Design of biomimetic catalysts by molecular imprinting in synthetic polymers: the role of transition state stabilization.
The impressive efficiency and selectivity of biological catalysts has engendered a long-standing effort to understand the details of enzyme action. It is widely accepted that enzymes accelerate reactions through their steric and electronic complementarity to the reactants in the rate-determining transition states. Thus, tight binding to the transition state of a reactant (rather than to the corresponding substrate) lowers the activation energy of the reaction, providing strong catalytic activity. Debates concerning the fundamentals of enzyme catalysis continue, however, and non-natural enzyme mimics offer important additional insight in this area. Molecular structures that mimic enzymes through the design of a predetermined binding site that stabilizes the transition state of a desired reaction are invaluable in this regard. Catalytic antibodies, which can be quite active when raised against stable transition state analogues of the corresponding reaction, represent particularly successful examples. Recently, synthetic chemistry has begun to match nature's ability to produce antibody-like binding sites with high affinities for the transition state. Thus, synthetic, molecularly imprinted polymers have been engineered to provide enzyme-like specificity and activity, and they now represent a powerful tool for creating highly efficient catalysts. In this Account, we review recent efforts to develop enzyme models through the concept of transition state stabilization. In particular, models for carboxypeptidase A were prepared through the molecular imprinting of synthetic polymers. On the basis of successful experiments with phosphonic esters as templates to arrange amidinium groups in the active site, the method was further improved by combining the concept of transition state stabilization with the introduction of special catalytic moieties, such as metal ions in a defined orientation in the active site. In this way, the imprinted polymers were able to provide both an electrostatic stabilization for the transition state through the amidinium group as well as a synergism of transition state recognition and metal ion catalysis. The result was an excellent catalyst for carbonate hydrolysis. These enzyme mimics represent the most active catalysts ever prepared through the molecular imprinting strategy. Their catalytic activity, catalytic efficiency, and catalytic proficiency clearly surpass those of the corresponding catalytic antibodies. The active structures in natural enzymes evolve within soluble proteins, typically by the refining of the folding of one polypeptide chain. To incorporate these characteristics into synthetic polymers, we used the concept of transition state stabilization to develop soluble, nanosized carboxypeptidase A models using a new polymerization method we term the "post-dilution polymerization method". With this methodology, we were able to prepare soluble, highly cross-linked, single-molecule nanoparticles. These particles have controlled molecular weights (39 kDa, for example) and, on average, one catalytically active site per particle. Our strategies have made it possible to obtain efficient new enzyme models and further advance the structural and functional analogy with natural enzymes. Moreover, this bioinspired design based on molecular imprinting in synthetic polymers offers further support for the concept of transition state stabilization in catalysis.


Prediction of superconducting iron-bismuth intermetallic compounds at high pressure.
The synthesis of materials in high-pressure experiments has recently attracted increasing attention, especially since the discovery of record breaking superconducting temperatures in the sulfur-hydrogen and other hydrogen-rich systems. Commonly, the initial precursor in a high pressure experiment contains constituent elements that are known to form compounds at ambient conditions, however the discovery of high-pressure phases in systems immiscible under ambient conditions poses an additional materials design challenge. We performed an extensive multi component ab initio structural search in the immiscible Fe-Bi system at high pressure and report on the surprising discovery of two stable compounds at pressures above ≈36 GPa, FeBi2 and FeBi3. According to our predictions, FeBi2 is a metal at the border of magnetism with a conventional electron-phonon mediated superconducting transition temperature of Tc = 1.3 K at 40 GPa.


Exploring the influence of short-term temperature patterns on temperature-related mortality: a case-study of Melbourne, Australia.
Several studies have identified the association between ambient temperature and mortality; however, several features of temperature behavior and their impacts on health remain unresolved. We obtain daily counts of nonaccidental all-cause mortality data in the elderly (65 + years) and corresponding meteorological data for Melbourne, Australia during 1999 to 2006. We then characterize the temporal behavior of ambient temperature development by quantifying the rates of temperature change during periods designated by pre-specified windows ranging from 1 to 30 days. Finally, we evaluate if the association between same day temperature and mortality in the framework of a Poisson regression and include our temperature trajectory variables in order to assess if associations were modified by the nature of how the given daily temperature had evolved. We found a positive significant association between short-term mortality risk and daily average temperature as mortality risk increased 6 % on days when temperatures were above the 90th percentile as compared to days in the referent 25-75th. In addition, we found that mortality risk associated with daily temperature varied by the nature of the temperature trajectory over the preceding twelve days and that peaks in mortality occurred during periods of high temperatures and stable trajectories and during periods of increasing higher temperatures and increasing trajectories. Our method presents a promising tool for improving understanding of complex temperature health associations. These findings suggest that the nature of sub-monthly temperature variability plays a role in the acute impacts of temperature on mortality; however, further studies are suggested.


Developing a context-general self-report approach to measure three-level situation awareness.
Situation awareness (SA) is considered to be crucial for work in safety critical organisations,yet its precise definition and an agreed upon measurement approach have yet to emerge. SA is often measured as an operator's overview of some specific parameters within a given work setting and a given time frame, an approach that entails both advantages and disadvantages. The current approach examines whether some aspects of SA relating to workplace safety can also be captured in a context-general inventory. 166 offshore maritime personnel answered the SA inventory with 13 items describing the respondent's typical cognitions concerning safety issues. Confirmatory factor analysis of response patterns showed that the internal pattern among the items reflected the three level structure predicted by the leading theoretical model. Strengths and weaknesses of the inventory itself, as well as the approach in general are discussed, and future research directions are outlined. It appears feasible to measure aspects of SA in a context-general inventory, though additional adjustment and validation is required.


Transcriptome-wide sites of collided ribosomes reveal principles of translational pausing.
Translation initiation is the major regulatory step defining the rate of protein production from an mRNA. Meanwhile, the impact of nonuniform ribosomal elongation rates is largely unknown. Using a modified ribosome profiling protocol based on footprints from two closely packed ribosomes (disomes), we have mapped ribosomal collisions transcriptome-wide in mouse liver. We uncover that the stacking of an elongating onto a paused ribosome occurs frequently and scales with translation rate, trapping ∼10% of translating ribosomes in the disome state. A distinct class of pause sites is indicative of deterministic pausing signals. Pause site association with specific amino acids, peptide motifs, and nascent polypeptide structure is suggestive of programmed pausing as a widespread mechanism associated with protein folding. Evolutionary conservation at disome sites indicates functional relevance of translational pausing. Collectively, our disome profiling approach allows unique insights into gene regulation occurring at the step of translation elongation.


Leadership and organisational effectiveness--lessons to be drawn from education?
The aim of this paper is to present findings of a case study on organisational effectiveness in an education setting and draw similarities with a healthcare setting, focusing on the school principal and nurse leader. The study was carried out in a primary school setting and focuses on a principal (as leader). The school, which will be named St Senan's for the case study, is a typical tall structure, has a staff of 30 (teachers and special needs' assistants) and a student number of 117. A case study methodology was used. Data was collected by interviewing the principal, two teachers, two students and a parent, in this order. In addition, a Parents' Council meeting was observed and document analysis was carried out on measurements which reflected some critical success factors for the school. Interviews from students and teachers in addition to observation notes indicate that the principal's leadership impacts on organisational effectiveness in the school. The findings are located in the context of education with similarities being drawn from nursing. It is how the leader leads in the context of the organisation setting which is paramount. In other words it is not possible to take a set of general critical success factors for a school or healthcare setting and apply these widely. The paper concludes by proposing the use of a quality framework to contextualise the findings of the case and promote further discussion in the context of nurse leaders. The paper suggests that comparisons can be made between school principals and nurse leaders.


Exercise, energy intake, glucose homeostasis, and the brain.
Here we summarize topics covered in an SFN symposium that considered how and why exercise and energy intake affect neuroplasticity and, conversely, how the brain regulates peripheral energy metabolism. This article is not a comprehensive review of the subject, but rather a view of how the authors' findings fit into a broader context. Emerging findings elucidate cellular and molecular mechanisms by which exercise and energy intake modify the plasticity of neural circuits in ways that affect brain health. By enhancing neurogenesis, synaptic plasticity and neuronal stress robustness, exercise and intermittent energy restriction/fasting may optimize brain function and forestall metabolic and neurodegenerative diseases. Moreover, brain-centered glucoregulatory and immunomodulating systems that mediate peripheral health benefits of intermittent energetic challenges have recently been described. A better understanding of adaptive neural response pathways activated by energetic challenges will enable the development and optimization of interventions to reduce the burden of disease in our communities.


Psychological treatment of depressive symptoms in patients with medical disorders: a meta-analysis.
It is widely acknowledged that the prevalence of depression in the general population is high, but that it is even higher for patients with medical disorders. Yet, the effectiveness of psychological treatments in these patient populations has not been firmly established. We conducted a meta-analysis of randomized controlled studies examining the effects of psychological treatments in patients with 1 of 10 different medical disorders and elevated levels of depression. Extensive searches were performed in PubMed, PsycINFO, Embase, and the Cochrane Central Register of Controlled Trials. We included 23 studies. The overall effect size of the 15 studies that compared psychological treatments with a waitlist or care-as-usual control group was d=1.00 [95% confidence interval (CI), 0.57-1.44] but declined to d=0.42 (95% CI, 0.27-0.58) after removing two outliers with extremely high effects. We tested the type of disorder, inclusion based on diagnostic criteria or symptoms, type of treatment, treatment format, type of control group, and intention-to-treat or completers analyses, but none of these variables were significantly associated with the effect. The four studies that compared one type of psychotherapy to another showed a positive effect of cognitive behavioral therapy and interpersonal therapy compared to supportive therapy (d=0.42; 95% CI, 0.14-0.69). There were not enough studies (n=3) to draw any conclusions about the comparison of psychotherapy to pharmacotherapy. We conclude that the effects of psychological treatment of patients with medical disorders are very similar to those found in otherwise healthy patients. Treating this comorbid depression should be one of the priorities in medical care settings.


