Thymoquinone inhibits growth of human medulloblastoma cells by inducing oxidative stress and caspase-dependent apoptosis while suppressing NF-κB signaling and IL-8 expression.
Medulloblastoma (MB) is the most common malignant brain tumor of childhood. The transcription factor NF-κB is overexpressed in human MB and is a critical factor for MB tumor growth. NF-κB is known to regulate the expression of interleukin-8 (IL-8), the chemokine that enhances cancer cell growth and resistance to chemotherapy. We have recently shown that thymoquinone (TQ) suppresses growth of hepatocellular carcinoma cells in part by inhibiting NF-κB signaling. Here we sought to extend these studies in MB cells and show that TQ suppresses growth of MB cells in a dose- and time-dependent manner, causes G2M cell cycle arrest, and induces apoptosis. TQ significantly increased generation of reactive oxygen species (ROS), while pretreatment of MB cells with the ROS scavenger N-acetylcysteine (NAC) abrogated TQ-induced cell death and apoptosis, suggesting that TQ-induced cell death and apoptosis are oxidative stress-mediated. TQ inhibitory effects were associated with inhibition of NF-κB and altered expression of its downstream effectors IL-8 and its receptors, the anti-apoptotic Bcl-2, Bcl-xL, X-IAP, and FLIP, as well as the pro-apoptotic TRAIL-R1, caspase-8, caspase-9, Bcl-xS, and cytochrome c. TQ-triggered apoptosis was substantiated by up-regulation of the executioner caspase-3 and caspase-7, as well as cleavage of the death substrate poly(ADP-ribose)polymerase. Interestingly, pretreatment of MB cells with NAC or the pan-caspase inhibitor zVAD-fmk abrogated TQ-induced apoptosis, loss of cyclin B1 and NF-κB activity, suggesting that these TQ-mediated effects are oxidative stress- and caspase-dependent. These findings reveal that TQ induces both extrinsic and intrinsic pathways of apoptosis in MB cells, and suggest its potential usefulness in the treatment of MB.


Control and Supervision Requirements for Floating Hybrid Generator Systems.
This work presents a series of devices that generate renewable energy from the marine environment which, in recent years, have aroused increasing interest. In particular, the main types of floating wind generators and marine current turbines are described. Over time, some of these floating generators have evolved in various hybrid modalities, integrating different generation devices into the same system, wind turbines, marine current turbines, wave energy converters, etc., with the objective of multiplying their generation capacity and optimizing the investment made in the floating system. However, this hybridization offers, in some cases, an opportunity to address the problem of controlling the structural stability of the system. Such stability enhancement has been considered a major challenge since the early days of floating wind turbine design. With this objective, in this work, a specific solution is proposed, consisting of a floating hybrid system composed of a wind generation subsystem and a generation subsystem with two marine current turbines. This proposal allows the development of an integrated control system which deals simultaneously with the structural stability of the system and the optimization of the generation capacity. Additionally, other requirements are also highlighted relating to the achievement of economic viability objectives, considering the reliability and availability of the system in the particularly aggressive marine environment, where maintenance operations are especially costly. In this sense, a model of intelligent integration of the tasks of supervision, diagnosis, and predictive maintenance is proposed.


PKB/Akt-dependent regulation of cell motility.
The prosurvival activity of phosphoinositide 3 kinase (PI3K)/Akt (also known as protein kinase B, PKB) pathway has been investigated in great detail in human physiology and disease. Accumulating evidence is emerging that this signaling axis also actively engages with the migratory process in motile cells, including metastatic cancer cells. Interference with the role of PI3K/Akt-mediated cell motility impairs cellular development and attenuates malignant progression of cancer metastasis. Because metastasis is responsible for 90% of mortality in cancer patients, the acceleration of cancer cell spreading observed in association with hyperactivation of the PI3K pathway, triggered for example by chemotherapy/radiotherapy in the clinic, has heightened awareness of the conflict between "good drugs" and unfavorable effects. Here, we discuss recent studies on PI3K/Akt-regulated cell motility in both physiological and pathological settings, with the aim of a better understanding of how activities of the PI3K/Akt axis initiate and transmit "migratory signals" that stimulate cell movement. We focus in particular on its direct influence on cell migration and invasion, epithelial-mesenchymal transition, and cancer metastasis.


A first-principles investigation of the structural and electrochemical properties of biredox ionic species in acetonitrile.
Biredox ionic liquids are a new class of functionalized electrolytes that may play an important role in future capacitive energy storage devices. By allowing additional storage of electrons inside the liquids, they can improve device performance significantly. However current devices employ nanoporous carbons in which the diffusion of the liquid and the adsorption of the ions could be affected by the occurrence of electron-transfer reactions. It is therefore necessary to understand better the thermodynamics and the kinetics of such reactions in biredox ionic liquids. Here we perform ab initio molecular dynamics simulations of both the oxidized and reduced species of several redox-active ionic molecules (used in biredox ionic liquids) dissolved in acetonitrile solvent and compare them with the bare redox molecules. We show that in all the cases, it is necessary to introduce a two Gaussian state model to calculate the reaction free energies accurately. These reaction free energies are only slightly affected by the presence of the IL group on the molecule. We characterize the structure of the solvation shell around the redox active part of the molecules and show that in the case of TEMPO-based molecules strong reorientation effects occur during the oxidation reaction.


Admission hyperglycemia and acute myocardial infarction: outcomes and potential therapies for diabetics and nondiabetics.
Hyperglycemia, in both diabetic and nondiabetic patients, has a significant negative impact on the morbidity and mortality of patients presenting with an acute myocardial infarction (AMI). Contemporary evidence indicates that persistent hyperglycemia after initial hospital admission continues to exert negative effects on AMI patients. There have been a number of studies demonstrating the benefit of tight glucose control in patients presenting with AMI, but a lack of convincing clinical data has led to loose guidelines and poor implementation of glucose targets for this group of patients. The CREATE-ECLA study, which hypothesized that a fixed high dose of glucose, insulin, and potassium (GIK) would change myocardial substrate utilization from free fatty acids to glucose and therefore protect ischemic myocardium, failed to demonstrate improved clinical outcomes in AMI patients. Studies that specifically investigated intensive insulin therapy, including DIGAMI-2 and HI-5, also failed to improve clinical outcomes such as mortality. There are a number of reasons that these trials may have fallen short, including the inability to reach glucose targets and inadequate power. There is now a need for a large placebo-controlled randomized trial with an adequate sample size and adherence to glucose targets in order to establish the benefit of treating hyperglycemia in patients presenting with AMI.


[The seasonal dynamic of fleas (Siphonaptera) abundance on apodemus uralensis in the northen part of Novgorod Region].
Seven fleas species were revealed on Apodemus uralensis. Only three of them (Ctenophthalmus agyrtes, Ct. uncinatus, Megabothris turbidus) are the main parasites of this rodent species and have similar phenology of imago. They appear in April, parasitise during spring and summer periods and disappear in autumn, in September-October. The abundance of all three species shows two peaks in a year, which correspond to two generations. Four species (Amalaraeus penicilliger, Ct. bisoctodentatus, Peromyscopsylla bidentata, P. silvatica) are not peculiar to Apodemus uralensis. They pass on this host species occasionally from other animals inhabiting forest biotopes.


Can super smart leaders suffer from too much of a good thing? The curvilinear effect of intelligence on perceived leadership behavior.
Although researchers predominately test for linear relationships between variables, at times there may be theoretical and even empirical reasons for expecting nonlinear functions. We examined if the relation between intelligence (IQ) and perceived leadership might be more accurately described by a curvilinear single-peaked function. Following Simonton's (1985) theory, we tested a specific model, indicating that the optimal IQ for perceived leadership will appear at about 1.2 standard deviations above the mean IQ of the group membership. The sample consisted of midlevel leaders from multinational private-sector companies. We used the leaders' scores on the Wonderlic Personnel Test (WPT)-a measure of IQ-to predict how they would be perceived on prototypically effective leadership (i.e., transformational and instrumental leadership). Accounting for the effects of leader personality, gender, age, as well as company, country, and time fixed effects, analyses indicated that perceptions of leadership followed a curvilinear inverted-U function of intelligence. The peak of this function was at an IQ score of about 120, which did not depart significantly from the value predicted by the theory. As the first direct empirical test of a precise curvilinear model of the intelligence-leadership relation, the results have important implications for future research on how leaders are perceived in the workplace. (PsycINFO Database Record


Detection and characterization of emerging psychoactive substances by ion mobility spectrometry.
Rapid detection and identification of novel psychoactive substances (NPS) continues to present significant analytical challenges to forensic and analytical chemists. Ion mobility spectrometry (IMS) has been traditionally considered as the analytical technique of choice to detect illicit drugs in security points in airports, borderlines and customs. Databases of the reduced mobility (K0 ) values of illicit drugs are available in the scientific literature and they should be completed with data of emerging designer drugs. In this paper, we have evaluated the effect of different measurement conditions and determined the K0 values of an important number of NPS including different families; such as phenethylamines, cathinones, synthetic cannabinoids and tryptamines among others to be incorporated to the existing data to provide a rapid detection and identification of this emerging threat.


Nanoparticle Regrowth Enhances Photoacoustic Signals of Semiconducting Macromolecular Probe for In Vivo Imaging.
Smart molecular probes that emit deep-tissue penetrating photoacoustic (PA) signals responsive to the target of interest are imperative to understand disease pathology and develop innovative therapeutics. This study reports a self-assembly approach to develop semiconducting macromolecular activatable probe for in vivo imaging of reactive oxygen species (ROS). This probe comprises a near-infrared absorbing phthalocyanine core and four poly(ethylene glycol) (PEG) arms linked by ROS-responsive self-immolative segments. Such an amphiphilic macromolecular structure allows it to undergo an ROS-specific cleavage process to release hydrophilic PEG and enhance the hydrophobicity of the nanosystem. Consequently, the residual phthalocyanine component self-assembles and regrows into large nanoparticles, leading to ROS-enhanced PA signals. The small size of the intact macromolecular probe is beneficial to penetrate into the tumor tissue of living mice, while the ROS-activated regrowth of nanoparticles prolongs the retention along with enhanced PA signals, permitting imaging of ROS during chemotherapy. This study thus capitalizes on stimuli-controlled self-assembly of macromolecules in conjunction with enhanced heat transfer in large nanoparticles for the development of smart molecular probes for PA imaging.


