Phylum Tardigrada: an "individual" approach.
Phylum Tardigrada consists of ∼1000 tiny, hardy metazoan species distributed throughout terrestrial, limno-terrestrial and oceanic habitats. Their phylogenetic status has been debated, with current evidence placing them in the Ecdysozoa. Although there have been efforts to explore tardigrade phylogeny using both morphological and molecular data, limitations such as their few morphological characters and low genomic DNA concentrations have resulted in restricted taxonomic coverage. Using a protocol that allows us to identify and extract DNA from individuals, we have sequenced 18S rDNA from 343 tardigrades from across the globe. Using maximum parsimony and Bayesian analyses we have found support for dividing Order Parachela into three super-families and further evidence that indicates the traditional taxonomic perspective of families in the class Eutardigrada are nonmonophyletic and require re-working. It appears that conserved morphology within Tardigrada has resulted in conservative taxonomy as we have found cases of several discrete lineages grouped into single genera. Although this work substantially adds to the understanding of the evolution and taxonomy of the phylum, we highlight that inferences gained from this work are likely to be refined with the inclusion of further taxa-specifically representatives of the nine families yet to be sampled. © The Willi Hennig Society 2008.


SLAM-based dense surface reconstruction in monocular Minimally Invasive Surgery and its application to Augmented Reality.
While Minimally Invasive Surgery (MIS) offers considerable benefits to patients, it also imposes big challenges on a surgeon's performance due to well-known issues and restrictions associated with the field of view (FOV), hand-eye misalignment and disorientation, as well as the lack of stereoscopic depth perception in monocular endoscopy. Augmented Reality (AR) technology can help to overcome these limitations by augmenting the real scene with annotations, labels, tumour measurements or even a 3D reconstruction of anatomy structures at the target surgical locations. However, previous research attempts of using AR technology in monocular MIS surgical scenes have been mainly focused on the information overlay without addressing correct spatial calibrations, which could lead to incorrect localization of annotations and labels, and inaccurate depth cues and tumour measurements. In this paper, we present a novel intra-operative dense surface reconstruction framework that is capable of providing geometry information from only monocular MIS videos for geometry-aware AR applications such as site measurements and depth cues. We address a number of compelling issues in augmenting a scene for a monocular MIS environment, such as drifting and inaccurate planar mapping. A state-of-the-art Simultaneous Localization And Mapping (SLAM) algorithm used in robotics has been extended to deal with monocular MIS surgical scenes for reliable endoscopic camera tracking and salient point mapping. A robust global 3D surface reconstruction framework has been developed for building a dense surface using only unorganized sparse point clouds extracted from the SLAM. The 3D surface reconstruction framework employs the Moving Least Squares (MLS) smoothing algorithm and the Poisson surface reconstruction framework for real time processing of the point clouds data set. Finally, the 3D geometric information of the surgical scene allows better understanding and accurate placement AR augmentations based on a robust 3D calibration. We demonstrate the clinical relevance of our proposed system through two examples: (a) measurement of the surface; (b) depth cues in monocular endoscopy. The performance and accuracy evaluations of the proposed framework consist of two steps. First, we have created a computer-generated endoscopy simulation video to quantify the accuracy of the camera tracking by comparing the results of the video camera tracking with the recorded ground-truth camera trajectories. The accuracy of the surface reconstruction is assessed by evaluating the Root Mean Square Distance (RMSD) of surface vertices of the reconstructed mesh with that of the ground truth 3D models. An error of 1.24 mm for the camera trajectories has been obtained and the RMSD for surface reconstruction is 2.54 mm, which compare favourably with previous approaches. Second, in vivo laparoscopic videos are used to examine the quality of accurate AR based annotation and measurement, and the creation of depth cues. These results show the potential promise of our geometry-aware AR technology to be used in MIS surgical scenes. The results show that the new framework is robust and accurate in dealing with challenging situations such as the rapid endoscopy camera movements in monocular MIS scenes. Both camera tracking and surface reconstruction based on a sparse point cloud are effective and operated in real-time. This demonstrates the potential of our algorithm for accurate AR localization and depth augmentation with geometric cues and correct surface measurements in MIS with monocular endoscopes.


Normative genetic profiles of RAAS pathway gene polymorphisms in North Indian and South Indian populations.
Population-based genetic association studies, popularly known as case-control studies, have continued to be the most preferred method for deciphering the genetic basis of various complex diseases, even in the post-human genome sequencing era. However, interpopulation differences in allele, genotype, and haplotype frequencies and linkage disequilibrium patterns lead to inconsistent results in candidate gene association studies. Therefore, for any meaningful disease association study, knowledge of the normative genetic background of the baseline population is a prerequisite. In addition, such genetic variation data also provide a ready-made menu of allele frequencies and linkage disequilibrium patterns of various polymorphisms in specific candidate genes in a particular population, which is a useful reference for further genetic association studies. Such genetic variation data are lacking for the Indian population, which represents about one-sixth of the world's population. In the present study we have reported the allele, genotype, and haplotype frequencies, Hardy-Weinberg equilibrium status, and linkage disequilibrium patterns of 12 polymorphisms in six candidate genes from the renin-angiotensin-aldosterone system among Indians. Because of their different history of origin, the Indian population is broadly divided into two subpopulations: North Indians (Caucasian Europeans) and South Indians (Dravidians). Considering this well-documented difference in gene pools, we have presented a comparative account of the normative genetic data of North Indian and South Indian populations with at least four individuals of urban and suburban origin from each of the representative states of northern and southern India.


Follow-up of potential novel Graves' disease susceptibility loci, identified in the UK WTCCC genome-wide nonsynonymous SNP study.
A recent association scan using a genome-wide set of nonsynonymous coding single-nucleotide polymorphisms (nsSNPs) conducted in four diseases including Graves' disease (GD), identified nine novel possible regions of association with GD. We used a case-control approach in an attempt to replicate association of these nine regions in an independent collection of 1578 British GD patients and 1946 matched Caucasian controls. Although none of these loci showed evidence of association with GD in the independent data set, when combined with the original Wellcome Trust Case-Control Consortium study group, minor differences in allele frequencies (P>or=10(-3)) remained in the combined collection of 5924 subjects for four of the nsSNPs, present within HDLBP, TEKT1, JSRP1 and UTX. An additional 29 Tag SNPs were screened within these four gene regions to determine if further associations could be detected. Similarly, minor differences only (P=0.042-0.002) were detected in two HDLBP and two TEKT1 Tag SNPs in the combined UK GD collection. In conclusion, it is unlikely that the SNPs selected in this replication study have a significant effect on the risk of GD in the United Kingdom. Our study confirms the need for large data sets and stringent analysis criteria when searching for susceptibility loci in common diseases.


An increase in mean platelet volume from baseline is associated with mortality in patients with severe sepsis or septic shock.
Mean platelet volume (MPV) is suggested as an index of inflammation, disease activity, and anti-inflammatory treatment efficacy in chronic inflammatory disorders; however, the effect of MPV on sepsis mortality remains unclear. Therefore, we investigated whether the change in MPV between hospital admission and 72 hours (ΔMPV72h-adm) predicts 28-day mortality in severe sepsis and/or septic shock. We prospectively enrolled 345 patients admitted to the emergency department (ED) who received standardized resuscitation (early goal-directed therapy) for severe sepsis and/or septic shock between November 2007 and December 2011. Changes in platelet indices, including ΔMPV72h-adm, were compared between survivors and non-survivors by linear mixed model analysis. The prognostic value of ΔMPV72h-adm for 28-day mortality was ascertained by Cox proportional hazards model analysis. Thirty-five (10.1%) patients died within 28 days after ED admission. MPV increased significantly during the first 72 hours in non-survivors (P = 0.001) and survivors (P < 0.001); however, the rate of MPV increase was significantly higher in non-survivors (P = 0.003). Nonetheless, the difference in the platelet decline rate over the first 72 hours did not differ significantly between groups (P = 0.360). In multivariate analysis, ΔMPV72h-adm was an independent predictor of 28-day mortality, after adjusting for plausible confounders (hazard ratio, 1.44; 95% confidence interval, 1.01-2.06; P = 0.044). An increase in MPV during the first 72 hours of hospitalization is an independent risk factor for adverse clinical outcomes. Therefore, continuous monitoring of MPV may be useful to stratify mortality risk in patients with severe sepsis and/or septic shock.


Membrane palmitoylated protein 2 is a synaptic scaffold protein required for synaptic SK2-containing channel function.
Mouse CA1 pyramidal neurons express apamin-sensitive SK2-containing channels in the post-synaptic membrane, positioned close to NMDA-type (N-methyl-D-aspartate) glutamate receptors. Activated by synaptically evoked NMDAR-dependent Ca(2+) influx, the synaptic SK2-containing channels modulate excitatory post-synaptic responses and the induction of synaptic plasticity. In addition, their activity- and protein kinase A-dependent trafficking contributes to expression of long-term potentiation (LTP). We have identified a novel synaptic scaffold, MPP2 (membrane palmitoylated protein 2; p55), a member of the membrane-associated guanylate kinase (MAGUK) family that interacts with SK2-containing channels. MPP2 and SK2 co-immunopurified from mouse brain, and co-immunoprecipitated when they were co-expressed in HEK293 cells. MPP2 is highly expressed in the post-synaptic density of dendritic spines on CA1 pyramidal neurons. Knocking down MPP2 expression selectively abolished the SK2-containing channel contribution to synaptic responses and decreased LTP. Thus, MPP2 is a novel synaptic scaffold that is required for proper synaptic localization and function of SK2-containing channels.