Genome-wide transcriptome study in wheat identified candidate genes related to processing quality, majority of them showing interaction (quality x development) and having temporal and spatial distributions.
The cultivated bread wheat (Triticum aestivum L.) possesses unique flour quality, which can be processed into many end-use food products such as bread, pasta, chapatti (unleavened flat bread), biscuit, etc. The present wheat varieties require improvement in processing quality to meet the increasing demand of better quality food products. However, processing quality is very complex and controlled by many genes, which have not been completely explored. To identify the candidate genes whose expressions changed due to variation in processing quality and interaction (quality x development), genome-wide transcriptome studies were performed in two sets of diverse Indian wheat varieties differing for chapatti quality. It is also important to understand the temporal and spatial distributions of their expressions for designing tissue and growth specific functional genomics experiments. Gene-specific two-way ANOVA analysis of expression of about 55 K transcripts in two diverse sets of Indian wheat varieties for chapatti quality at three seed developmental stages identified 236 differentially expressed probe sets (10-fold). Out of 236, 110 probe sets were identified for chapatti quality. Many processing quality related key genes such as glutenin and gliadins, puroindolines, grain softness protein, alpha and beta amylases, proteases, were identified, and many other candidate genes related to cellular and molecular functions were also identified. The ANOVA analysis revealed that the expression of 56 of 110 probe sets was involved in interaction (quality x development). Majority of the probe sets showed differential expression at early stage of seed development i.e. temporal expression. Meta-analysis revealed that the majority of the genes expressed in one or a few growth stages indicating spatial distribution of their expressions. The differential expressions of a few candidate genes such as pre-alpha/beta-gliadin and gamma gliadin were validated by RT-PCR. Therefore, this study identified several quality related key genes including many other genes, their interactions (quality x development) and temporal and spatial distributions. The candidate genes identified for processing quality and information on temporal and spatial distributions of their expressions would be useful for designing wheat improvement programs for processing quality either by changing their expression or development of single nucleotide polymorphisms (SNPs) markers.


Novel quantitative biosystem for modeling physiological fluid shear stress on cells.
The response of microbes to changes in the mechanical force of fluid shear has important implications for pathogens, which experience wide fluctuations in fluid shear in vivo during infection. However, the majority of studies have not cultured microbes under physiological fluid shear conditions within a range commonly encountered by microbes during host-pathogen interactions. Here we describe a convenient batch culture biosystem in which (i) the levels of fluid shear force can be varied within physiologically relevant ranges and quantified via mathematical models and (ii) large numbers of cells can be planktonically grown and harvested to examine the effect of fluid shear levels on microbial genomic and phenotypic responses. A quantitative model based on numerical simulations and in situ imaging analysis was developed to calculate the fluid shear imparted by spherical beads of different sizes on bacterial cell cultures grown in a rotating wall vessel (RWV) bioreactor. To demonstrate the application of this model, we subjected cultures of the bacterial pathogen Salmonella enterica serovar Typhimurium to three physiologically-relevant fluid shear ranges during growth in the RVW and demonstrated a progressive relationship between the applied fluid shear and the bacterial genetic and phenotypic responses. By applying this model to different cell types, including other bacterial pathogens, entire classes of genes and proteins involved in cellular interactions may be discovered that have not previously been identified during growth under conventional culture conditions, leading to new targets for vaccine and therapeutic development.


Coupling granular activated carbon adsorption with membrane bioreactor treatment for trace organic contaminant removal: breakthrough behaviour of persistent and hydrophilic compounds.
This study investigated the removal of trace organic contaminants by a combined membrane bioreactor - granular activated carbon (MBR-GAC) system over a period of 196 days. Of the 22 compounds investigated here, all six hydrophilic compounds with electron-withdrawing functional groups (i.e., metronidazole, carbamazepine, ketoprofen, naproxen, fenoprop and diclofenac) exhibited very low removal efficiency by MBR-only treatment. GAC post-treatment initially complemented MBR treatment very well; however, a compound-specific gradual deterioration of the removal of the above-mentioned problematic compounds was noted. While a 20% breakthrough of all four negatively charged compounds namely ketoprofen, naproxen, fenoprop and diclofenac occurred within 1000-3000 bed volumes (BV), the same level of breakthrough of the two neutral compounds metronidazole and carbamazepine did not occur until 11,000 BV. Single-solute isotherm parameters did not demonstrate any discernible correlation individually with any of the parameters that may govern adsorption onto GAC, such as log D, number of hydrogen-bond donor/acceptor groups, dipole moment or aromaticity ratio of the compounds. The isotherm data, however, could differentiate the breakthrough behaviour between negatively charged and neutral trace organic contaminants.


Transection of dysmyelinated optic nerve axons in adult rats lacking myelin basic protein.
Injury to myelin or oligodendrocytes may manifest as dysmyelinating or demyelinating conditions of the CNS. Previous studies using dysmyelinated animal models (myelin basic protein mutants) suggest possible axonal dysfunction with complete loss of myelin. In this present study, we evaluated retinal ganglion cell survival after axotomy in MBP mutants to determine if prolonged dysmyelination of CNS axons exerted a detrimental effect on neuronal survival. We demonstrated that the survival of retinal ganglion cells with dysmyelinated axons is identical to retinal ganglion cells with myelinated axons after survival times up to 180 days. In myelin diseases where axon transection is a consistent consequence of demyelination resulting in progressive neurological deterioration, the absence of myelin does not accelerate neuronal death.


Beneficial effects of tigerinin-1R on glucose homeostasis and beta cell function in mice with diet-induced obesity-diabetes.
This paper investigates the anti-diabetic effects of tigerinin-1R (RVCSAIPLPICH.NH2), a previously described amphibian host defence peptide, in mice with diet-induced obesity-diabetes. Proteolytic degradation of synthetic tigerinin-1R was investigated by reversed-phase HPLC and MALDI-TOF mass spectrometry. Changes in glycaemic responses and metabolic parameters were measured in mice with high fat diet-induced obesity-diabetes treated with twice-daily with of tigerinin-1R (75 nmol/kg bw) for 15 days. Indirect calorimetry and body composition were measured by CLAMS and DEXA whole body scanning. Insulin secretory responses of islets isolated from treated and untreated mice were examined. Tigerinin-1R was resistant to in vitro degradation by plasma enzymes. Twice-daily injection of tigerinin-1R for 15 days had no significant effect on food intake or body weight. Non-fasting glucose levels were significantly lowered, and insulin levels were elevated compared to saline treated controls. Glycaemic responses to both oral and intraperitoneal glucose administration were significantly improved by tigerinin-1R treatment. Plasma insulin was also significantly elevated. The peptide had no significant effect on insulin sensitivity but the beta cell responses of islets isolated from treated mice to a range of nutrients and peptidergic secretagogues were significantly improved. Oxygen consumption, CO2 production, respiratory exchange ratio, energy expenditure and body composition were not significantly altered by treatment with tigerinin-1R. Tigerinin-1R significantly improves glucose homeostasis and may have potential as a novel antidiabetic agent.


Results of nurse navigator follow-up after positive colorectal cancer screening test: a randomized trial.
Follow-up after a positive colorectal cancer screening test is necessary for screening to be effective. We hypothesized that nurse navigation would increase the completion of colonoscopy after a positive screening test. This study was conducted between 2008 and 2012 at 21 primary care medical centers in western Washington State. Participants in the Systems of Support to Increase Colorectal Cancer Screening study who had a positive fecal occult blood test (FOBT) or flexible sigmoidoscopy needing follow-up were randomized to usual care (UC) or a nurse navigator (navigation). UC included an electronic health record-based positive FOBT registry and physician reminder system. Navigation included UC plus care coordination and patient self-management support from a registered nurse who tracked and assisted patients until they completed or refused colonoscopy. The primary outcome was completion of colonoscopy within 6 months. After 6 months, both groups received navigation. We randomized 147 participants with a positive FOBT or sigmoidoscopy. Completion of colonoscopy was higher in the intervention group at 6 months, but differences were not statistically significant (91.0% in navigation group vs 80.8% in UC group; adjusted difference, 10.1%; P = .10). Reasons for no or late colonoscopies included refusal, failure to schedule or missed appointments, concerns about risks or costs, and competing health concerns. Navigation did not lead to a statistically significant incremental benefit at 6 months. Follow-up rates after a positive colorectal cancer (CRC) screening test are high in a health care system where UC included a registry and physician reminders. Because of high follow-up rates in a health care system where UC included a registry and physician reminders, and small sample size, we cannot rule out incremental benefits of nurse navigation.


The relationship of gender and trauma characteristics to posttraumatic stress disorder in a community sample of traumatized northern plains American Indian adolescents and young adults.
Previous studies have identified a high prevalence (25%-80%) of trauma among American Indian and non-American Indian adolescents and adults. However, only a fraction of traumatized individuals develop posttraumatic stress disorder (PTSD). This article examines the relationships of gender and trauma characteristics to a diagnosis of PTSD among a community sample of traumatized American Indian adolescents and young adults. Complete data were collected from 349 American Indians aged 15 to 24 years who participated in a cross-sectional community-based study from July 1997 to December 1999 and reported experiencing at least 1 traumatic event. Traumatic events and PTSD were assessed using a version of the Composite International Diagnostic Interview. Logistic regression determined the relationships of gender, trauma type, age at first trauma, and number of traumas to the development of PTSD. Forty-two participants (12.0% of those who experienced a traumatic event) met criteria for lifetime PTSD. While all 4 of the independent variables noted above demonstrated univariate associations with PTSD, multivariate logistic regression analyses indicated that only experiencing a sexual trauma (odds ratio [OR] = 4.45, 95% confidence interval [CI] = 1.76 to 11.28) and having experienced 6 or more traumas (OR = 2.53, 95% CI = 1.06 to 6.04) were independent predictors of meeting criteria for PTSD. American Indian children and adolescents who experience sexual trauma and multiple traumatic experiences may be at particularly high risk for developing PTSD.


