Dopamine-induced tyrosine phosphorylation of NR2B (Tyr1472) is essential for ERK1/2 activation and processing of novel taste information.
Understanding the heterosynaptic interaction between glutamatergic and neuromodulatory synapses is highly important for revealing brain function in health and disease. For instance, the interaction between dopamine and glutamate neurotransmission is vital for memory and synaptic plasticity consolidation, and it is known to converge on extracellular signal-regulated kinase (ERK)-MAPK signaling in neurons. Previous studies suggest that dopamine induces N-methyl-D-aspartate (NMDA) receptor phosphorylation at the NR2B Y1472 subunit, influencing receptor internalization at the synaptic plasma membrane. However, it is unclear whether this phosphorylation is upstream to and/or necessary for ERK1/2 activation, which is known to be crucial for synaptic plasticity and memory consolidation. Here, we tested the hypothesis that tyrosine phosphorylation of NR2B at Y1472 is correlated with ERK1/2 activation by dopamine and necessary for it as well. We find that dopamine receptor D1, but not D2, activates ERK1/2 and leads to NR2BY1472 phosphorylation in the mature hippocampus and cortex. Moreover, our results indicate that NR2B Y1472 phosphorylation is necessary for ERK1/2 activation. Importantly, application of dopamine or the D1 receptor agonist SKF38393 to hippocampal slices from NR2B F1472 mutant mice did not result in ERK1/2 activation, suggesting this site is not only correlated with ERK1/2 activation by dopamine stimulation, but also necessary for it. In addition, NR2B F1472 mice show impairment in learning of attenuation of taste neophobia but not associative taste learning. Our study shows that the dopaminergic and glutamatergic transmission converge on the NMDA receptor itself, at the Y1472 site of the NR2B subunit, and that this convergence is essential for ERK1/2 activation in the mature brain and for processing new sensory information in the cortex.


Oil shortages, climate change and collective action.
Concerns over future oil scarcity might not be so worrying but for the high carbon content of substitutes, and the limited capacity of the atmosphere to absorb additional CO(2) from burning fuel. The paper argues that the tools of economics are helpful in understanding some of the key issues in pricing fossil fuels, the extent to which pricing can be left to markets, the need for, and design of, international agreements on corrective carbon pricing, and the potential Prisoners' Dilemma in reaching such agreements, partly mitigated in the case of oil by current taxes and the probable incidence of carbon taxes on the oil price. The 'Green Paradox', in which carbon pricing exacerbates climate change, is theoretically possible, but empirically unlikely.


Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis.
Gastroparesis (GP) is a disabling chronic gastroenterologic disorder with high morbidity that severely impacts patients' quality of life. GP can present acutely after a viral-like gastrointestinal illness resulting in speculation that in some patients, neurologic damage caused by the infection might underlie the pathogenesis of idiopathic gastroparesis (IGP). The aim of this study is to document case reports of Enterovirus (EV) infection as a possible cause of IGP. Eleven patients referred with a diagnosis of GP underwent workup to exclude known causes of GP. Those with a history of flu-like symptoms or gastroenteritis prior to onset of GP symptoms had gastric biopsies taken during upper endoscopy to assess for the presence of gastric mucosal EV infection. Data on presenting symptoms, extra-intestinal symptoms and conditions, prior nutritional support requirements, upper endoscopy findings, and response to therapy were cataloged. Eleven patients were diagnosed as IGP. Nine had active EV infection on gastric biopsies and were included (7/9 female, mean age 43 years). Eight out of nine received EV treatment with antivirals and/or immune therapies, with a wide degree of variability in treatment regimens. Four out of eight who received EV treatment had symptomatic improvement. One patient had stable symptoms. Three patients are currently undergoing therapy. Gastric EV infection was frequently detected (82 %) in patients undergoing investigation for IGP. Antiviral and/or immune therapies against EV seem to be favorable, as most of our patients had resolution of their GP symptoms after treatment. This is the first study to identify EV as a possible infectious etiology of IGP.


A floral-derived compound attractive to the tephritid fruit fly parasitoid Diachasmimorpha longicaudata (Hymenoptera: Braconidae).
Many adult hymenopteran parasitoids, even host-feeding species, consume the nectar of flowering plants. Previous field studies had identified plants attractive (Lobularia maritima L.) and unattractive (Spermacoce verticillata L) to certain opiine braconids (Hymenoptera). Under laboratory conditions, Diachasmimorpha longicaudata (Ashmead), a parasitoid of tephritid fruit fly larvae and representative opiine, responded in flight tunnels to L. maritima but not to S. verticillata. Volatile chemicals of the two flowers were collected and analyzed by using capillary gas liquid chromatography and mass spectral analysis. Acetophenone was isolated from L. maritima but not from S. verticillata. In flight tunnels, D. longicaudata were exposed to 10 concentrations (doses) of acetophenone. Female parasitoids showed a significant attraction to several acetophenone doses, with concentrations of 25 and 50 ng the most attractive. No odor source, either floral or floral-derived, was attractive to male parasitoids. Reliable trapping systems for parasitoid species, particularly species such as D. longicaudata used for augmentative biological control, would be a valuable monitoring tool. At present, there are few, if any, florally derived synthetic lures for attracting hymenopteran parasitoids.


Increased risks of parkinsonism in the 3 years after chronic renal failure.
Movement disorders are one of the central nervous system complications in uremic patients. Asterixis, multifocal myoclonus, and restless leg syndrome are well-documented in this category. Acute parkinsonism, however, is only reported in rare series with a small number of cases. In this study, we investigated the risk for parkinsonism during a 3-year follow-up period after a diagnosis of uremia. The Longitudinal Health Insurance Database in Taiwan was utilised. We identified a total of 2862 patients who had visited ambulatory care centers with a diagnosis of chronic renal failure between 1999 and 2001 as the study cohort. We further randomly selected 14,310 enrollees matched with the study cohort in terms of gender, age, and year of their index visit for comparison. Each patient was individually tracked for 3 years to identify the occurrence of parkinsonism. Stratified Cox proportional hazard regressions (stratified by age and gender) were performed for analyses. We found the annual incidence rates of parkinsonism to be 1.2% and 0.6% in the uremic and non-uremic groups, respectively. Furthermore, uremic patients were more vulnerable to developing parkinsonism with a 1.81-fold higher risk [95%CI = (1.21-2.71)] than the non-uremic group after adjusting for diabetes mellitus, which did not augment the risk. The importance of raising awareness regarding the early symptoms of parkinsonism among patients with uremia is tied to its early identification, with timely aggressive dialysis being able to apply to slow the progression of the disease and its symptoms. Further study is warranted to elucidate the pathophysiology of uremic parkinsonism.


Polarity control in WSe2 double-gate transistors.
As scaling of conventional silicon-based electronics is reaching its ultimate limit, considerable effort has been devoted to find new materials and new device concepts that could ultimately outperform standard silicon transistors. In this perspective two-dimensional transition metal dichalcogenides, such as MoS2 and WSe2, have recently attracted considerable interest thanks to their electrical properties. Here, we report the first experimental demonstration of a doping-free, polarity-controllable device fabricated on few-layer WSe2. We show how modulation of the Schottky barriers at drain and source by a separate gate, named program gate, can enable the selection of the carriers injected in the channel, and achieved controllable polarity behaviour with ON/OFF current ratios >10(6) for both electrons and holes conduction. Polarity-controlled WSe2 transistors enable the design of compact logic gates, leading to higher computational densities in 2D-flatronics.


Assessment of Polarimetric SAR Interferometry for Improving Ship Classification based on Simulated Data.
This paper uses a complete and realistic SAR simulation processing chain, GRECOSAR, to study the potentialities of Polarimetric SAR Interferometry (POLInSAR) in the development of new classification methods for ships. Its high processing efficiency and scenario flexibility have allowed to develop exhaustive scattering studies. The results have revealed, first, vessels' geometries can be described by specific combinations of Permanent Polarimetric Scatterers (PePS) and, second, each type of vessel could be characterized by a particular spatial and polarimetric distribution of PePS. Such properties have been recently exploited to propose a new Vessel Classification Algorithm (VCA) working with POLInSAR data, which, according to several simulation tests, may provide promising performance in real scenarios. Along the paper, explanation of the main steps summarizing the whole research activity carried out with ships and GRECOSAR are provided as well as examples of the main results and VCA validation tests. Special attention will be devoted to the new improvements achieved, which are related to simulations processing a new and highly realistic sea surface model. The paper will show that, for POLInSAR data with fine resolution, VCA can help to classify ships with notable robustness under diverse and adverse observation conditions.


Integration of CellDesigner and SABIO-RK.
Understanding the logic and dynamics of gene-regulatory and biochemical networks is a major challenge for systems biology. To facilitate this research topic, we have developed CellDesigner to visualize, model and simulate biochemical networks. CellDesigner allows the users to easily create networks using solidly defined and comprehensive graphical notation. CellDesigner utilizes SBML to described models and can simulate models using an integrated SBML ODE Solver or third party simulation engine; thus enabling users to simulate through a sophisticated graphical user interface. Although CellDesigner can integrate with existing databases (KEGG, PubMed, BioModels, etc.), by calling a web browser, or connecting to its web page through HTTP, integration with SABIO-RK has the potential to expand connectivity and semi-automate visualization and model building. SABIO-RK contains information about biochemical reactions, related kinetic equations and parameters. Also information about the experimental conditions under which these parameters were measured is stored. By using the Web service API provided by the SABIO-RK team, we have succeeded to directly connect to the database, send search queries by ID or name of its component, and then import the query results into CellDesigner.