Genomic and functional characterization of a mucosal symbiont involved in early-stage colorectal cancer.
Colorectal cancer is a major health concern worldwide. Growing evidence for the role of the gut microbiota in the initiation of CRC has sparked interest in approaches that target these microorganisms. However, little is known about the composition and role of the microbiota associated with precancerous polyps. Here, we found distinct microbial signatures between patients with and without polyps and between polyp subtypes using sequencing and culturing techniques. We found a correlation between Bacteroides fragilis recovered and the level of inflammatory cytokines in the mucosa adjacent to the polyp. Additional analysis revealed that B. fragilis from patients with polyps are bft-negative, activate NF-κB through Toll-like receptor 4, induce a pro-inflammatory response, and are enriched in genes associated with LPS biosynthesis. This study provides fundamental insight into the microbial microenvironment of the pre-neoplastic polyp by highlighting strain-specific genomic and proteomic differences, as well as more broad compositional differences in the microbiome.


Active music therapy in Parkinson's disease: an integrative method for motor and emotional rehabilitation.
Modern management of Parkinson's disease (PD) aims to obtain symptom control, to reduce clinical disability, and to improve quality of life. Music acts as a specific stimulus to obtain motor and emotional responses by combining movement and stimulation of different sensory pathways. We explored the efficacy of active music therapy (MT) on motor and emotional functions in patients with PD. This prospective, randomized, controlled, single-blinded study lasted 3 months. It consisted of weekly sessions of MT and physical therapy (PT). Thirty-two patients with PD, all stable responders to levodopa and in Hoehn and Yahr stage 2 or 3, were randomly assigned to two groups of 16 patients each. We assessed severity of PD with the Unified Parkinson's Disease Rating Scale, emotional functions with the Happiness Measure, and quality of life using the Parkinson's Disease Quality of Life Questionnaire. MT sessions consisted of choral singing, voice exercise, rhythmic and free body movements, and active music involving collective invention. PT sessions included a series of passive stretching exercises, specific motor tasks, and strategies to improve balance and gait. MT had a significant overall effect on bradykinesia as measured by the Unified Parkinson's Disease Rating Scale (p < .034). Post-MT session findings were consistent with motor improvement, especially in bradykinesia items (p < .0001). Over time, changes on the Happiness Measure confirmed a beneficial effect of MT on emotional functions (p < .0001). Improvements in activities of daily living and in quality of life were also documented in the MT group (p < .0001). PT improved rigidity (p < .0001). MT is effective on motor, affective, and behavioral functions. We propose active MT as a new method for inclusion in PD rehabilitation programs.


Kinetics of Magnesiothermic Reduction of Natural Quartz.
In this work, the kinetics of natural quartz reduction by Mg to produce either Si or Mg2Si was studied through quantitative phase analysis. Reduction reaction experiments were performed at various temperatures, reaction times and Mg to SiO2 mole ratios of 2 and 4. Rietveld refinement of X-ray diffraction patterns was used to obtain phase distributions in the reacted samples. SEM and EPMA examinations were performed to evaluate the microstructural change during reduction. The results indicated that the reduction reaction rate was slower at a mole ratio of 2 than 4 at the same temperature, as illustrated by the total amount of Si formed (the percent of Si that is reduced to either Si or Mg2Si to total amount of Si) being 59% and 75%, respectively, after 240 min reaction time for mole ratios of 2 and 4. At the mole ratio of 4, the reaction rate was strongly dependent on the reaction temperature, where SiO2 was completely reduced after 20 min at 1273 K. At the lower temperatures of 1173 and 1073 K, total Si formed was 75% and 39%, respectively, after 240 min reaction time. The results of the current work show that Mg2Si can be produced through the magnesiothermic reduction of natural quartz with high yield. The obtained Mg2Si can be processed further to produce silane gas as a precursor to high purity Si. The combination of these two processes offers the potential for a more direct and low carbon method to produce Si with high purity.


Signaling mechanisms of growth hormone-releasing hormone receptor in LPS-induced acute ocular inflammation.
Ocular inflammation is a major cause of visual impairment attributed to dysregulation of the immune system. Previously, we have shown that the receptor for growth-hormone-releasing hormone (GHRH-R) affects multiple inflammatory processes. To clarify the pathological roles of GHRH-R in acute ocular inflammation, we investigated the inflammatory cascades mediated by this receptor. In human ciliary epithelial cells, the NF-κB subunit p65 was phosphorylated in response to stimulation with lipopolysaccharide (LPS), resulting in transcriptional up-regulation of GHRH-R. Bioinformatics analysis and coimmunoprecipitation showed that GHRH-R had a direct interaction with JAK2. JAK2, but not JAK1, JAK3, and TYK2, was elevated in ciliary body and iris after treatment with LPS in a rat model of endotoxin-induced uveitis. This elevation augmented the phosphorylation of STAT3 and production of proinflammatory factors, including IL-6, IL-17A, COX2, and iNOS. In explants of iris and ciliary body, the GHRH-R antagonist, MIA-602, suppressed phosphorylation of STAT3 and attenuated expression of downstream proinflammatory factors after LPS treatment. A similar suppression of STAT3 phosphorylation was observed in human ciliary epithelial cells. In vivo studies showed that blocking of the GHRH-R/JAK2/STAT3 axis with the JAK inhibitor Ruxolitinib alleviated partially the LPS-induced acute ocular inflammation by reducing inflammatory cells and protein leakage in the aqueous humor and by repressing expression of STAT3 target genes in rat ciliary body and iris and in human ciliary epithelial cells. Our findings indicate a functional role of the GHRH-R/JAK2/STAT3-signaling axis in acute anterior uveitis and suggest a therapeutic strategy based on treatment with antagonists targeting this signaling pathway.


Discussion of an environment quality standard based assessment procedure for permitting discharge.
The 'combined approach' as a requirement of the EC Water Framework Directive pools an emission-based approach with an approach based on environmental quality standards (EQS) to improve European water quality. The implementation of the EQS-based approach poses problems of defining a reference water discharge, defining a distance, where the EQS are obligatory and thus have to be controlled after point discharge, considering incomplete mixing. To elaborate a simple assessment procedure including the aspects mentioned above is the point of discussion in this paper. On the basis of easily available data and references from several European countries, recommendations for an Austrian assessment procedure are presented.


Generalized linear models provide a measure of virulence for specific mutations in SARS-CoV-2 strains.
This study aims to highlight SARS-COV-2 mutations which are associated with increased or decreased viral virulence. We utilize genetic data from all strains available from GISAID and countries' regional information, such as deaths and cases per million, as well as COVID-19-related public health austerity measure response times. Initial indications of selective advantage of specific mutations can be obtained from calculating their frequencies across viral strains. By applying modelling approaches, we provide additional information that is not evident from standard statistics or mutation frequencies alone. We therefore, propose a more precise way of selecting informative mutations. We highlight two interesting mutations found in genes N (P13L) and ORF3a (Q57H). The former appears to be significantly associated with decreased deaths and cases per million according to our models, while the latter shows an opposing association with decreased deaths and increased cases per million. Moreover, protein structure prediction tools show that the mutations infer conformational changes to the protein that significantly alter its structure when compared to the reference protein.


Towards Pervasive Augmented Reality: Context-Awareness in Augmented Reality.
Augmented Reality is a technique that enables users to interact with their physical environment through the overlay of digital information. While being researched for decades, more recently, Augmented Reality moved out of the research labs and into the field. While most of the applications are used sporadically and for one particular task only, current and future scenarios will provide a continuous and multi-purpose user experience. Therefore, in this paper, we present the concept of Pervasive Augmented Reality, aiming to provide such an experience by sensing the user's current context and adapting the AR system based on the changing requirements and constraints. We present a taxonomy for Pervasive Augmented Reality and context-aware Augmented Reality, which classifies context sources and context targets relevant for implementing such a context-aware, continuous Augmented Reality experience. We further summarize existing approaches that contribute towards Pervasive Augmented Reality. Based our taxonomy and survey, we identify challenges for future research directions in Pervasive Augmented Reality.


Retrograde Autobiographical Memory From PTA Emergence to Six-Month Follow-Up in Moderate to Severe Traumatic Brain Injury.
The overwhelming focus of research on memory following traumatic brain injury (TBI) has been on anterograde amnesia, and very little attention has been paid to retrograde amnesia. There is evidence to suggest that retrograde autobiographical memory deficits exist after severe TBI, although there have been no prospective studies of autobiographical memory in a representative sample of moderate to severe cases recruited from hospital admissions. The purpose of the present study was to report changes in autobiographical memory performance among a group of patients soon after emergence from posttraumatic amnesia (PTA) and at the 6-month follow-up compared with a healthy control (HC) group. The authors also examined associations with anterograde memory function and community integration to assist in understanding the functional impact of autobiographical memory deficits and potential underlying mechanisms. The Autobiographical Memory Interview and the Rey Auditory Verbal Learning Test were used as measures of retrograde and anterograde memory, respectively, and the Community Integration Questionnaire was used as a measure of functional outcome in the TBI group. The results demonstrated that both personal semantic and episodic autobiographical memory scores were impaired following emergence from PTA and at the 6-month follow-up. Only subtle differences emerged in change over time in different injury severity groups. Recent retrograde memory function was associated with anterograde memory performance, which supports some degree of overlap in underlying mechanisms. The findings suggest that autobiographical memory deficits are prevalent following moderate to severe TBI and warrant consideration in rehabilitation.