In vitro culture and characterization of enteric neural precursor cells from human gut biopsy specimens using polymer scaffold.
In vitro expansion and characterization of neural precursor cells from human gut biopsy specimens with or without Hirschsprung's disease using a novel thermoreversible gelation polymer (TGP) is reported aiming at a possible future treatment. Gut biopsy samples were obtained from five patients undergoing gut resection for Hirschsprung's disease (n = 1) or gastrointestinal disorders (n = 4). Cells isolated from the smooth muscle layer and the myenteric plexus were cultured in two groups for 18 to 28 days; Group I: conventional culture as earlier reported and Group II: using TGP scaffold. Neurosphere like bodies (NLBs) were observed in the cultures between 8th to 12th day and H & E staining was positive for neural cells in both groups including aganglionic gut portion from the Hirschsprung's disease patient. Immunohistochemistry using S-100 and neuron specific enolase (NSE) was positive in both groups but the TGP group (Group II) showed more number of cells with intense cytoplasmic granular positivity for both NSE and S-100 compared to Group I. TGP supports the in vitro expansion of human gut derived neuronal cells with seemingly better quality NLBs. Animal Studies can be tried to validate their functional outcome by transplanting the NLBs with TGP scaffolds to see whether this can enhance the outcome of cell based therapies for Hirschsprung's disease.


A pilot randomized controlled trial examining the impact of a sleep intervention targeting home routines on young children's (3-6 years) physical activity.
Given evidence suggesting that sleep impacts on metabolic processes, interventions targeting sleep may improve child physical activity (PA). To describe the potential effect of an intervention to increase sleep on young children's (3-6 years) moderate to vigorous PA (MVPA) and total PA. To determine adherence to the intervention, impact on sleep duration as well as feasibility, uptake and acceptability was also assessed. Pilot randomized controlled trial with 76 parent-child dyads randomly allocated to an intervention (n = 38) or control group (n = 38). Parents in the intervention group received a 3-month theory-informed intervention consisting of an online video, a telephone call and two text messages. Child PA was assessed using accelerometers at baseline and approximately 3 months. Parents also completed a sleep log and a telephone interview. The consent rate was 41% (76/186). Estimated effect size for the intervention relative to control was 10.8 min/day for MVPA, 2.7 min/day for PA and 0.9 h for sleep. Sixteen (44%) parents accessed the video, and 18 (50%) received the telephone call. Over 40% of parents found the video and telephone call useful/very useful. This study reports promising effects that an intervention targeting sleep may improve child MVPA and sleep duration. Some modifications to data collection methods and intervention delivery are needed.


An investigation of the action of disease modifying antirheumatic drugs on the rheumatoid synovial membrane: reduction in T lymphocyte subpopulations and HLA-DP and DQ antigen expression after gold or penicillamine therapy.
Synovial needle biopsy specimens from the knee joints of seven patients with rheumatoid arthritis (RA) were examined immunohistochemically before and after six months' treatment with either gold or penicillamine (disease modifying drugs, DMDs). There were significant reductions in the numbers of infiltrating T lymphocytes and a disproportionate fall in the numbers of lymphocytes of the helper/inducer subset when compared with those of the suppressor/cytotoxic subset. This resulted in a fall in the ratio of helper/inducer to suppressor/cytotoxic cells. The immunohistological changes correlated with improvements in erythrocyte sedimentation rate (ESR), serum immunoglobulins, visual analogue pain assessment, grip strength, and Ritchie articular index. A second group of nine patients with RA, already well established on DMD therapy, did not show similar changes after the six month period. The HLA class II antigens DR, DQ, and DP were widely expressed on lymphocytes, macrophages, and synovial lining cells of a group of patients with RA who had never received disease modifying drug therapy. After treatment there was a significant reduction in the expression of HLA-DP and DQ antigens.


A Rare Case of Thyrotoxic Periodic Paralysis After Epidural Steroid Injection: A Case Report and Literature Review.
BACKGROUND Thyrotoxic periodic paralysis (TPP) is a rare cause of acute paralysis, which if not promptly recognized and treated, can lead to significant morbidity and mortality. TPP can be precipitated by several factors, including a high carbohydrate diet and exercise. This report is of a rare case of TPP after epidural steroid injection in a young man, with a review of the literature of previous cases. CASE REPORT A 36-year-old Asian man presented to the emergency department with sudden onset of paralysis of all his limbs following epidural steroid injection for traumatic low back pain. At presentation, he was found to have severe hypokalemia of 1.8 mEq/L. Further investigations led to the diagnosis of hyperthyroidism and Graves' disease. In the process of correcting his potassium, there was an unexpected rebound hyperkalemia that was successfully corrected. He had a rapid recovery and an early discharge from hospital. CONCLUSIONS Although several factors can lead to paralysis after an epidural steroid injection, TPP should be considered in the differential diagnosis, especially in individuals who have predisposing factors of ethnicity and gender. If patients have undiagnosed hyperthyroidism on presentation, the diagnosis of TPP can be delayed or missed. In the management of patients with TPP, care should be taken when correcting potassium levels.


Induction of apoptosis in mouse and human carcinoma cell lines by Emblica officinalis polyphenols and its effect on chemical carcinogenesis.
Plant-derived phenolic compounds manifest many beneficial effects and can potentially inhibit several stages of carcinogenesis. In the present study, we investigated the efficacy of Emblica officinalis (E. officinalis) polyphenol fraction (EOP) on the induction of apoptosis in mouse and human carcinoma cell lineses and its modulatory effect on N- nitrosodiethylamine (NDEA) induced liver tumors in rats. The results indicate that EOP treatment could induce apoptosis in Dalton's Lymphoma Ascites (DLA) and CeHa cell lines At 200 microg/ml dose EOP induced membrane blebbing, chromatin condensation and intenucleosomal breaks as evident from the morphology and DNA ladder pattern obtained in gel electrophoresis. The results also suggested that EOP treatment could decrease the liver tumour development induced by NDEA. Animals administered (oral) with NDEA (0.02%, 2.5 ml/rat, 5 days a week, 20 weeks) developed visible liver tumours by the end of the 20th week and the liver weight raised to 5.2 +/- 1.1 g/ 100 g body weight. Only 11% of the animals treated with EOP (60 mg/kg, oral, 5 days a week for 20 weeks) developed visible liver tumours by this period and the liver weights were reduced to 3.2 +/- 0.7 g/ 100 g body weight. gamma-glutamyl transpeptidase activity was raised to 88.4 +/- 16.2 U/l in serum of NDEA treated group was reduced to 48.4 +/- 14.8 U/l by EOP treatment. Elevated levels of serum alkaline phosphatase (ALP), glutamate pyruvate transaminase (GPT), bilirubin, liver glutathione S-transferase (GST) and glutathione (GSH) in the NDEA administered group were significantly reduced by EOP treatment. The EOP was found to scavenge superoxide and hydroxyl radicals and inhibit lipid peroxidation in vitro. EOP also inhibited DNA topoisomerase I in Saccharomyces cervisiae mutant cell cultures and the activity of cdc25 tyrosine phosphatase.


Motion Normalized Proportional Control for Improved Pattern Recognition-Based Myoelectric Control.
This paper describes two novel proportional control algorithms for use with pattern recognition-based myoelectric control. The systems were designed to provide automatic configuration of motion-specific gains and to normalize the control space to the user's usable dynamic range. Class-specific normalization parameters were calculated using data collected during classifier training and require no additional user action or configuration. The new control schemes were compared to the standard method of deriving proportional control using a one degree of freedom Fitts' law test for each of the wrist flexion/extension, wrist pronation/supination and hand close/open degrees of freedom. Performance was evaluated using the Fitts' law throughput value as well as more descriptive metrics including path efficiency, overshoot, stopping distance and completion rate. The proposed normalization methods significantly outperformed the incumbent method in every performance category for able bodied subjects (p < 0.001) and nearly every category for amputee subjects. Furthermore, one proposed method significantly outperformed both other methods in throughput (p < 0.0001), yielding 21% and 40% improvement over the incumbent method for amputee and able bodied subjects, respectively. The proposed control schemes represent a computationally simple method of fundamentally improving myoelectric control users' ability to elicit robust, and controlled, proportional velocity commands.


