined based on ADNI cutpoints. We identified all Aβ-positive individuals from ADNI who had normal tau PET more than 5 years after their first abnormal Aβ PET (amyloid with low tau [ALT] group) and all Aβ-positive individuals with abnormal tau PET within 5 years (biomarker AD). In a case-control design, logistic regression was used to model the odds of biomarker AD vs ALT accounting for sex, age, APOE ε4 carriership, Aβ Centiloid, and hippocampal volume. We identified 45 individuals meeting criteria for ALT and 157 meeting criteria for biomarker AD. The ALT group had a lower proportion of APOE ε4 carriers, lower Aβ Centiloid, larger hippocampal volumes, and more preserved cognition, and were less likely to develop dementia, than the biomarker AD group. APOE ε4, higher Aβ Centiloid, and hippocampal atrophy were independently associated with increased odds of abnormal tau within 5 years. A Centiloid value of 50 effectively discriminated biomarker AD and ALT with 80% sensitivity and specificity. The majority of the ALT participants did not develop dementia throughout the 5-year interval. Aβ-positive individuals can remain tau-negative for at least 5 years. Baseline characteristics can help identify these ALT individuals who are less likely to develop dementia. Conservative Aβ cutpoints should be utilized for clinical trials to better capture individuals with high risk of developing biomarker AD.


Unusual Chromosomal Rearrangement Resulted in Interstitial Monosomy 9p: Case Report.
We report on a 4.5-year-old boy with interstitial monosomy 9p in a unique and complex de novo rearrangement. The patient had been referred for craniofacial dysmorphism, delayed psychomotor development, and various congenital malformations. We combined cytogenetic studies and FISH analyses to delineate the deletion. The result of our cytogenetic studies was 46,XY,der(9)(p22pter). In order to confirm the deletion, we also performed FISH analysis, which showed that the 9p subtelomeric region was inserted into chromosome 13. Molecular karyotyping was performed to describe the exact genomic breakpoints of the rearrangement. In conclusion, this case is a complex insertion/deletion abnormality which has not been reported before.


Detection of Helicobacter pylori DNA in inflamed dental pulp specimens from Japanese children and adolescents.
The oral cavity has been implicated as a source of Helicobacter pylori infection in childhood. Various PCR methods have been used to detect H. pylori DNA in oral specimens with various detection rates reported. Such disparity in detection rates complicates the estimation of the true infection rate of H. pylori in the oral cavity. In the present study, we constructed a novel PCR system for H. pylori detection and used it to analyse oral specimens. Firstly, the nucleotide alignments of genes commonly used for H. pylori detection were compared using the complete genome information for 48 strains registered in the GenBank database. Candidate primer sets with an estimated amplification size of approximately 300-400 bp were selected, and the specificity and sensitivity of the detection system using each primer set were evaluated. Five sets of primers targeting ureA were considered appropriate, of which a single primer set was chosen for inclusion in the PCR system. The sensitivity of the system was considered appropriate and its detection limit established as one to ten cells per reaction. The novel PCR system was used to examine H. pylori distribution in oral specimens (40 inflamed pulp tissues, 40 saliva samples) collected from Japanese children, adolescents and young adults. PCR analysis revealed that the detection rate of H. pylori in inflamed pulp was 15 %, whereas no positive reaction was found in any of the saliva specimens. Taken together, our novel PCR system was found to be reliable for detecting H. pylori. The results obtained showed that H. pylori was detected in inflamed pulp but not saliva specimens, indicating that an infected root canal may be a reservoir for H. pylori.