Preparation, properties and in vitro osteogensis of self-reinforcing injectable hydrogel.
As an attractive biomaterial for bone reconstruction, injectable biomaterials have many prominent characteristics such as good biocompatibility and bone-filling ability. However, there are weak as load-bearing scaffolds. In this study, polyvinyl alcohol (PVA) and bioactive glass (BAG) were interpenetrated into sodium alginate (SA) network to obtain self-enhanced injectable hydrogel. The optimum ratio of PVA/SA/BAG hydrogel was determined based on injectability, gelation time and chemical characterization. Results showed that the selected ratio had the shortest gelation time of 3.5min, and the hydrogel had a rough surface and good coagulation property. The hydrogel was capable of carrying 1kg of weight by mineralization for 14 d The compressive strength, compressive modulus, and fracture energy of the hydrogel reached 0.12MPa, 0.376MPa and 17.750kJ m-2, respectively. Meanwhile, the hydrogel had high moisture content and dissolution rate, and it was sensitive to temperature and ionic strength. Hydroxyapatite was generated on the hydrogel surface, and the hydrogel pores increased, and the pore size enlarged. The biocompatibility of PVA/SA/BAG hydrogel was analyzed using hemolysis and cytotoxicity assays. Results revealed its good biocompatibility with low hemolysis rate and no cytotoxicity to MC3T3-E1 cells. The hydrogel was also found to promote the differentiation of MC3T3-E1 cells with significantly increased in ALP activity and expression of relevant differentiation factors. In vitro mineralization assay showed an increase in calcium nodules and calcification area, indicating the ability of hydrogel to promote mineralization MC3T3-E1 cells. These findings indicated that PVA/SA/BAG hydrogel had potential uses in the field of irregular bone-defect repair due to its injectability, cytocompatibility, and tailorable functionality.


Uptake of selenite by Saccharomyces cerevisiae involves the high and low affinity orthophosphate transporters.
Although the general cytotoxicity of selenite is well established, the mechanism by which this compound crosses cellular membranes is still unknown. Here, we show that in Saccharomyces cerevisiae, the transport system used opportunistically by selenite depends on the phosphate concentration in the growth medium. Both the high and low affinity phosphate transporters are involved in selenite uptake. When cells are grown at low P(i) concentrations, the high affinity phosphate transporter Pho84p is the major contributor to selenite uptake. When phosphate is abundant, selenite is internalized through the low affinity P(i) transporters (Pho87p, Pho90p, and Pho91p). Accordingly, inactivation of the high affinity phosphate transporter Pho84p results in increased resistance to selenite and reduced uptake in low P(i) medium, whereas deletion of SPL2, a negative regulator of low affinity phosphate uptake, results in exacerbated sensitivity to selenite. Measurements of the kinetic parameters for selenite and phosphate uptake demonstrate that there is a competition between phosphate and selenite ions for both P(i) transport systems. In addition, our results indicate that Pho84p is very selective for phosphate as compared with selenite, whereas the low affinity transporters discriminate less efficiently between the two ions. The properties of phosphate and selenite transport enable us to propose an explanation to the paradoxical increase of selenite toxicity when phosphate concentration in the growth medium is raised above 1 mm.


Water intoxication: a possible complication during endurance exercise.
Four athletes developed water intoxication (hyponatremia) during endurance events lasting more than 7 h. The etiology of the condition appears to be voluntary hyperhydration with hypotonic solutions combined with moderate sweat sodium chloride losses. The reason why the fluid excess in these runners was not corrected by increased urinary losses is unknown. When advised to drink less during prolonged exercise, three of the athletes have subsequently completed prolonged endurance events uneventfully.


Laser-Doppler velocity profile sensor with submicrometer spatial resolution that employs fiber optics and a diffractive lens.
We report a novel laser-Doppler velocity profile sensor for microfluidic and nanofluidic applications and turbulence research. The sensors design is based on wavelength-division multiplexing. The high dispersion of a diffractive lens is used to generate a measurement volume with convergent and divergent interference fringes by means of two laser wavelengths. Evaluation of the scattered light from tracers allows velocity gradients to be measured in flows with submicrometer spatial resolution inside a measurement volume of 700-microm length. Using diffraction optics and fiber optics, we achieved a miniaturized and robust velocity profile sensor for highly resolved velocity measurements.


Quantum transport of disordered Weyl semimetals at the nodal point.
Weyl semimetals are paradigmatic topological gapless phases in three dimensions. We here address the effect of disorder on charge transport in Weyl semimetals. For a single Weyl node with energy at the degeneracy point and without interactions, theory predicts the existence of a critical disorder strength beyond which the density of states takes on a nonzero value. Predictions for the conductivity are divergent, however. In this work, we present a numerical study of transport properties for a disordered Weyl cone at zero energy. For weak disorder, our results are consistent with a renormalization group flow towards an attractive pseudoballistic fixed point with zero conductivity and a scale-independent conductance; for stronger disorder, diffusive behavior is reached. We identify the Fano factor as a signature that discriminates between these two regimes.


Exploring the biochemical mechanisms of cytotoxic gold compounds: a proteomic study.
We have recently shown that a group of structurally diverse gold compounds are highly cytotoxic toward a panel of 36 human tumor cell lines through a variety of biochemical mechanisms. A classic proteomic approach is exploited here to gain deeper insight into those mechanisms. This investigation is focused on Auoxo6, a novel binuclear gold(III) complex, and auranofin, a clinically established gold(I) antiarthritic drug. First, the 72-h cytotoxicity profiles of Auoxo6 and auranofin were determined against A2780 human ovarian carcinoma cells. Subsequently, protein extraction from gold-treated A2780 cells sensitive to cisplatin and 2D gel electrophoresis separation were carried out according to established procedures. Notably, both metallodrugs caused relatively modest changes in protein expression in comparison with controls as only 11 out of approximately 1,300 monitored spots showed appreciable quantitative changes. Very remarkably, six altered proteins were in common between the two treatments. Eight altered proteins were identified by mass spectrometry; among them was ezrin, a protein associated with the cytoskeleton and involved in apoptosis. Interestingly, two altered proteins, i.e., peroxiredoxins 1 and 6, are known to play crucial roles in the cell redox metabolism. Increased cleavage of heterogeneous ribonucleoprotein H was also evidenced, consistent with caspase 3 activation. Overall, the results of the present proteomic study point out that the mode of action of Auoxo6 is strictly related to that of auranofin, that the induced changes in protein expression are limited and selective, that both gold compounds trigger caspase 3 activation and apoptosis, and that a few affected proteins are primarily involved in cell redox homeostasis.


Follow-up clinical electrophysiological studies in a patient with myotonic dystrophy.
A 38-year-old male myotonic dystrophy patient with left hemiblock, bradycardia and ventricular arrhythmias underwent electrophysiologic studies 19 months after he developed dizziness. Rapid and significant progression of binodal disease required implantation of a permanent pacemaker, which responded favorably. We suggest that careful monitoring or electrophysiologic studies are indicated in patients with these findings.


Prediction of placebo response in 2 clinical trials of lisdexamfetamine dimesylate for the treatment of ADHD.
To search for predictors of placebo response in clinical trials of lisdexamfetamine dimesylate for the treatment of DSM-IV-TR-defined attention-deficit/hyperactivity disorder (ADHD) in children and adults. We used data from 2 clinical trials: (1) a 4-week, phase 3, multicenter, randomized, double-blind, forced-dose, parallel-group study of children aged 6 to 12 years with ADHD (n = 290) and (2) a 4-week, randomized, double-blind, placebo-controlled, parallel-group, forced-dose titration study in adult subjects, aged 18-55 years with ADHD (n = 420). Response and remission were defined using the ADHD Rating Scale-IV and the Clinical Global Impressions-Improvement scale. Symptom remission was inversely correlated with baseline severity in both children and adults (P < .001), with less robust effects seen for response. The time to response and remission was delayed in adult subjects prescribed placebo versus lisdexamfetamine dimesylate, while response time in children was also significantly slower with placebo versus lisdexamfetamine dimesylate (P < .01). We found little evidence that demographic factors, prior pharmacotherapy, the emergence of adverse events during the trial, or changes in ADHD symptoms from the screening to baseline assessments predicted placebo response. Certain comorbid medical symptoms reduced the response and remission rates to placebo in children (P < .001) and adults (P < .001). In both children and adults, baseline symptom severity was the most consistent predictor of remission with placebo while the temporal profile of response reliably differentiated placebo from medication responders. Placebo effects are most likely to be minimized in shorter trials enrolling more severely impaired subjects. The impact of medical and psychiatric comorbidities on placebo response merits further investigation. clinicaltrials.gov identifiers NCT00556296 and NCT00334880.


Human imprinted chromosomal regions are historical hot-spots of recombination.
Human recombination rates vary along the chromosomes as well as between the two sexes. There is growing evidence that epigenetic factors may have an important influence on recombination rates, as well as on crossover position. Using both public database analysis and wet-bench approaches, we revisited the relationship between increased rates of meiotic recombination and genome imprinting. We constructed metric linkage disequilibrium (LD) maps for all human chromosomal regions known to contain one or more imprinted genes. We show that imprinted regions contain significantly more LD units (LDU) and have significantly more haplotype blocks of smaller sizes than flanking nonimprinted regions. There is also an excess of hot-spots of recombination at imprinted regions, and this is likely to do with the presence of imprinted genes, per se. These findings indicate that imprinted chromosomal regions are historical "hot-spots" of recombination. We also demonstrate, by direct segregation analysis at the 11p15.5 imprinted region, that there is remarkable agreement between sites of meiotic recombination and steps in LD maps. Although the increase in LDU/Megabase at imprinted regions is not associated with any significant enrichment for any particular sequence class, major sequence determinants of recombination rates seem to differ between imprinted and control regions. Interestingly, fine-mapping of recombination events within the most male meiosis-specific recombination hot-spot of Chromosome 11p15.5 indicates that many events may occur within or directly adjacent to regions that are differentially methylated in somatic cells. Taken together, these findings support the involvement of a combination of specific DNA sequences and epigenetic factors as major determinants of hot-spots of recombination at imprinted chromosomal regions.