Lempel-Ziv complexity of cortical activity during sleep and waking in rats.
Understanding the dynamics of brain activity manifested in the EEG, local field potentials (LFP), and neuronal spiking is essential for explaining their underlying mechanisms and physiological significance. Much has been learned about sleep regulation using conventional EEG power spectrum, coherence, and period-amplitude analyses, which focus primarily on frequency and amplitude characteristics of the signals and on their spatio-temporal synchronicity. However, little is known about the effects of ongoing brain state or preceding sleep-wake history on the nonlinear dynamics of brain activity. Recent advances in developing novel mathematical approaches for investigating temporal structure of brain activity based on such measures, as Lempel-Ziv complexity (LZC) can provide insights that go beyond those obtained with conventional techniques of signal analysis. Here, we used extensive data sets obtained in spontaneously awake and sleeping adult male laboratory rats, as well as during and after sleep deprivation, to perform a detailed analysis of cortical LFP and neuronal activity with LZC approach. We found that activated brain states-waking and rapid eye movement (REM) sleep are characterized by higher LZC compared with non-rapid eye movement (NREM) sleep. Notably, LZC values derived from the LFP were especially low during early NREM sleep after sleep deprivation and toward the middle of individual NREM sleep episodes. We conclude that LZC is an important and yet largely unexplored measure with a high potential for investigating neurophysiological mechanisms of brain activity in health and disease.


Indian childhood cirrhosis (ICC) & ICC-like diseases: the changing scenario of facts versus notions.
Indian childhood cirrhosis (ICC), a disease considered to have been endemic in and unique to India has now been documented in children of non-Indian origin from other countries. More recently available findings from a large multicentre study sponsored by the Indian Council of Medical Research (ICMR) have dispelled some of the generally accepted notions and have established several new facts on different aspects of the disease. All relevant reports on ICC and ICC-like diseases, till date, were reviewed to obtain a proper perspective on the current state of our understanding on this non-Wilsonian copper overload liver disease. A primary role of exogenous copper in causing the disease was earlier debated on the basis of studies in India but investigators abroad studying some sporadic cases and a series of endemic ICC-like diseases supported a hepatotoxic injury by ingested copper in genetically susceptible infants and children in ICC- like disease and in ICC. Epidemiologic and morphologic findings in the well controlled ICMR study based on 225 cases of ICC and 426 controls, all confirmed on liver biopsy, have however, convincingly refuted this concept. Additionally, this study revealed that unlike what has been believed earlier, older children more than 3 yr age can get the disease and that in its natural course the hepatic histology can transform between the characteristic one considered diagnostic and some other patterns, any one of which can be the morphologic manifestation at first presentation of the patient. Older children and cases with milder morphologic changes at presentation had longer survival. The overall inference from critical analysis of all available data is that ICC and ICC-like diseases clinically manifest in a child of any age though common in younger ones, and a clinical diagnosis must be made in any child with so-called 'cryptogenic cirrhosis'. Exposure to exogenous copper in food, milk and water should not be a prerequisite for this consideration. A liver biopsy whenever feasible should be mandatory for confirmation with the understanding that the morphologic changes in liver can present a few other patterns besides the characteristic one currently taken to be diagnostic. The ascribed current decline in encountering ICC is likely to be due partly to missing a diagnosis and partly to a true reduction in incidence consequent on time related economic and socio-cultural changes.


Screening and characterization of surface-tethered cationic peptides for antimicrobial activity.
There is an urgent need to coat the surfaces of medical devices, including implants, with antimicrobial agents to reduce the risk of infection. A peptide array technology was modified to permit the screening of short peptides for antimicrobial activity while tethered to a surface. Cellulose-amino-hydroxypropyl ether (CAPE) linker chemistry was used to synthesize, on a cellulose support, peptides that remained covalently bound during biological assays. Among 122 tested sequences, the best surface-tethered 9-, 12-, and 13-mer peptides were found to be highly antimicrobial against bacteria and fungi, as confirmed using alternative surface materials and coupling strategies as well as coupling through the C and N termini of the peptides. Structure-activity modeling of the structural features determining the activity of tethered peptides indicated that the extent and positioning of positive charges and hydrophobic residues were influential in determining activity.


Pathways between under/unemployment and health among racialized immigrant women in Toronto.
We sought to document pathways between under/unemployment and health among racialized immigrant women in Toronto while exploring the ways in which gender, class, migration and racialization, as interlocking systems of social relations, structure these relationships. We conducted 30 interviews with racialized immigrant women who were struggling to get stable employment that matched their education and/or experience. Participants were recruited through flyers, partner agencies and peer researcher networks. Most interviews (21) were conducted in a language other than English. Interviews were transcribed, translated as appropriate and analyzed using NVivo software. The project followed a community-based participatory action research model. Under/unemployment negatively impacted the physical and mental health of participants and their families. It did so directly, for example through social isolation, as well as indirectly through representation in poor quality jobs. Under/unemployment additionally led to the intensification of job search strategies and of the household/caregiving workload which also negatively impacted health. Health problems, in turn, contributed to pushing participants into long-term substandard employment trajectories. Participants' experiences were heavily structured by their social location as low income racialized immigrant women. Our study provides needed qualitative evidence on the gendered and racialized dimensions of under/unemployment, and adverse health impacts resulting from this. Drawing on intersectional analysis, we unpack the role that social location plays in creating highly uneven patterns of under/unemployment and negative health pathways for racialized immigrant women. We discuss equity informed strategies to help racialized immigrant women overcome barriers to stable work that match their education and/or experience.


Human Pcf11 enhances degradation of RNA polymerase II-associated nascent RNA and transcriptional termination.
The poly(A) (pA) signal possesses a dual function in 3' end processing of pre-mRNA and in transcriptional termination of RNA polymerase II (Pol II) for most eukaryotic protein-coding genes. A key protein factor in yeast and Drosophila Pol II transcriptional termination is the 3'-end processing factor, Pcf11. In vitro studies suggest that Pcf11 is capable of promoting the dissociation of Pol II elongation complexes from DNA. Moreover, several mutant alleles of yeast Pcf11 effect termination in vivo. However, functions of human Pcf11 (hPcf11) in Pol II termination have not been explored. Here we show that depletion of hPcf11 from HeLa cells reduces termination efficiency. Furthermore, we provide evidence that hPcf11 is required for the efficient degradation of the 3' product of pA site cleavage. Finally, we show that these functions of hPcf11 require an intact pA signal.


Effects of a strategy for the promotion of physical activity in students from Bogotá.
To examine the effect of the promotion of physical activity during recess on the levels of physical activity, sedentary behaviors, and adiposity of Colombian students. Three schools were randomly selected by an intervention group in Bogotá, Colombia, in 2013: Intervention (Active Module of Active Recess - MARA) + Text Messages (SMS) (MARA+SMS group), intervention (MARA group), control (control group). Intervention was implemented for ten weeks. The duration and intensity of physical activity and sedentary behaviors were measured objectively using accelerometers Actigraph-GT3X+. Adiposity was measured by body mass index and fat percentage. We measured at baseline (T0) and during the tenth week of intervention (T1). We evaluated the effect of the intervention using a difference-in-difference analysis (DID). We included 120 students (57.5% girls; mean age = 10.5 years; standard deviation [SD] = 0.64). There was a significant increase in the mean daily minutes of moderate to vigorous physical activity in the MARA group (Difference T1-T0 = 6.1 minutes, standard error [SE] = 3.49, p = 0.005) in relation to the control group. There were no significant changes in the minutes of moderate to vigorous physical activity in the MARA+SMS group (Difference T1-T0 = -1.0 minute; SE = 3.06; p = 0.363). The minutes decreased in the control group (Difference T1-T0 = -7.7 minutes; SE = 3.15; p = 0.011). The minutes of sedentary behaviors decreased in the MARA and MARA+SMS groups and increased in the control group (MARA Difference T1-T0 = -15.8 minutes; SE = 10.05; p= 0.279; MARA+SMS Difference T1-T0 = -11.5 minutes; SE = 8.80; p= 0.869; Control Difference T1-T0 = 10.9 minutes; SE = 9.07; p = 0.407). There was a higher participation in the MARA group in relation to the MARA+SMS group (MARA group = 34.4%; MARA+SMS group = 12.1%). There were no significant changes in adiposity at 10 weeks according to difference-in-differences analysis (body mass index p: ΔMARA+SMS group versus Δcontrol group = 0.945, ΔMARA group versus Δcontrol group = 0.847, ΔMARA+SMS group versus ΔMARA group = 0.990; FP p ΔMARA+SMS group versus Δcontrol group = 0.788, ΔMARA group versus Δcontrol group = 0.915, ΔMARA+SMS group versus ΔMARA group = 0.975). The Active Module of Active Recess is a promising strategy to increase physical activity levels and decrease sedentary behavior in students. The addition of Text Messages was not associated with increased moderate to vigorous physical activity or changes in adiposity.


Antioxidant rich grape pomace extract suppresses postprandial hyperglycemia in diabetic mice by specifically inhibiting alpha-glucosidase.
Postprandial hyperglycemia is an early defect of type 2 diabetes and one of primary anti-diabetic targets. Treatment of postprandial hyperglycemia can be achieved by inhibiting intestinal α-glucosidase, the key enzyme for oligosaccharide digestion and further glucose absorption. Grape pomace is winemaking byproduct rich in bioactive food compounds such as phenolic antioxidants. This study evaluated the anti-diabetic potential of two specific grape pomace extracts by determining their antioxidant and anti-postprandial hyperglycemic activities in vitro and in vivo. The extracts of red wine grape pomace (Cabernet Franc) and white wine grape pomace (Chardonnay) were prepared in 80% ethanol. An extract of red apple pomace was included as a comparison. The radical scavenging activities and phenolic profiles of the pomace extracts were determined through the measurement of oxygen radical absorbance capacity, DPPH radical scavenging activity, total phenolic content and flavonoids. The inhibitory effects of the pomace extracts on yeast and rat intestinal α-glucosidases were determined. Male 6-week old C57BLKS/6NCr mice were treated with streptozocin to induce diabetes. The diabetic mice were then treated with vehicle or the grape pomace extract to determine whether the oral intake of the extract can suppress postprandial hyperglycemia through the inhibition of intestinal α-glucosidases. The red grape pomace extract contained significantly higher amounts of flavonoids and phenolic compounds and exerted stronger oxygen radical absorbance capacity than the red apple pomace extract. Both the grape pomace extracts but not the apple pomace extract exerted significant inhibition on intestinal α-glucosidases and the inhibition appears to be specific. In the animal study, the oral intake of the grape pomace extract (400 mg/kg body weight) significantly suppressed the postprandial hyperglycemia by 35% in streptozocin-induced diabetic mice following starch challenge. This is the first report that the grape pomace extracts selectively and significantly inhibits intestinal α-glucosidase and suppresses postprandial hyperglycemia in diabetic mice. The antioxidant and anti-postprandial hyperglycemic activities demonstrated on the tested grape pomace extract therefore suggest a potential for utilizing grape pomace-derived bioactive compounds in management of diabetes.