Neuromotor Adverse Effects in 342 Youth During 12 Weeks of Naturalistic Treatment With 5 Second-Generation Antipsychotics.
Second-generation antipsychotic (SGA) effects in youth were monitored to quantify extrapyramidal side effects (EPS) and to identify risk profiles for treatment-emergent EPS. Data were analyzed for the nonrandomized, prospective Second-generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) inception cohort study. EPS were assessed at baseline and 4, 8, and 12 weeks after naturalistic SGA initiation for schizophrenia, mood, disruptive behavior, and autism spectrum disorders using the Simpson-Angus Scale (SAS), Barnes Akathisia Scale, Abnormal Involuntary Movement Scale (AIMS), and Treatment Emergent Side Effect Scale. Drug-induced parkinsonism was defined by incident mean SAS score >0.33, anticholinergic initiation, or increasing total SAS score ≥2 in patients with baseline EPS. In 342 youth aged 13.6 ± 3.5 years (male = 58.2%, antipsychotic-naive = 65.8%), 15.2% developed drug-induced parkinsonism. Raw SGA-grouped drug-induced parkinsonism rates were as follows: quetiapine = 1.5%, olanzapine = 13.8%, risperidone = 16.1%, ziprasidone = 20.0%, and aripiprazole = 27.3%. SGA type, dose, higher age, and lower baseline functioning were jointly associated with drug-induced parkinsonism (R(2) = 0.18; p < .0001). Controlling for these factors, drug-induced parkinsonism rates were significantly lower only for quetiapine and olanzapine. Subjectively reported EPS (5%), EPS-related treatment discontinuation (3.3%), and anticholinergic initiation (3%) were infrequent. Anticholinergic initiation was most frequent with risperidone (10.2%; p = .0004). Treatment-emergent dyskinesia ranged from 4.5% (aripiprazole) to 15.5% (olanzapine). SGA type, younger age, white race/ethnicity, and baseline AIMS were jointly associated with treatment-emergent dyskinesia (R(2) = 0.31; p < .0001). Controlling for these factors, treatment-emergent dyskinesia rates differed among SGA subgroups, with higher rates with olanzapine and ziprasidone. At baseline, psychostimulant use was associated with dyskinesia, and number of psychotropic comedications was associated with subjective EPS. In youth, SGA-related EPS rates did not generally exceed those reported in adults, with particularly low rates with quetiapine and olanzapine.


Improving vaccine trials in infectious disease emergencies.
Unprecedented global effort is under way to facilitate the testing of countermeasures in infectious disease emergencies. Better understanding of the various options for trial design is needed in advance of outbreaks, as is preliminary global agreement on the most suitable designs for the various scenarios. What would enhance the speed, validity, and ethics of clinical studies of such countermeasures? Focusing on studies of vaccine efficacy and effectiveness in emergencies, we highlight three needs: for formal randomized trials-even in most emergencies; for individually randomized trials-even in many emergencies; and for six areas of innovation in trial methodology. These needs should inform current updates of protocols and roadmaps.


Respecting values and perspectives in biobanking and genetic research governance: Outcomes of a qualitative study in Bengaluru, India.
Background: The promise of biobanking and genetic research (BGR) in the context of translational research towards improving public health and personalised medicine has been recognised in India. Worldwide experience has shown that incorporating stakeholders' expectations and values into the governance of BGR is essential to address ethical aspects of BGR. This paper draws on engagement with various stakeholders in the South Indian city of Bengaluru to understand how incorporating people's values and beliefs can inform policy making decisions and strengthen BGR governance within India. Methods: We adopted a qualitative research approach and conducted six focus group discussions with civil society members and seven in-depth interviews with key informants in BGR, identified through a targeted web search and snowballing methods, until data saturation was reached. Data were thematically analysed to identify emergent patterns. Results: Specific themes relating to the ethics and governance of BGR emerged. Fears and uncertainty about future sample and data use, possibilities of discrimination and exploitation in the use of findings and the lack of comprehensive data protection policies in India along with expectations of enhanced contributor agency, control in future use of samples and data, benefit sharing, enhanced utility of samples, sustained BGR and public good, reflected tensions between different stakeholders' values and beliefs. Fair governance processes through an independent governance committee for biobanks and a system of ongoing engagement with stakeholders emerged as best practice towards building trust and respecting diversity of views and values. Conclusions: Ensuring public trust in BGR requires listening to stakeholders' voices, being open to counter narratives, and a commitment to long term engagement embedded in principles of participatory democracy. This is central to a 'people-centred governance framework' involving a negotiated middle ground and an equilibrium of governance which promotes social justice by being inclusive, transparent, equitable, and trustworthy.