Molecular insights into the surface morphology, layering structure, and aggregation kinetics of surfactant-stabilized graphene dispersions.
The production of graphene with open band gaps for the manufacturing of graphene-based electronic and optical devices requires synthesis methods to either control the number of layers to enrich AB-stacked bilayer or trilayer graphene or control the extent of functionalization of monolayer graphene. Solution-phase dispersion of graphene is promising for both methods to create printable electronics and nanocomposites. However, both methods face common challenges, including controlling the surface morphology, reducing the turbostratic layering, and enhancing the dispersion stability. To address these challenges at the molecular level, we successfully combined molecular simulations, theoretical modeling, and experimental measurements. First, we probed the surface structure and electrostatic potential of monolayer graphene dispersed in a sodium cholate (SC) surfactant aqueous solution, which exhibits 2D sheets partially covered with a monolayer of negatively charged cholate ions. Similar to the case of carbon nanotube functionalization, one may regulate the binding affinity of charged reactants for graphene functionalization by manipulating the surface morphology. Subsequently, we quantified the interactions between two graphene-surfactant assemblies by calculating the potential of mean force (PMF) between two surfactant-covered graphene sheets, which confirmed the existence of a metastable bilayer graphene structure due to the steric hindrance of the confined surfactant molecules. The traditional Derjaguin-Landau-Verwey-Overbeek (DLVO) theory was found to be adequate to explain the long-range electrostatic repulsions between the ionic surfactant-covered graphene sheets but was unable to account for the dominant, short-range steric hindrance imparted by the confined surfactant molecules. Interestingly, one faces a dilemma when using surfactants to disperse and stabilize graphene in aqueous solution: on the one hand, surfactants can stabilize graphene aqueous dispersions, but on the other hand, they prevent the formation of new AB-stacked bilayer and trilayer graphene resulting from the reaggregation process. Finally, the lifetime and time-dependent distribution of various graphene layer types were predicted using a kinetic model of colloid aggregation, and each graphene layer type was further decomposed into subtypes, including the AB-stacked species and various turbostratic species. The kinetic model of colloid aggregation developed here can serve as a useful tool to evaluate the quality of graphene dispersions for subsequent substrate-transferring or functionalization processes.


Relationships between age-related changes of sex steroids, obesity and body fat distribution among healthy Polish males.
During the process of aging in males a trend toward an unfavourable body fat accumulation, especially within the visceral depots, is observed. This fact is presumed to be associated with the age-related decline in androgen levels among aging men. The aim of this study was to determine the relationships between sex steroid levels (DHEAS, estradiol, free and total testosterone) and BMI, percent fat mass, WHR values in 190 healthy and professionally active men, aged 22-67, inhabitants of the city of Wroclaw, Poland. Hormonal levels were measured using standard immunoassays. BMI was used as a measurement of obesity. Obesity was also assessed using percent fat mass equations according to the Crook formula. WHR was used as an index of fat distribution. All the correlations between sex steroids, BMI, WHR, percent fat mass and age were evaluated using statistical non-parametric analyses (Spearman coefficient) in the entire group of examined subjects, and in two age-specific groups: a) younger males (aged 22-39) and b) older males (aged 40-67). The aging of Polish males is accompanied by both a significant increase of BMI, percent fat mass and WHR values, and by a decline in estradiol, gonadal and adrenal androgen levels. In the younger group only total testosterone levels were significantly negatively related to BMI, percent fat mass and WHR. Within the group of older men both estradiol and DHEAS levels are significantly positively related to WHR. The sex steroids seem to be associated with indices of overall obesity and distribution of fat in men, but these relationships differ considerably when they are evaluated in younger and older age categories. Worthy of notice is the fact that free testosterone levels are not related to any anthropometric parameters in any age category, although free testosterone (not total testosterone) is commonly recognised as a reliable and sensitive endocrinological indicator of the general psycho-physical status of an aging man.


Endothelial cell junctions.
In the course of a freeze-cleave study on intercellular junctions in the regenerating rat liver, we observed an unusual array of intramembranous particles located in regions of contact between endothelial cells lining the hepatic sinusoids. These arrays were characterized by an accumulation of particles which resembled a zonula occludens in their linear deployment but differed in that the contact regions were composed of individual particles which remained separated from each other by regular particle-free intervals.


Health-system reform and universal health coverage in Latin America.
Starting in the late 1980s, many Latin American countries began social sector reforms to alleviate poverty, reduce socioeconomic inequalities, improve health outcomes, and provide financial risk protection. In particular, starting in the 1990s, reforms aimed at strengthening health systems to reduce inequalities in health access and outcomes focused on expansion of universal health coverage, especially for poor citizens. In Latin America, health-system reforms have produced a distinct approach to universal health coverage, underpinned by the principles of equity, solidarity, and collective action to overcome social inequalities. In most of the countries studied, government financing enabled the introduction of supply-side interventions to expand insurance coverage for uninsured citizens--with defined and enlarged benefits packages--and to scale up delivery of health services. Countries such as Brazil and Cuba introduced tax-financed universal health systems. These changes were combined with demand-side interventions aimed at alleviating poverty (targeting many social determinants of health) and improving access of the most disadvantaged populations. Hence, the distinguishing features of health-system strengthening for universal health coverage and lessons from the Latin American experience are relevant for countries advancing universal health coverage.


Reduction of systematic bias in transcriptome data from human peripheral blood mononuclear cells for transportation and biobanking.
Transportation of samples is essential for large-scale biobank projects. However, RNA degradation during pre-analytical operations prior to transportation can cause systematic bias in transcriptome data, which may prevent subsequent biomarker identification. Therefore, to collect high-quality biobank samples for expression analysis, specimens must be transported under stable conditions. In this study, we examined the effectiveness of RNA-stabilizing reagents to prevent RNA degradation during pre-analytical operations with an emphasis on RNA from peripheral blood mononuclear cells (PBMCs) to establish a protocol for reducing systematic bias. To this end, we obtained PBMCs from 11 healthy volunteers and analyzed the purity, yield, and integrity of extracted RNA after performing pre-analytical operations for freezing PBMCs at -80°C. We randomly chose 7 samples from 11 samples individually, and systematic bias in expression levels was examined by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA sequencing (RNA-Seq) experiments and data analysis. Our data demonstrated that omission of stabilizing reagents significantly lowered RNA integrity, suggesting substantial degradation of RNA molecules due to pre-analytical freezing. qRT-PCR experiments for 19 selected transcripts revealed systematic bias in the expression levels of five transcripts. RNA-Seq for 25,223 transcripts also suggested that about 40% of transcripts were systematically biased. These results indicated that appropriate reduction in systematic bias is essential in protocols for collection of RNA from PBMCs for large-scale biobank projects. Among the seven commercially available stabilizing reagents examined in this study, qRT-PCR and RNA-Seq experiments consistently suggested that RNALock, RNA/DNA Stabilization Reagent for Blood and Bone Marrow, and 1-Thioglycerol/Homogenization solution could reduce systematic bias. On the basis of the results of this study, we established a protocol to reduce systematic bias in the expression levels of RNA transcripts isolated from PBMCs. We believe that these data provide a novel methodology for collection of high-quality RNA from PBMCs for biobank researchers.


A double-blind randomised controlled trial testing the effect of a barley product containing varying amounts and types of fibre on the postprandial glucose response of healthy volunteers.
The aim of the present study was to determine if the consumption of barley tortillas varying in fibre and/or starch composition affected postprandial glucose, insulin, glucagon-like peptide-1 (GLP-1) or peptide YY concentrations. A double-blind, randomised, controlled trial was performed with twelve healthy adults. They each consumed one of five barley tortillas or a glucose drink on six individual visits separated by at least 1 week. Tortillas were made from 100% barley flour blends using five different milling fractions to achieve the desired compositions. All treatments provided 50 g of available carbohydrate and were designed to make the following comparisons: (1) low-starch amylose (0%) v. high-starch amylose (42%) with similar β-glucan and insoluble fibre content; (2) low β-glucan (4.5 g) v. medium β-glucan (7.8 g) v. high β-glucan (11.6 g) with similar starch amylose and insoluble fibre content; and (3) low insoluble fibre (7.4 g) v. high insoluble fibre (19.6 g) with similar starch amylose and β-glucan content. Blood was collected at fasting and at multiple intervals until 180 min after the first bite/sip of the test product. Amylose and insoluble fibre content did not alter postprandial glucose and insulin, but high-β-glucan tortillas elicited a lower glucose and insulin response as compared to the low-β-glucan tortillas. The tortillas with high insoluble fibre had a higher AUC for GLP-1 as compared to the tortillas with low insoluble fibre, whereas amylose and β-glucan content had no effect. Results show that processing methods can be used to optimise barley foods to reduce postprandial blood glucose responses and factors that may influence satiety.


Molecular mechanisms of the potent and stereospecific nicotinic receptor agonist (+)-anatoxin-a.
Anatoxin-a (AnTX) was shown to be a highly potent and stereospecific agonist at nicotinic synapses in frog skeletal muscle and Torpedo electric organs. AnTX binds to the nicotinic-acetylcholine receptor with a higher affinity than for acetylcholine (ACh) but does not bind to sites in the receptor-gated ionic channel. (+)AnTX caused receptor desensitization, i.e., the loss of agonist-stimulated binding of histrionicotoxin to an allosteric site with time, at a rate significantly slower than that of ACh. Single channel patch clamp recordings indicated that the conductance of channels activated by (+)AnTX (28 pS) and ACh (27 pS) were similar. The (+)AnTX-activated channels contained rapid closing events, the burst times caused by the toxin were shorter than those caused by ACh but had similar voltage dependencies, and the number of short closures per burst was constant at all potentials with both agonists. The bursts of rapid openings and rapid closures (tau = 0.4 msec) appear to result from repetitive opening and closing of the (+)AnTX-bound receptor-ion channel. It is concluded that the semirigid molecule and secondary amine (+)AnTX is a more potent agonist than ACh or carbamylcholine because of a higher affinity for the receptor. At various concentrations the toxin activates the appearance of channels with the same conductances as ACh-induced channels but with a shorter channel lifetime.