The transcriptional repressor K-RBP modulates RTA-mediated transactivation and lytic replication of Kaposi's sarcoma-associated herpesvirus.
The replication and transcription activator (RTA) protein of Kaposi's sarcoma (KS)-associated herpesvirus (KSHV)/human herpesvirus 8 functions as the key regulator to induce KSHV lytic replication from latency through activation of the lytic cascade of KSHV. Elucidation of the host factors involved in RTA-mediated transcriptional activation is pivotal for understanding the transition between viral latency and lytic replication. KSHV-RTA binding protein (K-RBP) was previously isolated as a cellular RTA binding protein of unknown function. Sequence analysis showed that K-RBP contains a Kruppel-associated box (KRAB) at the N terminus and 12 adjacent zinc finger motifs. In similarity to other KRAB-containing zinc finger proteins, K-RBP is a transcriptional repressor. Mutational analysis revealed that the KRAB domain is responsible for the transcriptional suppression activity of this protein and that the repression is histone deacetylase independent. K-RBP was found to repress RTA-mediated transactivation and interact with TIF1beta (transcription intermediary factor 1beta), a common corepressor of KRAB-containing protein, to synergize with K-RBP in repression. Overexpression and knockdown experiment results suggest that K-RBP is a suppressor of RTA-mediated KSHV reactivation. Our findings suggest that the KRAB-containing zinc finger protein K-RBP can suppress RTA-mediated transactivation and KSHV lytic replication and that KSHV utilizes this protein as a regulator to maintain a balance between latency and lytic replication.


Microsatellites reveal high levels of population substructuring in the species-poor Eretmodine cichlid lineage from Lake Tanganyika.
This study investigated fine-scale population substructuring in an apparently monogamous, biparental mouth-brooding cichlid. Microsatellite allele frequencies were determined at four polymorphic loci for nine populations of Eretmodus cyanostictus. We provide empirical support for the hypothesis that a species employing this breeding strategy should exhibit high levels of population substructuring. Stretches of sand represent considerable barriers to dispersal and, in contrast to the rock-dwelling cichlids of Lake Malawi, distance alone, along a continuous rocky shoreline, is sufficient to reduce gene flow significantly There was a significant pattern of isolation by distance both along the whole study area and over the stretch of continuous shoreline, suggesting that this species has poor dispersal capabilities and that juveniles establish territories close to their natal site. Despite limited dispersal, E. cyanostictus populations are not significantly more inbred than a more-widely dispersing rock-dwelling cichlid from Lake Malawi. This finding may cast doubt on the hypothesis that polyandry has evolved as a mechanism for maintaining genetic diversity in Lake Malawi cichlids. High levels of substructuring may not always promote high levels of speciation, and other factors, such as the intensity of sexual selection, may be more important in determining the speciation potential of a lineage.


Optimizing experimental design for comparing models of brain function.
This article presents the first attempt to formalize the optimization of experimental design with the aim of comparing models of brain function based on neuroimaging data. We demonstrate our approach in the context of Dynamic Causal Modelling (DCM), which relates experimental manipulations to observed network dynamics (via hidden neuronal states) and provides an inference framework for selecting among candidate models. Here, we show how to optimize the sensitivity of model selection by choosing among experimental designs according to their respective model selection accuracy. Using Bayesian decision theory, we (i) derive the Laplace-Chernoff risk for model selection, (ii) disclose its relationship with classical design optimality criteria and (iii) assess its sensitivity to basic modelling assumptions. We then evaluate the approach when identifying brain networks using DCM. Monte-Carlo simulations and empirical analyses of fMRI data from a simple bimanual motor task in humans serve to demonstrate the relationship between network identification and the optimal experimental design. For example, we show that deciding whether there is a feedback connection requires shorter epoch durations, relative to asking whether there is experimentally induced change in a connection that is known to be present. Finally, we discuss limitations and potential extensions of this work.


Cross-Dataset Evaluation of Deep Learning Networks for Uterine Cervix Segmentation.
Evidence from recent research shows that automatic visual evaluation (AVE) of photographic images of the uterine cervix using deep learning-based algorithms presents a viable solution for improving cervical cancer screening by visual inspection with acetic acid (VIA). However, a significant performance determinant in AVE is the photographic image quality. While this includes image sharpness and focus, an important criterion is the localization of the cervix region. Deep learning networks have been successfully applied for object localization and segmentation in images, providing impetus for studying their use for fine contour segmentation of the cervix. In this paper, we present an evaluation of two state-of-the-art deep learning-based object localization and segmentation methods, viz., Mask R-convolutional neural network (CNN) and MaskX R-CNN, for automatic cervix segmentation using three datasets. We carried out extensive experimental tests and algorithm comparisons on each individual dataset and across datasets, and achieved performance either notably higher than, or comparable to, that reported in the literature. The highest Dice and intersection-over-union (IoU) scores that we obtained using Mask R-CNN were 0.947 and 0.901, respectively.


Relations of matrix remodeling biomarkers to blood pressure progression and incidence of hypertension in the community.
Biomarkers of extracellular matrix remodeling are associated with prevalent hypertension in cross-sectional studies, but their relations to longitudinal changes in blood pressure (BP) and hypertension incidence are unknown. We evaluated 595 nonhypertensive Framingham Offspring Study participants (mean age 55 years; 360 women) without prior heart failure or myocardial infarction who underwent routine measurements of plasma tissue inhibitor of metalloproteinase-1 (TIMP-1), metalloproteinase-9 (MMP-9), and procollagen III N-terminal peptide. We related plasma TIMP-1, procollagen III N-terminal peptide, and MMP-9 to the incidence of hypertension and progression of BP by >or=1 category (defined on the basis of the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure). On follow-up (4 years), 81 participants (51 women) developed hypertension, and 198 (114 women) progressed to a higher BP category. In multivariable models, a 1-SD increment of log-TIMP-1 was associated with a 50% higher incidence of hypertension (95% CI 1.08 to 2.08) and a 21% (95% CI 1.00 to 1.47) higher risk of BP progression. Individuals in the top TIMP-1 tertile had a 2.15-fold increased risk of hypertension (95% CI 0.99 to 4.68) and 1.68-fold (95% CI 1.05 to 2.70) increased risk of BP progression relative to the lowest tertile. Individuals with detectable MMP-9 had a 1.97-fold higher risk of BP progression (95% CI 1.06 to 3.64) than those with undetectable levels. Plasma procollagen III N-terminal peptide was not associated with hypertension incidence or BP progression. In the present community-based sample, higher TIMP-1 and MMP-9 concentrations were associated with BP progression on follow-up. Additional studies are warranted to confirm our findings.


Differential gene expression in the nucleus accumbens with ethanol self-administration in inbred alcohol-preferring rats.
The current study examined the effects of operant ethanol (EtOH) self-administration on gene expression kin the nucleus accumbens (ACB) and amygdala (AMYG) of inbred alcohol-preferring (iP) rats. Rats self-trained on a standard two-lever operant paradigm to administer either water-water, EtOH (15% v/v)-water, or saccharin (SAC; 0.0125% g/v)-water. Animals were killed 24 h after the last operant session, and the ACB and AMYG dissected; RNA was extracted and purified for microarray analysis. For the ACB, there were 513 significant differences at the p<0.01 level in named genes: 55 between SAC and water; 215 between EtOH and water, and 243 between EtOH and SAC. In the case of the AMYG (p<0.01), there were 48 between SAC and water, 23 between EtOH and water, and 63 between EtOH and SAC group. Gene Ontology (GO) analysis indicated that differences in the ACB between the EtOH and SAC groups could be grouped into 15 significant (p<0.05) categories, which included major categories such as synaptic transmission, cell and ion homeostasis, and neurogenesis, whereas differences between the EtOH and water groups had only 4 categories, which also included homeostasis and synaptic transmission. Several genes were in common between the EtOH and both the SAC and water groups in the synaptic transmission (e.g., Cav2, Nrxn3, Gabrb2, Gad1, Homer1) and homeostasis (S100b, Prkca, Ftl1) categories. Overall, the results suggest that changes in gene expression in the ACB of iP rats are associated with the reinforcing effects of EtOH.


Occupational trichloroethylene exposure and renal carcinoma risk: evidence of genetic susceptibility by reductive metabolism gene variants.
Trichloroethylene (TCE) is a suspected renal carcinogen. TCE-associated renal genotoxicity occurs predominantly through glutathione S-transferase (GST) conjugation and bioactivation by renal cysteine beta-lyase (CCBL1). We conducted a case-control study in Central Europe (1,097 cases and 1,476 controls) specifically designed to assess risk associated with occupational exposure to TCE through analysis of detailed job histories. All jobs were coded for organic/chlorinated solvent and TCE exposure (ever/never) as well as the frequency and intensity of exposure based on detailed occupational questionnaires, specialized questionnaires, and expert assessments. Increased risk was observed among subjects ever TCE exposed [odds ratio (OR) = 1.63; 95% confidence interval (95% CI), 1.04-2.54]. Exposure-response trends were observed among subjects above and below the median exposure [average intensity (OR = 1.38; 95% CI, 0.81-2.35; OR = 2.34; 95% CI, 1.05-5.21; P(trend) = 0.02)]. A significant association was found among TCE-exposed subjects with at least one intact GSTT1 allele (active genotype; OR = 1.88; 95% CI, 1.06-3.33) but not among subjects with two deleted alleles (null genotype; OR = 0.93; 95% CI, 0.35-2.44; P(interaction) = 0.18). Similar associations for all exposure metrics including average intensity were observed among GSTT1-active subjects (OR = 1.56; 95% CI, 0.79-3.10; OR = 2.77; 95% CI, 1.01-7.58; P(trend) = 0.02) but not among GSTT1 nulls (OR = 0.81; 95% CI, 0.24-2.72; OR = 1.16; 95% CI, 0.27-5.04; P(trend) = 1.00; P(interaction) = 0.34). Further evidence of heterogeneity was seen among TCE-exposed subjects with >or=1 minor allele of several CCBL1-tagging single nucleotide polymorphisms: rs2293968, rs2280841, rs2259043, and rs941960. These findings provide the strongest evidence to date that TCE exposure is associated with increased renal cancer risk, particularly among individuals carrying polymorphisms in genes that are important in the reductive metabolism of this chemical, and provides biological plausibility of the association in humans.


Teaching portfolios: an effective strategy for faculty development in occupational therapy.
The special challenge of the occupational therapy practitioner embracing the role of faculty member is discovering a formative process of continual improvement that will also serve as an authentic assessment of teaching and learning within the particular disciplinary boundaries of occupational therapy. Although other means achieve such complex aims, the teaching portfolio is a powerful tool for fostering reflective practice and for creating an ongoing record of substantial evidence. A teaching portfolio is an evidence-based written document in which a faculty member, working in collaboration with a mentor, concisely organizes selective details of teaching accomplishment and effort and uses such information to document his or her teaching enterprise. More importantly, the faculty member uses the information for reflective analysis, leading to improvement of teaching and student learning. The emphasis on reflection, analysis, evidence, and mentoring suggests that the teaching portfolio can set the stage for meaningful collaboration in a system of evaluation that is based appropriately on recorded evidence of improvement and demonstrated positive outcomes of student learning.


