The reliability, validity and factorial structure of the Swahili version of the 7-item generalized anxiety disorder scale (GAD-7) among adults living with HIV from Kilifi, Kenya.
Generalized Anxiety Disorder (GAD) is under-investigated in people living with HIV/AIDS from sub-Saharan Africa. In part, this is due to paucity of culturally appropriate measures for GAD which are psychometrically robust. This study aimed to evaluate the reliability, factorial structure, and validity of Swahili version of the 7-item GAD questionnaire (GAD-7) among adults living with HIV. Descriptive cross-sectional study. 450 adults receiving comprehensive care from an HIV specialized clinic in Kilifi County, coastal Kenya, were consecutively recruited. Swahili versions of GAD-7, Patient Health Questionnaire (PHQ-9) and a 12-item HIV stigma scale were administered alongside measures of psychosocial and health-related characteristics. Internal consistency, test-retest reliability, factorial structure, convergent validity, and discriminant validity of Swahili GAD-7 were examined using Cronbach's alpha (α), intra-class correlation coefficient (ICC), Confirmatory Factor Analysis (CFA), Pearson's correlation, and analysis of covariance (ANCOVA), respectively. Internal consistency of Swahili GAD-7 was good, α = 0.82 (95% CI 0.78, 0.85). Its test-retest reliability (2 weeks apart) was acceptable, ICC = 0.70 (95% CI 0.55, 0.81). A confirmatory analysis of a one-factor solution indicated an excellent fit to the hypothesized structure (RMSEA = 0.00 [95% confidence interval 0.00, 0.05], CFI = 1.00, TLI = 1.00). Multi-group CFA substantiated factorial invariance for sex and age for the one-factor structure of Swahili GAD-7. Scores of GAD-7, Swahili version, significantly correlated with those of PHQ-9 (r = 0.73; p < 0.001) and the HIV stigma scale (r = 0.36; p < 0.001) suggesting good convergent validity. Statistically significant differences were observed between participants on first-line antiretroviral therapy compared to those on second-line treatment (F [1, 441] = 5.55, p = 0.02) indicative of good discriminant validity of Swahili GAD-7. GAD-7 Swahili version retained its original unidimensional latent structure with good psychometric properties among adults living with HIV from Kilifi, Kenya. It can be used to identify symptoms of GAD in similar research settings. However, to confidently identify those in need of mental health treatment or referral services in HIV primary care clinics, more research on the validity of Swahili GAD-7 is needed especially its discriminant validity and diagnostic accuracy at different cut-off scores.


Interleukin-10 (IL-10) genotypes in inflammatory bowel disease.
Interleukin-10 (IL-10) is an anti-inflammatory cytokine. Its production in humans is under genetic control, and genotype defines high or low producers of this cytokine. This study addresses the hypothesis that idiopathic inflammatory bowel disease (IBD) patients are more likely to have the low IL-10 producer genotype and phenotype. DNA was extracted from blood cells of patients with Crohn's disease (CD) or with ulcerative colitis (UC) for IL-10 genotyping. The frequency of the high IL-10 producer allele (-1082*G) was decreased in the whole IBD group (41% vs. 51%, P = 0.03) and in the UC patients compared with normal controls (37% vs. 51%; P = 0.04). Hence, there appears to be an association between the IL-10 genotypes and IBD. This suggests that individuals genetically predisposed to produce less IL-10 are at a higher risk of developing IBD, in particular, UC.


Acute hospital administration of amiodarone and/or lidocaine in shockable patients presenting with out-of-hospital cardiac arrest: A nationwide cohort study.
Terminating ventricular fibrillation (VF) or pulseless ventricular tachyarrhythmia (VT) is critical for successful resuscitation of patients with shockable cardiac arrest. In the event of shock-refractory VF, applicable guidelines suggest use of anti-arrhythmic agents. However, subsequent long-term outcomes remain unclear. A nationwide cohort study was therefore launched, examining 1-year survival rates in patients given amiodarone and/or lidocaine for cardiac arrest. Medical records accruing between years 2004 and 2011 were retrieved from the Taiwan National Health Insurance Research Database (NHIRD) for review. This repository houses all insurance claims data for nearly the entire populace (>99%). Candidates for study included all non-traumatized adults receiving DC shock and cardiopulmonary resuscitation immediately or within 6h of emergency room arrival. Analysis was based on data from emergency rooms and hospitalization. One-year survival rates by treatment group were 8.27% (534/6459) for amiodarone, 7.15% (77/1077) for lidocaine, 11.10% (165/1487) for combined amiodarone/lidocaine use, and 3.26% (602/18,440) for use of neither amiodarone nor lidocaine (all, p<0.0001). Relative to those given neither medication, odds ratios for 1-year survival via multiple regression analysis were 1.84 (95% CI: 1.58-2.13; p<0.0001) for amiodarone, 1.88 (95% CI: 1.40-2.53; p<0.0001) for lidocaine, and 2.18 (95% CI: 1.71-2.77; p<0.0001) for dual agent use. In patients with shockable cardiac arrest, 1-year survival rates were improved with association of using amiodarone and/or lidocaine, as opposed to non-treatment. However, outcomes of patients given one or both medications did not differ significantly in intergroup comparisons.


Neural Index of Reinforcement Learning Predicts Improved Stimulus-Response Retention under High Working Memory Load.
Human learning and decision-making are supported by multiple systems operating in parallel. Recent studies isolating the contributions of reinforcement learning (RL) and working memory (WM) have revealed a trade-off between the two. An interactive WM/RL computational model predicts that although high WM load slows behavioral acquisition, it also induces larger prediction errors in the RL system that enhance robustness and retention of learned behaviors. Here, we tested this account by parametrically manipulating WM load during RL in conjunction with EEG in both male and female participants and administered two surprise memory tests. We further leveraged single-trial decoding of EEG signatures of RL and WM to determine whether their interaction predicted robust retention. Consistent with the model, behavioral learning was slower for associations acquired under higher load but showed parametrically improved future retention. This paradoxical result was mirrored by EEG indices of RL, which were strengthened under higher WM loads and predictive of more robust future behavioral retention of learned stimulus-response contingencies. We further tested whether stress alters the ability to shift between the two systems strategically to maximize immediate learning versus retention of information and found that induced stress had only a limited effect on this trade-off. The present results offer a deeper understanding of the cooperative interaction between WM and RL and show that relying on WM can benefit the rapid acquisition of choice behavior during learning but impairs retention.SIGNIFICANCE STATEMENT Successful learning is achieved by the joint contribution of the dopaminergic RL system and WM. The cooperative WM/RL model was productive in improving our understanding of the interplay between the two systems during learning, demonstrating that reliance on RL computations is modulated by WM load. However, the role of WM/RL systems in the retention of learned stimulus-response associations remained unestablished. Our results show that increased neural signatures of learning, indicative of greater RL computation, under high WM load also predicted better stimulus-response retention. This result supports a trade-off between the two systems, where degraded WM increases RL processing, which improves retention. Notably, we show that this cooperative interplay remains largely unaffected by acute stress.