Fibrinogen from human plasma: preparation by precipitation with heavy-metal coordination complex.
Potassium tetrathiocyanato-(S)mercurate II [K(2)Hg(SCN)(4)] is used in a mild and rapid procedure for the isolation of human fibrinogen from fresh plasma. The final product, 94 to 99 percent of which is coagulable by thrombin, represents an average yield of 80 percent and is stable in solution. It is free of plasmin, streptokinase-activatable plasminogen, and coagulation factors II, V, VIII, X and XIII. Sedimentation analysis reveals a single peak with a sedimentation coefficient equal to 7.0S at infinite dilution. Immunodiffusion on cellulose acetate results in two precipitin lines with rabbit antiserum to whole human serum. The fibrinogen precipitates are unusual in that they are flocculent and readily redissolve.


Open access phone triage for veterans with suspected malignant pleural mesothelioma.
Phone triaging patients with suspected malignant pleural mesothelioma (MPM) within the Veterans Healthcare Administration (VHA) system offers a model for rapid, expert guided evaluation for patients with rare and treatable diseases within a national integrated healthcare system. To assess feasibility of national open access telephone triage using evidence-based treatment recommendations for patients with MPM, measure timelines of the triage and referral process and record the impact on "intent to treat" for patients using our service. A retrospective study. The main outcome measures were: (1) ability to perform long distance phone triage, (2) to assess the speed of access to a mesothelioma surgical specialist for patients throughout the entire VHA, and (3) to determine if access to a specialist would alter the plan of care. Sixty veterans were screened by our phone triage program, 38 traveled an average of 997 miles to VA Boston Healthcare system. On average, 14 d elapsed from initial phone contact until the patient was physically evaluated in our general thoracic clinic in Boston. The treatment plan was altered for 71% of patients evaluated at VA Boston Healthcare system based on 2012 International Mesothelioma Interest Group guidelines. Our initial experience demonstrates that in-network centralized care for Veterans with MPM is feasible within the VHA. National open access phone triage improves access to expert surgical advice and can be delivered in a timely manner for Veterans using our service. Guideline-based treatment recommendations ("intent to treat") changed the therapeutic course for the majority of patients who used our service.


Peptide-Directed Assembly of Single-Helical Gold Nanoparticle Superstructures Exhibiting Intense Chiroptical Activity.
Chiral nanoparticle assemblies are an interesting class of materials whose chiroptical properties make them attractive for a variety of applications. Here, C18-(PEPAuM-ox)2 (PEPAuM-ox = AYSSGAPPMoxPPF) is shown to direct the assembly of single-helical gold nanoparticle superstructures that exhibit exceptionally strong chiroptical activity at the plasmon frequency with absolute g-factor values up to 0.04. Transmission electron microscopy (TEM) and cryogenic electron tomography (cryo-ET) results indicate that the single helices have a periodic pitch of approximately 100 nm and consist of oblong gold nanoparticles. The morphology and assembled structure of C18-(PEPAuM-ox)2 are studied using TEM, atomic force microscopy (AFM), Fourier transform infrared (FTIR) spectroscopy, circular dichroism (CD) spectroscopy, X-ray diffraction (XRD), and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. TEM and AFM reveal that C18-(PEPAuM-ox)2 assembles into linear amyloid-like 1D helical ribbons having structural parameters that correlate to those of the single-helical gold nanoparticle superstructures. FTIR, CD, XRD, and ssNMR indicate the presence of cross-β and polyproline II secondary structures. A molecular assembly model is presented that takes into account all experimental observations and that supports the single-helical nanoparticle assembly architecture. This model provides the basis for the design of future nanoparticle assemblies having programmable structures and properties.


Berry derived constituents in suppressing viral infection: Potential avenues for viral pandemic management.
Berries are acknowledged as a rich source of major dietary antioxidants and the fact that berry phenolics exhibit antioxidant property is widely accepted. Berries are abundant in Vitamin C and polyphenols such as anthocyanins, flavonoids, and phenolic acids. Polyphenols are found to have several therapeutic effects such as anti-inflammatory, antioxidant, and antimicrobial properties. Increasing studies are focusing on natural products and their components for alternative therapeutics against viral infections. In particular, berries such as elderberry, blueberry, raspberry, and cranberry have proven to be effective against viral infections. Of note, the decoction of Honeysuckle (Lonicera japonica) has been shown to treat viral epidemic diseases. Owing to the rich source of various antiviral constituents, berries could be an alternative source for managing viral infections. In this review, we provide insights into how berry derived components inhibit viral infection and their clinical usefulness in viral disease management.


Combinations of Aminocatalysts and Metal Catalysts: A Powerful Cooperative Approach in Selective Organic Synthesis.
The cooperation and interplay between organic and metal catalyst systems is of utmost importance in nature and chemical synthesis. Here innovative and selective cooperative catalyst systems can be designed by combining two catalysts that complement rather than inhibit one another. This refined strategy can permit chemical transformations unmanageable by either of the catalysts alone. This review summarizes innovations and developments in selective organic synthesis that have used cooperative dual catalysis by combining simple aminocatalysts with metal catalysts. Considerable efforts have been devoted to this fruitful field. This emerging area employs the different activation modes of amine and metal catalysts as a platform to address challenging reactions. Here, aminocatalysis (e.g., enamine activation catalysis, iminium activation catalysis, single occupied molecular orbital (SOMO) activation catalysis, and photoredox activation catalysis) is employed to activate unreactive carbonyl substrates. The transition metal catalyst complements by activating a variety of substrates through a range of interactions (e.g., electrophilic π-allyl complex formation, Lewis acid activation, allenylidene complex formation, photoredox activation, C-H activation, etc.), and thereby novel concepts within catalysis are created. The inclusion of heterogeneous catalysis strategies allows for "green" chemistry development, catalyst recyclability, and the more eco-friendly synthesis of valuable compounds.


Head injury in the United Kingdom.
This paper reviews aspects of head injury management and research in the United Kingdom (UK). We discuss evidence about the scale and etiology of head injury in Britain and how this information has supported a triage-based approach, incorporating risk analysis. A Cohesive organization based upon nationally accepted, yet regionally flexible head injury management guidelines is important. Research in the United Kingdom has clarified the effect of head injury on the brain and how this can be reduced. This clarification follows from improved understanding of the neurobiology of injury, of secondary damage and recovery, and information gained from new techniques aimed at investigating events in patients. Outcome is an important perspective and we highlight the increasing focus upon recovery and the extent of disability after so called mild head injury. Although we retain a UK perspective, comparisons with aspects of European head injury emphasize the increasing importance of an international approach in the future.


1xN plasmonic power splitters based on metal-insulator-metal waveguides.
Novel plasmonic power splitters constructed from a rectangular ring resonator with direct-connected input and output waveguides are presented and numerically investigated. An analytical model and systematic approach for obtaining the appropriate design parameters are developed by designing an equivalent lumped circuit model for the transmission lines and applying it to plasmonic waveguides. This approach can dramatically reduce simulation times required for determining the desired locations of the output waveguides. Three examples are shown, the 1 × 3, 1 × 4, and 1 × 5 equal-power splitters, with the design method being easily extended to any number of output ports.


Surgical and intensification procedures for defining visual pathways with cobaltous-lysine.
The introduction of heavy metals directly into living neuronal tissue has received little attention as a method for defining connections in the vertebrate nervous system. Procedures are described for the use of cobaltous-lysine to trace visual pathways with light microscopy. The success of the technique depends on a number of variables including: the method by which the tracer is applied, the survival period, and the method of intensification. Best results were obtained by soaking the optic nerve of living animals in the filling solution for 24 hr and by using a modification of the Timm's silver sulfide intensification procedure. Several factors that lead to poor results are discussed. Cobaltous-lysine is capable of both anterograde and retrograde labeling and can fill very sparse projections. Furthermore, the success of the fill can, at times, be evaluated prior to histology.


Three studies on self-report scales to detect bipolar disorder.
This study investigated the usefulness of self-report scales for detecting bipolar disorder in several settings. Study 1 developed a short form of the Hypomanic Personality Scale (the HPS-6) based on clinic/community and undergraduate samples. Study 2 used this scale for recruiting participants with bipolar disorder from the community. Study 3 administered the full-length Hypomanic Personality Scale, the Mood Disorder Questionnaire, and a short form of the General Behavior Inventory (the GBI-15) to an undergraduate sample. Each study featured a reference standard diagnostic interview. In Study 2, about half of those responding to the advertisement (based on the HPS-6 developed in Study 1) reported a history of at least one hypomanic episode on a telephone-based SCID. In Study 3, the most robust findings emerged for the GBI-15: about one-third of participants screening positive on that measure met criteria for bipolar disorder using the Structured Clinical Interview for the DSM-IV (SCID). Despite large sample sizes and stratified sampling, this study was limited by a low number of participants with bipolar I disorder. These three studies produced mixed findings regarding the detection of bipolar disorder via self-report. The HPS-6 was reasonably successful in recruiting participants with a history of at least one manic or hypomanic episode into a study on bipolar disorder. The GBI-15 showed some promise as a screening tool in an undergraduate setting, but there is a need for more sensitive and specific scales. Discussion focuses on potential strategies for developing such scales.


Lipopolysaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: pharmacological evaluation of nitric oxide synthase inhibitors.
The benefits of nitric oxide synthase (NOS) inhibitors in the treatment of endotoxemia or sepsis presumably arise from inhibition of the type II (inducible) NOS. However, inasmuch as the effect of these inhibitors on NOS function in vivo is rarely assessed, NOS activity was evaluated in rats and mice by measuring changes in plasma nitrite and nitrate concentrations ([NOx]) after administration of lipopolysaccharide (LPS). In both species, [NOx] peaked at 20 hr, returning to base line by 48 to 72 hr. The ED50 values (dose that elicited a 50% inhibition of the LPS-dependent increase in [NOx] 6 hr after LPS administration) for L-NG-monomethylarginine acetate, L-NG-nitroarginine methyl ester and aminoguanidine (administered 3 hr after LPS) were 34, 21 and 19 mg/kg in the rat and 32, 5 and 4 mg/kg in the mouse. These compounds also decreased the survival of LPS-challenged animals, which in the case of L-NG-nitroarginine methyl ester was reversed by L-arginine. Dexamethasone (which prevents the induction of type II NOS) also inhibited the LPS-dependent increase in [NOx] with ED50 values of 0.05 mg/kg (rat) and 1 mg/kg (mouse), but did not lead to decreased survival. Thus, inhibition of the type I (neuronal) or type III (endothelial) NOS, rather than the type II isoform, may be a possible mechanism for the animal mortality. These models provide a simple and reproducible means for assessing the in vivo inhibition of type II NOS by various compounds.