The marine bacterium Phaeobacter inhibens secures external ammonium by rapid buildup of intracellular nitrogen stocks.
Reduced nitrogen species are key nutrients for biological productivity in the oceans. Ammonium is often present in low and growth-limiting concentrations, albeit peaks occur during collapse of algal blooms or via input from deep sea upwelling and riverine inflow. Autotrophic phytoplankton exploit ammonium peaks by storing nitrogen intracellularly. In contrast, the strategy of heterotrophic bacterioplankton to acquire ammonium is less well understood. This study revealed the marine bacterium Phaeobacter inhibens DSM 17395, a Roseobacter group member, to have already depleted the external ammonium when only ∼⅓ of the ultimately attained biomass is formed. This was paralleled by a three-fold increase in cellular nitrogen levels and rapid buildup of various nitrogen-containing intracellular metabolites (and enzymes for their biosynthesis) and biopolymers (DNA, RNA and proteins). Moreover, nitrogen-rich cells secreted potential RTX proteins and the antibiotic tropodithietic acid, perhaps to competitively secure pulses of external ammonium and to protect themselves from predation. This complex response may ensure growing cells and their descendants exclusive provision with internal nitrogen stocks. This nutritional strategy appears prevalent also in other roseobacters from distant geographical provenances and could provide a new perspective on the distribution of reduced nitrogen in marine environments, i.e. temporary accumulation in bacterioplankton cells.


Detection of circulating miRNA levels in schizophrenia.
Diagnosis of schizophrenia is currently dependent on symptom-based criteria and lacks objective indicators. In this study, the authors investigated whether circulating miRNA can serve as a diagnostic biomarker for schizophrenia. Global plasma miRNAs were profiled in a test cohort of 164 schizophrenia patients and 187 control subjects, using Solexa sequencing, TaqMan Low Density Array, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. The captured miRNAs were then validated by qRT-PCR assays in an independent cohort of 400 schizophrenia patients, 213 control subjects, and 162 patients with nonschizophrenia psychiatric disorders; the 400 schizophrenia patients underwent a 12-month follow up study of regular treatment with an atypical antipsychotic (risperidone and aripiprazole). The global plasma miRNA screening revealed eight miRNAs that were up-regulated in schizophrenia, as revealed by both assay platforms. The qRT-PCR analysis showed the up-regulation of miR-130b and miR-193a-3p in schizophrenia but not in nonschizophrenia disorders. The up-regulation of miR-130b and miR-193a-3p is a state-independent biomarker for schizophrenia, and these two miRNAs could be used to develop a diagnostic tool for schizophrenia.


Eubacterium exiguum sp. nov., isolated from human oral lesions.
Eubacterium exiguum sp. nov. is the name proposed for organisms formerly described as Eubacterium group S strains and similar bacteria isolated from various types of oral lesions. This new species was established on the basis of the results of DNA-DNA hybridization experiments and DNA base composition determinations (G + C contents, 60 to 64 mol%). The results of an API ZYM analysis, Western blotting (immunoblotting) reactions, and phenotypic tests are also given. The type strain of E. exiguum is strain S-7.


Processes of change in treatment for chronic pain: the contributions of pain, acceptance, and catastrophizing.
Cognitive-behavioral therapy has a substantial evidence base with regard to its effectiveness for individuals with chronic pain. Historically, although there has been some investigation in to the processes by which treatment succeeds or fails, few data are available regarding the unique contributions of processes from distinct cognitive behavioral approaches and how these processes may interact to affect patient functioning. The present investigation sought to evaluate three proposed process variables that have garnered empirical support within chronic pain settings, namely: pain intensity, catastrophizing, and acceptance. Participants were 252 consecutive patients who completed treatment on an interdisciplinary pain management unit. Using multiple regression, the contributions of changes in process variables to changes in treatment outcomes were assessed. In general, changes in both acceptance and catastrophizing accounted for significant variance independent of, and larger than, that accounted for by change in pain intensity. Changes in acceptance and catastrophizing accounted for roughly equivalent amounts of variance when entered immediately following changes in pain, and when entered following one another. The potential impact of these results is discussed in relation to the particular treatment delivered. Issues relating to change at the level of frequency or content of psychological experiences are considered relative to change in the functions of these experiences.


Amlodipine-induced gingival hyperplasia in a Great Dane.
A 3 yr old, 70 kg (154 lbs) female spayed Great Dane developed gingival hyperplasia after treatment of systemic hypertension with amlodipine 7.5 mg q 12 hr for 16 mo. Physical examination was unremarkable except for systemic hypertension and severe gingival hyperplasia. Amlodipine was replaced with hydralazine (0.72 mg/kg [0.32 mg/lb]). Nine months later, gingival hyperplasia was nearly resolved and hypertension was well controlled. Calcium channel blockers such as amlodipine are a rare cause of gingival hyperplasia in the canine patient. Recognition of this side effect is important because a full recovery can be achieved when the offending agent is removed.


A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma.
Twenty-two patients with advanced colorectal carcinoma were enrolled in this study. Ten patients had received prior chemotherapy that included the combination of fluorouracil (5-FU) and leucovorin (LV). All patients required subcutaneous port insertion and portable external infusion pumps to allow outpatient treatment. 5-FU (2,600 mg/m2) was administered concurrently with LV (500 mg/m2) over 24 hours of continuous infusion. The mean steady-state plasma concentration of 5-FU was 10 mumol/L (range, 7 to 14 mumol/L). The 5-FU dose was based on our previous phase I study, in which maximum-tolerated dose (MTD) of 5-FU was determined to be 2,600 mg/m2 in combination with a fixed dose of LV at 500 mg/m2. The treatment was repeated weekly. Twenty-two patients received a total of 560 courses of treatment. Eleven instances of grade 2-3 toxicity were observed: diarrhea (five), stomatitis (three), hand/foot syndrome (three). The overall objective response was 45% (10 of 22) and among previously untreated patients was 58%. Three of the responders achieved complete response (CR), with lung and liver as the metastatic sites. The median duration of survival for the previously untreated patients was not reached at 22 months, and was 10 months for the previously treated patients. These results suggest that short-term infusional therapy of 5-FU and LV in patients with advanced metastatic colorectal cancer generates acceptable toxicity, with equivalent or superior survivability in previously treated and untreated patients versus alternative methods of administration of the two agents.


Effects of 5-HT2C, 5-HT1A receptor challenges and modafinil on the initiation and persistence of gambling behaviours.
Problematic patterns of gambling are characterised by loss of control and persistent gambling often to recover losses. However, little is known about the mechanisms that mediate initial choices to begin gambling and then continue to gamble in the face of losing outcomes. These experiments first assessed gambling and loss-chasing performance under different win/lose probabilities in C57Bl/6 mice, and then investigated the effects of antagonism of 5-HT2CR with SB242084, 5-HT1AR agonism with 8-OH-DPAT and modafinil, a putative cognitive enhancer. As seen in humans and other species, mice demonstrated the expected patterns of behaviour as the odds for winning were altered increasing gambling and loss-chasing when winning was more likely. SB242084 decreased the likelihood to initially gamble, but had no effects on subsequent gambling choices in the face of repeated losses. In contrast, 8-OH-DPAT had no effects on choosing to gamble in the first place, but once started 8-OH-DPAT increased gambling choices in a dose-sensitive manner. Modafinil effects were different to the serotonergic drugs in both decreasing the propensity to initiate gambling and chase losses. We present evidence for dissociable effects of systemic drug administration on different aspects of gambling behaviour. These data extend and reinforce the importance of serotonergic mechanisms in mediating discrete components of gambling behaviour. They further demonstrate the ability of modafinil to reduce gambling behaviour. Our work using a novel mouse paradigm may be of utility in modelling the complex psychological and neurobiological underpinnings of gambling problems, including the analysis of genetic and environmental factors.


Hand Force Estimation from Acoustic Myography Using Deep Wavelet Scattering Transform and Long Short-Term Memory.
The ability to estimate user intention from surface electromyogram (sEMG) signals is a crucial aspect in the design of powered prosthetics. Recently, researchers have been using regression techniques to connect the user's intent, as expressed through sEMG signals, to the force applied at the fingertips in order to achieve a natural and accurate form of control. However, there are still challenges associated with processing sEMG signals that need to be overcome to allow for widespread and clinical implementation of upper limb prostheses. As a result, alternative modalities functioning as promising control signals have been proposed as source of control input rather than the sEMG, such as Acoustic Myography (AMG). In this study, six high sensitivity array microphones were used to acquire AMG signals, with custom-built 3D printed microphone housing. To tackle the challenge of extracting the relevant information from AMG signals, the Wavelet Scattering Transform (WST) was utilized. alongside a Long Short-Term Memory (LSTM) neural network model for predicting the force from the AMG. The subjects were asked to use a hand dynamometer to measure the changes in force and correlate that to the force predicted by using the AMG features. Seven subjects were recruited for data collection in this study, using hardware designed by the research team. the performance results showed that the WST-LSTM model can be robustly utilized across varying window sizes and testing schemes, to achieve average NRMSE results of approximately 8%. These pioneering results suggest that AMG signals can be utilized to reliably estimate the force levels that the muscles are applying.Clinical Relevance- This research presents a new method for controlling upper limb prostheses using Acoustic Myography (AMG) signals. A novel method mapping the AMG signals to force applied by the corresponding muscles is developed. The presented findings have the potential to lead to the development of more natural and accurate control of human-machine interfaces.


Fusion loop peptide of the West Nile virus envelope protein is essential for pathogenesis and is recognized by a therapeutic cross-reactive human monoclonal antibody.
West Nile virus is an emerging pathogen that can cause fatal neurological disease. A recombinant human mAb, mAb11, has been described as a candidate for the prevention and treatment of West Nile disease. Using a yeast surface display epitope mapping assay and neutralization escape mutant, we show that mAb11 recognizes the fusion loop, at the distal end of domain II of the West Nile virus envelope protein. Ab mAb11 cross-reacts with all four dengue viruses and provides protection against dengue (serotypes 2 and 4) viruses. In contrast to the parental West Nile virus, a neutralization escape variant failed to cause lethal encephalitis (at higher infectious doses) or induce the inflammatory responses associated with blood-brain barrier permeability in mice, suggesting an important role for the fusion loop in viral pathogenesis. Our data demonstrate that an intact West Nile virus fusion loop is critical for virulence, and that human mAb11 targeting this region is efficacious against West Nile virus infection. These experiments define the molecular determinant on the envelope protein recognized by mAb11 and demonstrate the importance of this region in causing West Nile encephalitis.