The Collaborative Longitudinal Personality Disorders Study: reliability of axis I and II diagnoses.
Both the interrater and test-retest-retest reliability of axis I and axis II disorders were assessed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and the Diagnostic Interview for DSM-IV Personality Disorders (DIPD-IV). Fair-good median interrater kappa (.40-.75) were found for all axis II disorders diagnosed five times or more, except antisocial personality disorder (1.0). All of the test-retest kappa for axis II disorders, except for narcissistic personality disorder (1.0) and paranoid personality disorder (.39), were also found to be fair-good. Interrater and test-retest dimensional reliability figures for axis II were generally higher than those for their categorical counterparts; most were in the excellent range (> .75). In terms of axis I, excellent median interrater kappa were found for six of the 10 disorders diagnosed five times or more, whereas fair-good median interrater kappa were found for the other four axis I disorders. In general, test-retest reliability figures for axis I disorders were somewhat lower than the interrater reliability figures. Three test-retest kappa were in the excellent range, six were in the fair-good range, and one (for dysthymia) was in the poor range (.35). Taken together, the results of this study suggest that both axis I and axis II disorders can be diagnosed reliably when using appropriate semistructured interviews. They also suggest that the reliability of axis II disorders is roughly equivalent to that reliability found for most axis I disorders.


Genome of Ochrobactrum anthropi ATCC 49188 T, a versatile opportunistic pathogen and symbiont of several eukaryotic hosts.
Ochrobactrum anthropi is a common soil alphaproteobacterium that colonizes a wide spectrum of organisms and is being increasingly recognized as an opportunistic human pathogen. Potentially life-threatening infections, such as endocarditis, are included in the list of reported O. anthropi infections. These reports, together with the scant number of studies and the organism's phylogenetic proximity to the highly pathogenic brucellae, make O. anthropi an attractive model of bacterial pathogenicity. Here we report the genome sequence of the type strain O. anthropi ATCC 49188, which revealed the presence of two chromosomes and four plasmids.


Development of a stroke-specific quality of life scale.
Clinical stroke trials are increasingly measuring patient-centered outcomes such as functional status and health-related quality of life (HRQOL). No stroke-specific HRQOL measure is currently available. This study presents the initial development of a valid, reliable, and responsive stroke-specific quality of life (SS-QOL) measure, for use in stroke trials. Domains and items for the SS-QOL were developed from patient interviews. The SS-QOL, Short Form 36, Beck Depression Inventory, National Institutes of Health Stroke Scale, and Barthel Index were administered to patients 1 and 3 months after ischemic stroke. Items were eliminated with the use of standard psychometric criteria. Construct validity was assessed by comparing domain scores with similar domains of established measures. Domain responsiveness was assessed with standardized effect sizes. All 12 domains of the SS-QOL were unidimensional. In the final 49-item scale, all domains demonstrated excellent internal reliability (Cronbach's alpha values for each domain >/=0.73). Most domains were moderately correlated with similar domains of established outcome measures (r2 range, 0.3 to 0.5). Most domains were responsive to change (standardized effect sizes >0.4). One- and 3-month SS-QOL scores were associated with patients' self-report of HRQOL compared with before their stroke (P<0.001). The SS-QOL measures HRQOL, its primary underlying construct, in stroke patients. Preliminary results regarding the reliability, validity, and responsiveness of the SS-QOL are encouraging. Further studies in diverse stroke populations are needed.


Room Temperature Weak-to-Strong Coupling and the Emergence of Collective Emission from Quantum Dots Coupled to Plasmonic Arrays.
Colloidal quantum dot (CQD) assemblies exhibit interesting optoelectronic properties when coupled to optical resonators ranging from Purcell-enhanced emission to the emergence of hybrid electronic and photonic polariton states in the weak and strong coupling limits, respectively. Here, experiments exploring the weak-to-strong coupling transition in CQD-plasmonic lattice hybrid devices at room temperature are presented for varying CQD concentrations. To interpret these results, generalized retarded Fano-Anderson and effective medium models are developed. Individual CQDs are found to interact locally with the lattice yielding Purcell-enhanced emission. At high CQD densities, polariton states emerge as two-peak structures in the photoluminescence, with a third polariton peak, due to collective CQD emission, appearing at still higher CQD concentrations. Our results demonstrate that CQD-lattice plasmon devices represent a highly flexible platform for the manipulation of collective spontaneous emission using lattice plasmons, which could find applications in optoelectronics, ultrafast optical switches, and quantum information science.