Protein-protein interaction between Bacillus stearothermophilus tyrosyl-tRNA synthetase subdomains revealed by a bacterial two-hybrid system.
We have recently developed a bacterial two-hybrid system (BACTH), based on functional complementation between two fragments of the catalytic domain of Bordetella pertussis adenylate cyclase (AC), that allows an easy in vivo screening and selection of functional interactions between two proteins in Escherichia coli. In this work, we have further explored the potentialities of the BACTH system to study protein-protein interactions, using as a model, the interactions between various subdomains of the dimeric tyrosyl-tRNA synthetase (TyrRS) of Bacillus stearothermophilus. Using the BACTH system we confirmed the known interactions of the alpha/beta domains and those between the alpha/beta domain and the alpha domain that could be anticipated from the three-dimensional structure of TyrRS. Interestingly, the BACTH system revealed the unexpected interaction between the TyrRS alpha domains which is presumably mediated by a pseudo-leucine zipper motif. This study illustrates the interest of the bacterial two-hybrid system to delineate interacting domains of proteins and shows that it can reveal interactions that occur in vivo and that were not anticipated from the three-dimensional structure of the protein of interest.


Manufacturing and service supply chain resilience to the COVID-19 outbreak: Lessons learned from the automobile and airline industries.
There has been an increased interest among scholars to investigate supply chain resilience (SCRes) in manufacturing and service operations during emerging situations. Grounded in the SCRes theory, this study provides insights into the impact of the COVID-19 outbreak on the automobile and airline supply chain. Both the short and long-term response strategies adopted by the two supply chains are assessed, using a combination of qualitative and quantitative techniques in three distinct phases. In phase one, we use a sequential mixed-method for resilience evaluation, integrating Time-to-Recovery (TTR) and Financial Impact (FI) analysis. In phase two, we conduct an empirical survey involving 145 firms to evaluate the short-term SCRes response strategies. In the third phase, we conduct semi-structured interviews with supply chain executives both from the automobile and airline industries to understand the long-term SCRes response strategies. Our findings indicate that: (i) the automobile industry perceived that the best strategies to mitigate risks related to COVID-19, were to develop localized supply sources and use advanced industry 4.0 (I4.0) technologies. (ii) The airline industry on the other hand, perceived that the immediate need was to get ready for business continuity challenges posed by COVID-19, by defining their operations both at the airports and within the flights. (iii) Importantly, both the sectors perceived Big Data Analytics (BDA) to play a significant role by providing real-time information on various supply chain activities to overcome the challenges posed by COVID-19. (iv) Cooperation among supply chain stakeholders is perceived, as needed to overcome the challenges of the pandemic, and to accelerate the use of digital technologies.


Processing structure in language and music: a case for shared reliance on cognitive control.
The relationship between structural processing in music and language has received increasing interest in the past several years, spurred by the influential Shared Syntactic Integration Resource Hypothesis (SSIRH; Patel, Nature Neuroscience, 6, 674-681, 2003). According to this resource-sharing framework, music and language rely on separable syntactic representations but recruit shared cognitive resources to integrate these representations into evolving structures. The SSIRH is supported by findings of interactions between structural manipulations in music and language. However, other recent evidence suggests that such interactions also can arise with nonstructural manipulations, and some recent neuroimaging studies report largely nonoverlapping neural regions involved in processing musical and linguistic structure. These conflicting results raise the question of exactly what shared (and distinct) resources underlie musical and linguistic structural processing. This paper suggests that one shared resource is prefrontal cortical mechanisms of cognitive control, which are recruited to detect and resolve conflict that occurs when expectations are violated and interpretations must be revised. By this account, musical processing involves not just the incremental processing and integration of musical elements as they occur, but also the incremental generation of musical predictions and expectations, which must sometimes be overridden and revised in light of evolving musical input.


The Effects of Maternal Position and Habitus on Maternal Cardiovascular Parameters as Measured by Cardiac Magnetic Resonance.
To evaluate left ventricular stroke volume (LVSV) and cardiac output (CO) according to maternal position and habitus throughout pregnancy and postpartum using serial cardiac magnetic resonance imaging (c-MRI). This was a prospective study of normotensive nulliparous women using 1.5-T c-MRI performed in both left lateral decubitus and supine positions during three epochs in pregnancy and at 12 weeks' postpartum. Women were stratified according to prepregnancy body mass indices (BMIs) as normal or overweight/obese and compared for LVSV and CO using repeated measures, mixed-random, and fixed-effects model. Between October 2012 and December 2014, 14 normal-weight (BMI 22.2 ± 1.3) and 9 overweight/obese (BMI 29.1 ± 2.0) women underwent c-MRI. During early pregnancy, position did not alter LVSV or CO for either cohort. Beginning at 26 to 30 weeks and continuing to 32 to 36 weeks, normal-weight women demonstrated significant positional differences for LVSV and CO (both p < 0.01). In contrast, positional differences did not influence these parameters in overweight/obese women. At 12 weeks' postpartum, all influence of position had dissipated for both cohorts. Maternal position has no effect on LVSV or CO during the first half of pregnancy. In the second half, however, only normal-weight women exhibit significant changes in cardiac parameters when comparing the left lateral decubitus with supine position.


Occurrence of anti-Neospora caninum and anti-Toxoplasma gondii IgG antibodies in goats and sheep in western Maranhão, Brazil.
Neosporosis and toxoplasmosis are parasitic diseases which can cause reproductive problems in goats and sheep. The current study aimed to determine the occurrence of anti-Neospora caninum and anti-Toxoplasma gondii IgG antibodies in goats and sheep from the districts of Amarante do Maranhão and Buritirana, Imperatriz microregion, western area of Maranhão State, northeastern Brazil, and to assess factors associated to infection by these etiologic agents. Blood samples from 110 animals (46 goats and 64 sheep) from five herds were collected, and indirect immunofluorescence assay was used for serological testing. Of 46 goat samples, 17.39% (n = 8) showed anti-N. caninum antibodies and 4.35% (n = 2) anti-T. gondii, while of 64 sheep samples 4.69% (n = 3) and 18.75% (n = 12) showed anti-N. caninum and anti-T. gondii antibodies, respectively. No significant difference regarding the presence of domestic cats and/or dogs on the property and veterinary care was seen for both etiologic agents studied. However, food supplementation and animal reproductive failure were significantly (p < 0.05) for N. caninum among sheep and goats, respectively. The current study showed that goats and sheep in western Maranhão are exposed to N. caninum and T. gondii. It is the first evidence of these agents in small ruminants in this region.