Induced circular dichroism of polyoxometalates via electrostatic encapsulation with chiral organic cations.
To explore the principle of chiral induction in inorganic clusters, chiral organic cations with two stereocenters, R- and S-BPEA, are used to encapsulate a series of polyoxometalates (POMs) bearing different structures and transition absorption bands in aqueous solution, constructing a series of chiral supramolecular complexes. Due to the induction of chiral organic cations, POMs possessing both chiral and achiral structures show an induced circular dichroism (ICD) effect. ICD signals in the absorption bands corresponding to ligand to metal charge transfer (LMCT) transitions, d-d transitions and intervalence charge transfer (IVCT) transitions are observed for different complexes. Moreover, the ICD of the POMs exhibits a direct correlation with the degree of POM distortion and the distance between the chiral center and the POM surface. The encapsulation of POMs with chiral organic cations via electrostatic interactions provides a facile and effective method for constructing optically pure POM-based materials.


Understanding the interplay between size, morphology and energy gap in photoactive TiO2 nanoparticles.
Anatase TiO2 nanoparticles (NPs) have the potential to photocatalyse water splitting using UV light, to thus provide hydrogen fuel in a clean and sustainable manner. Such NPs have optical gaps covering a small range of relatively high energy solar photons, giving rise to low photo-efficiencies. Although anatase NPs with 10-20 nm diameters thermodynamically prefer crystalline faceted morphologies, application of physico-chemical procedures can produce more rounded NPs with amorphous shells. Such engineered metastable core-shell NPs (so-called black TiO2 NPs) have reduced band gaps due to shell-induced band edge broadening, resulting in higher photoactivities. For <5 nm diameters, TiO2 NPs typically exhibit spherical-like NP morphologies, which also display enhanced photoactivity. For smaller NPs it is difficult to experimentally determine their thermodynamic stability and internal atomic structure, to help rationalise their higher photoactivities. Employing accurate electronic structure calculations, we establish the relative stability of spherical and faceted stoichiometric TiO2 NPs with 1-3.4 nm diameters. Mirroring experimental preparation, simulated thermal annealing is found to significantly stabilise relaxed spherical cut anatase NPs. We find that the smallest spherical NPs become amorphized by annealing, but, for diameters >2 nm, annealing yields NPs with anatase-cores and amorphous-shells. Like larger black TiO2 core-shell NPs, we confirm that our core-shell NPs are metastable relative to faceted anatase NPs and have significantly smaller optical gaps than faceted NPs. Our calculated gaps are in excellent agreement with experimental data, strongly supporting the validity of our NP models. Energy gap narrowing in these core-shell NPs is found to be due to broadening of valence band states induced by the amorphous shell, analogous to the mechanism proposed for black TiO2 NPs. Our stoichiometric NPs also show that this band narrowing effect does not require the disordered shells to be non-stoichiometric or for incorporation of other atom types. Instead, we find that this effect mainly arises from 4-coordinated Ti atoms in the amorphous shell. Our careful and systematic computational investigation, using NP models of unprecedented realism, thus provides direct confirmation that the enhanced photoactivity in small spherical TiO2 NP observed in experiment is due to the formation of metastable core-shell NPs with 4-coordinated Ti centres.


A retrospective study on rapid plasma reagin testing in patients with Pityriasis rosea.
Pityriasis rosea (PR) is an acute self-limited exanthem characterized by oval erythematous patches with scale and may be difficult to differentiate from secondary syphilis. A rapid plasma reagin (RPR) test can be used to rule in secondary syphilis with high sensitivity and specificity. A retrospective study was performed on patients at Weill Cornell Medicine, who were diagnosed with PR from 2000 to 2016 and also received RPR testing at the time of diagnosis. The objective was to assess the frequency of secondary syphilis when the initial clinical impression was PR. Only 2/142 patients (1.4%) had a reactive RPR test. Based on our results, we advocate that careful social and sexual histories be taken in all patients presenting with atypical PR and syphilis screening performed if risk factors are present.


Objective three-dimensional analysis of cranial morphology.
The lack of adequate means to objectively characterize cranial shape contributes to ongoing controversies in the surgical management of craniosynostosis. Cranial shape analysis must address relevant clinical questions objectively and thoroughly and must be broadly applicable across the spectrum of normal and abnormal. Herein, we demonstrate and statistically validate an automated computed tomography (CT)-based application for 3-dimensional characterization of skull morphology. The technology is intended for application to diagnostic imaging, surgical planning, and outcomes assessment. Three-dimensional vector analysis (3DVA) was applied to craniofacial CT data, generating three-dimensional cranial surface point clouds. To assess accuracy, measurements derived from the 3DVA analysis of a CT scan of a skull phantom were compared to those made directly from the Digital Imaging and Communications in Medicine data on a Vitrea workstation. To assess reproducibility, 3 readers independently analyzed human head CT scans using 3DVA. A normative database of 86 age-incremental pediatric patients was created. Preoperative craniosynostosis case datasets were analyzed using 3DVA and were compared with age-matched normative datasets. Accuracy and reproducibility of less than 1% mean error and less than 0.5 mm standard error in all cases validated 3DVA-derived distances. Three-dimensional vector analysis point clouds provide qualitative and quantitative representations of morphology. Regional dysmorphology in craniosynostosis cases is demonstrated graphically. Three-dimensional vector analysis generated accurate, reproducible, and comprehensive craniofacial morphometric data. 3DVA may be used for paired data analysis (eg, a single subject undergoing surgical correction), comparative group data analysis, and craniofacial data archiving. The technique can provide objective characterization of craniofacial morphology previously not possible.


Determination of pathogen-related enzyme action by mass spectrometry analysis of pectin breakdown products of plant cell walls.
An analytical approach using matrix-assisted laser desorption/ionization mass spectrometry for the structural characterization and assessment of the degree of polymerization of cell wall pectin-derived oligosaccharides (PDOs) in three regions of Botrytis cinerea-infected tomato fruit tissue is described. The PDOs were isolated from lesion centers (extensively macerated tissue), the area just beyond visible lesion margins, and healthy and intact tissue of an inoculated fruit, sampled at a distance from developing lesions. PDO mixtures were directly analyzed by mass spectrometry without chromatographic separation, after minimum cleanup by membrane drop dialysis. The structures identified implied the action of three different pathogen pectin-modifying enzymes. Modifications such as methyl esterification were identified by determination of exact PDO molecular masses and tandem mass spectrometry via collision-induced dissociation. We have identified four PDO series that were generated through the breakdown of homogalacturonan pectins. The decayed and lesion edge areas had fewer and less diverse PDOs than healthy tissues, possibly due to metabolic by-products of the pathogen. This analytical technique provides a simple and rapid method to characterize the pectin-derived oligosaccharides produced by in vivo digestion during pathogen infection.


Interictal hyposexuality in male patients with epilepsy.
The purpose of this study was to compare the serum levels of androgens between hyposexual and non-hyposexual patients with epilepsy. Adult male patients with epilepsy were investigated. Serum levels of testosterone (T) and free-T, estradiol, and sex hormone binding globulin (SHBG) were measured and the free androgen index (FAI) was calculated. While there were no differences between hyposexual and non-hyposexual patients in the serum levels of T, free-T, and estradiol, or to the FAI, the serum levels of SHBG were significantly higher in hyposexual patients than in non-hyposexual patients. Thus, the effects of increased SHBG upon serum levels of testosterone biologically active in patients with epilepsy and hyposexuality were not detected by the methods used in this study. Four (44%) of nine hyposexual patients who were re-evaluated after two years follow-up improved sexual performance. Thus, clinical treatment that results in good seizure control may improve sexual performance in some patients with epilepsy.


An integrated approach to inferring gene-disease associations in humans.
One of the most important tasks of modern bioinformatics is the development of computational tools that can be used to understand and treat human disease. To date, a variety of methods have been explored and algorithms for candidate gene prioritization are gaining in their usefulness. Here, we propose an algorithm for detecting gene-disease associations based on the human protein-protein interaction network, known gene-disease associations, protein sequence, and protein functional information at the molecular level. Our method, PhenoPred, is supervised: first, we mapped each gene/protein onto the spaces of disease and functional terms based on distance to all annotated proteins in the protein interaction network. We also encoded sequence, function, physicochemical, and predicted structural properties, such as secondary structure and flexibility. We then trained support vector machines to detect gene-disease associations for a number of terms in Disease Ontology and provided evidence that, despite the noise/incompleteness of experimental data and unfinished ontology of diseases, identification of candidate genes can be successful even when a large number of candidate disease terms are predicted on simultaneously. www.phenopred.org.


[Comparative studies on the spectral behavior between SO4(2-)/TiO2 and TiO2 photocatalysts].
The differences of spectral behavior between SO4(2-)/TiO2 and TiO2 photocatalysts were studied by using IR, Raman as well as UV-Vis diffuse reflectance spectroscopy(DRS). The results showed that both L and B acid sites exist on SO4(2-)/TiO2 photocatalyst while only L acid sites on TiO2 photocatalyst. As compared with unmodified TiO2, the sulfated TiO2 (SO4(2-)/TiO2) exhibits higher resistance to crystal phase transition from anatase to rutile, higher resistance to growth of crystal grain. As the results of sulfation, SO4(2-)/TiO2 samples possess higher anatase content, smaller crystal grain, and the blue-shifted band edge of adsorption spectra, which increases the optical absorption threshold value and yield larger redox potential.


Protein kinase D activity controls endothelial nitric oxide synthesis.
Vascular endothelial growth factor (VEGF) regulates key functions of the endothelium, such as angiogenesis or vessel repair in processes involving endothelial nitric oxide synthase (eNOS) activation. One of the effector kinases that become activated in endothelial cells upon VEGF treatment is protein kinase D (PKD). Here, we show that PKD phosphorylates eNOS, leading to its activation and a concomitant increase in NO synthesis. Using mass spectrometry, we show that the purified active kinase specifically phosphorylates recombinant eNOS on Ser1179. Treatment of endothelial cells with VEGF or phorbol 12,13-dibutyrate (PDBu) activates PKD and increases eNOS Ser1179 phosphorylation. In addition, pharmacological inhibition of PKD and gene silencing of both PKD1 and PKD2 abrogate VEGF signaling, resulting in a clear diminished migration of endothelial cells in a wound healing assay. Finally, inhibition of PKD in mice results in an almost complete disappearance of the VEGF-induced vasodilatation, as monitored through determination of the diameter of the carotid artery. Hence, our data indicate that PKD is a new regulatory kinase of eNOS in endothelial cells whose activity orchestrates mammalian vascular tone.