Joint attention, shared goals, and social bonding.
There has recently been interest in the ways in which coordinated movements encourage coactors to feel socially closer to one another, but this has generally overlooked the importance of necessary precursors to this joint action. Here we target two low-level behaviours involved in social coordination that may mediate a relationship between joint actions and social bonding, namely joint attention and shared goals. Participants engaged in a simple reaction time task while sitting next to a partner performing the same task. In a joint attention condition, both participants attended to stimuli presented on the same half of a computer screen, while in a control condition, they attended to opposite sides of the computer screen. Shared goals were manipulated by giving participants the instruction to keep below a threshold score for both individual response times and accuracy (individual goal), or their joint mean response time and accuracy (i.e., averaging their mean response time and accuracy with that of their partner: shared goal). Attending to the same side of the screen led to higher ratings on a composite social bonding index directed towards a partner, while shared goals did not cause any effects on partner ratings. Joint attention was sufficient to encourage social closeness with an interaction partner, which suggests that any activities which encourage attending to the same point in space could have some influence on how connected coactors feel about one another.


Positive emotionality is associated with baseline metabolism in orbitofrontal cortex and in regions of the default network.
Positive emotionality (PEM) (personality construct of well-being, achievement/motivation, social and closeness) has been associated with striatal dopamine D2 receptor availability in healthy controls. As striatal D2 receptors modulate activity in orbitofrontal cortex (OFC) and cingulate (brain regions that process natural and drug rewards), we hypothesized that these regions underlie PEM. To test this, we assessed the correlation between baseline brain glucose metabolism (measured with positron emission tomography and [(18)F]fluoro-deoxyglucose) and scores on PEM (obtained from the multidimensional personality questionnaire or MPQ) in healthy controls (n = 47). Statistical parametric mapping (SPM) analyses revealed that PEM was positively correlated (P(c)<0.05, voxel corrected) with metabolism in various cortical regions that included orbitofrontal (Brodman area, BA 11, 47) and cingulate (BA 23, 32) and other frontal (BA 10, 9), parietal (precuneus, BA 40) and temporal (BA 20, 21) regions that overlap with the brain's default mode network (DMN). Correlations with the other two main MPQ personality dimensions (negative emotionality and constraint) were not significant (SPM P(c)<0.05). Our results corroborate an involvement of orbitofrontal and cingulate regions in PEM, which is considered a trait that protects against substance use disorders. As dysfunction of OFC and cingulate is a hallmark of addiction, these findings support a common neural basis underlying protective personality factors and brain dysfunction underlying substance use disorders. In addition, we also uncovered an association between PEM and baseline metabolism in regions from the DMN, which suggests that PEM may relate to global cortical processes that are active during resting conditions (introspection, mind wandering).


Customizing kernel functions for SVM-based hyperspectral image classification.
Previous research applying kernel methods such as support vector machines (SVMs) to hyperspectral image classification has achieved performance competitive with the best available algorithms. However, few efforts have been made to extend SVMs to cover the specific requirements of hyperspectral image classification, for example, by building tailor-made kernels. Observation of real-life spectral imagery from the AVIRIS hyperspectral sensor shows that the useful information for classification is not equally distributed across bands, which provides potential to enhance the SVM's performance through exploring different kernel functions. Spectrally weighted kernels are, therefore, proposed, and a set of particular weights is chosen by either optimizing an estimate of generalization error or evaluating each band's utility level. To assess the effectiveness of the proposed method, experiments are carried out on the publicly available 92AV3C dataset collected from the 220-dimensional AVIRIS hyperspectral sensor. Results indicate that the method is generally effective in improving performance: spectral weighting based on learning weights by gradient descent is found to be slightly better than an alternative method based on estimating "relevance" between band information and ground truth.


Consensus Modeling of Median Chemical Intake for the U.S. Population Based on Predictions of Exposure Pathways.
Prioritizing the potential risk posed to human health by chemicals requires tools that can estimate exposure from limited information. In this study, chemical structure and physicochemical properties were used to predict the probability that a chemical might be associated with any of four exposure pathways leading from sources-consumer (near-field), dietary, far-field industrial, and far-field pesticide-to the general population. The balanced accuracies of these source-based exposure pathway models range from 73 to 81%, with the error rate for identifying positive chemicals ranging from 17 to 36%. We then used exposure pathways to organize predictions from 13 different exposure models as well as other predictors of human intake rates. We created a consensus, meta-model using the Systematic Empirical Evaluation of Models framework in which the predictors of exposure were combined by pathway and weighted according to predictive ability for chemical intake rates inferred from human biomonitoring data for 114 chemicals. The consensus model yields an R2 of ∼0.8. We extrapolate to predict relevant pathway(s), median intake rate, and credible interval for 479 926 chemicals, mostly with minimal exposure information. This approach identifies 1880 chemicals for which the median population intake rates may exceed 0.1 mg/kg bodyweight/day, while there is 95% confidence that the median intake rate is below 1 μg/kg BW/day for 474572 compounds.


We look like our names: The manifestation of name stereotypes in facial appearance.
Research demonstrates that facial appearance affects social perceptions. The current research investigates the reverse possibility: Can social perceptions influence facial appearance? We examine a social tag that is associated with us early in life-our given name. The hypothesis is that name stereotypes can be manifested in facial appearance, producing a face-name matching effect, whereby both a social perceiver and a computer are able to accurately match a person's name to his or her face. In 8 studies we demonstrate the existence of this effect, as participants examining an unfamiliar face accurately select the person's true name from a list of several names, significantly above chance level. We replicate the effect in 2 countries and find that it extends beyond the limits of socioeconomic cues. We also find the effect using a computer-based paradigm and 94,000 faces. In our exploration of the underlying mechanism, we show that existing name stereotypes produce the effect, as its occurrence is culture-dependent. A self-fulfilling prophecy seems to be at work, as initial evidence shows that facial appearance regions that are controlled by the individual (e.g., hairstyle) are sufficient to produce the effect, and socially using one's given name is necessary to generate the effect. Together, these studies suggest that facial appearance represents social expectations of how a person with a specific name should look. In this way a social tag may influence one's facial appearance. (PsycINFO Database Record


Survival of cutaneous melanoma based on sex, age, and stage in the United States, 1992-2011.
Women diagnosed with cutaneous melanoma have a survival advantage compared to men, which has been hypothesized to be due to difference in behavior and/or biology (sex hormones). It remains controversial whether this advantage is dependent on age or stage of disease. We sought to compare melanoma-specific survival between females in pre, peri, and postmenopausal age groups to males in the same age group, adjusting for stage of disease. This is a retrospective population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed from 1 January 1992 through 31 January 2011 with primary invasive cutaneous melanoma were included in our cohort. Melanoma-specific survival was the main outcome studied. Of the 106,511 subjects that were included, 45% were female. Females in all age groups (18-45, 46-54, and ≥55) with localized and regional disease, were less likely to die from melanoma compared to males in the same age group. Among patients with localized and regional disease, the relative risk of death due to melanoma increased with advancing age at diagnosis; this increase was more pronounced among females than males. In contrast, we observed no female survival advantage among patients with distant disease and no effect of age on relative risk of death from melanoma. Females with localized and regional melanoma have a decreased risk of death compared to males within all age groups. Our data show no differences in survival between men and women with metastatic melanoma, indicating that the influence of sex on survival is limited to early stage disease but not confined to pre or perimenopausal age groups.


Molecularly imprinted microgels as enzyme inhibitors.
We demonstrate, on the example of trypsin, the use of water-soluble molecularly imprinted polymer microgels as specific enzyme inhibitors. Using a strong anchoring monomer, methacryloylaminobenzamidine, the growing polymer chains are confined to close proximity of the substrate recognition site of our model enzyme. The microgels bind selectively trypsin over other proteins of similar size and molecular weight, and show competitive inhibition of trypsin with an inhibition constant K(i) of 79 nM, making them more potent inhibitors than the low molecular-weight competitive inhibitor benzamidine by almost 3 orders of magnitude. We believe that these tailor-made materials with biological activity have potential for future drug development that extends beyond enzyme inhibition.


Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression.
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the ΔF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous ΔF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of ΔF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface ΔF508-CFTR density and function. VX-770-induced destabilization of ΔF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)-NBD2 interface. The reduced correction efficiency of ΔF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF.


Bicaudal-D and its role in cargo sorting by microtubule-based motors.
Many cytoplasmic cargoes are transported along microtubules using dynein or kinesin molecular motors. As the sorting machinery of the cell needs to be tightly controlled, associated factors are employed to either recruit cargoes to motors or to regulate their activities. In the present review, we concentrate on the BicD (Bicaudal-D) protein, which has recently emerged as an essential element for transport of several important cargoes by the minus-end-directed motor cytoplasmic dynein. BicD was proposed to be a linker bridging cargo and dynein, although recent studies suggest that it may also have roles in the regulation of cargo motility. Here we summarize the current knowledge of the role that BicD plays in the transport of diverse cellular constituents. We catalogue the molecular interactions that underpin these functions and also highlight important questions to be addressed in the future.