1,25-dihydroxycholecalciferol: metabolite of vitamin D3 active on bone in anephric rats.
Nephrectomy prevents completely the bone calcium mobilization response to 25-hydroxycholecalciferol. In contrast it does not prevent this response to 1,25-dihydroxycholecalciferol. Because it is known that the kidney is the site of 1,25-dihydroxycholecalciferol formation, these results provide evidence that 1,25-dihydroxycholecalciferol or a further metabolite thereof and not 25-hydroxycholecalciferol is the metabolically active form of vitamin D(3) responsible for bone calcium mobilization.


Independent Co-Option of a Tailed Bacteriophage into a Killing Complex in Pseudomonas.
Competition between microbes is widespread in nature, especially among those that are closely related. To combat competitors, bacteria have evolved numerous protein-based systems (bacteriocins) that kill strains closely related to the producer. In characterizing the bacteriocin complement and killing spectra for the model strain Pseudomonas syringae B728a, we discovered that its activity was not linked to any predicted bacteriocin but is derived from a prophage. Instead of encoding an active prophage, this region encodes a bacteriophage-derived bacteriocin, termed an R-type syringacin. This R-type syringacin is striking in its convergence with the well-studied R-type pyocin of P. aeruginosa in both genomic location and molecular function. Genomic alignment, amino acid percent sequence identity, and phylogenetic inference all support a scenario where the R-type syringacin has been co-opted independently of the R-type pyocin. Moreover, the presence of this region is conserved among several other Pseudomonas species and thus is likely important for intermicrobial interactions throughout this important genus. Evolutionary innovation is often achieved through modification of complexes or processes for alternate purposes, termed co-option. Notable examples include the co-option of a structure functioning in locomotion (bacterial flagellum) to one functioning in protein secretion (type three secretion system). Similar co-options can occur independently in distinct lineages. We discovered a genomic region in the plant pathogen Pseudomonas syringae that consists of a fragment of a bacteriophage genome. The fragment encodes only the tail of the bacteriophage, which is lethal toward strains of this species. This structure is similar to a previously described structure produced by the related species Pseudomonas aeruginosa. The two structures, however, are not derived from the same evolutionary event. Thus, they represent independent bacteriophage co-options. The co-opted bacteriophage from P. syringae is found in the genomes of many other Pseudomonas species, suggesting ecological importance across this genus.


ISEcp1-mediated transposition of blaKPC into the chromosome of a clinical isolate of Acinetobacter baumannii from Puerto Rico.
Carbapenems are the last-resort antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative bacilli. Klebsiella pneumoniae carbapenemase (KPC) hydrolyses β-lactam antibiotics including the carbapenems. KPCs have been detected in Enterobacteriaceae and Pseudomonas aeruginosa isolates worldwide associated with transposon Tn4401 commonly located in plasmids. Acinetobacter baumannii has become an important multidrug-resistant nosocomial pathogen capable of hydrolysing the carbapenem antibiotics. KPC-producing A. baumannii has so far only been reported in Puerto Rico. During a surveillance study, four KPC-producing A. baumannii with identical pulse type were identified in a single institution. The objectives of this study were to characterize the KPC genetic background and the allelic diversity of one of the isolates. Next-generation sequencing and multilocus sequence typing (MLST) were performed. Molecular characterization of the isolate demonstrated blaKPC in Tn4401b located in the bacterial chromosome within a 26.5 kb DNA fragment, which included a KQ-like element (18.9 kb) very similar to that described previously in a K. pneumoniae plasmid and a 7.6 kb DNA fragment with 98 % homology to a putative plasmid from Yersinia pestis strain PY-95. Our data suggested that the 26.5 kb DNA fragment harbouring blaKPC was integrated in the chromosome by a transposition event mediated by the transposase of ISEcp1 found in the KQ-like element. MLST showed a novel sequence type, ST250. To our knowledge, this is the first report of the identification of the genetic background of blaKPC in A. baumannii.


Nondestructive, real-time determination and visualization of cellulose, hemicellulose and lignin by luminescent oligothiophenes.
Enabling technologies for efficient use of the bio-based feedstock are crucial to the replacement of oil-based products. We investigated the feasibility of luminescent conjugated oligothiophenes (LCOs) for non-destructive, rapid detection and quality assessment of lignocellulosic components in complex biomass matrices. A cationic pentameric oligothiophene denoted p-HTEA (pentamer hydrogen thiophene ethyl amine) showed unique binding affinities to cellulose, lignin, hemicelluloses, and cellulose nanofibrils in crystal, liquid and paper form. We exploited this finding using spectrofluorometric methods and fluorescence confocal laser scanning microscopy, for sensitive, simultaneous determination of the structural and compositional complexities of native lignocellulosic biomass. With exceptional photostability, p-HTEA is also demonstrated as a dynamic sensor for real-time monitoring of enzymatic cellulose degradation in cellulolysis. These results demonstrate the use of p-HTEA as a non-destructive tool for the determination of cellulose, hemicellulose and lignin in complex biomass matrices, thereby aiding in the optimization of biomass-converting technologies.


Pt promotion and spill-over processes during deposition and desorption of upd-H(ad) and OH(ad) on Pt(x)Ru(1-x)/Ru(0001) surface alloys.
The electrochemical adsorption of underpotential deposited hydrogen (upd-H(ad)) and OH(ad) on structurally well-defined Pt(x)Ru(1-x)/Ru(0001) surface alloys was investigated by cyclic voltammetry and density functional theory (DFT) calculations. The adsorption energies of both upd-H(ad) and OH(ad) decrease with increasing Pt content in the adsorption ensemble, shifting the onset of upd-H(ad) and OH(ad) formation to increasingly cathodic and anodic potentials, respectively. For bare Ru(0001) and for Ru(3) sites in the surface alloy, the stability regions of these two species overlap or almost overlap, respectively. Similar to previous findings for upd-H(ad) adsorption/desorption on partly Pt monolayer island covered Ru(0001) surfaces (J. Phys. Chem. B 2004, 108, 14780), we find a sharp peak at approximately 100 mV vs. RHE in each scan direction, which is attributed to a Pt catalyzed OH(ad)<--> upd-H(ad) replacement on Ru(3) sites, via adsorption on Pt rich sites and spill-over to Ru(3) sites. The decrease of the integrated charge in these peaks with the third power of the Ru surface concentration, which for a random distribution of surface atoms reflects the availability of Ru(3) sites, supports the above assignment.