Dominant-negative diabetes insipidus and other endocrinopathies.
Familial neurohypophyseal diabetes insipidus (FNDI) in humans is an autosomal dominant disorder caused by a variety of mutations in the arginine vasopressin (AVP) precursor. A new report demonstrates how heterozygosity for an AVP mutation causes FNDI (see the related article beginning on page 1697). Using an AVP knock-in mutation in mice, the study shows that FNDI is caused by retention of AVP precursors and progressive loss of AVP-producing neurons.


Feasibility and findings of colonoscopy for living-donor liver transplant candidates.
Living-donor liver transplantation (LDLT) has been widely performed in patients with end-stage liver disease and hepatocellular carcinoma in Japan. Although extrahepatic cancer survey for LDLT candidates is absolutely required, few reports have indicated the optimal surveillance method for colorectal cancer. The aim of this study is to investigate the feasibility and findings of colonoscopy before LDLT. From January 2004 to August 2006, we prospectively enrolled all of the scheduled LDLT candidates of our hospital for pretransplant colonoscopy examination. A total of 81 patients were enrolled for colonoscopy. Of these patients, 67 (83%) could actually undergo colonoscopy. Patients who could not undergo colonoscopy exhibited more impaired liver function than those who could (median Model End-Stage Liver Disease score; 25.5 vs. 14.5, P=0.0003). Among patients who underwent colonoscopy, observation of total colon was attained in 64 (96%). Neoplasia was found in 28 (42%) patients, including 4 patients with adenomas > or =10 mm, 1 patient with adenomas with high-grade dysplasia, and 3 patients with invasive cancer. Patients who had advanced neoplasia (adenoma > or =10 mm, adenomas with high-grade dysplasia, or invasive cancer) were likely to have a lower performance status (PS) (7/8 were PS 3) than those who did not (P=0.054). Clinically significant tumors were found in a considerable portion of LDLT candidates, particularly in lower PS patients. Because immunosuppressive agents after transplantation may worsen malignant tumors, colonoscopy before transplantation is recommended in patients who can tolerate the procedure.


Contralateral prophylactic mastectomy and its association with reduced mortality: evidence for selection bias.
Contralateral prophylactic mastectomy (CPM) refers to removal of the opposite uninvolved breast in women with unilateral breast cancer, and rates are increasing worldwide. In observational studies, CPM is often associated with reductions in breast cancer-specific and all-cause mortality when compared to unilateral surgical treatment alone, but this may reflect selection of a healthier cohort for CPM (selection bias). To further explore this possibility, we examined the association between CPM and non-cancer mortality, an indicator of selection bias. We identified 449,178 adult women diagnosed with unilateral, primary American Joint Committee on Cancer (AJCC) stage I-III ductal or lobular breast cancer, utilizing the 1998-2010 Surveillance, Epidemiology, and End Results dataset. Of these, 5.8% (n = 25,961) underwent CPM as their first course of treatment. We examined associations between CPM and breast cancer-specific, all-cause, and non-cancer mortality utilizing multivariate logistic regression, adjusting for age, race, AJCC stage, estrogen receptor status, progesterone receptor status, and histologic grade of the tumor. Among all patients receiving CPM as first course of treatment, CPM was associated with lower breast cancer-specific [HR 0.84 (95% CI 0.79-0.89)], all-cause [HR 0.83 (95% CI 0.80-0.88)], and non-cancer [HR 0.71 (95% CI 0.64-0.80)] 5-year hazard of death. Although our results are consistent with other observational studies showing associations between CPM and reductions in breast cancer-specific and all-cause mortality, we demonstrate an even stronger association between CPM and reduced non-cancer mortality. Thus, the reported associations between CPM and reductions in mortality might at least partly be attributable to selection bias.


Evidence for an ATP-independent long-chain phosphatidylcholine translocator in hepatocyte membranes.
Transport of phosphatidylcholine (PC) molecules across canalicular plasma membranes of the liver is essential for their secretion into bile. To test for evidence of protein-mediated translocation of natural long-chain PCs, we investigated whether hepatocyte membrane subfractions reconstituted into proteoliposomes promoted transmembrane translocation of radiolabeled PCs. Translocation of PC molecules in proteoliposomes was measured by an assay that employed multilamellar acceptor vesicles and the specific PC transfer protein purified from liver. As inferred from the percentage of radiolabel removed from proteoliposomes, facilitated PC translocation occurred in microsomes and canalicular and basolateral plasma membranes from rat liver but not in erythrocyte ghosts, microsomes, homogenates of COS and H35 cells, or Xenopus laevis oocytes. Heat denaturation in the presence of 2-mercaptoethanol and Pronase digestion of solubilized membrane proteins inhibited translocation. In contrast to the mdr2 gene product (Mdr2), which promotes ATP-dependent, verapamil-inhibitable PC translocation, ATP did not enhance and verapamil failed to block PC translocation. These data support the possibility that an ATP-independent PC translocator, possibly distinct from Mdr2, may be present in hepatocyte canalicular plasma membranes.


Relationship between stroke etiology and collateral status in anterior circulation large vessel occlusion.
Clinical outcome after mechanical thrombectomy (MT) for large vessel occlusion (LVO) stroke is influenced by the intracerebral collateral status. We tested the hypothesis that patients with preexisting ipsilateral extracranial carotid artery stenosis (CAS) would have a better collateral status compared to non-CAS patients. Additionally, we evaluated MT-related adverse events and outcome for both groups. Over a 7-year period, we identified all consecutive anterior circulation MT patients (excluding extracranial carotid artery occlusion and dissection). Patients were grouped into those with CAS ≥ 50% according to the NASCET criteria and those without significant carotid stenosis (non-CAS). Collateral status was rated on pre-treatment CT- or MR-angiography according to the Tan Score. Furthermore, we assessed postinterventional infarct size, adverse events and functional outcome at 90 days. We studied 281 LVO stroke patients, comprising 46 (16.4%) with underlying CAS ≥ 50%. Compared to non-CAS stroke patients (n = 235), patients with CAS-related stroke more often had favorable collaterals (76.1% vs. 46.0%). Recanalization rates were comparable between both groups. LVO stroke patients with underlying CAS more frequently had adverse events after MT (19.6% vs. 6.4%). Preexisting CAS was an independent predictor for favorable collateral status in multivariable models (Odds ratio: 3.3, p = 0.002), but post-interventional infarct size and functional 90-day outcome were not different between CAS and non-CAS patients. Preexisting CAS ≥ 50% was associated with better collateral status in LVO stroke patients. However, functional 90-day outcome was independent from CAS, which could be related to a higher rate of adverse events.


Agressive inflammatory myofibroblastic tumor of the liver with underlying schistosomiasis: a case report.
Inflammatory myofibroblastic tumor (IMT) occurs infrequently in the liver. It is controversial whether it represents a low grade mesenchymal neoplasm or a reactive inflammatory lesion. Local recurrence and metastasis are rare and some tumors are associated with infectious agents. We report on a case of a large and partially resected IMT with local recurrence and diaphragm and kidney infiltration detected on routine surveillance two years later. Histologically, the tumor showed spindle cells without atypia, mitosis or necrotic areas in a myxoid and collagenized background with inflammatory cells. In the liver portal tracts, granulomatous lesions with viable eggs of Schistosoma mansoni were identified. Immunohistochemistry demonstrated spindle cells which were smooth-muscle actin and vimentin positive. In conclusion, this case points out that these histological patterns do not predict the aggressive biological behavior of the lesion. A reason for the recurrence and the infiltration may be incomplete tumor resection. Further investigation is necessary in order to better clarify an infectious cause in some IMTs.


Frequency-Wavelet Domain Deconvolution for terahertz reflection imaging and spectroscopy.
In terahertz reflection imaging, a deconvolution process is often employed to extract the impulse function of the sample of interest. A band-pass filter such as a double Gaussian filter is typically incorporated into the inverse filtering to suppress the noise, but this can result in over-smoothing due to the loss of useful information. In this paper, with a view to improving the calculation of terahertz impulse response functions for systems with a low signal to noise ratio, we propose a hybrid Frequency-Wavelet Domain Deconvolution (FWDD) for terahertz reflection imaging. Our approach works well; it retrieves more accurate impulse response functions than existing approaches and these impulse functions can then also be used to better extract the terahertz spectroscopic properties of the sample.


Understanding Indigenous Australians' experiences of cancer care: stakeholders' views on what to measure and how to measure it.
Disparities in cancer outcomes amongst Indigenous Australians reflect a pattern of reduced access to and engagement with health services. A growing emphasis on patient-centred care has increased efforts to measure patient experiences, but it is unclear whether existing approaches: a) assess the most critical aspects of care that shape the experiences of Indigenous people with cancer; and b) facilitate the engagement and participation of Indigenous people with the measurement of care experiences. Two rounds of semi-structured interviews and focus groups were used to elicit stakeholders' views on priorities for measuring the cancer care experiences of Indigenous cancer patients and on the acceptability of various methods for capturing such information. Participants included Indigenous people affected by cancer (n = 17), health professionals (n = 28) and individuals in both groups (n = 7). Recruitment occurred through a national web-based network and through four cancer services in urban and regional areas in three jurisdictions across Australia. Several aspects of cancer care were identified as critical in shaping Indigenous patients' experiences. Key themes included: feeling safe in the system; importance of Indigenous staff; barriers to care; the role of family and friends; effective communication and education; and coordination of care and transition between services. Those participants affected by carers' wellbeing and palliative care strongly advocated for the importance of these topics. Participants expressed support for a face-to-face interview with a trusted person as the most appropriate means of collecting cancer care experience information. While existing experience measurement tools would partially capture some important aspects of care, other critical areas would likely be missed. Appropriate tools and approaches, developed by and with Indigenous people, are urgently needed to determine the extent to which health services are meeting the needs of Indigenous people with cancer, and to identify areas for action to improve these services.