Differential expression of two MADS box genes in wild-type and mutant petunia flowers.
We isolated and characterized two flower-specific genes from petunia. The protein products of these genes, designated floral binding protein 1 (FBP1) and 2 (FBP2), are putative transcription factors with the MADS box DNA binding domain. RNA gel blot analysis showed that the fbp1 gene is exclusively expressed in petals and stamen of petunia flowers. In contrast, the FBP1 protein was only detectable in petals and not in stamens, suggesting post-transcriptional regulation of the fbp1 gene in these tissues. The fbp2 gene is expressed in petals, stamen, carpels, and at a very low level in sepals but not in vegetative tissues. We analyzed the spatial expression of these fbp genes in floral organs of two homeotic flower mutants. In the blind mutant, whose flower limbs are transformed into antheroid structures on top of normal tubes, identical expression levels of both genes were observed in the antheroid structures as in normal anthers. In the homeotic mutant green petals, the petals are replaced by sepaloid organs in which the expression of fbp1 is strongly reduced but not completely abolished. Our results suggest a regulation of the fbp1 gene expression by the green petals (gp) gene. Expression of the fbp2 gene was not affected in the green petals mutant. In contrast to the proposed models describing floral morphogenesis, our data indicated that homeotic genes can be functional in one whorl only.


Radicular Perforation Repair with Mineral Trioxide Aggregate: A Case Report with 10-Year Follow-up.
Iatrogenic complications such as accidental perforation of the root or the floor of the pulp chamber may occur. Patient was referred for root canal retreatment of the mandibular left second molar with periapical lesion evidenced through radiographic examination. During post removal, iatrogenic perforation occurred at the mesial face of the distal root. After clinical localization of the perforation and bleeding control, MTA was applied. In a second appointment, the root canal filling was removed and the chemical-surgical retreatment of the canals was performed, followed by the obturation with gutta-percha and sealer. Patient returned after three days reporting no pain. After 6 months, 3, 7 and 10 years of follow-up. Absence of pain, normal periodontal probing and lack of radiolucent area at the region of perforation and the periapices were detected, which evidenced the successful repair of the tooth.


Evidence for a conditioning effect of inhalational anesthetics on angiographic vasospasm after aneurysmal subarachnoid hemorrhage.
Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is characterized by large-artery vasospasm, distal autoregulatory dysfunction, cortical spreading depression, and microvessel thrombi. Large-artery vasospasm has been identified as an independent predictor of poor outcome in numerous studies. Recently, several animal studies have identified a strong protective role for inhalational anesthetics against secondary brain injury after SAH including DCI-a phenomenon referred to as anesthetic conditioning. The aim of the present study was to assess the potential role of inhalational anesthetics against cerebral vasospasm and DCI in patients suffering from an SAH. After IRB approval, data were collected retrospectively for all SAH patients admitted to the authors' hospital between January 1, 2010, and December 31, 2013, who received general anesthesia with either inhalational anesthetics only (sevoflurane or desflurane) or combined inhalational (sevoflurane or desflurane) and intravenous (propofol) anesthetics during aneurysm treatment. The primary outcomes were development of angiographic vasospasm and development of DCI during hospitalization. Univariate and logistic regression analyses were performed to identify independent predictors of these endpoints. The cohort included 157 SAH patients whose mean age was 56 ± 14 (± SD). An inhalational anesthetic-only technique was employed in 119 patients (76%), while a combination of inhalational and intravenous anesthetics was employed in 34 patients (22%). As expected, patients in the inhalational anesthetic-only group were exposed to significantly more inhalational agent than patients in the combination anesthetic group (p < 0.05). Multivariate logistic regression analysis identified inhalational anesthetic-only technique (OR 0.35, 95% CI 0.14-0.89), Hunt and Hess grade (OR 1.51, 95% CI 1.03-2.22), and diabetes (OR 0.19, 95% CI 0.06-0.55) as significant predictors of angiographic vasospasm. In contradistinction, the inhalational anesthetic-only technique had no significant impact on the incidence of DCI or functional outcome at discharge, though greater exposure to desflurane (as measured by end-tidal concentration) was associated with a lower incidence of DCI. These data represent the first evidence in humans that inhalational anesthetics may exert a conditioning protective effect against angiographic vasospasm in SAH patients. Future studies will be needed to determine whether optimized inhalational anesthetic paradigms produce definitive protection against angiographic vasospasm; whether they protect against other events leading to secondary brain injury after SAH, including microvascular thrombi, autoregulatory dysfunction, blood-brain barrier breakdown, neuroinflammation, and neuronal cell death; and, if so, whether this protection ultimately improves patient outcome.


Wording effects and the factor structure of the 12-item General Health Questionnaire (GHQ-12).
The 12-item version of the General Health Questionnaire (GHQ-12) has become a popular screening instrument with which to measure general psychological health in different settings. Previous studies into the factorial structure of the GHQ-12 have mainly supported multifactor solutions, and only a few recent works have shown that the GHQ-12 was best represented by a single substantive factor when method effects associated with negatively worded items were considered. Confirmatory factor analysis was applied to compare competing measurement models from previous research, including correlated traits-correlated methods and correlated traits-correlated uniquenesses approaches, to obtain further evidence about the factorial structure of the GHQ-12. This goal was achieved with data from 3,050 participants who completed the GHQ-12 included in the Catalonian Survey of Working Conditions (Catalonian Labor Relations and Quality of Work Department, 2012). The results showed additional evidence that the GHQ-12 has a unidimensional structure after controlling for method effects associated with negatively worded items. Furthermore, we found evidence for our hypothesis about the spurious nature of the 3-factor solution in Graetz's (1991) model after comparing its fit with that found for alternative models resulting from different combinations of the negatively worded items. An implication of our results is that future research about the factor structure of the GHQ-12 should take method effects associated with negative wording into account in order to avoid reaching inaccurate conclusions about its dimensionality.


Model-Based Condition Monitoring of the Sensors and Actuators of an Electric and Automated Vehicle.
Constant monitoring of driving conditions and observation of the surrounding area are essential for achieving reliable, high-quality autonomous driving. This requires more reliable sensors and actuators, as there is always the potential that sensors and actuators will fail under real-world conditions. The sensitive condition-monitoring methods of sensors and actuators should be used to improve the reliability of the sensors and actuators. They should be able to detect and isolate the abnormal situations of faulty sensors and actuators. In this paper, a developed model-based method for condition monitoring of the sensors and actuators in an electric vehicle is presented that can determine whether a sensor has a fault and further reconfigure the sensor signal, as well as detect the abnormal behavior of the actuators with the reconfigured sensor signals. Through the simulation data obtained by the vehicle model in complex road conditions, it is proved that the method is effective for the state detection of sensors and actuators.


Focus issue introduction: nonlinear optics.
It is now fifty years since the original observation of second harmonic generation ushered in the field of nonlinear optics, close on the heels of the invention of the laser. This feature issue celebrates this anniversary with papers that span the range from new nonlinear optical materials, through the increasingly novel methods that have been developed for phase matching, to emerging areas such as nonlinear metamaterials and plasmonic enhancement of optical properties. It is clear that the next fifty years of nonlinear optics will witness a proliferation of new applications with increasing technological impact.


Correlates of and couples' concordance in reports of recent sexual behavior and contraceptive use.
This study uses couple-level data to measure couples' concordance of self-reported time since last coitus and of condom and other contraceptive use at last sexual intercourse among monogamous couples in Liberia (N = 1,673), Madagascar (N = 4,138), and Namibia (N = 588). The study also examines the characteristics associated with sexual behavior and contraceptive use occurring in the 28 days prior to the interviews among couples whose reports are concordant. Overall, our study finds less than 75 percent concordance in reporting of time since last coitus. Use of condoms and other contraceptives yielded fair (0.27) to substantial (0.67) agreement on the kappa index. Factors predicting a shorter time since last coitus among concordant couples in at least two of the countries included wealth, spousal age difference, education, and both partners wanting another child. The discordant reports of recent sexual behavior and contraceptive use suggest that caution should be exercised when inferring couples' behavior from the report of one spouse, that concordant reports should be examined when possible, that methodological changes to improve the validity of spousal reports should be pursued, and that family planning and HIV-prevention programs should target those groups found to be using condoms and other contraceptives less frequently, particularly poorer couples.


OUTCOME OF LAPAROSCOPIC CHOLECYSTECTOMY IN PATIENTS WITH GALLSTONE DISEASE AT A SECONDARY LEVEL CARE HOSPITAL.
Laparoscopic cholecystectomy is the most commonly performed operation of the digestive tract. )It is considered as the gold standard treatment for cholelithiasis. To evaluate the outcome of it regarding length of hospital stay, complications, morbidity and mortality at a secondary hospital. Data of 492 patients who underwent laparoscopic cholecystectomy were retrospectively reviewed. Patients' demographics, co-morbid diseases, previous abdominal surgery, conversion to open cholecystectomy, operative time, intra and postoperative complications, and hospital stay were collected and analyzed from patients' files. Out of 492 patients, 386 (78.5%) were females and 106 (21.5%) males. The mean age of the patients was 49.35±8.68 years. Mean operative time was 65.94±11.52 min. Twenty-four cases (4.9%) were converted to open surgery, four due to obscure anatomy (0.8%), 11 due to difficult dissection in Calot's triangle (2.2%) and nine by bleeding (1.8%). Twelve (2.4%) cases had biliary leakage, seven (1.4%) due to partial tear in common bile duct, the other five due to slipped cystic duct stables. Mean hospital stay was 2.6±1.5 days. Twenty-one (4.3%) developed wound infection. Port site hernia was detected in nine (1.8%) patients. There was no cases of bowel injury or spilled gallstones. There was no mortality recorded in this series. Laparoscopic cholecystectomy is a safe and effective line for management of gallstone disease that can be performed with acceptable morbidity at a secondary hospital.