Individuality in bacteria.
While traditionally microbiologists have examined bacterial behavior averaged over large populations, increasingly we are becoming aware that bacterial populations can be composed of phenotypically diverse individuals generated by a variety of mechanisms. Though the results of different mechanisms, the phenomena of bistability, persistence, variation in chemotactic response, and phase and antigenic variation are all strategies to develop population-level diversity. The understanding of individuality in bacteria requires an appreciation of their environmental and ecological context, and thus evolutionary theory regarding adaptations to time-variable environments is becoming more applicable to these problems. In particular, the application of game and information theory to bacterial individuality has addressed some interesting problems of bacterial behavior. In this review we discuss the mechanisms of generating population-level variability, and the application of evolutionary theory to problems of individuality in bacteria.


Cross Pathogenicity and Vegetative Compatibility of Fusarium oxysporum Isolated from Sugar Beet.
Fusarium oxysporum f. sp. betae causes Fusarium yellows in sugar beet (Beta vulgaris). The F. oxysporum population from sugar beet can be highly variable in virulence and morphology and many isolates are nonpathogenic. Rapid and reliable methods to identify pathogenic isolates from nonpathogenic F. oxysporum generally are unavailable. Little is known about nonpathogenic isolates, including the role they may play in population diversity or virulence to sugar beet. Sugar beet is often grown in rotation with other crops, including dry edible bean (Phaseolus vulgaris) and onion (Allium cepa), with F. oxysporum able to cause disease on all three crops. Thirty-eight F. oxysporum isolates were collected from symptomatic sugar beet throughout the United States to investigate diversity of the F. oxysporum population and the influence of crop rotation on pathogenic variation. These isolates were characterized for pathogenicity to sugar beet, dry edible bean, and onion, as well as vegetative compatibility. Pathogenicity testing indicated that some F. oxysporum isolates from sugar beet may cause disease on onion and dry edible bean. Furthermore, vegetative compatibility testing supported previous reports that F. oxysporum f. sp. betae is polyphyletic and that pathogenic isolates cannot be differentiated from nonpathogenic F. oxysporum using vegetative compatibility.


Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs.
Accurate and complete measurement of single nucleotide (SNP) and copy number (CNV) variants, both common and rare, will be required to understand the role of genetic variation in disease. We present Birdsuite, a four-stage analytical framework instantiated in software for deriving integrated and mutually consistent copy number and SNP genotypes. The method sequentially assigns copy number across regions of common copy number polymorphisms (CNPs), calls genotypes of SNPs, identifies rare CNVs via a hidden Markov model (HMM), and generates an integrated sequence and copy number genotype at every locus (for example, including genotypes such as A-null, AAB and BBB in addition to AA, AB and BB calls). Such genotypes more accurately depict the underlying sequence of each individual, reducing the rate of apparent mendelian inconsistencies. The Birdsuite software is applied here to data from the Affymetrix SNP 6.0 array. Additionally, we describe a method, implemented in PLINK, to utilize these combined SNP and CNV genotypes for association testing with a phenotype.


Isometric handgrip training improves local flow-mediated dilation in medicated hypertensives.
Bilateral isometric handgrip (IHG) training lowers resting arterial blood pressure (BP) in medicated hypertensives. Numerous mechanisms have been suggested, but have yet to be investigated. One such mechanism is that of improved systemic endothelial-dependent vasodilation. The purpose of this investigation was twofold: (1) to determine if Bilateral IHG training had any beneficial effects on endothelial-dependent vasodilation, and (2) to see if improved systemic endothelial-dependent vasodilation was responsible for lowering BP. Sixteen participants performed four, 2 min IHG contractions at 30% of their maximal voluntary effort, using either a Bilateral (n = 7) or a Unilateral IHG protocol (n = 9), three times per week for 8 weeks. Brachial artery (BA) flow-mediated dilation (FMD, an index of endothelial-dependent vasodilation, measured in both arms) was assessed pre-and post-training. Following Bilateral IHG training, BA FMD improved in both arms (normalized to peak shear rate, 0.005 +/- 0.001 to 0.02 +/- 0.002 s(-1), P < 0.01). Following Unilateral IHG training, BA FMD improved in the trained arm only (normalized: 0.009 +/- 0.002 to 0.02 +/- 0.005 s(-1), P < 0.01). These findings suggest that although IHG training improves endothelial-dependent vasodilation, the improvements occur only locally in the trained limbs. This suggests that enhanced systemic endothelial-dependent vasodilation is not the mechanism responsible for the observed post-IHG training reductions in BP in medicated hypertensives.


Heterologous expression of a gene that codes for Pg8, a scorpion toxin of Parabuthus granulatus, capable of generating protecting antibodies in mice.
A novel peptide named Pg8 was purified from the venom of the South African scorpion Parabuthus granulatus and its primary structure was determined. It contains 63 amino acid residues tightly folded by 4 disulfide bridges. The gene coding for this peptide was cloned from a cDNA library. By recursive PCR strategy a hybrid gene was constructed having a factor X recognition site for proteolysis and a modified sequence for preferential codon usage of E. coli. A pQE30 molecular vector already contained a His-tag was used for expression. This construction was expressed in BL21 and Origami strains. The fusion protein from inclusion bodies was separated by HPLC (yield approximately 5mg/L) and properly folded in vitro. Lethality tests showed that the recombinant peptide was toxic and was used to immunize mice. A volume of 0.25ml of the anti-serum produced was capable of protecting up to 3 LD(50) doses of pure toxin Pg8 but also, and more importantly, the entire soluble venom.


The Red Tooth Hypothesis: A computational model of predator-prey relations, protean escape behavior and sexual reproduction.
This paper presents an extension of the Red Queen Hypothesis (hereafter, RQH) that we call the Red Tooth Hypothesis (RTH). This hypothesis suggests that predator-prey relations may play a role in the maintenance of sexual reproduction in many higher animals. RTH is based on an interaction between learning on the part of predators and evolution on the part of prey. We present a simple predator-prey computer simulation that illustrates the effects of this interaction. This simulation suggests that the optimal escape strategy from the prey's standpoint would be to have a small number of highly reflexive, largely innate (and, therefore, very fast) escape patterns, but that would also be unlearnable by the predator. One way to achieve this would be for each individual in the prey population to have a small set of hard-wired escape patterns, but which were different for each individual. We argue that polymorphic escape patterns at the population level could be produced via sexual reproduction at little or no evolutionary cost and would be as, or potentially more, efficient than individual-level protean (i.e., random) escape behavior. We further argue that, especially under high predation pressure, sexual recombination would be a more rapid, and therefore more effective, means of producing highly variable escape behaviors at the population level than asexual reproduction.


Neuropsychological Test Performance in Cognitively Normal Spanish-speaking Nonagenarians with Little Education.
To find associations of age, sex, and education with neuropsychological test performance in cognitively normal Spanish-speaking Costa Rican nonagenarians with little education; to provide norms; and to compare their performance with similar Puerto Ricans. For 95 Costa Ricans (90-102 years old, 0-6 years of education), multiple regression assessed associations with demographics of performance on six neuropsychological tests. Analyses of covariance compared them with 23 Puerto Ricans (90-99 years old). Younger age and being female-but not education-were associated with better performance on some neuropsychological tests, in particular episodic memory. The Puerto Ricans performed better on learning and memory tasks. In cognitively intact Spanish-speaking nonagenarians with little or no education, education did not affect test performance. Additional studies of the effect of education on cognitive performance are warranted in other samples with extremely low education or old age. National differences in performance highlight the importance of group-specific norms.


Design and specification criteria for optical data processors.
The specification of coherent optical data processor components on the basis of approximate analogs and the inability of the optical designer to relate actual performance requirements to lens ray tracing computations have often resulted in systems that are disappointing in their results. Designing and manufacturing such systems to desired performance standards require a knowledge of both the communications and practical optical engineering aspects of the problem. The manner in which real coherent optical systems can be designed and assessed is illustrated by two examples. Quantitative criteria have been developed that are analogous to, but that differ significantly from, those used for assessing the quality of incoherent optical imaging systems. The usual computational methods available to optical designers are easily adapted to the evaluation of these criteria. The user can apply them to set specifications that are quantitatively related to the level at which his systems will perform.


Momentum-resolved observations of the phonon instability driving geometric improper ferroelectricity in yttrium manganite.
Magnetoelectrics offer tantalizing opportunities for devices coupling ferroelectricity and magnetism but remain difficult to realize. Breakthrough strategies could circumvent the mutually exclusive origins of magnetism and ferroelectricity by exploiting the interaction of multiple phonon modes in geometric improper and hybrid improper ferroelectrics. Yet, the proposed instability of a zone-boundary phonon mode, driving the emergence of ferroelectricity via coupling to a polar mode, remains to be directly observed. Here, we provide previously missing evidence for this scenario in the archetypal improper ferroelectric, yttrium manganite, through comprehensive scattering measurements of the atomic structure and phonons, supported with first-principles simulations. Our experiments and theoretical modeling resolve the origin of the unusual temperature dependence of the polarization and rule out a reported double-step ferroelectric transition. These results emphasize the critical role of phonon anharmonicity in rationalizing lattice instabilities in improper ferroelectrics and show that including these effects in simulations could facilitate the design of magnetoelectrics.