Conveyor: a workflow engine for bioinformatic analyses.
The rapidly increasing amounts of data available from new high-throughput methods have made data processing without automated pipelines infeasible. As was pointed out in several publications, integration of data and analytic resources into workflow systems provides a solution to this problem, simplifying the task of data analysis. Various applications for defining and running workflows in the field of bioinformatics have been proposed and published, e.g. Galaxy, Mobyle, Taverna, Pegasus or Kepler. One of the main aims of such workflow systems is to enable scientists to focus on analysing their datasets instead of taking care for data management, job management or monitoring the execution of computational tasks. The currently available workflow systems achieve this goal, but fundamentally differ in their way of executing workflows. We have developed the Conveyor software library, a multitiered generic workflow engine for composition, execution and monitoring of complex workflows. It features an open, extensible system architecture and concurrent program execution to exploit resources available on modern multicore CPU hardware. It offers the ability to build complex workflows with branches, loops and other control structures. Two example use cases illustrate the application of the versatile Conveyor engine to common bioinformatics problems. The Conveyor application including client and server are available at http://conveyor.cebitec.uni-bielefeld.de.


Expression of growth factor and growth factor receptor RNA in rat pleural mesothelial cells in culture.
Mineral fiber-induced pleural mesothelioma in the rat is a suitable model for asbestos-induced mesothelioma in humans. A proposed mechanism for the genesis of mesotheliomas is the initiation of an autocrine pathway leading to unregulated growth of the mesothelium. To understand if changes in the expression of mRNA of critical growth factors and receptors occur in target mesothelial cells, it is first necessary to characterize the pattern of expression of these genes in normal mesothelial cells. Rat mesothelial cells were isolated from the parietal pleura and strains of these cells were propagated in vitro. The cells were diploid, had epithelial gross morphology and ultrastructure, and coexpressed keratins and vimentin. Northern blot analysis demonstrated that the cells expressed transforming growth factor beta 1 and fibroblast growth factor. Transcripts for transforming growth factor alpha, platelet-derived growth factor A-chain, and platelet-derived growth factor B-chain were not detected. Receptors for platelet-derived growth factor, epidermal growth factor, and insulin were detected. Although normal mesothelial cells express receptors for these growth factors, no production of their corresponding ligands by these cells could be detected, suggesting that autocrine stimulation of growth via the production of such factors may be specific to transformed mesothelial cells.


Nearly half of families in high-deductible health plans whose members have chronic conditions face substantial financial burden.
High-deductible health plans-typically with deductibles of at least $1,000 per individual and $2,000 per family-require greater enrollee cost sharing than traditional plans. But they also may provide more affordable premiums and may be the lowest-cost, or only, coverage option for many families with members who are chronically ill. We surveyed families with chronic conditions in high-deductible plans and families in traditional plans to compare health care-related financial burden-such as experiencing difficulty paying medical or basic bills or having to set up payment plans. Almost half (48 percent) of the families with chronic conditions in high-deductible plans reported health care-related financial burden, compared to 21 percent of families in traditional plans. Almost twice as many lower-income families in high-deductible plans spent more than 3 percent of income on health care expenses as lower-income families in traditional plans (53 percent versus 29 percent). As health reform efforts advance, policy makers must consider how to modify high-deductible plans to reduce the financial burden for families with chronic conditions.


Chemical modification with high molecular weight polyethylene glycol reduces transduction of hepatocytes and increases efficacy of intravenously delivered oncolytic adenovirus.
Oncolytic adenoviruses are anticancer agents that replicate within tumors and spread to uninfected tumor cells, amplifying the anticancer effect of initial transduction. We tested whether coating the viral particle with polyethylene glycol (PEG) could reduce transduction of hepatocytes and hepatotoxicity after systemic (intravenous) administration of oncolytic adenovirus serotype 5 (Ad5). Conjugating Ad5 with high molecular weight 20-kDa PEG but not with 5-kDa PEG reduced hepatocyte transduction and hepatotoxicity after intravenous injection. PEGylation with 20-kDa PEG was as efficient at detargeting adenovirus from Kupffer cells and hepatocytes as virus predosing and warfarin. Bioluminescence imaging of virus distribution in two xenograft tumor models in nude mice demonstrated that PEGylation with 20-kDa PEG reduced liver infection 19- to 90-fold. Tumor transduction levels were similar for vectors PEGylated with 20-kDa PEG and unPEGylated vectors. Anticancer efficacy after a single intravenous injection was retained at the level of unmodified vector in large established prostate carcinoma xenografts, resulting in complete elimination of tumors in all animals and long-term tumor-free survival. Anticancer efficacy after a single intravenous injection was increased in large established hepatocellular carcinoma xenografts, resulting in significant prolongation of survival as compared with unmodified vector. The increase in efficacy was comparable to that obtained with predosing and warfarin pretreatment, significantly extending the median of survival. Shielding adenovirus with 20-kDa PEG may be a useful approach to improve the therapeutic window of oncolytic adenovirus after systemic delivery to primary and metastatic tumor sites.


Experience with microelectrode guided subthalamic nucleus deep brain stimulation.
Subthalamic deep brain stimulation (DBS) has rapidly become the standard surgical therapy for medically refractory Parkinson disease. However, in spite of its wide acceptance, there is considerable variability in the technical approach. This study details our technique and experience in performing microelectrode recording (MER) guided subthalamic nucleus (STN) DBS in the treatment of Parkinson disease. Forty patients underwent surgery for the implantation of 70 STN DBS electrodes. Stereotactic localization was performed using a combination of magnetic resonance and computed tomographic imaging. We used an array of three microelectrodes, separated by 2 mm, for physiological localization of the STN. The final location was selected based on MER and macrostimulation through the DBS electrode. The trajectory selected for the DBS electrode had an average pass through the STN of 5.6 +/- 0.4 mm on the left and 5.7 +/- 0.4 mm on the right. The predicted location was used in 42% of the cases but was modified by MER in the remaining 58%. Patients were typically discharged on the second postoperative day. Eighty-five percent of patients were sent home, 13% required short-term rehabilitation, and one patient required long-term nursing services. Seven complications occurred over 4 years. Four patients suffered small hemorrhages, one patient experienced a lead migration, one developed an infection of the pulse generator, and one patient suffered from a superficial cranial infection. Simultaneous bilateral MER-guided subthalamic DBS is a relatively safe and well-tolerated procedure. MER plays an important role in optimal localization of the DBS electrodes.


Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains.
Long-term and short-term memories differ primarily in the duration of their retention. At a molecular level, long-term memory (LTM) is distinguished from short-term memory (STM) by its requirement for new gene expression. In addition to transcription (nuclear gene expression) the translation of stored mRNAs is necessary for LTM formation. The mechanisms and functions for temporal and spatial regulation of mRNAs required for LTM is a major contemporary problem, of interest from molecular, cell biological, neurobiological and clinical perspectives. This review discusses primary evidence in support for translational regulatory events involved in LTM and a model in which different phases of translation underlie distinct phases of consolidation of memories. However, it focuses largely on mechanisms of memory persistence and the role of prion-like domains in this defining aspect of long-term memory. We consider primary evidence for the concept that Cytoplasmic Polyadenylation Element Binding (CPEB) protein enables the persistence of formed memories by transforming in prion-like manner from a soluble monomeric state to a self-perpetuating and persistent polymeric translationally active state required for maintaining persistent synaptic plasticity. We further discuss prion-like domains prevalent on several other RNA-binding proteins involved in neuronal translational control underlying LTM. Growing evidence indicates that such RNA regulatory proteins are components of mRNP (RiboNucleoProtein) granules. In these proteins, prion-like domains, being intrinsically disordered, could mediate weak transient interactions that allow the assembly of RNP granules, a source of silenced mRNAs whose translation is necessary for LTM. We consider the structural bases for RNA granules formation as well as functions of disordered domains and discuss how these complicate the interpretation of existing experimental data relevant to general mechanisms by which prion-domain containing RBPs function in synapse specific plasticity underlying LTM.


Tocopherols in the Prevention and Treatment of Atherosclerosis and Related Cardiovascular Disease.
Oxidants/antioxidants play an important role in cellular homeostasis. The human body has endogenous molecules that work as antioxidants, such as glutathione, superoxide dismutase, peroxidases, and catalase. Exogenous substances in the diet, such as β-carotene, ascorbate, and vitamin E, are vital antioxidants. Of these, vitamin E is likely the most important antioxidant in the human diet, and many studies have been performed to elucidate its role in health and disease. Vitamin E is a family of several compounds, of which α-tocopherol is the most widely known analog. α-Tocopherol exhibits antioxidative property in vitro and inhibits oxidation of low-density lipoprotein cholesterol. In addition, α-tocopherol shows anti-inflammatory activity and modulates expression of proteins involved in the uptake, transport, and degradation of atherogenic lipids. Though α-tocopherol exhibits important antioxidant, anti-inflammatory, and antiatherogenic features in vitro, α-tocopherol supplements have failed to consistently reduce atherosclerosis-related events in human trials. The conflicting results have led to reconsideration of the importance previously given to α-tocopherol and led to interest in other members of vitamin E family, especially γ-tocopherol, which exerts a much more potent antioxidant, anti-inflammatory, and cardioprotective effect than α-tocopherol. This reconsideration has been backed by solid laboratory and clinical research. We suggest that the absence of γ-tocopherol in traditional preparations may be one reason for the lack of consistent salutary effects of vitamin E preparations in clinical trials. This review summarizes our current understanding of tocopherols as antioxidant molecules and emerging evidence of an important role of γ-tocopherol in the pathophysiology of atherosclerosis-related cardiovascular disease.