Enhancement of Visual Comfort and Sense of Presence on Stereoscopic 3D Images.
Conventional stereoscopic 3D (S3D) displays do not provide accommodation depth cues of the 3D image or video contents being viewed. The sense of content depths is thus limited to cues supplied by motion parallax (for 3D video), stereoscopic vergence cues created by presenting left and right views to the respective eyes, and other contextual and perspective depth cues. The absence of accommodation cues can induce two kinds of accommodation vergence mismatches (AVM) at the fixation and peripheral points, which can result in severe visual discomfort. With the aim of alleviating discomfort arising from AVM, we propose a new visual comfort enhancement approach for processing S3D visual signals to deliver a more comfortable 3D viewing experience at the display. This is accomplished via an optimization process whereby a predictive indicator of visual discomfort is minimized, while still aiming to maintain the viewer's sense of 3D presence by performing a suitable parallax shift, and by directed blurring of the signal. Our processing framework is defined on 3D visual coordinates that reflect the nonuniform resolution of retinal sensors and that uses a measure of 3D saliency strength. An appropriate level of blur that corresponds to the degree of parallax shift is found, making it possible to produce synthetic accommodation cues implemented using a perceptively relevant filter. By this method, AVM, the primary contributor to the discomfort felt when viewing S3D images, is reduced. We show via a series of subjective experiments that the proposed approach improves visual comfort while preserving the sense of 3D presence.


Progression of Local Glaucomatous Damage Near Fixation as Seen with Adaptive Optics Imaging.
Deep glaucomatous defects near fixation were followed over time with an adaptive optics-scanning light ophthalmoscope (AO-SLO) to better understand the progression of these defects and to explore the use of AO-SLO in detecting them. Six eyes of 5 patients were imaged with an AO-SLO from 2 to 4 times for a range of 14.6 to 33.6 months. All eyes had open-angle glaucoma with deep defects in the superior visual field (VF) near fixation as defined by 10-2 VFs with 5 or more points less than -15 dB; two of the eyes had deep defects in the inferior VF as well. AO-SLO images were obtained around the temporal edge of the disc. In 4 of the 6 eyes, the edge of the inferior-temporal disc region of the retinal nerve fiber (RNF) defect seen on AO-SLO moved closer to fixation within 10.6 to 14.7 months. In 4 eyes, RNF bundles in the affected region appeared to lose contrast and/or disappear. Progressive changes in RNF bundles associated with deep defects on 10-2 VFs can be seen within about 1 year with AO-SLO imaging. These changes are well below the spatial resolution of the 10-2 VF. On the other hand, subtle thinning of regions with RNF bundles is not easy to see with current AO-SLO technology, and may be better followed with OCT. AO-SLO imaging may be useful in clinical trials designed to see very small changes in deep defects.


Endocannabinoid signaling in glioma.
High-grade gliomas constitute the most frequent and aggressive form of primary brain cancer in adults. These tumors express cannabinoid CB1 and CB2 receptors, as well as other elements of the endocannabinoid system. Accruing preclinical evidence supports that pharmacological activation of cannabinoid receptors located on glioma cells exerts overt anti-tumoral effects by modulating key intracellular signaling pathways. The mechanism of this cannabinoid receptor-evoked anti-tumoral activity in experimental models of glioma is intricate and may involve an inhibition not only of cancer cell survival/proliferation, but also of invasiveness, angiogenesis, and the stem cell-like properties of cancer cells, thereby affecting the complex tumor microenvironment. However, the precise biological role of the endocannabinoid system in the generation and progression of glioma seems very context-dependent and remains largely unknown. Increasing our basic knowledge on how (endo)cannabinoids act on glioma cells could help to optimize experimental cannabinoid-based anti-tumoral therapies, as well as the preliminary clinical testing that is currently underway.


Five-to-six membered ring-rearrangements in the reaction of 5-perfluoroalkyl-1,2,4-oxadiazoles with hydrazine and methylhydrazine.
The hydrazinolysis reaction of 5-perfluoroalkyl-1,2,4-oxadiazoles with hydrazine or methylhydrazine as bidentate nucleophiles has been investigated. The reaction occurred through the addition of the bidentate nucleophile to the C(5)-N(4) double bond of the 1,2,4-oxadiazole followed by ring-opening and ring-closure (ANRORC) involving the second nucleophilic site of the reagent. This ring-closure step could involve either the original C(3) of the 1,2,4-oxadiazole (giving a five-to-five membered ring rearrangement) or an additional electrophilic center linked to it (exploiting a five-to-six membered ring rearrangement). An alternative initial nucleophilic attack may involve the additional electrophilic center linked at C(3), that is the carbonyl group, leading to the formation of the hydrazones which undergo the Boulton-Katritzky rearrangement (BKR). The chosen reaction path is a function of the used nucleophile and of the nature of the substituent at C(3). At variance with previous hypotheses, when methylhydrazine was used, the observed regiochemistry always showed the preferred initial attack by the less hindered NH(2) end of the nucleophile on C(5). Moreover, new spectroscopic evidence allowed the assignment of correct structures to the products formed by reaction of 5-perfluoroalkyl-3-phenyl-1,2,4-oxadiazoles with methylhydrazine.