Multiline short-pulse solid-state seeded carbon dioxide laser for extreme ultraviolet employing multipass radio frequency excited slab amplifier.
In this Letter we describe in more detail a solid-state seeded, nanosecond pulse, multiline CO(2) oscillator designed and built for the extreme ultraviolet (EUV) laser-produced-plasma (LPP) source. Our oscillator featured quantum cascade laser seeders, a diffraction-type seed beam combiner, and a radio-frequency-discharge-excited, diffusion-cooled, slab-waveguide CO(2) gain cell in a compact multipass regenerative amplifier configuration. The oscillator generated pulses of exceptional stability in terms of envelope, energy, and spectrum. Excellent stability of output was achieved without any additional techniques. The output spectrum consisted of two laser lines of a 00(0)1-10(0)0 band of a CO(2) molecule, P20 and P22, with a target of four lines P18-P24. The pulse duration was electronically adjustable between 11 and 35 ns at a repetition frequency from a few hertz to hundreds of kilohertz. Electronic adjustment of the pulse duration was achieved by relative timing offsets of individual seeders, opening an avenue to a range of on-line adjustments of pulse shape and spectral content timing. The jitter-tolerant operation allows for easy synchronization with an external event, such as a droplet target in an EUV LPP source. A resistance to parasitic seeding of more than 40 dB was recorded. The oscillator produced up to 20 W of average output power at a repetition rate of 100 kHz in a near-diffraction-limited beam of M(2)<1.3 and a pointing stability below 50 μrad.


Successful implementation of a pediatric sedation protocol for mechanically ventilated patients.
To evaluate the effect of a nursing-driven sedation protocol for mechanically ventilated pediatric patients on duration of use of analgesic and sedative medications. We hypothesized that a protocol would decrease length of sedation use and decrease days of mechanical ventilation and length of stay. Retrospective cohort study with historical controls. Thirty-one-bed tertiary care, medical-surgical-cardiac pediatric intensive care unit in a metropolitan university-affiliated children's hospital. Children requiring mechanical ventilation longer than 48 hrs not meeting exclusion criteria. Before protocol implementation, sedation was managed per individual physician orders. During the intervention period, analgesia and sedation were managed by nurses following an algorithm-based sedation protocol based on a comfort score. The observation group included consecutive patients admitted during the 12-month period before protocol education and implementation (n = 153). The intervention group included patients admitted during the 12 months following protocol implementation (n = 166). The median duration of total sedation days (intravenous plus enteral) was 7 days for the observation period and 5 days for the intervention period (p = .026). Specifically, the median duration of morphine infusion was 6 days for the observation period and 5 days for the intervention period (p = .015), whereas the median duration of lorazepam infusion was 2 days for the observation period and 0 days for the intervention period. After adjusting for severity of illness with the pediatric risk of mortality III (PRISM III) score, the Cox proportional hazards regression analysis demonstrated that at any point in time, patients in the intervention group were 23% more likely to be off all sedation (heart rate 0.77, p = .020). Additionally, the intervention group tended to be associated with fewer days of mechanical ventilation (heart rate 0.81, p = .060) and decreased pediatric intensive care unit length of stay (heart rate 0.81, p = .058), although these associations did not quite reach statistical significance. A pediatric sedation protocol can significantly decrease days of benzodiazepine and opiate administration, which may improve pediatric intensive care unit resource utilization.


De-smokeGCN: Generative Cooperative Networks for Joint Surgical Smoke Detection and Removal.
Surgical smoke removal algorithms can improve the quality of intra-operative imaging and reduce hazards in image-guided surgery, a highly desirable post-process for many clinical applications. These algorithms also enable effective computer vision tasks for future robotic surgery. In this article, we present a new unsupervised learning framework for high-quality pixel-wise smoke detection and removal. One of the well recognized grand challenges in using convolutional neural networks (CNNs) for medical image processing is to obtain intra-operative medical imaging datasets for network training and validation, but availability and quality of these datasets are scarce. Our novel training framework does not require ground-truth image pairs. Instead, it learns purely from computer-generated simulation images. This approach opens up new avenues and bridges a substantial gap between conventional non-learning based methods and which requiring prior knowledge gained from extensive training datasets. Inspired by the Generative Adversarial Network (GAN), we have developed a novel generative-collaborative learning scheme that decomposes the de-smoke process into two separate tasks: smoke detection and smoke removal. The detection network is used as prior knowledge, and also as a loss function to maximize its support for training of the smoke removal network. Quantitative and qualitative studies show that the proposed training framework outperforms the state-of-the-art de-smoking approaches including the latest GAN framework (such as PIX2PIX). Although trained on synthetic images, experimental results on clinical images have proved the effectiveness of the proposed network for detecting and removing surgical smoke on both simulated and real-world laparoscopic images.


Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer.
Nivolumab, a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody, has demonstrated improved survival in previously treated patients with advanced non-small-cell lung cancer (NSCLC). CheckMate 012, a phase I, multicohort study, was conducted to explore the safety and efficacy of nivolumab as monotherapy or combined with current standard therapies in first-line advanced NSCLC. Here, we report results for nivolumab plus platinum-based doublet chemotherapy (PT-DC). Patients (N = 56) received nivolumab (intravenously) plus PT-DC concurrently every 3 weeks for four cycles followed by nivolumab alone until progression or unacceptable toxicity. Regimens were nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies). The primary objective was to assess safety and tolerability. Secondary objectives included objective response rate and 24-week progression-free survival rate (per Response Evaluation Criteria in Solid Tumors version 1.1); exploratory objectives included overall survival (OS) and response by tumor programmed death ligand-1 expression. No dose-limiting toxicities occurred during the first 6 weeks of treatment. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) discontinued all study therapy as a result of treatment-related AEs. Objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week progression-free survival rates were 51%, 71%, 38%, and 51%, respectively; 2-year OS rates were 25%, 33%, 27%, and 62%, respectively. Responses were achieved regardless of tumor programmed death ligand-1 expression. The safety profile of nivolumab plus PT-DC was consistent with that expected for individual agents; however, treatment discontinuation related to AEs was greater with the combination. Encouraging activity was observed, especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%.


Real-time digital holographic microscopy using the graphic processing unit.
Digital holographic microscopy (DHM) is a well-known powerful method allowing both the amplitude and phase of a specimen to be simultaneously observed. In order to obtain a reconstructed image from a hologram, numerous calculations for the Fresnel diffraction are required. The Fresnel diffraction can be accelerated by the FFT (Fast Fourier Transform) algorithm. However, real-time reconstruction from a hologram is difficult even if we use a recent central processing unit (CPU) to calculate the Fresnel diffraction by the FFT algorithm. In this paper, we describe a real-time DHM system using a graphic processing unit (GPU) with many stream processors, which allows use as a highly parallel processor. The computational speed of the Fresnel diffraction using the GPU is faster than that of recent CPUs. The real-time DHM system can obtain reconstructed images from holograms whose size is 512 x 512 grids in 24 frames per second.


Early and late effects of clopidogrel in patients with acute coronary syndromes.
The risk of ischemic events is high, both early and late after acute coronary syndromes (ACS). We examine the benefits and risks associated with the use of adding clopidogrel to aspirin within the first 30 days and later (31 days to 12 months) in 12 562 patients with ACS. A total of 12 562 ACS patients were randomized to receive clopidogrel (300 mg initially followed by 75 mg/d) or placebo for 3 to 12 months. The proportion of patients experiencing cardiovascular death, myocardial infarction, or strokes (primary outcome) at 30 days was 5.4% in the placebo group and 4.3% in the active group (relative risk 0.79, 95% CI 0.67 to 0.92). Beyond 30 days, the corresponding rates were 6.3% versus 5.2% (relative risk 0.82, 95% CI 0.70 to 0.95). There was no significant excess in life-threatening bleeds in each period (0.97% versus 1.28%, relative risk 1.32, 95% CI 0.95 to 1.84 for 0 to 30 days; 0.83% versus 0.91%, relative risk 1.09, 95% CI 0.75 to 1.59 for 31 days to 12 months). Further subdivision of the early data indicates benefits within 24 hours with consistently lower rates of the primary outcome in combination with refractory or severe ischemia. Clopidogrel reduces the risk of ischemic vascular events, with the benefits emerging within 24 hours of initiation of treatment and continuing throughout the 12 months (mean 9 months) of the study.


The effect of adrenalectomy on leptin levels and some metabolic parameters in rats with diet-induced obesity.
Recently, there has been many investigations on the relationship between leptin and obesity, which is the main health problem in developed countries. In some reports, it has been claimed that the adrenalectomy has lead to weight loss and thus prevented obesity induced in rodents in various ways. It has also been accepted that diet-induced obesity in animals is very similar to obesity in humans beings. In this study, obesity has been developed with high-calorie diet given for 8 weeks in Sprague-Dawley rats. Then, it has been investigated how leptin and some metabolic parameters change in blood samples obtained from rats 15 d after adrenalectomy. Leptin levels was determined with Radio Immun Assay (RIA, Linco Research Co) method. Our study showed that, there were statistically significant increases in leptin (p<0.001), glucose (p<0.05), triglyceride (p<0.01) levels in diet-induced obese rats (n=19) when compared with the findings of control rats, lean ones (n=16), (Tables 3, 4). Adrenalectomy led to decreased serum leptin (p<0.001) and triglyceride (p<0.01) levels both in the obese and lean rats (Table 5). As a conclusion, it could be claimed that the decrease in leptin levels may be attributed to reduced adipose tissue due to adrenalectomy. On the other hand, the decreases in glucose and triglyceride levels might be the consequence of reduced lipogenesis and impaired gluconeogenesis with the effect of adrenalectomy. It was concluded that adrenalectomy might prevent obesity by affecting leptin and intermediate metabolism.


Diet and Genetic Risk Factors of Colorectal Cancer in Palestine: A Case-Control Study.
To add evidence to the limited data available on colorectal cancer (CRC) from Palestine, we examine the risk factors associated with CRC using a matched hospital-based case-control study. A structured questionnaire was used to collect data from 105 cases and 105 controls. A multivariable conditional regression model was used to adjust for the association between study factors and CRC risk. In the model, compared with controls, cases from villages were significantly less likely to have CRC (Adjusted Odds Ratio, AOR = 0.194); taking aspirin lowered the likelihood of CRC by 24%; and having a multiple birth sibling by 33%. Also, the likelihood of CRC was lowered significantly by consuming five servings of fruits/vegetables per week or more (5-6 servings: AOR = 0.21, 7-8 servings per week: AOR = 0.04). However, cases had a significantly higher likelihood of CRC if they consumed 2-4 servings of grilled red meat per week (AOR = 4.25); smoked (AOR = 4.38); had a sedentary lifestyle (AOR = 2.53); reported parental consanguinity (AOR = 3.88); or had a family history of cancer (AOR = 6.39). Our results confirmed the association between CRC and red meat intake and smoking, and proved that parental consanguinity and family history of cancer are also risk factors for CRC.