Evaluation of Visible-Near Infrared Reflectance Spectra of Avocado Leaves as a Non-destructive Sensing Tool for Detection of Laurel Wilt.
Laurel wilt, caused by the fungus Raffaelea lauricola, affects the growth, development, and productivity of avocado, Persea americana. This study evaluated the potential of visible-near infrared spectroscopy for non-destructive sensing of this disease. The symptoms of laurel wilt are visually similar to those caused by freeze damage (leaf necrosis). In this work, we performed classification studies with visible-near infrared spectra of asymptomatic and symptomatic leaves from infected plants, as well as leaves from freeze-damaged and healthy plants, both of which were non-infected. The principal component scores computed from principal component analysis were used as input features in four classifiers: linear discriminant analysis, quadratic discriminant analysis (QDA), Naïve-Bayes classifier, and bagged decision trees (BDT). Among the classifiers, QDA and BDT resulted in classification accuracies of higher than 94% when classifying asymptomatic leaves from infected plants. All of the classifiers were able to discriminate symptomatic-infected leaves from freeze-damaged leaves. However, the false negatives mainly resulted from asymptomatic-infected leaves being classified as healthy. Analyses of average vegetation indices of freeze-damaged, healthy (non-infected), asymptomatic-infected, and symptomatic-infected leaves indicated that the normalized difference vegetation index and the simple ratio index were statistically different.


Impact of the counterion on the solubility and physicochemical properties of salts of carboxylic acid drugs.
Salt formation is a widely used approach to improve the physicochemical and solid state properties of an active pharmaceutical ingredient. In order to better understand the relationships between the active drug, the selected counterion and the resultant salt form, crystalline salts were formed using four different carboxylic acid drugs and a closely related series of amine counterions. Thirty-six related crystalline salts were prepared, characterized and the relationship between solubility and dissolution behaviour and other properties of the salt and the counterion studied. Salts of four model acid drugs, gemfibrozil, flurbiprofen, ibuprofen and etodolac were prepared using the counterions butylamine, hexylamine, octylamine, benzylamine, cyclohexylamine, tert-butylamine, 2-amino-2-methylpropan-1-ol, 2-amino-2-methylpropan-1,3-diol and tris(hydroxymethyl)aminomethane. Salt formation was confirmed, the salts were characterized and their corresponding solubilities determined and rationalized with respect to the counterions' properties. The properties of the salt highly dependent on the nature of the counterion and, although there is considerable variation, some general conclusion can be drawn. For the alkyl amines series, increasing chain length leads to a reduction in solubility across all the acidic drugs studied and a reduction in melting point, thus contradicting simplistic relationships between solubility and melting point. Small, compact counterions consistently produce crystalline salts with high melting point accompanied with a modest improvement in solubility and the nature of hydrogen bonding between the ions has a major impact on the solubility.


Prevalence and associated factors of adolescent undernutrition in Ethiopia: a systematic review and meta-analysis.
In Ethiopia, there are different pocket studies that assessed adolescent undernutrition which came up with inconsistent and inconclusive findings. Therefore, estimating the pooled prevalence and associated factors of the adolescent undernutrition using meta-analysis is crucial in Ethiopia. A systematic review of eligible articles was conducted using preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. A comprehensive searching of the literature was made in Pub Med, Scopus, Google, Google Scholar, Cochrane Library and CINAHL. The quality of the articles included in the review was assessed using the Newcastle-Ottawa Scale (NOS) for non-randomized studies in meta-analyses. The pooled prevalence and odds ratio of the associated factors with their 95% confidence interval was computed using STATA version 14 software. Twenty-two studies were included in the meta-analysis with a total of 17,854 adolescents. Using the random-effects model analysis, the pooled prevalence of stunting and underweight was 20.7% (95% CI: 16.08, 25.33) and 27.5% (95% CI: 17.9, 57.14), respectively. Rural residence, having family size≥5, households with an unprotected water source for drinking and food-insecure household were significant associated factors for adolescent stunting. Early adolescent age (10-14 years), family size≥5, food-insecure household, lack of latrine, WHO diet diversity score < 4, mother educational status (with no formal education) were significant associated factors for adolescent underweight. Adolescent undernutrition remains one of the most important public health problems in Ethiopia. Almost a quarter of Ethiopian adolescents were affected by stunting and underweight. Large family size, rural residence and unprotected source of drinking water were the associated factors for adolescent stunting. Similarly, large family size, early age of adolescent, lack of latrine, low dietary diversity score, mother illiteracy, and food insecure household were the associated factors for adolescent underweight. It would be good to give high emphasis on adolescent undernutrition and it is important to address the above mentioned associated factors during adolescent nutritional interventions in Ethiopia.


International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors.
The calcitonin family of peptides comprises calcitonin, amylin, two calcitonin gene-related peptides (CGRPs), and adrenomedullin. The first calcitonin receptor was cloned in 1991. Its pharmacology is complicated by the existence of several splice variants. The receptors for the other members the family are made up of subunits. The calcitonin-like receptor (CL receptor) requires a single transmembrane domain protein, termed receptor activity modifying protein, RAMP1, to function as a CGRP receptor. RAMP2 and -3 enable the same CL receptor to behave as an adrenomedullin receptor. Although the calcitonin receptor does not require RAMP to bind and respond to calcitonin, it can associate with the RAMPs, resulting in a series of receptors that typically have high affinity for amylin and varied affinity for CGRP. This review aims to reconcile what is observed when the receptors are reconstituted in vitro with the properties they show in native cells and tissues. Experimental conditions must be rigorously controlled because different degrees of protein expression may markedly modify pharmacology in such a complex situation. Recommendations, which follow International Union of Pharmacology guidelines, are made for the nomenclature of these multimeric receptors.


Prevalence and clinical implications of Staphylococcus aureus with a vancomycin MIC of 4 microg/ml in Korea.
In addition to vancomycin-intermediate Staphylococcus aureus (VISA), S. aureus with a vancomycin MIC of 4 microg/ml has been reported to be the cause of therapeutic failure. This study was designed to determine the prevalence of methicillin-resistant S. aureus (MRSA) with a vancomycin MIC of 4 microg/ml and to clarify the clinical characteristics of infections caused by these isolates. During the 8-week period from April to May, 2001, 27 hospitals participated in a nationwide surveillance program for VISA and vancomycin-resistant S. aureus (VRSA) in Korea. After screening on brain-heart infusion agar containing 4 microg/ml of vancomycin as previously described, 100 isolates with confluent growth were tested. The medical records of the patients involved were reviewed. Even though VISA or VRSA was not detected among 3,756 MRSA isolates, 18 (0.5%) had a vancomycin MIC of 4 microg/ml. The infections in 12 of these patients, excluding 5 that were colonized, were 8 chronic osteomyelitis, 1 surgical site infection, 1 pneumonia, 1 intra-abdominal infection, and 1 catheter-related infection. Although 11 cases were exposed to glycopeptides for a long time (median 56 days), the site of infection became culture-negative in only 1 case. Two patients died of their S. aureus infections. MRSA with a vancomycin MIC of 4 microg/ml was rare. Chronic osteomyelitis was the most common type of infection, and prolonged exposure to glycopeptides was associated with reduced susceptibility to vancomycin.


Successful termination of a furunculosis outbreak due to lukS-lukF-positive, methicillin-susceptible Staphylococcus aureus in a German village by stringent decolonization, 2002-2005.
Skin infections due to Staphylococcus aureus have recently become a public concern, mainly because of emerging resistance against widely used antibiotics and specific virulence determinants. Strains harboring the lukS-lukF gene (which codes for Panton-Valentine leukocidin) are frequently associated with severe furunculosis. Generally applicable strategies for the control of community outbreaks of furunculosis have not been defined. We report the investigation and successful termination of an outbreak of furunculosis due to lukS-lukF-positive S. aureus in a German village (n=144). Nasal swab specimens were obtained from village residents. A retrospective cohort study was conducted. Nasally colonized persons, persons who had current furuncles or who had experienced relapsing furuncles since 2002, and their family members underwent stringent decolonization measures using mupirocin nasal ointment and disinfecting wash solution. Multiple nasal swab specimens were obtained to monitor the long-term outcome of decolonization measures. From January 1998 through December 2004, 42 cases and 59 relapses of furunculosis were identified by active case finding. Of 140 participants tested, 51 (36%) were found to be nasally colonized with S. aureus. In 9 participants, the strain was positive for lukS-lukF. No methicillin resistance was detected. Risk of furunculosis was associated with contact with case patients (relative risk, 6.8; 95% confidence interval, 3.2-14.3) and nasal colonization with a lukS-lukF-positive strain of S. aureus (relative risk, 3.6; 95% confidence interval, 2.3-5.9). Passive surveillance implemented in January 2005 did not detect any case of lukS-lukF-positive, S. aureus-associated furuncles in this village. This report describes a successful strategy for terminating the transmission of epidemic strains of S. aureus among a nonhospitalized population.


The ts13 mutation in the TAF(II)250 subunit (CCG1) of TFIID directly affects transcription of D-type cyclin genes in cells arrested in G1 at the nonpermissive temperature.
The general transcription initiation factor TFIID contains the TATA-binding protein (TBP) and TBP-associated factors (TAFs) implicated in the function of gene-specific activators. Previous studies have indicated that a hamster cell line (ts13) with a point mutation in the TAF(II)250/CCG1 (TAF(II)250) gene shows temperature-sensitive expression of a subset of genes and arrests in late G1 at 39.5 degrees C. Here, we report the identification of cell cycle-specific (G1-specific) genes that appear to be regulated directly through TAF(II)250 both in vivo and in vitro. Transcription rates of several cell cycle-regulatory genes were determined by run-on assays in nuclei from ts13 cells grown at permissive (33 degrees C) and nonpermissive (39.5 degrees C) temperatures. Temperature-dependent differences in transcription rates were observed for cyclin A, D1, and D3 genes. In transient-transfection assays, the human cyclin D1 promoter fused to a luciferase reporter showed a temperature-dependent reduction in activity in ts13 cells but not in parental BHK cells. In in vitro assays, upstream sequence-dependent transcription from the human cyclin D1 promoter was significantly reduced in ts13 nuclear extracts preincubated at 30 degrees C but not in similarly treated BHK nuclear extracts, and transcription in the ts13 extract was restored by addition of an affinity-purified human TFIID. Preincubation of the ts13 nuclear extracts did not affect the function of several GAL4-activation domain fusion proteins (GAL4-VP16, GAL4-p65, and GAL4-p53) on either the adenovirus major late or cyclin D1 core promoter bearing GAL4 sites, further indicating that the effect of the TAF(II)250 mutation is both core promoter and activator specific.