Oral human papilloma virus infection: an overview of clinical-laboratory diagnosis and treatment.
The aim of this review is to describe the "hot points" of current clinical governance for oral HPV comprising the use of new diagnostic molecular procedures, namely, Pyrosequencing and Next Generation Sequencing. The data on oral HPV was collected through two levels of research. First for all, we used the canonical medical search engines, PubMed, and Medline, followed by the study of current commercial tools for HPV diagnosis, particularly within commercial companies involved in the molecular procedures for HPV detecting and genotyping. Different medical procedures are now described and used throughout the world in HPV diagnosis and treatment. However, the laboratory methods are often validated and used for genital infections, and, in these cases, data are missing in the literature as regards the clinical approach for oral lesions. Dental care units are often the front line for a clinical evaluation of a possible HPV lesion in the oral cavity, which means that correct clinical governance could avoid a viral neoplastic progression of this disease with great advantages for the patient. In this case, the problem is due to the difficulty in lesion recognition but also and more especially the absence of correct laboratory diagnosis and subsequent treatment in the clinical course.


High virulence in hamsters of four dominant Leptospira serovars isolated from rats in the Philippines.
Leptospirosis is caused by pathogenic species of Leptospira. The aim of this study was to determine and characterize the pathogenicity of four dominant Leptospira isolates prevailing among rats in the Philippines. The isolates were Leptospira interrogans serovar Manilae strain K64, L. interrogans serovar Losbanos strain K37, L. interrogans serovar Ratnapura strain K5 and Leptospira borgpetersenii serovar Javanica strain K6. Pathogenicities were studied using hamsters, which reproduce severe human leptospirosis. The minimum lethal doses were 10(0) ( = 1) leptospires for K64, K37 and K5, and 10(1) leptospires for K6. Weight loss amongst the Leptospira-infected hamsters was observed from 1 day before death (K64-, K37- and K5-infected hamsters) to as much as 1 week before death for K6-infected hamsters. Similar and varied gross and microscopic lesions were observed amongst infected hamsters, even for strains belonging to the same species (i.e. L. interrogans). The most significant and common histopathological findings were congestion of the glomerulus, disarrangement of hepatic cords and erythrophagocytosis. Other findings were foamy splenic macrophages for K6, severe petechial pulmonary haemorrhage for K64, and hematuria and severe pulmonary congestion for K37. Immunostaining and culture revealed the presence of leptospires in different organs of the infected hamsters. Based on these results, Leptospira isolates from rats in the Philippines were shown to be highly virulent, causing pulmonary haemorrhage, severe hepato-renal damage and death in hamsters even at lower doses. The present findings on experimental leptospirosis support clinical data showing that patients with severe manifestations of leptospirosis, such as pulmonary haemorrhage, are increasing in the Philippines. These findings may serve as a basis to strengthen the early diagnosis and treatment of human leptospirosis.


Hypoxia and Hypoglycemia synergistically regulate mRNA stability.
Ischemic events, common in many diseases, result from decreased blood flow and impaired delivery of oxygen and glucose to tissues of the body. While much is known about the cellular transcriptional response to ischemia, much less is known about the posttranscriptional response to oxygen and glucose deprivation. The goal of this project was to investigate one such posttranscriptional response, the regulation of mRNA stability. To that end, we have identified several novel ischemia-related mRNAs that are synergistically stabilized by oxygen and glucose deprivation including VEGF, MYC, MDM2, and CYR61. This increase in mRNA half-life requires the synergistic effects of both low oxygen (1%) as well as low glucose (≤ 1 g/L) conditions. Oxygen or glucose deprivation alone fails to initiate the response, as exposure to either high glucose (4 g/L) or normoxic conditions inhibits the response. Furthermore, in response to hypoxia/hypoglycemia, the identified mRNAs are released from the RNA binding protein KHSRP which likely contributes to their stabilization.


Treating people with arthritis with traditional Chinese medicine (TCM): an examination of the perception of TCM practitioners.
Emerging evidence has shown that traditional Chinese medicine (TCM) has a positive effect on arthritis. This research provides the first critical, systematic examination of TCM practitioners' perceptions of TCM use for people with arthritis. An online survey was distributed to all TCM professionals including acupuncturists and Chinese herbal medicine practitioners registered with the Practitioner Research and Collaborate Initiative (PRACI) practitioner database. The survey questions focus on practitioner characteristics, practice characteristics and clinical management approaches regarding arthritis care. The survey attracted a response rate of 53% (n=52). The average age of the respondents was 49.9 years, more than half were female, and the majority held a bachelor degree or higher qualification. More than two thirds of TCM practitioners in our study worked with other health professionals, while they had a high level of referral relationships with a wide range of conventional, allied health and complementary and alternative medicine (CAM) providers. Most of the TCM practitioners reported that their patients with arthritis used other treatments alongside TCM and a large number of the TCM practitioners who participated believed that TCM was effective for treating arthritis. The TCM profession represents a substantial component of the healthcare field in Australia, and treating patients with arthritis appears to be an important area of TCM practice, among others. Further detailed research is needed to help ensure effective, safe patient care for those with arthritis who may be utilising TCM alongside a broader range of conventional medicine, allied health, and other CAM treatments.


Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification.
Cell lines derived from human cancers provide critical tools to study disease mechanisms and develop novel therapies. Recent reports indicate that up to 36% of cell lines are cross- contaminated. We evaluated 40 reported thyroid cancer-derived cell lines using short tandem repeat and single nucleotide polymorphism array analysis. Only 23 of 40 cell lines tested have unique genetic profiles. The following groups of cell lines are likely derivatives of the same cell line: BHP5-16, BHP17-10, BHP14-9, and NPA87; BHP2-7, BHP10-3, BHP7-13, and TPC1; KAT5, KAT10, KAT4, KAT7, KAT50, KAK1, ARO81-1, and MRO87-1; and K1 and K2. The unique cell lines include BCPAP, KTC1, TT2609-C02, FTC133, ML1, WRO82-1, 8505C, SW1736, Cal-62, T235, T238, Uhth-104, ACT-1, HTh74, KAT18, TTA1, FRO81-2, HTh7, C643, BHT101, and KTC-2. The misidentified cell lines included the DRO90-1, which matched the melanoma-derived cell line, A-375. The ARO81-1 and its derivatives matched the HT-29 colon cancer cell line, and the NPA87 and its derivatives matched the M14/MDA-MB-435S melanoma cell line. TTF-1 and Pax-8 mRNA levels were determined in the unique cell lines. Many of these human cell lines have been widely used in the thyroid cancer field for the past 20 yr and are not only redundant, but not of thyroid origin. These results emphasize the importance of cell line integrity, and provide the short tandem repeat profiles for a panel of thyroid cancer cell lines that can be used as a reference for comparison of cell lines from other laboratories.


The relationship of muscular endurance and coordination and dexterity with behavioral and neuroelectric indices of attention in preschool children.
This study investigated the associations of non-aerobic fitness (NAF) and motor competence (MC) with attention in 4-6 year-old preschoolers. The allocation of attentional resources and speed of stimulus categorization were examined using the amplitude and latency of P3 of event-related potentials respectively, while cortical activation related to general attention and task-specific discriminative processes were examined using event-related desynchronization (ERD) at lower (8-10 Hz) and upper (10-12 Hz) alpha frequencies, respectively. Seventy-six preschoolers completed NAF (muscular power, muscular endurance, flexibility, balance) and MC (coordination and dexterity, ball skills, agility and balance) test batteries. Electroencephalogram was recorded while participants performed an auditory oddball task. After controlling for age and MC, muscular endurance was positively related to P3 amplitude. MC and its coordination and dexterity sub-component were positively related to task performance, with higher levels of coordination and dexterity showing an additional association with greater upper alpha ERD between 700 and 1000 ms following stimulus onset after controlling for age and NAF. These findings suggest relationships of NAF and MC with early childhood neurocognitive function. Specifically, muscular endurance is related to the neuroinhibition in facilitating effective allocation of attentional resources to stimulus evaluation while coordination and dexterity are related to cortical activation underlying strategic attentional preparation for subsequent stimulus evaluation.


Adenosine Receptors Influence Hypertension in Dahl Salt-Sensitive Rats: Dependence on Receptor Subtype, Salt Diet, and Sex.
The influence of adenosine receptors on blood pressure in salt-sensitive hypertension is unknown. Here, we examined the effects of salt diets on arterial blood pressures (radiotelemetry) in female and male Dahl salt-sensitive wild-type versus female and male Dahl salt-sensitive A1, A2A, or A2B receptor knockouts (A1KOs, A2AKOs, and A2BKOs, respectively). At baseline, all rats were on a 0.3% salt diet; then separate groups were switched to either 4% or 8% salt diet for 2 weeks. Compared with wild-types, baseline pressures were not affected by knockout of A1 or A2B receptors; yet, mean, systolic, and diastolic pressures were significantly (P<0.01) higher in A2AKOs versus wild-types, an effect independent of sex. During the second week on a 4% salt diet, mean, systolic, and diastolic blood pressures (mm Hg, mean±SEM) in female A1KOs (176±5, 209±5, and 147±4, respectively) and A2BKOs (166±8, 198±9, and 139±8, respectively) were significantly lower (P<0.001) than wild-type on a 4% salt diet (202±4, 240±5, and 172±3, respectively). Male A1KOs and A2BKOs were not protected against 4% salt diet-induced hypertension. This female advantage was overwhelmed by an 8% salt diet. Female and male A2AKOs were more salt sensitive, a phenotype that was apparent in male A2AKOs on 4% and 8% salt diets and in females on 8% salt diet. Female A1KOs and A2BKOs were less susceptible to salt-induced stroke and experienced improved survival. Adenosine receptors influence blood pressure and survival in salt-sensitive rats, and the impact of deleting adenosine receptors on blood pressure and survival depends on salt diet and sex.


Farmer Perceptions of Pig Aggression Compared to Animal-Based Measures of Fight Outcome.
Several animal welfare issues persist in practice despite extensive research which has been linked to the unwillingness of stakeholders to make changes. For example, most farmers do not perceive pig aggression to be a problem that requires action despite the fact that stress and injuries are common, and that several solutions exist. Frequent exposure to animal suffering could affect farmer responses to distressed animals. This study investigated for the first time whether this occurs, using pig aggression as a focus. Using video clips, 90 pig farmers judged the severity of aggression, level of pig exhaustion and the strength of their own emotional response. Their judgments were compared to objective measures of severity (pigs' skin lesions and blood lactate), and against control groups with similar pig experience (10 pig veterinarians) and without experience (26 agricultural students; 24 animal science students). Famers did not show desensitization to aggression. However, all groups underestimated the outcome of aggression when they did not see the fight occurring as compared to witnessing a fight in progress. We suggest that farmers be provided with evidence of the economic and welfare impact of aggression as indicated by lesions and that they be advised to score lesions on affected animals.