Fracture resistance of implant-supported screw-retained zirconia-based molar restorations.
The objective of this in vitro study was to investigate fracture loads of screw-retained zirconia-based molar restorations (hybrid abutment crown) fabricated with different restorative materials and designs. Forty-four screw-retained zirconia-based molar restorations were fabricated on dental implants and divided into four groups (n = 11): porcelain-layered zirconia-based restorations (PLZ), indirect composite-layered zirconia-based restorations (ILZ), metal-ceramic restorations (MC), and monolithic zirconia restorations (MONO). The zirconia-based restorations in the PLZ, ILZ, and MONO groups were adhesively bonded on implant abutments with a dual-polymerized resin material. All restorations were tightened on implant bodies with titanium screws and were tested for fracture resistance. The Kruskal-Wallis test and Steel-Dwass test were used to evaluate differences in fracture loads (α = 0.05). As compared with the other groups, the MONO specimens had a significantly higher mean fracture resistance (7.54 kN); no significant differences were found among the PLZ (1.96 kN), ILZ (1.80 kN), and MC (1.45 kN) groups (P > 0.05). For the PLZ, ILZ, and MC groups, all specimens fractured within the layering materials. In contrast, the fracture mode for the MONO group was complete fracture of the restorations. All restorations withstood the masticatory forces. Fracture loads were significantly higher for screw-retained implant-supported monolithic zirconia restorations than for screw-retained bilayered restorations. For the screw-retained bilayered zirconia-based restorations, the fracture resistance of ILZ restorations was comparable to that of PLZ restorations and MC restorations.


Mini-Mental State Examination (MMSE) for the detection of Alzheimer's disease and other dementias in people with mild cognitive impairment (MCI).
Dementia is a progressive global cognitive impairment syndrome. In 2010, more than 35 million people worldwide were estimated to be living with dementia. Some people with mild cognitive impairment (MCI) will progress to dementia but others remain stable or recover full function. There is great interest in finding good predictors of dementia in people with MCI. The Mini-Mental State Examination (MMSE) is the best-known and the most often used short screening tool for providing an overall measure of cognitive impairment in clinical, research and community settings. To determine the diagnostic accuracy of the MMSE at various thresholds for detecting individuals with baseline MCI who would clinically convert to dementia in general, Alzheimer's disease dementia or other forms of dementia at follow-up. We searched ALOIS (Cochrane Dementia and Cognitive Improvement Specialized Register of diagnostic and intervention studies (inception to May 2014); MEDLINE (OvidSP) (1946 to May 2014); EMBASE (OvidSP) (1980 to May 2014); BIOSIS (Web of Science) (inception to May 2014); Web of Science Core Collection, including the Conference Proceedings Citation Index (ISI Web of Science) (inception to May 2014); PsycINFO (OvidSP) (inception to May 2014), and LILACS (BIREME) (1982 to May 2014). We also searched specialized sources of diagnostic test accuracy studies and reviews, most recently in May 2014: MEDION (Universities of Maastricht and Leuven, www.mediondatabase.nl), DARE (Database of Abstracts of Reviews of Effects, via the Cochrane Library), HTA Database (Health Technology Assessment Database, via the Cochrane Library), and ARIF (University of Birmingham, UK, www.arif.bham.ac.uk). No language or date restrictions were applied to the electronic searches and methodological filters were not used as a method to restrict the search overall so as to maximize sensitivity. We also checked reference lists of relevant studies and reviews, tracked citations in Scopus and Science Citation Index, used searches of known relevant studies in PubMed to track related articles, and contacted research groups conducting work on MMSE for dementia diagnosis to try to locate possibly relevant but unpublished data. We considered longitudinal studies in which results of the MMSE administered to MCI participants at baseline were obtained and the reference standard was obtained by follow-up over time. We included participants recruited and clinically classified as individuals with MCI under Petersen and revised Petersen criteria, Matthews criteria, or a Clinical Dementia Rating = 0.5. We used acceptable and commonly used reference standards for dementia in general, Alzheimer's dementia, Lewy body dementia, vascular dementia and frontotemporal dementia. We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. We assessed the identified full papers for eligibility and extracted data to create two by two tables for dementia in general and other dementias. Two authors independently performed quality assessment using the QUADAS-2 tool. Due to high heterogeneity and scarcity of data, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic curve. In this review, we included 11 heterogeneous studies with a total number of 1569 MCI patients followed for conversion to dementia. Four studies assessed the role of baseline scores of the MMSE in conversion from MCI to all-cause dementia and eight studies assessed this test in conversion from MCI to Alzheimer´s disease dementia. Only one study provided information about the MMSE and conversion from MCI to vascular dementia. For conversion from MCI to dementia in general, the accuracy of baseline MMSE scores ranged from sensitivities of 23% to 76% and specificities from 40% to 94%. In relationship to conversion from MCI to Alzheimer's disease dementia, the accuracy of baseline MMSE scores ranged from sensitivities of 27% to 89% and specificities from 32% to 90%. Only one study provided information about conversion from MCI to vascular dementia, presenting a sensitivity of 36% and a specificity of 80% with an incidence of vascular dementia of 6.2%. Although we had planned to explore possible sources of heterogeneity, this was not undertaken due to the scarcity of studies included in our analysis. Our review did not find evidence supporting a substantial role of MMSE as a stand-alone single-administration test in the identification of MCI patients who could develop dementia. Clinicians could prefer to request additional and extensive tests to be sure about the management of these patients. An important aspect to assess in future updates is if conversion to dementia from MCI stages could be predicted better by MMSE changes over time instead of single measurements. It is also important to assess if a set of tests, rather than an isolated one, may be more successful in predicting conversion from MCI to dementia.


Rapid induction of functional and morphological continuity between severed ends of mammalian or earthworm myelinated axons.
The inability to rapidly restore the loss of function that results from severance (cutting or crushing) of PNS and CNS axons is a severe clinical problem. As a novel strategy to help alleviate this problem, we have developed in vitro procedures using Ca2+-free solutions of polyethylene glycol (PEG solutions), which within minutes induce functional and morphological continuity (PEG-induced fusion) between the cut or crushed ends of myelinated sciatic or spinal axons in rats. Using a PEG-based hydrogel that binds to connective tissue to provide mechanical strength at the lesion site and is nontoxic to nerve tissues in earthworms and mammals, we have also developed in vivo procedures that permanently maintain earthworm myelinated medial giant axons whose functional and morphological integrity has been restored by PEG-induced fusion after axonal severance. In all these in vitro or in vivo procedures, the success of PEG-induced fusion of sciatic or spinal axons and myelinated medial giant axons is measured by the restored conduction of action potentials through the lesion site, the presence of intact axonal profiles in electron micrographs taken at the lesion site, and/or the intra-axonal diffusion of fluorescent dyes across the lesion site. These and other data suggest that the application of polymeric fusiogens (such as our PEG solutions), possibly combined with a tissue adherent (such as our PEG hydrogels), could lead to in vivo treatments that rapidly and permanently repair cut or crushed axons in the PNS and CNS of adult mammals, including humans.


Distinct Roles for CXCR6(+) and CXCR6(-) CD4(+) T Cells in the Pathogenesis of Chronic Colitis.
CD4(+) T cells play a central role in the development of inflammatory bowel disease (IBD) via high-level production of effector cytokines such as IFN-γ and TNF-α. To better characterize the colitogenic CD4(+) T cells, we examined their expression of CXCR6, a chemokine receptor that is expressed by T cells upon activation and is upregulated in several inflammatory diseases. We found that 80% of colonic lamina propria CD4(+) T cells expressed CXCR6 in the CD45RB(high) T cell-transferred colitis model. CXCR6 expression was similarly upregulated in inflamed mucosa of patients with Crohn's disease. Although surface marker analysis demonstrated that both CXCR6(+) and CXCR6(-) CD4(+) T-cell subsets consist of the cells with effector and effector-memory cells, the more cells in the CXCR6(+) subset produced IFN-γ and TNF-α compared to CXCR6(-) subset, and only the CXCR6(+) subset produced IL-17A. Nevertheless, adoptive retransfer of lamina propria CXCR6(+) T cells into Rag1 (-/-) recipients failed to induce the disease due to limited expansion of the transferred cells. By contrast, retransfer of CXCR6(-) cells evoked colitis similar to that observed in CD4(+)CD45RB(high) T cell-transferred mice, and resulted in their conversion into CXCR6(+) cells. Collectively, these observations suggest that the CXCR6(+)CD4(+) T-cell subset consists of terminally differentiated effector cells that serve as the major source of effector cytokines in the inflamed tissue, whereas CXCR6(-)CD4(+) T-cell subset serves as a colitogenic memory compartment that retains the ability to proliferate and differentiate into CXCR6(+)CD4(+) T cells.


Hepatic radiation toxicity: avoidance and amelioration.
The refinement of radiation therapy and radioembolization techniques has led to a resurgent interest in radiation-induced liver disease (RILD). The awareness of technical and clinical parameters that influence the chance of RILD is important to guide patient selection and toxicity minimization strategies. "Classic" RILD is characterized by anicteric ascites and hepatomegaly and is unlikely to occur after a mean liver dose of approximately 30 Gy in conventional fractionation. By maintaining a low mean liver dose and sparing a "critical volume" of liver from radiation, stereotactic delivery techniques allow for the safe administration of higher tumor doses. Caution must be exercised for patients with hepatocellular carcinoma or pre-existing liver disease (eg, Child-Pugh score of B or C) because they are more susceptible to RILD that can manifest in a nonclassic pattern. Although no pharmacologic interventions have yet been proven to mitigate RILD, preclinical research shows the potential for therapies targeting transforming growth factor-β and for the transplantation of stem cells, hepatocytes, and liver progenitor cells as strategies that may restore liver function. Also, in the clinical setting of veno-occlusive liver disease after high-dose chemotherapy, agents with fibrinolytic and antithrombotic properties can reverse liver failure, suggesting a possible role in the setting of RILD.