High Mobility Group Box 1 Expression in Oral Inflammation and Regeneration.
High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein of about 30 kDa. It is released from a variety of cells into the extracellular milieu in response to inflammatory stimuli and acts on specific cell-surface receptors, such as receptors for advanced glycation end-products (RAGE), Toll-like receptor (TLR)2, TLR4, with or without forming a complex with other molecules. HMGB1 mediates various mechanisms such as inflammation, cell migration, proliferation, and differentiation. On the other hand, HMGB1 enhances chemotaxis acting through the C-X-C motif chemokine ligand (CXCL)12/C-X-C chemokine receptor (CXCR)4 axis and is involved in regeneration. In the oral cavity, high levels of HMGB1 have been detected in the gingival tissue from periodontitis and peri-implantitis patients, and it has been shown that secreted HMGB1 induces pro-inflammatory cytokine expression, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which prolong inflammation. In contrast, wound healing after tooth extraction or titanium dental implant osseointegration requires an initial acute inflammation, which is regulated by secreted HMGB1. This indicates that secreted HMGB1 regulates angiogenesis and bone remodeling by osteoclast and osteoblast activation and promotes bone healing in oral tissue repair. Therefore, HMGB1 can prolong inflammation in the periodontal tissue and, conversely, can regenerate or repair damaged tissues in the oral cavity. In this review, we highlight the role of HMGB1 in the oral cavity by comparing its function and regulation with its function in other diseases. We also discuss the necessity for further studies in this field to provide more specific scientific evidence for dentistry.


Sex differences in anti-allodynic, anti-hyperalgesic and anti-edema effects of Δ(9)-tetrahydrocannabinol in the rat.
Cannabinoid agonists such as Δ(9)-tetrahydrocannabinol (THC) are more potent and/or efficacious antinociceptive agents in female than male rats using acute pain models. We tested the hypothesis that THC is more effective in females than males using a model of longer-lasting, inflammatory pain. THC's anti-allodynic, anti-hyperalgesic, and anti-edema effects were examined 1, 3, and 7 days after injection of complete Freund's adjuvant (CFA) into the hind paw. Systemically administered THC (0.32-3.2mg/kg, intraperitoneally [i.p.], same dose each day) was significantly more effective in females than males in attenuating CFA-induced thermal hyperalgesia, but was also more sedative in females. When administered locally into the inflamed hind paw, THC (250-500 μg intraplantar, i.pl.) did not affect locomotor activity in either sex, yet produced greater anti-allodynic and anti-hyperalgesic effects in females than males. Despite THC's greater anti-allodynic and anti-hyperalgesic effects in females, both i.p. and i.pl. THC reduced hind paw thickness (edema) more in males. The anti-hyperalgesic effect of i.p. THC was blocked by the CB1 receptor-selective antagonist rimonabant in both sexes. Similarly, i.pl. rimonabant antagonized i.pl. THC's effects in both sexes; in contrast, the CB2 antagonist SR144528 significantly attenuated i.pl. THC's anti-allodynic effect only in females. Intraplantar SR144528 also antagonized i.pl. THC's anti-edema effect in males. This study suggests that cannabinoids may be better at reducing edema in males while being more effective against inflammatory pain in females. Furthermore, sex differences in THC's peripheral effects against inflammatory pain may be a result of activation of both types of cannabinoid receptors in females, in contrast to predominantly CB1 receptors in males.


Engineering the Yeast Saccharomyces cerevisiae for the Production of L-(+)-Ergothioneine.
L-(+)-Ergothioneine (ERG) is an unusual, naturally occurring antioxidant nutraceutical that has been shown to help reduce cellular oxidative damage. Humans do not biosynthesise ERG, but acquire it from their diet; it exploits a specific transporter (SLC22A4) for its uptake. ERG is considered to be a nutraceutical and possible vitamin that is involved in the maintenance of health, and seems to be at too low a concentration in several diseases in vivo. Ergothioneine is thus a potentially useful dietary supplement. Present methods of commercial production rely on extraction from natural sources or on chemical synthesis. Here we describe the engineering of the baker's yeast Saccharomyces cerevisiae to produce ergothioneine by fermentation in defined media. After integrating combinations of ERG biosynthetic pathways from different organisms, we screened yeast strains for their production of ERG. The highest-producing strain was also engineered with known ergothioneine transporters. The effect of amino acid supplementation of the medium was investigated and the nitrogen metabolism of S. cerevisiae was altered by knock-out of TOR1 or YIH1. We also optimized the media composition using fractional factorial methods. Our optimal strategy led to a titer of 598 ± 18 mg/L ergothioneine in fed-batch culture in 1 L bioreactors. Because S. cerevisiae is a GRAS ("generally recognized as safe") organism that is widely used for nutraceutical production, this work provides a promising process for the biosynthetic production of ERG.


Validity of the ActiReg system and a physical activity interview in assessing total energy expenditure in long-term survivors after total gastrectomy.
Malnutrition is common after total gastrectomy. There is a need for clinically useful methods to assess energy requirements. We aimed to validate measurements of energy expenditure by an activity monitor (ActiReg) and a physical activity interview (HPAQ(modified)), in long-term survivors after gastrectomy for gastric carcinoma, using doubly labelled water as reference method. Total energy expenditure (TEE) was estimated by DLW (14 days), ActiReg (3 days) and HPAQ(modified) (7 days) in 15 patients. Measurements were repeated after 12 months. Basal metabolic rate was measured with indirect calorimetry. ActiReg and HPAQ(modified) both underestimated TEE by 180 (+/-254 SD) and 130 (+/-326 SD)kcalday(-1), i.e. 14% vs. 12%, respectively. However, this was evident only at higher levels of physical activity (PAL(DLW)> or =1.65), whereas at lower levels (PAL<1.65) no difference was found. There were no changes in TEE over time independent of the method used. DLW and ActiReg had approximately the same width of the 95% confidence interval of this estimate, while it was 2.4 times larger by HPAQ(modified). Both simple methods underestimated total energy expenditure at higher, but not at lower physical activity levels. The ActiReg method appears useful to estimate changes in TEE over time.


Phylogenetic profiling: how much input data is enough?
Phylogenetic profiling is a well-established approach for predicting gene function based on patterns of gene presence and absence across species. Much of the recent developments have focused on methodological improvements, but relatively little is known about the effect of input data size on the quality of predictions. In this work, we ask: how many genomes and functional annotations need to be considered for phylogenetic profiling to be effective? Phylogenetic profiling generally benefits from an increased amount of input data. However, by decomposing this improvement in predictive accuracy in terms of the contribution of additional genomes and of additional annotations, we observed diminishing returns in adding more than ∼ 100 genomes, whereas increasing the number of annotations remained strongly beneficial throughout. We also observed that maximising phylogenetic diversity within a clade of interest improves predictive accuracy, but the effect is small compared to changes in the number of genomes under comparison. Finally, we show that these findings are supported in light of the Open World Assumption, which posits that functional annotation databases are inherently incomplete. All the tools and data used in this work are available for reuse from http://lab.dessimoz.org/14_phylprof. Scripts used to analyse the data are available on request from the authors.


Alien insects in Italy: comparing patterns from the regional to European level.
The introduction of species outside their native range contributes to the loss of biodiversity, alters the structure and functioning of ecosystems, and damages economy and human health. Insects are one of the taxa with the highest frequency of introduction due to their high diversity, biological properties, and close association with human activities. Here, the allodiversity of Italian entomofauna was analyzed, with a focus on Tuscany (Central Italy). A list of alien insects in Tuscany is included. The status of the alien entomofauna in Italy was updated. The number of alien insects amounts to 122 in Tuscany and 923 in Italy. An introduction rate of 98 species per decade was estimated in Italy. In Tuscany, alien insects belong to 10 orders, mostly Coleoptera (38%), Hemiptera (Sternorrhyncha and Auchenorrhyncha) (23%), and Hymenoptera (13%). They have been most often introduced through vegetable items (ornamental plants or crops). Most species come from the Nearctic region (26%) and are both phytophagous (63%) and amphigonic (80%). Differences and similarities in introduction patterns and in insect abundances across orders among regional, national, and European scales, also considering worldwide abundances, are discussed. Finally, a paucity of information regarding the negative impacts of many species, except for economic pests, phytosanitary threats, and vectors of disease, is underlined. A deeper understanding of the alien insects' ecological impact might help designate policies aimed at preventing further introductions and control the invasive populations of already established species.


Switching single chain magnet behavior via photoinduced bidirectional metal-to-metal charge transfer.
The preparation of single-chain magnets (SCMs) with photo-switchable bistable states is essential for the development of high-density photo-recording devices. However, the reversible switching of the SCM behavior upon light irradiation is a formidable challenge. Here we report a well-isolated double zigzag chain {[Fe(bpy)(CN)4]2[Co(phpy)2]}·2H2O (bpy = 2,2'-bipyridine, phpy = 4-phenylpyridine), which exhibits reversible redox reactions with interconversion between FeIIILS(μ-CN)CoIIHS(μ-NC)FeIIILS (LS = low-spin, HS = high-spin) and FeIIILS(μ-CN)CoIIILS(μ-NC)FeIILS linkages under alternating irradiation with 808 and 532 nm lasers. The bidirectional photo-induced metal-to-metal charge transfer results in significant changes of anisotropy and intrachain magnetic interactions, reversibly switching the SCM behavior. The on-switching SCM behavior driven by light irradiation at 808 nm could be reversibly switched off by irradiation at 532 nm. The results provide an additional and independent way to control the bistable states of SCMs by switching in the 0 → 1 → 0 sequence, with potential applications in high density storage and molecular switches.


Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma.
HOX genes are a family of developmental genes that are expressed neither in the developing forebrain nor in the normal brain. Aberrant expression of a HOX-gene dominated stem-cell signature in glioblastoma has been linked with increased resistance to chemo-radiotherapy and sustained proliferation of glioma initiating cells. Here we describe the epigenetic and genetic alterations and their interactions associated with the expression of this signature in glioblastoma. We observe prominent hypermethylation of the HOXA locus 7p15.2 in glioblastoma in contrast to non-tumoral brain. Hypermethylation is associated with a gain of chromosome 7, a hallmark of glioblastoma, and may compensate for tumor-driven enhanced gene dosage as a rescue mechanism by preventing undue gene expression. We identify the CpG island of the HOXA10 alternative promoter that appears to escape hypermethylation in the HOX-high glioblastoma. An additive effect of gene copy gain at 7p15.2 and DNA methylation at key regulatory CpGs in HOXA10 is significantly associated with HOX-signature expression. Additionally, we show concordance between methylation status and presence of active or inactive chromatin marks in glioblastoma-derived spheres that are HOX-high or HOX-low, respectively. Based on these findings, we propose co-evolution and interaction between gene copy gain, associated with a gain of chromosome 7, and additional epigenetic alterations as key mechanisms triggering a coordinated, but inappropriate, HOX transcriptional program in glioblastoma.


Epilepsy-related mortality is low in children: a 30-year population-based study in Olmsted County, MN.
Epilepsy is a common childhood neurologic disorder, affecting 0.5-1% of children. Increased mortality occurs due to progression of underlying disease, seizure-related accidents, suicide, status epilepticus, aspiration during seizures, and sudden unexplained death in epilepsy (SUDEP). Previous studies show mortality rates of 2.7-6.9 per 1,000 person-years. Potential risk factors include poor seizure control, intractable epilepsy, status epilepticus, tonic-clonic seizures, mental retardation, and remote symptomatic cause of epilepsy. Few population-based studies of mortality and SUDEP in childhood-onset epilepsy have been published. The purpose of this study is to report mortality and SUDEP from a 30-year population-based cohort of children with epilepsy. The Medical Diagnostic Index of the Rochester Epidemiology Project was searched for all codes related to seizure and convulsion in children living in Olmsted County, Minnesota and of ages birth through 17 years from 1980 through 2009. The medical records of these children were reviewed to identify all those with new-onset epilepsy, and to abstract other baseline and follow-up information. Potential risk factors including seizure type, epilepsy syndrome, history of status epilepticus, the presence and severity of neurologic impairment, and epilepsy outcome was reviewed. Epilepsy outcome was characterized by seizure frequency, number of antiseizure medications (antiepileptic drugs, AEDs) used, and number of AEDs failed due to lack of efficacy, and epilepsy intractability at 1 year and 2, 3, 5, 10, 15, and 20 years after epilepsy onset. We followed all children through their most recent visit to determine vital status, cause of death, and whether autopsy was performed. From 1980 to 2009, there were 467 children age birth through 17 years diagnosed with epilepsy while residents of Olmsted County, Minnesota, and who had follow-up beyond the time of epilepsy diagnosis. Children were followed for a median of 7.87 years after the time of diagnosis (range 0.04-29.49 years) for a total of 4558.5 person-years. Sixteen (3.4%) of the children died, or 3.51 deaths per 1,000 person-years. Two deaths were epilepsy related (12.5%) for a rate of 0.44 per 1,000 person-years. One of these children died of probable SUDEP and one died of aspiration during a seizure. The remaining 14 deaths (87.5%) were caused by other complications of underlying disease. Several risk factors for mortality were found, including abnormal cognition, abnormal neurologic examination, structural/metabolic etiology for epilepsy, and poorly controlled epilepsy. Although mortality in children with epilepsy was higher than what would be expected in the general pediatric population, death occurred significantly more in children with neurologic impairment and poorly controlled epilepsy. Epilepsy-related death, including SUDEP, was rare and mortality due to epilepsy alone was similar to the expected mortality in the general population (observed deaths = 2, expected deaths = 1.77; standardized mortality ratio 1.13, 95% confidence interval 0.19-3.73, p = 0.86). By contrast, most children died of complications of the underlying neurologic disease or unrelated disease rather than the epilepsy.


Attenuated relationship between salivary oxytocin levels and attention to social information in adolescents and adults with autism spectrum disorder: a comparative study.
Previous research studies have assessed the relationship between attention to social information and peripheral (e.g., plasma and salivary) oxytocin (OT) levels in typically developing (TD) children and children with autism spectrum disorder (ASD). A relationship between them was observed in TD children, but not in children with ASD. However, this relationship remains unexamined in other age groups. To clarify whether this lack of association is maintained throughout development in individuals with ASD, we aimed to assess the relationship between salivary OT levels and attention to social information in adolescents and adults with and without ASD. We recruited male adolescents and adults with ASD (n = 17) and TD participants (n = 24). Using the all-in-one eye-tracking system Gazefinder, we measured the percentage fixation time allocated to social information. We also measured the salivary OT levels and Autism Spectrum Quotient (AQ) of participants. Subsequently, we confirmed group differences and conducted a correlation analysis to investigate the relationships between these three measures. Salivary OT levels did not show any significant difference between the ASD and TD groups and were negatively correlated with the AQ in the whole-group analysis, but not in within-group analysis. Individuals with ASD had significantly lower percentage fixation times than did TD individuals for eye regions in human faces with/without mouth motion, for upright biological motion, and for people regions in the people and geometry movies. The percentage of fixation for geometric shapes in the people and geometry movies was significantly higher in the ASD than in the TD group. In the TD group, salivary OT levels were positively correlated with percentage fixation times for upright biological motion and people and negatively correlated with inverted biological motion and geometry. However, no significant correlations were found in the ASD group. Our exploratory results suggest that salivary OT levels in adolescents and adults with ASD are less indicative of attention to social stimuli than they are in TD adolescents and adults. It is suggested that their association is slightly weaker in adolescents and adults with ASD and that this attenuated relationship appears to be maintained throughout development.


The adaptive capacity of smallholder mixed-farming systems to the impact of climate change: The case of KwaZulu-Natal in South Africa.
Climate change poses a serious threat to efforts by developing countries to ensure food security and poverty reduction. The National Development goals of South Africa envisage the agricultural sector as a key driver for job creation and economic growth. This article seeks to investigate the adaptive capacity of the Ncunjane farming community in Msinga, KwaZulu-Natal in response to drought spells of 2010 and 2014. This article draws on data collected using both qualitative and quantitative methods in 2011 and later in 2015 with the data analysed through the Statistical Package for Social Science to determine significant correlations between variables. Analysis of the vulnerability and adaptive capacity is performed using conceptual framework. This study found that both smallholder farmers who engaged in livestock and crop production have experienced high cattle mortalities and stagnant crop productivity, which in turn put pressure on already constrained disposable household income because of increased food costs and agricultural input costs, particularly supplementary animal feed. Cattle owners were more vulnerable to drought because of poor risk management and thus became highly dependent on government to provide drought relief. Application for government drought relief was found not to be effective in cases of large herds of cattle. Variability of rainfall and prolonged heat spells has a significant impact on the sustainability of smallholder mixed-farming systems, leaving agriculture as a highly questionable form of livelihood for rural farming communities such as Msinga. The article recommends strengthened institutional mechanisms so that stakeholders should play a more meaningful role within provincial and local agriculture in leveraging government support but places emphasis on the adoption of innovative strategies that can potentially yield significantly resilient smallholder mixed-farming systems in the wake of climate variability.


Treatment decision making in women newly diagnosed with breast cancer.
The purpose of this study was to explore the hypothesis that women with breast cancer had specific preferences about the degree of control they wanted over treatment decision making. One hundred fifty women, newly diagnosed with breast cancer, were interviewed and their preferences for participation in treatment decision making were established using a measurement tool designed to elicit decision-making preferences (Degner LF, Sloan JF. Decision making during serious illness: What role do patients really want to play? J Clin Epidemiol 1992;45:944-50). Two hundred women with benign breast disease served as a descriptive comparison group. Unfolding theory (Coombs CH. A theory of data. New York: John Wiley & Sons, 1964) provided a means of analyzing the data so that the degree of control preferred by each woman could be established. The majority of the newly diagnosed women preferred to play a passive role in treatment decision making, leaving the decision-making responsibility to their physician, whereas the benign control group preferred a collaborative role in which joint decisions could be made between the patient and the physician. The implications of the results for patient participation are discussed.


NSAID-exacerbated respiratory disease: a meta-analysis evaluating prevalence, mean provocative dose of aspirin and increased asthma morbidity.
The prevalence and mean provocative dose of oral aspirin (MPDA) triggering respiratory reactions in people with asthma have been inconsistently reported, and the relationship between NSAID-exacerbated respiratory disease (NERD) and asthma morbidity was less well quantified. A systematic review was performed by identifying studies diagnosing NERD using blinded, placebo-controlled oral provocation challenge tests (OPCTs) or by self-reported history in people with asthma. Data were extracted, and effect estimates for changes in respiratory function, MPDA and asthma morbidity were pooled using random-effects meta-analysis. The prevalence of NERD in adults with asthma was 9.0% (95% CI 6-12%) using OPCTs and 9.9% (95% CI 9.4-10.5%) using self-reported history from questionnaires. The MPDA in adults with NERD was 85.8 mg (95% CI 73.9-97.6). In people with NERD, the risk of: uncontrolled asthma was increased twofold (RR 1.96 (95% CI 1.25-3.07)); severe asthma and asthma attacks was increased by 60% (RR 1.58 (95% CI 1.15-2.16) and RR 1.59 (95% CI 1.21-2.09), respectively); emergency room visits was increased by 80% (RR 1.79 (95% CI 1.29-2.49)); and asthma hospitalization was increased by 40% (RR 1.37 (95% CI 1.12-1.67)) compared to people with NSAID-tolerant asthma. Respiratory reactions triggered by oral aspirin in people with asthma are relatively common. At the population level, the prevalence of NERD was similar when measured using appropriately conducted OPCTs or by self-reported history. On average, respiratory reactions were triggered by clinically relevant doses of oral aspirin. Asthma morbidity was significantly increased in people with NERD who potentially require more intensive monitoring and follow-up.