The impact of cross-modal correspondences on working memory performance.
Cross-modal correspondences influence perceptual performance in adults, infants, and even nonhuman primates across a variety of different sensory modalities, including tasks involving speeded detection and categorization. However, to date, it is still unclear whether and how correspondences could modulate post-perceptual processes, such as working memory (WM). We investigated this issue using an audiovisual two-back task. In Experiment 1, 3 kinds of correspondences were used: audio/visual numerosity, pitch/shape, and pitch/elevation, each presented congruently (e.g., for numerosity: 3 tones along with 3 shapes) or incongruently (3 tones/2 shapes). Participants attended to the visual or auditory modalities, or both, simultaneously. The results revealed faster target-detection latencies following congruent as compared to incongruent stimulation, especially for numerosity congruence. In Experiment 2, we focused on numerosity, varying the correspondence of the unattended modality, thus having correspondences at both sample (e.g., 3 tones/3 shapes) and target (e.g., 3 tones/3 shapes), only at sample (sample: 3 tones/3 shapes; target: 3 tones/2 shapes), only at target (sample: 3 tones/2 shapes; target: 3 tones/3 shapes), or never. To investigate the information format we included "symbolic" quantities (i.e., visually/auditorily presented digits). The results confirmed the congruence effects, specifically when the correspondence operates at the target display, thus affecting response selection. The experiment revealed modal effects, showing how task-irrelevant digits affect performance only in the auditory modality, while task-irrelevant quantities affect it only when presented visually. Overall, these findings highlight the impact of cross-modal correspondences on WM, adding new light on the link between perceptual and post-perceptual stages of human information processing. (PsycINFO Database Record


Formation and subdivision of deformation structures during plastic deformation.
During plastic deformation of metals and alloys, dislocations arrange in ordered patterns. How and when these self-organization processes take place have remained elusive, because in situ observations have not been feasible. We present an x-ray diffraction method that provided data on the dynamics of individual, deeply embedded dislocation structures. During tensile deformation of pure copper, dislocation-free regions were identified. They showed an unexpected intermittent dynamics, for example, appearing and disappearing with proceeding deformation and even displaying transient splitting behavior. Insight into these processes is relevant for an understanding of the strength and work-hardening of deformed materials.


Ontario pharmacists practicing in family health teams and the patient-centered medical home.
The patient-centered medical home (PCMH) approach continues to gather momentum in the United States and Canada as a broad approach to reform the delivery of the complete primary care system. The family health team (FHT) model implemented in Ontario, Canada, best mirrors the PCMH approach of the United States. The integration of pharmacists as key members of the health care team providing on-site, in-office coordinated care to FHT patients was included from the start of planning the FHT model and represents a substantial opportunity for pharmacists to realize their professional vision. Several research projects in Canada and elsewhere have contributed to providing evidence to support the integration of pharmacists into primary care practice sites. Two major research programs, the Seniors Medication Assessment Research Trial (SMART) cluster randomized controlled trial and the Integrating Family Medicine and Pharmacy to Advance Primary Care Therapeutics (IMPACT) multipronged demonstration project made substantial contributions to evidence-informed policy decisions supporting the integration of pharmacists into FHTs. These projects can provide useful information to support the integration of pharmacists into the PCMH and to encourage further research to better measure the effect of the pharmacist from the holistic patient-centered perspective.