A novel gene expression profile in lymphatics associated with tumor growth and nodal metastasis.
Invasion of lymphatic vessels is a key step in the metastasis of primary tumors to draining lymph nodes. Although the process is enhanced by tumor lymphangiogenesis, it is unclear whether this is a consequence of increased lymphatic vessel number, altered lymphatic vessel properties, or both. Here we have addressed the question by comparing the RNA profiles of primary lymphatic endothelial cells (LEC) isolated from the vasculature of normal tissue and from highly metastatic T-241/vascular endothelial growth factor (VEGF)-C fibrosarcomas implanted in C57BL/6 mice. Our findings reveal significant differences in expression of some 792 genes (i.e., >or=2-fold up- or down-regulated, P <or= 0.05) that code for a variety of proteins including components of endothelial junctions, subendothelial matrix, and vessel growth/patterning. The tumor LEC profile, validated by immunohistochemical staining, is distinct from that of normal, inflammatory cytokine, or mitogen-activated LEC, characterized by elevated expression of such functionally significant molecules as the tight junction regulatory protein endothelial specific adhesion molecule (ESAM), the transforming growth factor-beta coreceptor Endoglin (CD105), the angiogenesis-associated leptin receptor, and the immunoinhibitory receptor CD200, and reduced expression of subendothelial matrix proteins including collagens, fibrillin, and biglycan. Moreover, we show similar induction of ESAM, Endoglin, and leptin receptor within tumor lymphatics in a series of human head and neck and colorectal carcinomas, and uncover a dramatic correlation between ESAM expression and nodal metastasis that identifies this marker as a possible prognostic indicator. These findings reveal a remarkable degree of phenotypic plasticity in cancer lymphatics and provide new insight into the processes of lymphatic invasion and lymph node metastasis.


Fine resolution mapping of population age-structures for health and development applications.
The age-group composition of populations varies considerably across the world, and obtaining accurate, spatially detailed estimates of numbers of children under 5 years is important in designing vaccination strategies, educational planning or maternal healthcare delivery. Traditionally, such estimates are derived from population censuses, but these can often be unreliable, outdated and of coarse resolution for resource-poor settings. Focusing on Nigeria, we use nationally representative household surveys and their cluster locations to predict the proportion of the under-five population in 1 × 1 km using a Bayesian hierarchical spatio-temporal model. Results showed that land cover, travel time to major settlements, night-time lights and vegetation index were good predictors and that accounting for fine-scale variation, rather than assuming a uniform proportion of under 5 year olds can result in significant differences in health metrics. The largest gaps in estimated bednet and vaccination coverage were in Kano, Katsina and Jigawa. Geolocated household surveys are a valuable resource for providing detailed, contemporary and regularly updated population age-structure data in the absence of recent census data. By combining these with covariate layers, age-structure maps of unprecedented detail can be produced to guide the targeting of interventions in resource-poor settings.


Miltefosine inhibits the membrane remodeling caused by phospholipase action by changing membrane physical properties.
Miltefosine (hexadecylphosphocholine or HePC) is an alkylphosphocholine approved for the treatment of visceral and cutaneous Leishmaniasis. HePC exerts its effect by interacting with lipid membranes and affecting membrane-dependent processes. The molecular geometry of HePC suggests that the pharmacological function of HePC is to alter membrane curvature. As a model system, we studied the enzyme production in model membranes of diacylglycerol (DAG) or ceramide (CER), lipids involved in cell signaling which alter the structure of membranes. Here, we studied the effect of HePC on changes in phospholipase activity and on the effect that the lipid products have on the curvature and fusogenicity of membranes where they accumulate. Our results indicate that HePC inhibits the long-time restructuring of membranes, characteristic of the DAG and CER enzyme formation processes. In addition, the drug also reduces the fusogenicity of phospholipase-derived products. We postulate that the effect of HePC is due to a non-specific geometric compensation of HePC to the inverted cone-shape of DAG and CER products, acting as a relaxation agent of membrane curvature stress. These data are important for understanding the mechanism of action by which HePC regulates the lipid metabolism and signal transduction pathways in which these enzymes are involved.


Retention in the endoplasmic reticulum is the underlying mechanism of some hereditary haemorrhagic telangiectasia type 2 ALK1 missense mutations.
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterised by vascular dysplasia and increased bleeding that affect 1 in 5,000 people world-wide. Pathology is linked to mutations in genes encoding components of the heteromeric transforming growth factor-beta receptor (TGF-beta) and SMAD signalling pathway. Indeed HHT1 and HHT2 result from mutations in the genes encoding endoglin and activin-like kinase 1 (ALK1), TGF-beta receptor components. However, the fundamental cellular defects underlying HHT is poorly understood. Previously using confocal microscopy and N-glycosylation analysis, we found evidence that defective trafficking of endoglin from the endoplasmic reticulum (ER) to the plasma membrane is a mechanism underlying HHT1 in some patients. In this study, we used confocal microscopy to investigate whether a similar mechanism contributes to HHT2 pathology. To do this we expressed wild-type ALK1 and a number of HHT2 patient mutant variants as C-terminally tagged EGFP fusion proteins and tested their localisation in HeLa cells. We found that wild-type ALK1-EGFP was targeted predominantly to the plasma membrane, as evidenced by its colocalisation with the co-expressed HA-tagged endoglin. However, we found that in the majority of cases analysed the HHT2 patient mutant protein was retained within the ER as indicated by their colocalisation with the ER resident marker (calnexin) and lack of colocalisation with cell surface associated HA-endoglin. We conclude that defective trafficking and retention in the ER of mutant ALK1 protein is a possible mechanism of HHT2 in some patients.


AGA Technical Review on the Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D).
The evaluation of patients with chronic watery diarrhea represents a diagnostic challenge for clinicians because organic causes, including inflammatory bowel disease, microscopic colitis, and chronic infection, must be differentiated from functional diarrhea and diarrhea-predominant irritable bowel syndrome. The purpose of this review is to summarize the available evidence on the usefulness of diagnostic tests in such patients. We searched MEDLINE and EMBASE via OVID, from 1978 until April 2017. We included diagnostic test accuracy studies reporting on the use of fecal and blood tests for the evaluation of adult patients with functional diarrhea, including irritable bowel syndrome. We assessed the risk of bias of included studies using a modified version of the Quality Assessment of Diagnostic Accuracy Studies II, and the certainty in the evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. We calculated pooled sensitivity and specificity, and the proportion of patients with true and false positive and negative results. We evaluated the following tests: erythrocyte sedimentation rate, C-reactive protein, fecal lactoferrin, fecal calprotectin, serologic tests for celiac disease, tests for bile acid diarrhea, the commercially available version of anti-cytolethal distending toxin B and anti-vinculin antibodies, and tests for Giardia infection. We did not evaluate breath tests for small intestinal bacterial overgrowth, as they are not part of a standard diarrhea workup. Thirty-eight studies proved eligible to evaluate 1 or more of these tests. Erythrocyte sedimentation rate and C-reactive protein were similar at discriminating organic from functional disease, with sensitivity and specificity, respectively, of 0.54-0.78 and 0.46-0.95 for erythrocyte sedimentation rate and 0.73 and 0.78 for C-reactive protein. Among fecal tests, fecal calprotectin in a range of 50-60 μg/g (pooled sensitivity 0.81; 95% confidence interval [CI], 0.75-0.86; pooled specificity 0.87; 95% CI, 0.78-0.92) and fecal lactoferrin in a range of 4.0-7.25 μg/g (pooled sensitivity 0.79; 95% CI, 0.73-0.84; pooled specificity 0.93; 95%CI 0.63-0.99) presented the lowest proportion of false-negative results (low certainty in the evidence). Among tests for celiac disease, IgA tissue transglutaminase presented the best diagnostic test accuracy (sensitivity range, 0.79-0.99; specificity range, 0.90-0.99) with moderate certainty in the evidence. Among tests for bile acid diarrhea, the 75selenium homotaurocholic acid test performed better than serum fibroblast growth factor 19 and 7α-hydroxy-4-cholesten-3-one, but is not available in the United States. There was insufficient evidence to recommend serologic tests for irritable bowel syndrome at this time. There are several good diagnostic tests for Giardia infection. Moderate to low certainty in the evidence indicates that available fecal and blood tests may play a role in the diagnostic workup of adult patients with functional diarrhea. At the moment, no tests are available to reliably rule in irritable bowel syndrome.