Perceptions of traditional Chinese medicine for chronic disease care and prevention: a cross-sectional study of Chinese hospital-based health care professionals.
In China, demands for disease prevention and health care and the prevalence of chronic non-communicable diseases have increased. TCM and general hospitals are increasingly utilizing TCM strategies for chronic non-communicable disease care and prevention. This study aimed to investigate health care professionals' (HCPs') perceptions of TCM for prevention, their TCM knowledge, and their abilities to provide such services in TCM and general hospitals. This cross-sectional study investigated Chinese medicine hospitals and Chinese medicine departments in general hospitals in five Chinese cities. A self-designed questionnaire used to study 400 HCPs focused on basic demographic data, the demand for and effects of TCM for prevention and treatment, and their perceptions of such service implementation. The data analysis included chi-squared tests and descriptive and multi-factor analyses. The 335 HCP respondents comprised 230 (68.7%) females and 105 (31.3%) males, 75.5% of whom overall had knowledge of TCM preventive and health care services. Respondents older than 40 years (28.6%) had greater knowledge of and satisfaction with TCM for preventive and health care services than younger respondents. Moreover, 97.7% of the older respondents were clearly willing to provide TCM preventive services for chronic diseases, 67.8% of whom indicated that their hospitals already provided TCM for prevention and treatment. According to the chi-squared test results, the TCM service characteristics in hospitals, hospital outlooks regarding TCM and TCM development in hospitals were the primary factors affecting the respondents' perceptions of TCM for chronic disease care and prevention. The multivariate analysis showed high satisfaction as significantly associated with older providers and those with lengthier work experience, particularly among those who worked in hospitals that provided typical TCM services and had positive attitudes towards TCM. The study HCPs had relatively satisfactory knowledge of and positive attitudes towards TCM for chronic disease care and prevention and would use it in practice. Their perceptions and satisfaction levels correlated closely with the successful application of TCM for preventive care and treatment in hospitals. While the use of TCM for prevention and treatment was well developed in some hospitals, further improvements are warranted.


The role of lateralisation and sex on insular cortex: 3D volumetric analysis
The insula has attracted the attention of many neuroimaging studies because of its key role between brain structures. However, the number of studies investigating the effect of sex and laterality on insular volume is insufficient. The aim of this study was to investigate the differences in insular volume between sexes and hemispheres. A total of 47 healthy participants [24 males (20.08 ± 1.44 years) and 23 females (19.57 ± 0.90 years)] underwent magnetic resonance imaging (MRI). Imaging was performed using the 3T MRI scanner. The insular volume was measured using the Individual Brain Atlases using Statistical Parametric Mapping (IBASPM); total intracranial, cerebral, grey and white matter volumes were measured using volBrain. The right insular volume was significantly higher than the left insular volume in the participants, and the left cerebral volume was significantly higher than the right cerebral volume (p < 0.05). The total brain, total cerebral, left and right insular, and cerebral volumes were significantly larger in males than in females (p < 0.001). Also, the ratios of the insular volume to total brain and cerebral volume were significantly higher in males than in females (p < 0.05). This study shows that insular volume differs with laterality and sex. This outcome may be explained by the anatomical relationship between the insula and behavioural functions and emotional reactions and the fact that the right side of the brain is best at expressive and creative tasks.


From Innovation to Diversification: A Simple Competitive Model.
Few attempts have been proposed in order to describe the statistical features and historical evolution of the export bipartite matrix countries/products. An important standpoint is the introduction of a products network, namely a hierarchical forest of products that models the formation and the evolution of commodities. In the present article, we propose a simple dynamical model where countries compete with each other to acquire the ability to produce and export new products. Countries will have two possibilities to expand their export: innovating, i.e. introducing new goods, namely new nodes in the product networks, or copying the productive process of others, i.e. occupying a node already present in the same network. In this way, the topology of the products network and the country-product matrix evolve simultaneously, driven by the countries push toward innovation.


Renal cancer-derived exosomes induce tumor immune tolerance by MDSCs-mediated antigen-specific immunosuppression.
Although Myeloid-derived suppressor cells (MDSCs) have a prominent ability to suppress the immune responses of T lymphocytes and propel tumor immune escape, a lack of profound systemic immunesuppression in tumor-bearing mice and tumor patients. The underlying mechanism of these remains unclear. For this purpose, renal cancer-derived exosomes (RDEs) were first labeled with PKH67 and been observed the internalization by MDSCs. Flow cytometry analysis showed the proportion and activity change of MDSCs in spleen and bone marrow induced by RDEs. Further, western blot experiments were used to verify triggered mechanism of MDSCs by RDEs. Finally, proliferation and cytotoxicity of cytotoxic T lymphocytes (CTLs) co-cultured with MDSCs in vitro and a series of experiments in vivo were performed to demonstrate the specific inhibitory effect of RDEs-induced MDSCs. This study suggested that RDEs crucially contributed to presenting antigenic information, activating and driving specific immunosuppressive effect to MDSCs. HSP70, which is highly expressed in RDEs, initiate this process in a toll like receptor 2 (TLR2)-dependent manner. Importantly, RDEs-induced MDSCs could exert an antigen-specific immunosuppression effect on CTL and specific promote renal tumors-growth and immune escape in consequence. The immunosuppression mediated by MDSCs which is induced by RDEs is antigen-specific. HSP70, which is highly expressed in RDEs, plays a pivotal role in this process. Targeted abrogating the function of MDSCs, or eliminating the expression of HSP70 in exosomes, or blocking the crosstalk between them provides a new direction and theoretical support for future immunotherapy. Video abstract.


In vitro analysis of antigen induced T cell-monocyte conjugates by imaging flow cytometry.
There is a lack of suitable correlates of immune protection against Mycobacterium tuberculosis (Mtb) infection. T cells and monocytes play key roles in host immunity against Mtb. Thus, a method that allows assessing their interaction would contribute to the understanding of immune regulation in tuberculosis (TB). We have established imaging flow cytometer (IFC) based in vitro assay for the analysis of early events in T cell-monocyte interaction, upstream of cytokine production and T cell proliferation. This was achieved through short term stimulation of peripheral blood mononuclear cells (PBMC) from healthy Norwegian blood donors with Mycobacterium bovis Bacille Calmette-Guérin (BCG). In our assay, we examined the kinetics of BCG uptake by monocytes using fluorescently labeled BCG and T cell-monocyte interaction based on synapse formation (CD3/TCR polarization). Our results showed that BCG stimulation induced a gradual increase in the proportion of conjugated T cells displaying NF-κB translocation to the nucleus in a time dependent manner, with the highest frequency observed at 6 h. We subsequently tested PBMC from a small cohort of active TB patients (n = 7) and observed a similar BCG induced NF-κB translocation in T cells conjugated with monocytes. The method allowed for simultaneous evaluation of T cell-monocyte conjugates and T cell activation as measured by NF-κB translocation, following short-term challenge of human PBMC with BCG. Whether this novel approach could serve as a diagnostic or prognostic marker needs to be investigated using a wide array of Mtb specific antigens in a larger cohort of patients with different TB infection status.


Estimating food portions. Influence of unit number, meal type and energy density.
Estimating how much is appropriate to consume can be difficult, especially for foods presented in multiple units, those with ambiguous energy content and for snacks. This study tested the hypothesis that the number of units (single vs. multi-unit), meal type and food energy density disrupts accurate estimates of portion size. Thirty-two healthy weight men and women attended the laboratory on 3 separate occasions to assess the number of portions contained in 33 foods or beverages of varying energy density (1.7-26.8 kJ/g). Items included 12 multi-unit and 21 single unit foods; 13 were labelled "meal", 4 "drink" and 16 "snack". Departures in portion estimates from reference amounts were analysed with negative binomial regression. Overall participants tended to underestimate the number of portions displayed. Males showed greater errors in estimation than females (p=0.01). Single unit foods and those labelled as 'meal' or 'beverage' were estimated with greater error than multi-unit and 'snack' foods (p=0.02 and p<0.001 respectively). The number of portions of high energy density foods was overestimated while the number of portions of beverages and medium energy density foods were underestimated by 30-46%. In conclusion, participants tended to underestimate the reference portion size for a range of food and beverages, especially single unit foods and foods of low energy density and, unexpectedly, overestimated the reference portion of high energy density items. There is a need for better consumer education of appropriate portion sizes to aid adherence to a healthy diet.


Vitamin D status and its determinants in children and adults among families in late summer in Denmark.
The impact of the familial relationship on vitamin D status has not been investigated previously. The objective of the present cross-sectional study was to assess serum 25-hydroxyvitamin D (25(OH)D) concentration and its determinants in children and adults among families in late summer in Denmark (56°N). Data obtained from 755 apparently healthy children (4-17 years) and adults (18-60 years) recruited as families (n 200) in the VitmaD study were analysed. Blood samples were collected in September-October, and serum 25(OH)D concentration was measured by liquid chromatography-tandem MS. Information on potential determinants was obtained using questionnaires. The geometric mean serum 25(OH)D concentration was 72·1 (interquartile range 61·5-86·7) nmol/l (range 9-162 nmol/l), with 9 % of the subjects having 25(OH)D concentrations < 50 nmol/l. The intra-family correlation was 0·27 in all subjects, 0·24 in the adults and 0·42 in the children. Serum 25(OH)D concentration was negatively associated with BMI (P< 0·001) and positively associated with dietary vitamin D intake (P= 0·008), multivitamin use (P= 0·019), solarium use (P= 0·006), outdoor stay (P= 0·001), sun preference (P= 0·002) and sun vacation (P< 0·001), but was not associated with lifestyle-related factors in the adults when these were assessed together with the other determinants. In conclusion, the majority of children and adults among the families had serum 25(OH)D concentrations >50 nmol/l in late summer in Denmark. Both dietary and sun-related factors were determinants of vitamin D status and the familial component was stronger for the children than for the adults.


Ruxolitinib versus standard therapy for the treatment of polycythemia vera.
Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two groups, respectively, had at least a 35% reduction in spleen volume. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P=0.003); 49% versus 5% had at least a 50% reduction in the total symptom score at week 32. In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in 5%; the corresponding percentages in the standard-therapy group were 0% and 4%. Herpes zoster infection was reported in 6% of patients in the ruxolitinib group and 0% of those in the standard-therapy group (grade 1 or 2 in all cases). Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy. In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera. (Funded by Incyte and others; RESPONSE ClinicalTrials.gov number, NCT01243944.).