Metabolic gene profile in early human fetal heart development.
The primitive cardiac tube starts beating 6-8 weeks post fertilization in the developing embryo. In order to describe normal cardiac development during late first and early second trimester in human fetuses this study used microarray and pathways analysis and created a corresponding 'normal' database. Fourteen fetal hearts from human fetuses between 10 and 18 weeks of gestational age (GA) were prospectively collected at the time of elective termination of pregnancy. RNA from recovered tissues was used for transcriptome analysis with Affymetrix 1.0 ST microarray chip. From the amassed data we investigated differences in cardiac development within the 10-18 GA period dividing the sample by GA in three groups: 10-12 (H1), 13-15 (H2) and 16-18 (H3) weeks. A fold change of 2 or above adjusted for a false discovery rate of 5% was used as initial cutoff to determine differential gene expression for individual genes. Test for enrichment to identify functional groups was carried out using the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Array analysis correctly identified the cardiac specific genes, and transcripts reported to be differentially expressed were confirmed by qRT-PCR. Single transcript and Ontology analysis showed first trimester heart expression of myosin-related genes to be up-regulated >5-fold compared with second trimester heart. In contrast the second trimester hearts showed further gestation-related increases in many genes involved in energy production and cardiac remodeling. In conclusion, fetal heart development during the first trimester was dominated by heart-specific genes coding for myocardial development and differentiation. During the second trimester, transcripts related to energy generation and cardiomyocyte communication for contractile coordination/proliferation were more dominant. Transcripts related to fatty acid metabolism can be seen as early as 10 weeks and clearly increase as the heart matures. Retinol receptor and gamma-aminobutyric acid (GABA) receptor transcripts were detected, and have not been described previously in human fetal heart during this period. For the first time global gene expression of heart has been described in human samples to create a database of normal development to understand and compare with known abnormal fetal heart development.


The neural changes in connectivity of the voice network during voice pitch perturbation.
Voice control is critical to communication. To date, studies have used behavioral, electrophysiological and functional data to investigate the neural correlates of voice control using perturbation tasks, but have yet to examine the interactions of these neural regions. The goal of this study was to use structural equation modeling of functional neuroimaging data to examine network properties of voice with and without perturbation. Results showed that the presence of a pitch shift, which was processed as an error in vocalization, altered connections between right STG and left STG. Other regions that revealed differences in connectivity during error detection and correction included bilateral inferior frontal gyrus, and the primary and pre motor cortices. Results indicated that STG plays a critical role in voice control, specifically, during error detection and correction. Additionally, pitch perturbation elicits changes in the voice network that suggest the right hemisphere is critical to pitch modulation.


Repeatability and Validity of MNREAD Test in Children With Vision Impairment.
To evaluate the test-retest reliability and validity of the MNREAD test for use in children with vision impairment (VI) and to compare their performance on the test to that of normally sighted children. Children with VI (n = 62) and without VI (n = 40) were administered the MNREAD test and the Basic Reading Inventory (BRI) on two study visits, 1 to 3 weeks apart. The maximum reading rate, critical print size, and reading acuity were determined for the MNREAD test, and test-retest reliability was evaluated. The reading rate for the MNREAD test was compared to the BRI results. Strong correlations between visits were found for all MNREAD parameters (0.68-0.99). Older, but not younger, children with VI read significantly more slowly on both the MNREAD and the BRI than children with normal vision (P < 0.05). Reading rates between the two tests were strongly correlated (r = 0.88). For the MNREAD test, the reading rate increased 4.4 words per minute (wpm) per year for VI and 10.6 wpm/y for those with normal vision. For the BRI, the reading rate increased by 5.9 wpm/y for VI and 9.7 wpm/y for those with normal vision. Poorer visual acuity was associated with slower reading rates on the MNREAD test but not on the BRI, as the MNREAD relies largely on visual factors but the BRI also relies on linguistic and grammar skills. The MNREAD test are reliable and valid for use in children with vision impairment. The MNREAD test can be utilized by clinicians, as they are a quick, easy-to-administer method for evaluating reading vision in children with VI.


Anisotropic softening of magnetic excitations along the nodal direction in superconducting cuprates.
The high-Tc cuprate superconductors are close to antiferromagnetic order. Recent measurements of magnetic excitations have reported an intriguing similarity to the spin waves--magnons--of the antiferromagnetic insulating parent compounds, suggesting that magnons may survive in damped, broadened form throughout the phase diagram. Here we show by resonant inelastic X-ray scattering on Bi(2)Sr(2)CaCu(2)O(8+δ) (Bi-2212) that the analogy with spin waves is only partial. The magnon-like features collapse along the nodal direction in momentum space and exhibit a photon energy dependence markedly different from the Mott-insulating case. These observations can be naturally described by the continuum of charge and spin excitations of correlated electrons. The persistence of damped magnons could favour scenarios for superconductivity built from quasiparticles coupled to spin fluctuations. However, excitation spectra composed of particle-hole excitations suggest that superconductivity emerges from a coherent treatment of electronic spin and charge in the form of quasiparticles with very strong magnetic correlations.


Costs and Resource Use Associated with Community-Dwelling Patients with Alzheimer's Disease in Japan: Baseline Results from the Prospective Observational GERAS-J Study.
As the Japanese population ages, caring for people with Alzheimer's disease (AD) dementia is becoming a major socioeconomic issue. To determine the contribution of patient and caregiver costs to total societal costs associated with AD dementia. Baseline data was used from the longitudinal, observational GERAS-J study. Using the Mini-Mental State Examination (MMSE) score, patients routinely visiting memory clinics were stratified into three groups based on AD severity. Health care resource utilizationwas recorded using the Resource Utilization in Dementia questionnaire. Total monthly societal costs were estimated using Japan-specific unit costs of services and products (patient direct health care use, patient social care use, and informal caregiving time). Uncertainty around mean costs was estimated using bootstrapping methods. Overall, 553 community-dwelling patients withADdementia (28.3% mild[MMSE21-26], 37.8% moderate[MMSE 15-20], and 34.0% moderately severe/severe [MMSE < 14]) and their caregivers were enrolled. Patient characteristics were: mean age 80.3 years, 72.7% female, and 13.6% living alone. Caregiver characteristics were: mean age 62.1 years, 70.7% female, 78.8% living with patient, 49.0% child of patient, and 39.2% sole caregiver. Total monthly societal costs of AD dementia (Japanese yen) were: 158,454 (mild), 211,301 (moderate), and 294,224 (moderately severe/severe). Informal caregiving costs comprised over 50% of total costs. Baseline results of GERAS-J showed that total monthly societal costs associated with AD dementia increased with AD severity. Caregiver-related costs were the largest cost component. Interventions are needed to decrease informal costs and decrease caregiver burden.


The Effect of a Slowly Rocking Bed on Sleep.
Rocking movements appear to affect human sleep. Recent research suggested a facilitated transition from wake to sleep and a boosting of slow oscillations and sleep spindles due to lateral rocking movements during an afternoon nap. This study aimed at investigating the effect of vestibular stimulation on sleep onset, nocturnal sleep and its potential to increase sleep spindles and slow waves, which could influence memory performance. Polysomnography was recorded in 18 males (age: 20-28 years) during three nights: movement until sleep onset (C1), movement for 2 hours (C2), and one baseline (B) without motion. Sleep dependent changes in memory performance were assessed with a word-pair learning task. Although subjects preferred nights with vestibular stimulation, a facilitated sleep onset or a boost in slow oscillations was not observed. N2 sleep and the total number of sleep spindles increased during the 2 h with vestibular stimulation (C2) but not over the entire night. Memory performance increased over night but did not differ between conditions. The lack of an effect might be due to the already high sleep efficiency (96%) and sleep quality of our subjects during baseline. Nocturnal sleep in good sleepers might not benefit from the potential facilitating effects of vestibular stimulation.


In vitro effects of bevacizumab treatment on newborn rat retinal cell proliferation, death, and differentiation.
Vascular endothelial growth factor (VEGF) is an important signal protein in vertebrate nervous development, promoting neurogenesis, neuronal patterning, and glial cell growth. Bevacizumab, an anti-VEGF agent, has been extensively used for controlling pathological retinal neovascularization in adult and newborn patients, although its effect on the developing retina remains largely unknown. The purpose of this study was to investigate the effect of bevacizumab on cell death, proliferation, and differentiation in newborn rat retina. Retinal explants of sixty 2-day-old Lister hooded rats were obtained after eye enucleation and maintained in culture media with or without bevacizumab for 2 days. Immunohistochemical staining was assessed against proliferating cell nuclear antigen (PCNA, to detect cell proliferation); caspase-3 and beclin-1 (to investigate cell death); and vimentin and glial fibrillary acidic protein (GFAP, markers of glial cells). Gene expressions were quantified by real-time reverse-transcription polymerase chain reaction. Results from treatment and control groups were compared. No significant difference in the staining intensity (on immunohistochemistry) of PCNA, caspase-3, beclin-1, and GFAP, or in the levels of PCNA, caspase-3, beclin-1, and vimentin mRNA was observed between the groups. However, a significant increase in vimentin levels and a significant decrease in GFAP mRNA expression were observed in bevacizumab-treated retinal explants compared with controls. Bevacizumab did not affect cell death or proliferation in early developing rat retina but appeared to interfere with glial cell maturation by increasing vimentin levels and downregulating GFAP gene expression. Thus, we suggest anti-VEGF agents be used with caution in developing retinal tissue.


Aerosol observations by lidar in the nocturnal boundary layer.
Aerosol observations by lidar in the nocturnal boundary layer (NBL) were performed in Potenza, Southern Italy, from 20 January to 20 February 1997. Measurements during nine winter nights were considered, covering a variety of boundary-layer conditions. The vertical profiles of the aerosol backscattering coefficient at 355 and 723.37 nm were determined through a Klett-modified iterative procedure, assuming the extinction-to-backscattering ratio within the NBL has a constant value. Aerosol average size characteristics were retrieved from almost simultaneous profiles of the aerosol backscattering coefficient at 355 and 723.37 nm, the measurements being consistent with an accumulation mode radius not exceeding 0.4 microm. Similar results in terms of aerosol sizes were obtained from measurements of the extinction-to-backscattering ratio profile at 355 nm performed on six nights during the measurement campaign. Backscattering profiles at 723.37 nm were also converted into profiles of aerosol liquid water content.