Compliance with guidelines in the surgical management of cutaneous melanoma across the USA.
The National Comprehensive Cancer Network has formulated guidelines for the management of cutaneous malignant melanoma with regard to resection margins (RMs) and regional staging. The aim of this study was to assess compliance with these recommendations in the general population of the USA. The Surveillance, Epidemiology and End-Results database was examined to identify 60 194 patients with malignant melanoma from 2004 to 2008. Multivariate logistic regression analysis was used to identify factors predictive of RM less than 1 cm and noncompliance with sentinel lymph node biopsy (SLNB). The median age of the population was 60 years and the mean Breslow thickness was 1.20±0.16 mm. The majority of patients had a RM of less than 1 cm (58%) and only 53% of eligible patients had undergone SLNB. Regional nodal dissection was performed in 69% of patients with a positive SLNB and in 78% with palpable lymphadenopathy. On multivariate analysis age more than 80 years [odds ratio (OR) 1.3, 95% confidence interval (CI) 1.2-1.4], T1 stage (OR 1.5, 95% CI 1.4-1.6), and head and neck primary (OR 1.4, 95% CI 1.3-1.4) all predicted RM of less than 1 cm. Factors predictive of noncompliance with SLNB recommendations included age more than 60 years (OR 1.6, 95% CI 1.5-1.8), T1 stage (OR 2.0, 95% CI 1.8-2.2), head and neck primary (OR 2.0, 95% CI 1.9-2.2), and RM less than 1 cm (OR 2.1, 95% CI 2.0-2.2). RMs and appropriate SLNB are inadequate in the majority of patients currently being treated for malignant melanoma in the USA. A combination of patient and physician education and perhaps regionalization of melanoma care is needed to improve compliance.


Pancreaticoduodenectomy without homologous blood transfusion in an anemic Jehovah's Witness.
Whipple pancreaticoduodenectomy is an accepted procedure for management of periampullary and pancreatic carcinomas and has modern mortality rates of less than 10%. The procedure is associated with significant operative blood loss. Therefore, blood transfusion is an important supportive measure. We report the case of a bleeding ampullary carcinoma in a Jehovah's Witness who refused transfusion of all homologous blood products. Despite a preoperative hemoglobin level of 51 g/L, curative pancreaticoduodenectomy was successfully performed. The success of the procedure can be primarily attributed to careful surgical technique, intraoperative autotransfusion, avoidance of postoperative complications, minimization of perioperative phlebotomies, use of human recombinant erythropoietin, and, possibly, the use of the perfluorocarbon emulsion Fluosol DA-20%. The case illustrates several important principles for the surgical treatment of patients with severe anemia who refuse transfusion of homologous blood products.


Involvement of interstitial telomeric sequences in two new cases of mosaicism for autosomal structural rearrangements.
Mosaicism for an autosomal structural rearrangement that does not involve ring or marker chromosomes is rare. The mechanisms responsible for genome instability have not always been explained. Several studies have shown that interstitial telomeric sequences (ITSs), involved in some mosaic constitutional anomalies, are potent sources of genomic instability. Here we describe two cases of mosaicism for uncommon constitutional autosomal rearrangements, involving ITSs, identified by karyotyping and characterized by FISH and SNP-array analysis. The first patient, a boy with global developmental delay, had a rare type of pure distal 1q inverted duplication (1q32-qter), attached to the end of the short arm of the same chromosome 1, in approximately 35% of his cells. The second patient, a phenotypically normal man, was diagnosed as having mosaic for a balanced non-reciprocal translocation of the distal segment of 7q (7q33qter), onto the terminal region of the short arm of a whole chromosome 12, in approximately 80% of his cells. The remaining 20% of the cells showed an unbalanced state of the translocation, with only the der(7) chromosome. He was ascertained through his malformed fetus carrying a non-mosaic partial monosomy 7q, identified at prenatal diagnosis. We show that pan-telomeric and subtelomeric sequences were observed at the interstitial junction point of the inv dup(1q) and of the der(12)t(7;12), respectively. The present cases and review of the literature suggest that the presence of ITSs at internal sites of the chromosomes may explain mechanisms of the patients's mosaic structural rearrangements.