The health-system benefits and cost-effectiveness of using Mycobacterium tuberculosis direct nucleic acid amplification testing to diagnose tuberculosis disease in the United States.
The utility of Mycobacterium tuberculosis direct nucleic acid amplification testing (MTD) for pulmonary tuberculosis disease diagnosis in the United States has not been well described. We analyzed a retrospective cohort of reported patients with suspected active pulmonary tuberculosis in 2008-2010 from Georgia, Hawaii, Maryland, and Massachusetts to assess MTD use, effectiveness, health-system benefits, and cost-effectiveness. Among 2140 patients in whom pulmonary tuberculosis was suspected, 799 (37%) were M. tuberculosis-culture-positive. Eighty percent (680/848) of patients having acid-fast-bacilli-smear-positive specimens had MTD performed; MTD positive-predictive value (PPV) was 98% and negative-predictive value (NPV) was 94%. Nineteen percent (240/1292) of patients having smear-negative specimens had MTD; MTD PPV was 90% and NPV was 88%. Among patients suspected of tuberculosis but not having MTD, smear PPV for lab-confirmed tuberculosis was 77% and NPV 78%. Compared with no MTD, MTD significantly decreased time to diagnosis in patients with smear-positive/MTD-positive specimens, decreased respiratory isolation for patients having smear-positive/MTD-negative/culture-negative specimens, decreased outpatient days of unnecessary tuberculosis medications, and reduced resources expended on contact investigation. While MTD generally cost more than no MTD, incremental cost savings occurred in patients with human immunodeficiency virus (HIV) or homelessness to diagnose or to exclude tuberculosis, and in patients with substance abuse having smear-negative specimens to exclude tuberculosis. MTD improved diagnostic accuracy and timeliness and reduced unnecessary respiratory isolation, treatment, and contact investigations. It was cost saving in patients with HIV, homelessness, or substance abuse, but not in others.


Parenteral and enteral nutrition in the management of neurosurgical patients in the intensive care unit.
The iatrogenic malnutrition of neurosurgical patients in intensive care units (ICU) is an underestimated problem. It may cause a decrease in plasma albumin and oncotic pressure, leading to an increase in the amount of water entering the brain and increased intracranial pressure (ICP). This study was conducted to test the hypothesis that combined high-protein parenteral and enteral nutrition is beneficial for neurosurgical patients in ICU. A total of 202 neurosurgical patients in ICU (mean age+/-standard deviation, 56 years+/-16 years; male:female=1.2:1) were studied. Two consecutive 1-year time periods were compared, during which two different nutritional regimens were followed. In the first time period (Y1) patients were given a low-protein/high-fat formulation parenterally, followed by a standard enteral regimen. In the second time period (Y2) a protein-rich, combined parenteral and enteral diet was prospectively administered. The Glasgow Outcome Score was measured at 3-6 months after discharge. The following clinical parameters were recorded during the first 2 weeks after admission: ICP; albumin; cholinesterase (CHE); daily hours of ICP > 20 mmHg and cerebral perfusion pressure<70 mmHg; and Acute Physiology and Chronic Health Evaluation II (APACHE II) score. It was found that overall albumin (32.4 g/L+/-4.1g/L vs. 27.5 g/L+/-3.6g/L) and CHE was higher during Y2, although the total energy supply, glucose and fat intake was lower. Higher GOS scores were seen when patients had lower APACHE II scores and received the Y2 nutritional regimen. During Y2, the total hours of ICP > 20 mmHg were fewer. With the Y2 nutrition, maintenance of adequate cerebral perfusion required less catecholamine medication and colloidal fluid replacement. Therefore, adequate nutrition is an important parameter in the management of neurosurgical patients in ICU.


What happens for informal caregivers during transition to increased levels of care for the person with dementia? A systematic review protocol.
Dementia is a globally prevalent disease that requires ongoing and increasing levels of care, often provided in the first instance by informal caregivers. Supporting transitions in informal caregiving in dementia is a pertinent issue for caregivers, care providers and governments. There is no existing systematic review that seeks to identify and map the body of literature regarding the review question: 'What happens for informal caregivers during transition to increased levels of care for the person with dementia?' ASSIA, CINAHL+, MEDLINE, PsycINFO, SCIE, Social Service Abstracts and Web of Science will be systematically searched. Specialist dementia research libraries will be contacted. Reviews identified as relevant during the search process, their reference lists, and reference lists of accepted papers will be hand-searched. Qualitative, quantitative and mixed methods studies that seek to represent the experiences of, or examine the impact upon, informal caregivers during transition to increased formal care for the person with dementia will be eligible for inclusion. Synthesis will be segregated into qualitative and quantitative papers. Findings will be summarised, and the review will be prepared for publication. The review will seek to identify potentially vulnerable groups in need of support and as such, inform the practice of those offering support. It will also inform future research by highlighting areas in which current literature is insubstantial. PROSPERO CRD42017067248.


The experience of making treatment decisions for women with early stage breast cancer: a diagrammatic representation.
Women who are making decisions about treatment for early stage breast cancer interact with a number of people when they are considering their treatment options and the impact breast cancer will have on their lives. Previous research has considered patient preferences for involvement in treatment decision-making and proposed factors that may influence breast cancer treatment decisions. However, to date, there has been a paucity of research focusing on the experience of making treatment decisions from the women's perspective. The aim of this paper is to describe the relationships between the women, the medical practitioners and other people, and to consider features that may be influential in the experience of making treatment decisions. Two models are proposed to represent concepts that are linked to the experience of making treatment decisions. The first model proposed has been formulated to represent factors that may influence the treatment decision. The second model highlights aspects of the women's lives that may be affected. This paper discusses concepts that are presented in the conceptual models and makes suggestions for future studies relating to the experience of making treatment decisions for women with breast cancer.


H55N polymorphism as a likely cause of variation in citrate synthase activity of mouse skeletal muscle.
Citrate synthase (CS) is an enzyme of the Krebs cycle that plays a key role in mitochondrial metabolism. The aim of this study was to investigate the mechanisms underlying low activity of citrate synthase (CS) in A/J mice compared with other inbred strains of mice. Enzyme activity, protein content, and mRNA levels of CS were studied in the quadriceps muscles of A/J, BALB/cByJ, C57BL/6J, C3H/HeJ, DBA/2J, and PWD/PhJ strains of mice. Cytochrome c protein content was also measured. The results of the study indicate that A/J mice have a 50-65% reduction in CS activity compared with other strains despite similar levels of Cs mRNA and lack of differences in CS and cytochrome c protein content. CS from A/J mice also showed lower Michaelis constant (K(m)) for both acetyl CoA and oxaloacetate compared with the other strains of mice. In silico analysis of the genomic sequence identified a nonsynonymous single nucleotide polymorphism (SNP) (rs29358506, H55N) in Cs gene occurring near the site of the protein interacting with acetyl CoA. Allelic variants of the polymorphism segregated with the catalytic properties of CS enzyme among the strains. In summary, H55N polymorphism in Cs could be the underlying cause of low CS activity and its high affinity for substrates in A/J mice compared with other strains. This SNP might also play a role in resistance to obesity of A/J mice.


Photoradiation therapy for the treatment of malignant tumors.
Administration of hematoporphyrin derivative i.v. followed by local exposure to red light has resulted in complete or partial response in 111 of 113 cutaneous or s.c. malignant lesions. Tumors treated have included carcinomas of the breast, colon, prostate, squamous cell, basal cell, and endometrium; malignant melanoma; mycosis fungoides; chondrosarcoma; and angiosarcoma. No type has been found to be unresponsive. In several cases complete clearing of chest wall metastatis has been achieved in treated areas. Deep-seated and pigmented tumors required a higher dose of drug for effective treatment than did the more superficial and nonpigmented lesions. A high therapeutic ratio between tumor and skin response has been obtained by allowing at least 3 days between drug injection and exposure to the therapeutic light for 2,5-mg/kg doses and at least a 4-day interval for 5.0-mg/kg doses.


Survival and ocular preservation in a long-term cohort of Japanese patients with retinoblastoma.
Retinoblastoma is an ocular tumor in infants with cancer predisposition. Treatment of the rare tumor needs to be optimized for ocular preserved survival without second primary malignancy (SPM). We studied the outcomes of all patients with retinoblastoma at a tertiary center in 1984-2016, when preservation method changed from radiotherapy (1984-2001) to systemic chemotherapy (2002-2016). One-hundred sixteen infants developed unilateral- (n = 77), bilateral- (n = 38), or trilateral-onset (n = 1) tumor. Ten (8.6%) had a positive family history, despite a few studies on RB1 gene. Contralateral disease occurred in one unilateral-onset case. One-hundred eight of 155 eyes (70%) were enucleated. Nine binocular survivors were from 5 bilateral- and 4 unilateral-onset cases. Two survivors received bilateral enucleation. Six deaths occurred; brain involvement (including 3 trilateral diseases) in 4 bilateral-onset, systemic invasion in a unilateral-onset, and SPM (osteosarcoma) in a bilateral-onset case(s). Two others survived SPM of osteosarcoma or lymphoma. The 10-year overall survival (OS: 98.5% vs. 91.3%, p = 0.068) and binocular survivors (13.2% vs. 5.2%, p = 0.154) between bilateral- and unilateral-onsets did not differ statistically. The 10-year OS and cancer (retinoblastoma/SPM)-free survival (CFS) rates of all patients were 94.9 and 88.5%, respectively. The proportion of preserved eyes did not differ between radiotherapy and chemotherapy eras. The CFS rate of bilateral-onset cases in systemic chemotherapy era was higher than that in radiotherapy era (p = 0.042). The CFS rates of bilateral-onset patients with neoadjuvant chemotherapy (upfront systemic therapy for preservation) was higher than those without it (p = 0.030). Systemic chemotherapy and local therapy raised OS and binocular survival rates of bilateral-onset patients similarly to those of unilateral-onset patients. All but one death was associated with a probable germline defect of the RB1 gene. Neoadjuvant stratified chemotherapy may support the long-term binocular life with minimized risk of SPM.