Polymorphism of oligomers of a peptide from β-amyloid.
This contribution reports solution-phase structural studies of oligomers of a family of peptides derived from the β-amyloid peptide (Aβ). We had previously reported the X-ray crystallographic structures of the oligomers and oligomer assemblies formed in the solid state by a macrocyclic β-sheet peptide containing the Aβ(15-23) nonapeptide. In the current study, we set out to determine its assembly in aqueous solution. In the solid state, macrocyclic β-sheet peptide 1 assembles to form hydrogen-bonded dimers that further assemble in a sandwich-like fashion to form tetramers through hydrophobic interactions between the faces bearing V18 and F20. In aqueous solution, macrocyclic β-sheet peptide 1 and homologue 2a form hydrogen-bonded dimers that assemble to form tetramers through hydrophobic interactions between the faces bearing L17, F19, and A21. In the solid state, the hydrogen-bonded dimers are antiparallel, and the β-strands are fully aligned, with residues 17-23 of one of the macrocycles aligned with residues 23-17 of the other. In solution, residues 17-23 of the hydrogen-bonded dimers are shifted out of alignment by two residues toward the C-termini. The two hydrogen-bonded dimers are nearly orthogonal in the solid state, while in solution the dimers are only slightly rotated. The differing morphology of the solution-state and solid-state tetramers is significant, because it may provide a glimpse into some of the structural bases for polymorphism among Aβ oligomers in Alzheimer's disease.


Arabidopsis NIP3;1 Plays an Important Role in Arsenic Uptake and Root-to-Shoot Translocation under Arsenite Stress Conditions.
In Arabidopsis, the nodulin 26-like intrinsic protein (NIP) subfamily of aquaporin proteins consists of nine members, five of which (NIP1;1, NIP1;2, NIP5;1, NIP6;1, and NIP7;1) were previously identified to be permeable to arsenite. However, the roles of NIPs in the root-to-shoot translocation of arsenite in plants remain poorly understood. In this study, using reverse genetic strategies, Arabidopsis NIP3;1 was identified to play an important role in both the arsenic uptake and root-to-shoot distribution under arsenite stress conditions. The nip3;1 loss-of-function mutants displayed obvious improvements in arsenite tolerance for aboveground growth and accumulated less arsenic in shoots than those of the wild-type plants, whereas the nip3;1 nip1;1 double mutant showed strong arsenite tolerance and improved growth of both roots and shoots under arsenite stress conditions. A promoter-β-glucuronidase analysis revealed that NIP3;1 was expressed almost exclusively in roots (with the exception of the root tips), and heterologous expression in the yeast Saccharomyces cerevisiae demonstrated that NIP3;1 was able to mediate arsenite transport. Taken together, our results suggest that NIP3;1 is involved in arsenite uptake and root-to-shoot translocation in Arabidopsis, probably as a passive and bidirectional arsenite transporter.


Structural insights into serine-rich fimbriae from Gram-positive bacteria.
The serine-rich repeat family of fimbriae play important roles in the pathogenesis of streptococci and staphylococci. Despite recent attention, their finer structural details and precise adhesion mechanisms have yet to be determined. Fap1 (Fimbriae-associated protein 1) is the major structural subunit of serine-rich repeat fimbriae from Streptococcus parasanguinis and plays an essential role in fimbrial biogenesis, adhesion, and the early stages of dental plaque formation. Combining multidisciplinary, high resolution structural studies with biological assays, we provide new structural insight into adhesion by Fap1. We propose a model in which the serine-rich repeats of Fap1 subunits form an extended structure that projects the N-terminal globular domains away from the bacterial surface for adhesion to the salivary pellicle. We also uncover a novel pH-dependent conformational change that modulates adhesion and likely plays a role in survival in acidic environments.


New thiophene-based C60 fullerene derivatives as efficient electron transporting materials for perovskite solar cells.
The synthesis of new C60 fullerene derivatives functionalized with thiophene moieties as well as with electron donating or electron withdrawing groups, bromine (Br) or cyano (CN), respectively, using Bingel reactions is reported. The synthesized derivatives were used as the electron transporting materials (ETMs) in inverted perovskite solar cells (PSCs). Compared to devices fabricated with [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM), the new derivatives showed similar electrochemical properties and electron mobilities. However, PSCs based on the new derivatives synthesized in this work exhibited higher power conversion efficiencies (PCEs) than PC61BM based devices, which were ascribed to their better passivation ability, likely due to specific interactions between the fullerene addend and the perovskite layer surface. Devices based on the fullerene bearing the CN group exhibited an additionally improved efficiency due to the increased dielectric constant (ε r) of this derivative. These results show that the new functionalized fullerene derivatives can act as efficient ETMs in inverted PSCs.