Histologically defined intratumoral sequencing uncovers evolutionary cues into conserved molecular events driving gliomagenesis.
Glioblastoma represents an archetypal example of a heterogeneous malignancy. To understand the diverse molecular consequences of this complex tumor ecology, we analyzed RNA-seq data generated from commonly identified intratumoral structures in glioblastoma enriched using laser capture microdissection. Raw gene-level values of fragments per kilobase of transcript per million reads mapped and the associated clinical data were acquired from the publicly available Ivy Glioblastoma Atlas Project database and analyzed using MetaboAnalyst (v3.0). The database includes gene expression data generated from multiple structural features commonly identified in glioblastoma enriched by laser capture microdissection. We uncovered a relationship between subtype heterogeneity in glioblastoma and its unique tumor microenvironment, with infiltrating cells harboring a proneural signature while the mesenchymal subtype was enriched in perinecrotic regions. When evaluating the tumors' transcriptional profiles in the context of their derived structural regions, there was a relatively small amount of intertumoral heterogeneity in glioblastoma, with individual regions from different tumors clustering tightly together. Analyzing the transcriptional profiles in the context of evolutionary progression identified unique cellular programs associated with specific phases of gliomagenesis. Mediators of cell signaling and cell cycle progression appear to be critical events driving proliferation in the tumor core, while in addition to a multiplex strategy for promoting angiogenesis and/or an immune-tolerant environment, transformation to perinecrotic zones involved global metabolic alterations. These findings suggest that intratumoral heterogeneity in glioblastoma is a conserved, predictable consequence to its complex microenvironment, and combinatorial approaches designed to target these unequivocally present tumor biomes may lead to therapeutic gains.


20-year follow-up study of Danish HHT patients-survival and causes of death.
Hereditary Haemorrhagic Telangiectasia (HHT) is a dominantly inheritable disorder, with a wide variety of clinical manifestations due to presence of multiple arteriovenous manifestations. The most common mutations are found in HHT1 (ENG) and HHT2 (ACVRL1) patients, causing alterations in the TGF-β pathway which is responsible for angiogenesis. Modulations of angiogenesis may influence cancer rates. The objective of the study was to evaluate 20-year survival according to HHT subtype, as well as to evaluate differences in causes of death comparing HHT patients and controls. We also wanted to investigate whether cancer morbidity among HHT patients differs from that among controls. We included all HHT patients in the County of Fyn, Denmark, prevalent as of January 1st 1995 in total 73 HHT patients. In addition three age- and sex- matched controls per HHT patient were evaluated, in total 218 controls (one was lost due to registration failure). The controls were defined at start of follow-up in 1995. Information on lifestyle factors was not available. A total of 32 (44%) HHT patients and 97 (44%) controls passed away during follow-up. The survival curves were evenly distributed showing similar survival rates in the two groups. Cancer diagnoses had been registered in the follow-up period in 4 (5%) HHT patients and in 38 (17%) controls. The mortality was not increased among Danish HHT patients compared to controls. This study is based on a clinical unselected series of HHT patients with the whole spectrum of severity, independent of need for medical care. Our data also suggest that HHT patients to a lesser degree than the background population are affected by cancer.


Lessons from history for designing and validating epidemiological surveillance in uncounted populations.
Due to scanty individual health data in low- and middle-income countries (LMICs), health planners often use imperfect data sources. Frequent national-level data are considered essential, even if their depth and quality are questionable. However, quality in-depth data from local sentinel populations may be better than scanty national data, if such local data can be considered as nationally representative. The difficulty is the lack of any theoretical or empirical basis for demonstrating that local data are representative where data on the wider population are unavailable. Thus these issues can only be explored empirically in a complete individual dataset at national and local levels, relating to a LMIC population profile. Swedish national data for 1925 were used, characterised by relatively high mortality, a low proportion of older people and substantial mortality due to infectious causes. Demographic and socioeconomic characteristics of Sweden then and LMICs now are very similar. Rates of livebirths, stillbirths, infant and cause-specific mortality were calculated at national and county levels. Results for six million people in 24 counties showed that most counties had overall mortality rates within 10% of the national level. Other rates by county were mostly within 20% of national levels. Maternal mortality represented too rare an event to give stable results at the county level. After excluding obviously outlying counties (capital city, island, remote areas), any one of the remaining 80% closely reflected the national situation in terms of key demographic and mortality parameters, each county representing approximately 5% of the national population. We conclude that this scenario would probably translate directly to about 40 LMICs with populations under 10 million, and to individual states or provinces within about 40 larger LMICs. Unsubstantiated claims that local sub-national population data are "unrepresentative" or "only local" should not therefore predominate over likely representativity.