Conditioned taste aversion following acutely administered acrylamide.
Fischer-344 rats were acclimated to a daily 15 min period of water availability. After water consumption had stabilized, the rats were permitted a 15 min access to 0.15% (w/v) solution of saccharin. One to two min following saccharin presentation, they were given various doses of acrylamide (10-50 mg/kg) or lithium chloride (LiCl; 3 mEq/kg) by gavage. Three days later, aversion to the saccharin solution was determined. Acrylamide, like LiCl, produced an aversion to saccharin. The effect of acrylamide appeared to be dose-related with the threshold dose being 10 mg/kg.


ROBOTICS: Rescue Droids Stumble in an Urban Jungle.
AUSTIN, TEXAS--Here at the 17th Annual National Conference on Artificial Intelligence, four teams of engineers fielded mechanical contestants in the first annual urban ruin search-and-rescue competition--a simulated catastrophe created to test intelligent lifesaving robots that may one day lead rescuers to people trapped in the precarious rubble of collapsed buildings. The competition indicated that the technology still has a way to go.


Seed-specific expression of seven Arabidopsis promoters.
Seeds contain storage compounds, from various carbohydrates to proteins and lipids, which are synthesized during seed development. For the purposes of many plant researches or commercial applications, developing promoter systems expressing specifically in seeds or in particular constituents or tissues/compartments of seeds are indispensable. To screen genes dominantly or specifically expressed in seed tissues, we analyzed Arabidopsis ATH1 microarray data open to the public. Thirty-two candidate genes were selected and their expressions in seed tissues were confirmed by RT-PCR. Finally, seven genes were selected for promoter analysis. The promoters of seven genes were cloned into pBI101 vector and transformed into Arabidopsis to assay histochemical β-glucuronidase (GUS) activity. We found that Pro-at3g03230 promoter drove GUS expression in a chalazal endosperm, Pro-at4g27530:GUS expressed in both chalazal endosperm and embryo, Pro-at4g31830 accelerated GUS expression both in radicle and procambium, Pro-at5g10120 and Pro-at5g16460 drove GUS expression uniquely in embryo, Pro-at5g53100:GUS expressed only in endosperm, and Pro-at5g54000 promoted GUS expression in both embryo and inner integument. These promoters can be used for expressing any genes in specific seed tissues for practical application.


Distance distribution in random graphs and application to network exploration.
We consider the problem of determining the proportion of edges that are discovered in an Erdos-Rényi graph when one constructs all shortest paths from a given source node to all other nodes. This problem is equivalent to the one of determining the proportion of edges connecting nodes that are at identical distance from the source node. The evolution of this quantity with the probability of existence of the edges exhibits intriguing oscillatory behavior. In order to perform our analysis, we introduce a different way of computing the distribution of distances between nodes. Our method outperforms previous similar analyses and leads to estimates that coincide remarkably well with numerical simulations. It allows us to characterize the phase transitions appearing when the connectivity probability varies.


Comparative evaluation of root canal preparations of maxillary first molars with self-adjusting file, reciproc single file, and revo-s rotary file: A micro-computed tomography study.
This study was aimed to use micro-computed tomography (μ-CT) to evaluate the canal shaping properties of three nickel-titanium instruments, Self-Adjusting File (SAF), Reciproc, and Revo-S rotary file, in maxillary first molars. Thirty maxillary molars were scanned preoperatively by using micro-computed tomography (μ-CT) scans at 13,68 μm resolution. The teeth were randomly assigned to three groups (n = 10). The root canals were shaped with SAF, Reciproc, and Revo-S, respectively. The shaped root canals were rescanned. Changes in canal volumes and surface areas were compared with preoperative values. The data were analyzed using Kruskal-Wallis and Conover's post hoc tests, with p < .05 denoting a statistically significant difference. Preoperatively canal volumes and surface area were statistically similar among the three groups (p > .05). There were statistically significant differences in all measures comparing preoperative and postoperative canal models (p = 0.0001). These differences occurred after instrumentation among the three experimental groups showed no statistically significant difference for volume (p > .05). Surface area showed the similar activity in buccal canals in each of the three techniques whereas no statistically significant difference was detected among surface area, the SAF, and the Revo-S in the palatal (P) canal. Each of three shaping system showed the similar volume activity in all canals, but SAF and Revo-S provided more effectively root planning in comparison with Reciproc in P canal.


Toilet training: situation at 2 years of age in a birth cohort.
Acquisition of bladder and bowel control is influenced by physiological, psychological and sociocultural factors. The objective of this study was to evaluate the prevalence of children out of diapers by 24 months of age and the factors associated with this finding. A total of 3,281 children born in Pelotas, RS, Brazil in 2004 were enrolled on a longitudinal study. At 24 months their mothers were visited at home and replied to a questionnaire containing questions about sociodemographic data and the characteristics of their children's urinary and intestinal evacuation habits, with special attention to toilet training. Multivariate analyses were carried out using Poisson regression. From the total, 24.3% were out of diapers during the day, with the female sex predominating (27.8 vs. 21.1%, p < 0.001) and 8.6% were out of diapers at night, also with the female sex predominating (10.6 vs. 6.8%, p < 0.001). The abilities needed to start toilet training were present in 85.5% of the children. Guidance was received from a pediatrician in 10% of cases, and more frequently among richer mothers than among poorer mothers (22.9 vs. 4.8%). Mothers who spent more years in education (13.2%) and were from higher social classes (14%) took their children out of diapers later; a greater number of children living at home (relative risk = 1.32) and being able to communicate the need to go to the toilet (relative risk = 11.74) both increased the probability of being out of diapers; previous unsuccessful attempts delayed removal of diapers (relative risk = 0.59). Although the abilities needed for acquisition of bladder and bowel control were already present at 24 months, indicating that toilet training could be started, the majority of children had not yet started this training. Better-informed mothers delayed training the most.


Alcohol exposure during the first two trimesters equivalent alters granule cell number and neurotrophin expression in the developing rat olfactory bulb.
Although alcohol has been shown to affect brain development adversely, the underlying mechanism of alcohol's actions are poorly understood. The present study addressed the hypothesis that alcohol affects growth factor availability during critical periods of neural growth by measuring the mRNA expression of brain-derived neurotrophic factor (BDNF), a potent developmental growth factor. Multiple offspring of timed-pregnant rat dams given alcohol (6.0 g/kg per day) or control treatments during gestation were sacrificed at either embryonic (E) day 21 or E33 (usually postnatal day 10) when their olfactory bulbs were processed for molecular analyses or neuron counting. BDNF mRNA levels were measured by reverse-transcription-polymerase chain reaction, and DNA methylation of the BDNF gene was quantified by Southern blot analyses following digestion with methylation-sensitive enzymes. Estimates of total granule cell number were obtained by counting those cells using unbiased stereological techniques. There was a significant decrease in BDNF mRNA levels in the alcohol-exposed offspring of both ages compared with controls. In addition, the number of olfactory bulb granule cells significantly decreased in the E33 but not the E21 rat pups exposed to alcohol compared with their appropriate aged controls. Finally, BDNF DNA of alcohol-exposed animals was less susceptible to digestion with the methylation-sensitive enzyme HpaII compared with controls, suggesting that the DNA of the alcohol exposed pups was hypermethylated. Our results indicate that exposure to alcohol during early brain development in the rat, a period equivalent to the first two trimesters in humans, can have a detrimental effect on normal development of the olfactory bulb by reducing the number of BDNF-synthesizing neurons. Although the exact mechanism for the alcohol-induced neuronal loss is unknown, the inappropriate transcription of the BDNF gene is one mechanism that may account for the complexity of effects observed in offspring exposed to heavy alcohol exposure in utero.


Hierarchical spatial modeling of uncertainty in air pollution and birth weight study.
In environmental health studies air pollution measurements from the closest monitor are commonly used as a proxy for personal exposure. This technique assumes that air pollution concentrations are spatially homogeneous in the neighborhoods associated with the monitors and consequently introduces measurement error into a resultant model. To model the relationship between maternal exposure to air pollution and birth weight, we build a hierarchical model that accounts for the associated measurement error. We allow four possible scenarios, with increasing flexibility, for capturing this uncertainty. In the two simplest cases, we specify models with a constant variance term and a variance component that allows uncertainty in the exposure measurements to increase as the distance between maternal residence and the location of the closest monitor increases. In the remaining two models, we introduce spatial dependence using random effects. The models are illustrated using Bayesian hierarchical modeling techniques that relate pregnancy outcomes from the North Carolina Detailed Birth Records to air pollution data from the U.S. Environmental Protection Agency.


Functional interactions in the use of direct and indirect defences in native Nicotiana plants.
Nicotiana attenuata has both direct (induced nicotine production) and indirect (induced release of mono- and sesquiterpenes) defences induced by herbivore attack; both are activated by the jasmonate cascade, albeit in different tissues (roots and shoots, respectively). The fact that both types of defences are induced suggests that their benefits are conditional. Indeed, jasmonate treatment of roots to induce nicotine production increases plant fitness correlates (lifetime viable seed production) when plants are grown in environments with herbivores, but decreases fitness when they are not. Because inducing nicotine production can make 6% of a plant's nitrogen budget unavailable for seed production, it can exact a resource-based cost. Volatile production is likely to be less costly but could make plants more 'apparent' to herbivores and thereby exact an ecological cost. Direct defences could also have ecological costs if they are sequestered by specialist herbivores and used against their enemies. Herbivory by the nicotine-tolerant herbivore Manduca sexta dramatically amplifies the increase in jasmonates and the quantity of volatiles released, but decreases the nicotine response in comparison to mechanical simulations of the wounding that larval feeding causes. The apparent switching from nicotine production to the release of volatiles may reflect incompatibilities in the use of direct and indirect defences with specialist herbivores.