Improving residents' clinical approach to obesity: impact of a multidisciplinary didactic curriculum.
Obesity has been declared a 21st century pandemic by WHO. Yet surveys reveal physicians-in-training are uncomfortable managing obesity. One major barrier is the lack of residency education on obesity management. This study incorporates an obesity-specific didactic curriculum into an internal medicine (IM) residency programme and assesses its impact on residents' knowledge, attitudes, practice behaviours, and clinical outcomes in patients with obesity. The intervention consisted of four, 1 h, obesity-specific lectures in the University of Florida Resident Noon Conference. Lectures were taught by multidisciplinary experts and offered to 75 IM residents every 2 weeks from 5 November 2010 to 17 December 2010. Impact on IM residents' knowledge and attitudes was assessed by a pre- and post-intervention Obesity Awareness Questionnaire (OAQ). IM residents' clinical performance was assessed by chart reviews of 238 patients with body mass index >25 kg/m(2) in residents' clinics 4 months pre- and 6 months post-intervention for three clinical outcomes and seven practice behaviours on obesity management. Pre- and post-intervention outcomes were compared via paired t tests (quantitative data) or McNemar's test (binary data). Mean lecture attendance was 25/75 residents (33%) per lecture. Survey response was 67/75 residents (89%) pre-OAQ and 63/75 residents (84%) post-OAQ. While most attitudes remained unchanged, IM residents gained significant confidence in exercise counselling, safety of bariatric surgery, and patients' weight loss potential; they were more likely to address obesity in the plan and referrals to bariatric surgery. Clinical outcomes and IM residents' knowledge demonstrated no improvement. Our brief lecture-based curriculum has the potential to improve IM residents' attitudes and practice behaviours towards obesity. The lack of improvement in clinical outcomes and resident knowledge prompts the need for multimodal, longitudinal curricula with experiential application of obesity medicine.


Socio-economic inequalities in exposure to industrial air pollution emissions in Quebec public schools.
We aimed to assess the relationships between deprivation at Quebec public schools, their proximity to polluting industries, and their exposure to industrial air emission sources including ambient fine particulate matter (PM2.5), sulphur dioxide (SO2) and nitrogen dioxide (NO2). We obtained four indicators of school deprivation using data from the 2006 Canadian census called the low-income threshold indicator, the neighbourhood SES indicator, and the social and material deprivation indicators of Pampalon. Using proximity spatial tools, we constructed three buffers of 2.5, 5 and 7.5 km around each school and summed up total emissions of PM2.5, SO2 and NO2 for each school. Industrial air emissions were estimated using data from the 2006 Canadian National Pollutant Release Inventory. The Pearson correlations and LOESS regressions and natural log-transformed industrial air emissions were evaluated for Quebec public schools within the three buffers. Of the 2189 public schools in Quebec, 608 (27.8%), 1108 (50.6%) and 1384 (63.2%) schools were located near at least one industry emitting one or more pollutants of interest in buffers of 2.5 km, 5 km and 7.5 km of schools respectively. Weak positive Pearson correlations (r) were found between log-transformed tons of industrial emissions of PM2.5, SO2 and NO2 and both the social deprivation (r = {0.23; 0.33}) and low-income threshold (r = {0.17; 0.29}) indicators in a buffer of 2.5 km. However, we found negative associations between emissions and the neighbourhood SES (r = {0.06; 0.16}) and material deprivation (r = {-0.04; 0.08}) indicators. Our study suggests that schools in Quebec with higher rates of socio-economic deprivation among their students may be more likely to be exposed to higher emissions of industrial air pollutants.


Characterizing preferred motif choices and distance impacts.
People's daily travels are structured and can be expressed as networks. Few studies explore how people organize their daily travels and which behavioral principles result in the choices of specific network types. In this study, we first reconstruct location networks and activity networks for numerous individuals from high-resolution mobile phone positioning data and define frequent networks as motifs. The results suggest that 99.9% of people's travels can be characterized by a limited set of location-based motifs and activity-based motifs. The results further reveal that the least effort principle governs the preferred motif choices through quantifying the rank-frequency properties. The scaling properties of distance characteristically impact motifs, and their scaling differences by node numbers and motif types coincide with the popularities of motifs, verifying the self-adaptions in motif choices; that is, although individuals travel with unique propensities, they always tend to choose the motif with the lowest consumption that satisfies their demand.


Menstrual function among women exposed to polybrominated biphenyls: a follow-up prevalence study.
Alteration in menstrual cycle function is suggested among rhesus monkeys and humans exposed to polybrominated biphenyls (PBBs) and structurally similar polychlorinated biphenyls (PCBs). The feedback system for menstrual cycle function potentially allows multiple pathways for disruption directly through the hypothalamic-pituitary-ovarian axis and indirectly through alternative neuroendocrine axes. The Michigan Female Health Study was conducted during 1997-1998 among women in a cohort exposed to PBBs in 1973. This study included 337 women with self-reported menstrual cycles of 20-35 days (age range: 24-56 years). Current PBB levels were estimated by exponential decay modeling of serum PBB levels collected from 1976-1987 during enrollment in the Michigan PBB cohort. Linear regression models for menstrual cycle length and the logarithm of bleed length used estimated current PBB exposure or enrollment PBB exposure categorized in tertiles, and for the upper decile. All models were adjusted for serum PCB levels, age, body mass index, history of at least 10% weight loss in the past year, physical activity, smoking, education, and household income. Higher levels of physical activity were associated with shorter bleed length, and increasing age was associated with shorter cycle length. Although no overall association was found between PBB exposure and menstrual cycle characteristics, a significant interaction between PBB exposures with past year weight loss was found. Longer bleed length and shorter cycle length were associated with higher PBB exposure among women with past year weight loss. This study suggests that PBB exposure may impact ovarian function as indicated by menstrual cycle length and bleed length. However, these associations were found among the small number of women with recent weight loss suggesting either a chance finding or that mobilization of PBBs from lipid stores may be important. These results should be replicated with larger numbers of women exposed to similar lipophilic compounds.


CD40/CD40L interaction induces Abeta production and increases gamma-secretase activity independently of tumor necrosis factor receptor associated factor (TRAF) signaling.
CD40, a member of tumor necrosis factor receptor superfamily, and its cognate ligand CD40L are both elevated in the brain of Alzheimer's disease (AD) patients compared to controls. We have shown that pharmacological or genetic interruption of CD40/CD40L interaction results in mitigation of AD-like pathology in vivo in transgenic AD mouse models, and in vitro. Recently, we showed that CD40L stimulation could increase Abeta levels via NFkappaB signaling, presumably through TRAFs. In the present work, using CD40 mutants, we show that CD40L can increase levels of Abeta(1-40), Abeta(1-42), sAPPbeta, sAPPalpha and CTFbeta independently of TRAF signaling. We report an increase in mature/immature APP ratio after CD40L treatment of CD40wt and CD40-mutant cells, reflecting alterations in APP trafficking. In addition, results from CD40L treatment of a neuroblastoma cell line over-expressing the C-99 APP fragment suggest that CD40L has an effect on gamma-secretase. Furthermore, inhibition of gamma-secretase activity significantly reduces sAPPbeta levels in the CD40L treated HEK/APPsw CD40wt and the CD40-mutant cells. The latter suggests CD40/CD40L interaction primarily acts on gamma-secretase and affects beta-secretase via a positive feedback mechanism. Taken together, our data suggest that CD40/CD40L interaction modulates APP processing independently of TRAF signaling.