Optimizing timing performance of silicon photomultiplier-based scintillation detectors.
Precise timing resolution is crucial for applications requiring photon time-of-flight (ToF) information such as ToF positron emission tomography (PET). Silicon photomultipliers (SiPM) for PET, with their high output capacitance, are known to require custom preamplifiers to optimize timing performance. In this paper, we describe simple alternative front-end electronics based on a commercial low-noise RF preamplifier and methods that have been implemented to achieve excellent timing resolution. Two radiation detectors with L(Y)SO scintillators coupled to Hamamatsu SiPMs (MPPC S10362-33-050C) and front-end electronics based on an RF amplifier (MAR-3SM+), typically used for wireless applications that require minimal additional circuitry, have been fabricated. These detectors were used to detect annihilation photons from a Ge-68 source and the output signals were subsequently digitized by a high speed oscilloscope for offline processing. A coincident resolving time (CRT) of 147 ± 3 ps FWHM and 186 ± 3 ps FWHM with 3 × 3 × 5 mm(3) and with 3 × 3 × 20 mm(3) LYSO crystal elements were measured, respectively. With smaller 2 × 2 × 3 mm(3) LSO crystals, a CRT of 125 ± 2 ps FWHM was achieved with slight improvement to 121 ± 3 ps at a lower temperature (15° C). Finally, with the 20 mm length crystals, a degradation of timing resolution was observed for annihilation photon interactions that occur close to the photosensor compared to shallow depth-of-interaction (DOI). We conclude that commercial RF amplifiers optimized for noise, besides their ease of use, can produce excellent timing resolution comparable to best reported values acquired with custom readout electronics. On the other hand, as timing performance degrades with increasing photon DOI, a head-on detector configuration will produce better CRT than a side-irradiated setup for longer crystals.


Environmental health in the east Baltic region--pesticides and persistent organic compounds.
Exposure to, and the potential effects of, pesticides and persistent organic pollutants in the East Baltic region are reviewed. Exposure of the average population to chlorinated compounds seems lower than in most of western Europe, and current pesticide use is very low. However, due to infrastructure failures and poor management controls, industrial hot spots and inadequate storage sites exist that cause high risks to small population fractions. The low exposure of the general population is indicated by low concentrations of polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls in milk fat. Chlorophenol concentrations are also generally lower than in Scandinavia. Some organic pesticides have been found at higher concentrations in Baltic countries and the St. Petersburg area than in Norway, but the range is roughly similar to that in central Europe. Thus the overall risk caused by pesticide residues and persistent organic compounds in the Baltic countries and northwestern Russia is low, but local sites of concern exist.


Susac Syndrome: Clinical characteristics, diagnostic findings and treatment in 19 cases.
Susac's Syndrome (SS), which was first described in 1979, is a rare and presumably autoimmune disorder characterized by encephalopathy, hearing loss, and visual disturbance resulting from branch retinal artery occlusion (BRAO). This study reports 19 SS patients' clinical characteristics, MRI features, CSF analysis, treatment strategies and outcomes. At initial presentation, only three of 19 patients demonstrated the complete clinical triad. Clinic presentation varied from isolated hemiparesis to the full triad (encephalopathy, hearing loss and visual disturbances). Corpus callosum (CC) involvement was noted in the MRI of 18 patients (97%) and BRAO was detected in 17 (95%) patients. All patients were treated with intravenous methylprednisolone after the initial assessment. This case series is presented to emphasize the differences in clinical presentation of SS and the importance of MRI and FFA in diagnosis.


The impact of violence against women on reproductive health and child mortality in Timor-Leste.
To determine differences in reproductive health and infant and child mortality and health between abused and non-abused ever-married women in Timor-Leste. Secondary data analysis of Timor-Leste Demographic Health Survey (1,959 ever-married women aged 15-49 years). Associations with violence estimated using multinomial logistic regression adjusted for sociodemographic variables and age of first intercourse. Overall, 45% of ever-married women experienced violence: 34% reported physical only and 11% reported combined physical, sexual and/or emotional violence. Compared to non-abused women, women reporting physical violence only were more likely to use traditional contraception (AdjOR 2.35, 95%CI 1.05-5.26) or report: a sexually transmitted infection (AdjOR 4.46, 95%CI 3.27-6.08); a pregnancy termination (AdjOR 1.42, 95%CI 1.03-1.96); a child who had died (AdjOR 1.30, 95%CI 1.05-1.60), a low birth weight infant (AdjOR 2.08, 95%CI 1.64-2.64); and partially vaccinated children (AdjOR 1.35, 95%CI 1.05-1.74). Women who reported combined abuse were more likely to report: a sexually transmitted infection (AdjOR 3.51, 95%CI 2.26-5.44); a pregnancy termination (AdjOR 1.95, 95%CI 1.27-3.01); few antenatal visits (AdjOR 1.76 95%CI 1.21-2.55); and a child who had died (AdjOR 1.45, 95%CI 1.06-2.00). Violence exposes women to poor reproductive health, infant and child mortality and poor infant and child health. Preventing and reducing violence against women should improve women and children's health outcomes in Timor-Leste.


SR Ca2+ pump heterogeneity in coronary artery: free radicals and IP3-sensitive and -insensitive pools.
Reactive oxygen species are known to decrease the action of agents that mobilize Ca2+ from sarcoplasmic reticulum (SR) in pig coronary artery smooth muscle. Potentially, this may be due to damage to the SR Ca2+ pump or to the myo-inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release channels. Here we report on the effects of peroxide and superoxide on the SR Ca2+ pump and the subsequent IP3-induced Ca2+ release. Smooth muscle cells cultured from pig left coronary arteries were permeabilized using saponin and then loaded with 45Ca2+ in the presence of an ATP-regenerating system and the mitochondrial Ca2+ uptake inhibitor sodium azide. IP3 caused a release of up to 65% of the loaded 45Ca2+, whereas the Ca2+ ionophore A-23187 caused a release of > 95%. The nature of the IP3-insensitive component of the Ca2+ uptake is not known. The IP3-induced Ca2+ release occurred at 0 or 37 degrees C and was complete in < 30 s. The 50% effective concentration for IP3 was 2.7 +/- 1.0 microM at pH 6.8 and 37 degrees C. At pH 7.4 the IP3-induced Ca2+ release was slightly lower than at pH 6.4-6.8. The IP3-induced release was also inhibited by Ca2+ concentration in the release medium. To investigate the effects of peroxide or superoxide, the cells were treated with these agents, washed, skinned, and then used to examine the IP3-sensitive and -insensitive Ca2+ pools under the conditions in which the IP3-sensitive pool was 60-65% of the total. Peroxide pretreatment was equipotent in inhibiting loading into the IP3-sensitive and -insensitive Ca2+ pools. In contrast, superoxide pretreatment inhibited loading into the IP3-sensitive pool but not into the IP3-insensitive pool. These data are consistent with a model in which the SR Ca2+ pumps are heterogeneous: those required to pump Ca2+ into the IP3-sensitive pool are inhibited by peroxide and superoxide, but those loading the IP3-insensitive pool are inhibited by peroxide only.


Selection of antibody repertoires by anti-idiotypes can occur at multiple steps of B cell differentiation.
These experiments were designed to evaluate whether alterations in Id expression after anti-Id treatments result from direct modulation of Id-producing B cells, and whether idiotypic selection operates in bone marrow or spleen B cells. By using the NPb Id model, we have studied the functional behavior of isolated LPS-reactive B cells transferred from B6 mice into histocompatible LPS-NR B10.Cr hosts and primed with LPS conjugates of anti-Id antibodies. We have found that previous anti-idiotypic manipulation of host mice by neonatal administration of suppressive doses of Ac 38 antibodies, or adult injection of enhancing doses of Ac 146 antibodies, modulated the T cell-independent Id response of either immature bone marrow or mature splenic responding cells, transferred from normal, untreated donors. These results are interpreted to suggest that selection of antibody repertoires by anti-Id may occur at multiple steps of B cell differentiation.


Factors Associated With Interest in Pursuing a Fourth Year of Family Medicine Residency Training.
The optimal length of residency training in family medicine, as with emergency medicine, is an ongoing debate due to several factors, but perceptions of graduating residents are missing from this debate. We used data from 3,054 family medicine residents who registered for the American Board of Family Medicine certification examination in 2014. A practice demographic questionnaire was a mandatory component of registration. The survey included the question, "If another year of training were available in your residency program, how likely would you be to pursue that?" We examined several factors potentially associated with interest in additional training. The sample was predominantly female (53.9%), white (65.7%), and non-Hispanic (91.7%), with a mean age of 32.5 years. Overall, 52.8% of respondents reported being not at all likely to pursue additional training if available, 26.4% reported being somewhat likely, and 21.4% reported being moderately or extremely likely to do so. Male respondents were more likely than females to express no interest in an additional year of training (57.7% versus 48.1%). As educational debt increased, the likelihood of interest in additional training decreased. Anticipated practice settings, planned scope of practice, and intention to perform specific procedures also influenced interest in pursuing additional training. Slightly less than half of graduating family medicine residents expressed interest in a fourth year of training. Interest in a fourth year was associated with several characteristics that may help the discipline decide on the optimal length of training.


Identification and characterization of cell type-specific and ubiquitous chromatin regulatory structures in the human genome.
The identification of regulatory elements from different cell types is necessary for understanding the mechanisms controlling cell type-specific and housekeeping gene expression. Mapping DNaseI hypersensitive (HS) sites is an accurate method for identifying the location of functional regulatory elements. We used a high throughput method called DNase-chip to identify 3,904 DNaseI HS sites from six cell types across 1% of the human genome. A significant number (22%) of DNaseI HS sites from each cell type are ubiquitously present among all cell types studied. Surprisingly, nearly all of these ubiquitous DNaseI HS sites correspond to either promoters or insulator elements: 86% of them are located near annotated transcription start sites and 10% are bound by CTCF, a protein with known enhancer-blocking insulator activity. We also identified a large number of DNaseI HS sites that are cell type specific (only present in one cell type); these regions are enriched for enhancer elements and correlate with cell type-specific gene expression as well as cell type-specific histone modifications. Finally, we found that approximately 8% of the genome overlaps a DNaseI HS site in at least one the six cell lines studied, indicating that a significant percentage of the genome is potentially functional.