Utilizing elementary mode analysis, pathway thermodynamics, and a genetic algorithm for metabolic flux determination and optimal metabolic network design.
Microbial hosts offer a number of unique advantages when used as production systems for both native and heterologous small-molecules. These advantages include high selectivity and benign environmental impact; however, a principal drawback is low yield and/or productivity, which limits economic viability. Therefore a major challenge in developing a microbial production system is to maximize formation of a specific product while sustaining cell growth. Tools to rationally reconfigure microbial metabolism for these potentially conflicting objectives remain limited. Exhaustively exploring combinations of genetic modifications is both experimentally and computationally inefficient, and can become intractable when multiple gene deletions or insertions need to be considered. Alternatively, the search for desirable gene modifications may be solved heuristically as an evolutionary optimization problem. In this study, we combine a genetic algorithm and elementary mode analysis to develop an optimization framework for evolving metabolic networks with energetically favorable pathways for production of both biomass and a compound of interest. Utilization of thermodynamically-weighted elementary modes for flux reconstruction of E. coli central metabolism revealed two clusters of EMs with respect to their Delta Gp degrees. For proof of principle testing, the algorithm was applied to ethanol and lycopene production in E. coli. The algorithm was used to optimize product formation, biomass formation, and product and biomass formation simultaneously. Predicted knockouts often matched those that have previously been implemented experimentally for improved product formation. The performance of a multi-objective genetic algorithm showed that it is better to couple the two objectives in a single objective genetic algorithm. A computationally tractable framework is presented for the redesign of metabolic networks for maximal product formation combining elementary mode analysis (a form of convex analysis), pathway thermodynamics, and a genetic algorithm to optimize the production of two industrially-relevant products, ethanol and lycopene, from E. coli. The designed algorithm can be applied to any small-scale model of cellular metabolism theoretically utilizing any substrate and applied towards the production of any product.


Gene expression in mouse ovarian follicle development in vivo versus an ex vivo alginate culture system.
Ovarian follicle maturation results from a complex interplay of endocrine, paracrine, and direct cell-cell interactions. This study compared the dynamic expression of key developmental genes during folliculogenesis in vivo and during in vitro culture in a 3D alginate hydrogel system. Candidate gene expression profiles were measured within mouse two-layered secondary follicles, multi-layered secondary follicles, and cumulus-oocyte complexes (COCs). The expression of 20 genes involved in endocrine communication, growth signaling, and oocyte development was investigated by real-time PCR. Gene product levels were compared between i) follicles of similar stage and ii) COCs derived either in vivo or by in vitro culture. For follicles cultured for 4 days, the expression pattern and the expression level of 12 genes were the same in vivo and in vitro. Some endocrine (cytochrome P450, family 19, subfamily A, polypeptide 1 (Cyp19a1) and inhibin βA subunit (Inhba)) and growth-related genes (bone morphogenetic protein 15 (Bmp15), kit ligand (Kitl), and transforming growth factor β receptor 2 (Tgfbr2)) were downregulated relative to in vivo follicles. For COCs obtained from cultured follicles, endocrine-related genes (inhibin α-subunit (Inha) and Inhba) had increased expression relative to in vivo counterparts, whereas growth-related genes (Bmp15, growth differentiation factor 9, and kit oncogene (Kit)) and zona pellucida genes were decreased. However, most of the oocyte-specific genes (e.g. factor in the germline α (Figla), jagged 1 (Jag1), and Nlrp5 (Mater)) were expressed in vitro at the same level and with the same pattern as in vivo-derived follicles. These studies establish the similarities and differences between in vivo and in vitro cultured follicles, guiding the creation of environments that maximize follicle development and oocyte quality.


Effect of long-term storage in TRIzol on microarray-based gene expression profiling.
Although TRIzol is widely used for preservation and isolation of RNA, there is suspicion that prolonged sample storage in TRIzol may affect array-based gene expression profiling (GEP) through premature termination during reverse transcription. GEP on Illumina arrays compared paired aliquots (cryopreserved or stored in TRIzol) of primary samples of multiple myeloma (MM) and acute myeloid leukemia (AML). Data were analyzed at the "probe level" (a single consensus value) or "bead level" (multiple measurements provided by individual beads). TRIzol storage does not affect standard probe-level comparisons between sample groups: different preservation methods did not generate differentially expressed probes (DEP) within MM or AML sample groups, or substantially affect the many DEPs distinguishing between these groups. Differences were found by gene set enrichment analysis, but these were dismissible because of instability with permutation of sample labels, unbalanced restriction to TRIzol aliquots, inconsistency between MM and AML groups, and lack of biological plausibility. Bead-level comparisons found many DEPs within sample pairs, but most (73%) were <2-fold changed. There was no consistent evidence that TRIzol causes premature reverse transcription termination. Instead, a subset of DEPs were systematically due to increased signals in TRIzol-preserved samples from probes near the 5' end of transcripts, suggesting better mRNA preservation with TRIzol. TRIzol preserves RNA quality well, without a deleterious effect on GEP. Samples stored frozen with and without TRIzol may be compared by GEP with only minor concern for systematic artifacts. The standard practice of prolonged sample storage in TRIzol is suitable for GEP.


Inflammation and positive affect are associated with subjective health in women of the general population.
Poor subjective health has been associated with higher levels of inflammatory cytokines. We investigated whether such an association would apply to women of the general population. Levels of cytokines, affect and subjective health were assessed in 347 women of the general population aged 45 to 90 years. Higher levels of interleukin-6 were associated with poor subjective health, especially in participants over 65 years of age. Positive affect was a more robust determinant of subjective health than negative affect. The presence of low-grade inflammation and absence of positive affect, rather than presence of negative affect, may be important determinants of subjective health.


A protocol for investigation of the effects of outdoor air pollution on stroke incidence, phenotypes and survival using the South London Stroke Register.
Stroke is a major cause of death and disability. About 5.3 million people die every year from stroke worldwide with over 9 million people surviving at any one time after suffering a stroke. About 1 in 4 men and 1 in 5 women aged 45 years will suffer a stroke if they live to their 85th year. It is estimated that by 2023 there will be an absolute increase in the number of people experiencing a first ever stroke of about 30% compared with 1983. In the UK, stroke is the third commonest cause of death and the most common cause of adult physical disability and consumes 5% of the health and social services budget. Stroke is assuming strategic public health importance because of increased awareness in society, an ageing population and emerging new treatments. It is an NHS health service and research priority, being identified as a target in Our Healthier Nation and the NSF for Older People for prevention and risk factor control and in the NHS Plan as a disease requiring intermediate care planning and reduction in inequalities of care. Whilst a number of risk factors for stroke are well known (e.g. increasing age, ethnicity, socioeconomic deprivation, hypertension), the potential importance of outdoor air pollution as a modifiable risk factor is much less well recognised. This is because studies to date are inconclusive or have methodological limitations. In Sheffield, we estimated that 11% of stroke deaths may be linked to current levels of outdoor air pollution and this high figure is explained by the fact that so many people are exposed to air pollution.We plan to study the effects of outdoor air pollution on stroke using a series of epidemiological (i.e. population based) studies. The purpose of this project is: to examine if short term increases in pollution can trigger a stroke in susceptible individuals, to investigate if the occurrence of stroke is higher amongst people living in more polluted areas (which would be explained by a combination of exposure to short term increases and longer term exposure to higher pollution levels), and to see if people living in more polluted areas have reduced survival following their stroke. We will use geographical information systems, robust statistical methods and powerful grid computing facilities to link and analyse the data. The datasets we will use are the South London Stroke Register database, daily monitored pollution data from national monitoring networks and modelled pollution data for London from the Greater London Authority. The South London Stroke Register records information on all patients who suffer a stroke ("incident" cases) living within a defined area. This stroke incidence dataset offers major advantages over previous studies examining the effects of pollution on hospital admissions and mortality, as not all patients with stroke are admitted or die and there may be a delay between the onset of stroke and admission or death. In addition, it contains other useful information, particularly the type of stroke people have suffered. Air pollution is a potentially modifiable risk factor for stroke. This study will provide robust population level evidence regarding the effects of outdoor air pollution on stroke. If it confirms the link, it will suggest to policy-makers at national and international levels that targeting policy interventions at high pollution areas may be a feasible option for stroke prevention.


The columnar organization of the neocortex.
The modular organization of nervous systems is a widely documented principle of design for both vertebrate and invertebrate brains of which the columnar organization of the neocortex is an example. The classical cytoarchitectural areas of the neocortex are composed of smaller units, local neural circuits repeated iteratively within each area. Modules may vary in cell type and number, in internal and external connectivity, and in mode of neuronal processing between different large entities; within any single large entity they have a basic similarity of internal design and operation. Modules are most commonly grouped into entities by sets of dominating external connections. This unifying factor is most obvious for the heterotypical sensory and motor areas of the neocortex. Columnar defining factors in homotypical areas are generated, in part, within the cortex itself. The set of all modules composing such an entity may be fractionated into different modular subsets by different extrinsic connections. Linkages between them and subsets in other large entities form distributed systems. The neighborhood relations between connected subsets of modules in different entities result in nested distributed systems that serve distributed functions. A cortical area defined in classical cytoarchitectural terms may belong to more than one and sometimes to several distributed systems. Columns in cytoarchitectural areas located at some distance from one another, but with some common properties, may be linked by long-range, intracortical connections.