The ERK Cascade: Distinct Functions within Various Subcellular Organelles.
The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is a central signaling pathway that regulates a wide variety of stimulated cellular processes, including mainly proliferation, differentiation, and survival, but apoptosis and stress response as well. The ability of this linear cascade to induce so many distinct and even opposing effects after various stimulations raises the question as to how the signaling specificity of the cascade is regulated. Over the past years, several specificity-mediating mechanisms have been elucidated, including temporal regulation, scaffolding interactions, crosstalks with other signaling components, substrate competition, and multiple components in each tier of the cascade. In addition, spatial regulation of various components of the cascade is probably one of the main ways by which signals can be directed to some downstream targets and not to others. In this review, we describe first the components of the ERK1/2 cascade and their mode of regulation by kinases, phosphatases, and scaffold proteins. In the second part, we focus on the role of MEK1/2 and ERK1/2 compartmentalization in the nucleus, mitochondria, endosomes, plasma membrane, cytoskeleton, and Golgi apparatus. We explain that this spatial distribution may direct ERK1/2 signals to regulate the organelles' activities. However, it can also direct the activity of the cascade's components to the outer surface of the organelles in order to bring them to close proximity to specific cytoplasmic targets. We conclude that the dynamic localization of the ERK1/2 cascade components is an important regulatory mechanism in determining the signaling specificity of the cascade, and its understanding should shed a new light on the understanding of many stimulus-dependent processes.


Genome-wide conserved consensus transcription factor binding motifs are hyper-methylated.
DNA methylation can regulate gene expression by modulating the interaction between DNA and proteins or protein complexes. Conserved consensus motifs exist across the human genome ("predicted transcription factor binding sites": "predicted TFBS") but the large majority of these are proven by chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) not to be biological transcription factor binding sites ("empirical TFBS"). We hypothesize that DNA methylation at conserved consensus motifs prevents promiscuous or disorderly transcription factor binding. Using genome-wide methylation maps of the human heart and sperm, we found that all conserved consensus motifs as well as the subset of those that reside outside CpG islands have an aggregate profile of hyper-methylation. In contrast, empirical TFBS with conserved consensus motifs have a profile of hypo-methylation. 40% of empirical TFBS with conserved consensus motifs resided in CpG islands whereas only 7% of all conserved consensus motifs were in CpG islands. Finally we further identified a minority subset of TF whose profiles are either hypo-methylated or neutral at their respective conserved consensus motifs implicating that these TF may be responsible for establishing or maintaining an un-methylated DNA state, or whose binding is not regulated by DNA methylation. Our analysis supports the hypothesis that at least for a subset of TF, empirical binding to conserved consensus motifs genome-wide may be controlled by DNA methylation.


Knowledge of obstetric danger signs amongst women of reproductive age in PATHS2 Zaria cluster, Kaduna Nigeria.
The Partnership for Transforming Health Systems 2 (PATHS2) in Nigeria is implementing selected Behavior Change Communication (BCC) models to increase the knowledge of obstetric danger signs amongst women of reproductive age in Kaduna, Nigeria. The objective of this survey was to establish baseline proportions for knowledge of at least four danger signs of pregnancy, delivery and postpartum period respectively amongst women age 15-49, residing within 25 selected communities in Zaria. A cross-sectional survey was carried out amongst the eligible women within the communities. A pre-tested structured questionnaire was used for interview. 617 (94.5% response) eligible women participated in the study. Only 113 (18.31%) knew at least four danger signs during pregnancy. 61 (9.89%) knew at least four danger signs that can occur during labor and delivery and only 57 (9.24%) knew at least four danger signs that can occur during the postpartum period. A high proportion of the respondents are unaware of obstetric danger signs. It is recommended that radio broadcast be used as part of efforts towards increasing the proportion of women with knowledge of four or more obstetric danger signs in the study population.


A process-specific functional dissociation of the amygdala in emotional memory.
Converging evidence highlights the important role of the amygdala in the enhanced memory for emotional material. However, it is unknown whether any regional and/or hemispheric specificity exists regarding its involvement in the different memory stages, such as encoding and retrieval. We directly addressed this issue by conducting an event-related functional magnetic resonance imaging study of memory for faces with different emotional expressions, in which both encoding and recognition were scanned. We found significant amygdala activation associated with both successful encoding and retrieval of fearful faces. Critically, a direct comparison between both stages revealed that whereas the right amygdala was involved in emotional memory formation, the retrieval of those memories relied on the left amygdala. Thus, this study demonstrates a hemispheric dissociation of amygdala involvement in different stages of emotional memory in humans.


Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder.
Patients with schizophrenia show elevated brain levels of the neuroactive tryptophan metabolite kynurenic acid (KYNA). This astrocyte-derived mediator acts as a neuroprotectant and modulates sensory gating and cognitive function. We measured the levels of KYNA in the cerebrospinal fluid (CSF) of patients with bipolar disorder and healthy volunteers to investigate the putative involvement of KYNA in bipolar disorder. We obtained CSF by lumbar puncture from 23 healthy men and 31 euthymic men with bipolar disorder. We analyzed the samples using high-performance liquid chromatography. Patients with bipolar disorder had increased levels of KYNA in their CSF compared with healthy volunteers (1.71 nM, standard error of the mean [SEM] 0.13 v. 1.13 nM, SEM 0.09; p = 0.002. The levels of KYNA were positively correlated with age among bipolar patients but not healthy volunteers. The influence of ongoing drug treatment among patients cannot be ruled out. We conducted our study during the euthymic phase of the disease. Brain KYNA levels are increased in euthymic men with bipolar disorder. In addition, KYNA levels increased with age in these patients. These findings indicate shared mechanisms between bipolar disorder and schizophrenia. Elevated levels of brain KYNA may provide further insight to the pathophysiology and progression of bipolar disorder.


Postnatal alterations in elastic fiber organization precede resistance artery narrowing in SHR.
Resistance artery narrowing and stiffening are key elements in the pathogenesis of essential hypertension, but their origin is not completely understood. In mesenteric resistance arteries (MRA) from spontaneously hypertensive rats (SHR), we have shown that inward remodeling is associated with abnormal elastic fiber organization, leading to smaller fenestrae in the internal elastic lamina. Our current aim is to determine whether this alteration is an early event that precedes vessel narrowing, or if elastic fiber reorganization in SHR arteries occurs because of the remodeling process itself. Using MRA from 10-day-old, 30-day-old, and 6-mo-old SHR and normotensive Wistar Kyoto rats, we investigated the time course of the development of structural and mechanical alterations (pressure myography), elastic fiber organization (confocal microscopy), and amount of elastin (radioimmunoassay for desmosine) and collagen (picrosirius red). SHR MRA had an impairment of fenestrae enlargement during the first month of life. In 30-day-old SHR, smaller fenestrae and more packed elastic fibers in the internal elastic lamina were paralleled by increased wall stiffness. Collagen and elastin levels were unaltered at this age. MRA from 6-mo-old SHR also had smaller fenestrae and a denser network of adventitial elastic fibers, accompanied by increased collagen content and vessel narrowing. At this age, elastase digestion was less effective in SHR MRA, suggesting a lower susceptibility of elastic fibers to enzymatic degradation. These data suggest that abnormal elastic fiber deposition in SHR increases resistance artery stiffness at an early age, which might participate in vessel narrowing later in life.


Does teaching style matter? A randomised trial of group discussion versus lectures in orthopaedic undergraduate teaching.
Educational theory suggests that lectures may not be the best way to impart knowledge to students. The aim of this study was to compare the use of didactic lectures with that of interactive discussion sessions in undergraduate teaching of orthopaedics and trauma. A total of 77 medical students were assessed in 3 consecutive cohorts. The students were randomised into 2 groups. The first group received a series of 12 formal lectures. The second group covered the same topics in 12 group-discussion sessions with self-directed learning. The students in the interactive discussion group rated the presentation of their teaching more highly than those in the lecture group (P = 0.003). However, there was no difference in their rating of the content of the sessions. The students in the discussion group also performed better on their end-of-placement written test (P = 0.025). We found that interactive teaching styles are more popular than didactic lectures in undergraduate orthopaedic and trauma teaching. We also found some evidence that knowledge retention is better following an interactive teaching style.


Action recognition using mined hierarchical compound features.
The field of Action Recognition has seen a large increase in activity in recent years. Much of the progress has been through incorporating ideas from single-frame object recognition and adapting them for temporal-based action recognition. Inspired by the success of interest points in the 2D spatial domain, their 3D (space-time) counterparts typically form the basic components used to describe actions, and in action recognition the features used are often engineered to fire sparsely. This is to ensure that the problem is tractable; however, this can sacrifice recognition accuracy as it cannot be assumed that the optimum features in terms of class discrimination are obtained from this approach. In contrast, we propose to initially use an overcomplete set of simple 2D corners in both space and time. These are grouped spatially and temporally using a hierarchical process, with an increasing search area. At each stage of the hierarchy, the most distinctive and descriptive features are learned efficiently through data mining. This allows large amounts of data to be searched for frequently reoccurring patterns of features. At each level of the hierarchy, the mined compound features become more complex, discriminative, and sparse. This results in fast, accurate recognition with real-time performance on high-resolution video. As the compound features are constructed and selected based upon their ability to discriminate, their speed and accuracy increase at each level of the hierarchy. The approach is tested on four state-of-the-art data sets, the popular KTH data set to provide a comparison with other state-of-the-art approaches, the Multi-KTH data set to illustrate performance at simultaneous multiaction classification, despite no explicit localization information provided during training. Finally, the recent Hollywood and Hollywood2 data sets provide challenging complex actions taken from commercial movie sequences. For all four data sets, the proposed hierarchical approach outperforms all other methods reported thus far in the literature and can achieve real-time operation.