A natural CCL5/RANTES variant antagonist for CCR1 and CCR3.
The N-terminal domain of the chemokine CCL5/regulated upon activation normal T cell expressed and secreted (RANTES) has been shown to be critical for its biological activity on leukocytes. Several N-terminus-modified CCL5/RANTES derivatives, such as N-Terminal truncated CCL5/RANTES, Met-RANTES, and amino-oxypentane (AOP)-RANTES exhibited antagonist or partial agonist functions when investigated on the properties of their receptors CCR1, CCR3, and CCR5. Studying 95 African samples from Cameroon, we found a naturally occurring variant of CCL5/RANTES containing a missense mutation located in the first amino acid of the secreted form (S24F). S24F binds CCR1, CCR3, and CCR5 and triggers receptor down-modulation comparable to CCL5/RANTES. Moreover, in CCR5 positive cells, S24F elicits cellular calcium mobilization equivalent to that obtained with CCL5/RANTES. By contrast, S24F does not provoke any response in CCR1 and CCR3 positive cells. As CCL5/RANTES is able to attract different subtypes of leukocytes into inflamed tissue and intervenes in a wide range of allergic and autoimmune diseases, the discovery of this natural N-terminus-modified CCL5/RANTES analogue exhibiting differential effects on CCL5/RANTES receptors, opens up additional perspectives for therapeutic intervention.


Response of desert biological soil crusts to alterations in precipitation frequency.
Biological soil crusts, a community of cyanobacteria, lichens, and mosses that live on the soil surface, occur in deserts throughout the world. They are a critical component of desert ecosystems, as they are important contributors to soil fertility and stability. Future climate scenarios predict alteration of the timing and amount of precipitation in desert environments. Because biological soil crust organisms are only metabolically active when wet, and as soil surfaces dry quickly in deserts during late spring, summer, and early fall, the amount and timing of precipitation is likely to have significant impacts on the physiological functioning of these communities. Using the three dominant soil crust types found in the western United States, we applied three levels of precipitation frequency (50% below-average, average, and 50% above-average) while maintaining average precipitation amount (therefore changing both timing and size of applied events). We measured the impact of these treatments on photosynthetic performance (as indicated by dark-adapted quantum yield and chlorophyll a concentrations), nitrogenase activity, and the ability of these organisms to maintain concentrations of radiation-protective pigments (scytonemin, beta-carotene, echinenone, xanthophylls, and canthaxanthin). Increased precipitation frequency produced little response after 2.5 months exposure during spring (1 April-15 June) or summer (15 June-31 August). In contrast, most of the above variables had a large, negative response after exposure to increased precipitation frequency for 6 months spring-fall (1 April-31 October) treatment. The crusts dominated by the soil lichen Collema, being dark and protruding above the surface, dried the most rapidly, followed by the dark surface cyanobacterial crusts (Nostoc- Scytonema- Microcoleus), and then by the light cyanobacterial crusts (Microcoleus). This order reflected the magnitude of the observed response: crusts dominated by the lichen Collema showed the largest decline in quantum yield, chlorophyll a, and protective pigments; crusts dominated by Nostoc-Scytonema-Microcoleus showed an intermediate decline in these variables; and the crusts dominated by Microcoleus showed the least negative response. Most previous studies of crust response to radiation stress have been short-term laboratory studies, where organisms were watered and kept under moderate temperatures. Such conditions would give crust organisms access to ample carbon to respond to imposed stresses (e.g., production of UV-protective pigments, replacement of degraded chlorophyll). In contrast, our longer-term study showed that under field conditions of high air temperatures and frequent, small precipitation events, crust organisms appear unable to produce protective pigments in response to radiation stress, as they likely dried more quickly than when they received larger, less frequent events. Reduced activity time likely resulted in less carbon available to produce or repair chlorophyll a and/or protective pigments. Our findings may partially explain the global observation that soil lichen cover and richness declines as the frequency of summer rainfall increases.


Akt phosphorylates and suppresses the transactivation of retinoic acid receptor alpha.
The transactivation of nuclear receptors is regulated by both ligand binding and phosphorylation. We previously showed that RARalpha (retinoic acid receptor alpha) phosphorylation by c-Jun N-terminal kinase contributes to retinoid resistance in a subset of NSCLC cells (non-small cell lung cancer cells), but the aetiology of this resistance in the remainder has not been fully elucidated [Srinivas, Juroske, Kalyankrishna, Cody, Price, Xu, Narayanan, Weigel and Kurie (2005) Mol. Cell. Biol. 25, 1054-1069]. In the present study, we report that Akt, which is constitutively activated in NSCLC cells, phosphorylates RARalpha and inhibits its transactivation. Biochemical and functional analyses showed that Akt interacts with RARalpha and phosphorylates the Ser96 residue of its DNA-binding domain. Mutation of Ser96 to alanine abrogated the suppressive effect of Akt. Overexpression of a dominant-negative form of Akt in an NSCLC cell line decreased RAR phosphorylation, increased RAR transactivation and enhanced the growth-inhibitory effects of an RAR ligand. The findings presented here show that Akt inhibits RAR transactivation and contributes to retinoid resistance in a subset of NSCLC cells.


Sensitivity and uncertainty analysis for the annual phosphorus loss estimator model.
Models are often used to predict phosphorus (P) loss from agricultural fields. Although it is commonly recognized that model predictions are inherently uncertain, few studies have addressed prediction uncertainties using P loss models. In this study we assessed the effect of model input error on predictions of annual P loss by the Annual P Loss Estimator (APLE) model. Our objectives were (i) to conduct a sensitivity analyses for all APLE input variables to determine which variables the model is most sensitive to, (ii) to determine whether the relatively easy-to-implement first-order approximation (FOA) method provides accurate estimates of model prediction uncertainties by comparing results with the more accurate Monte Carlo simulation (MCS) method, and (iii) to evaluate the performance of the APLE model against measured P loss data when uncertainties in model predictions and measured data are included. Our results showed that for low to moderate uncertainties in APLE input variables, the FOA method yields reasonable estimates of model prediction uncertainties, although for cases where manure solid content is between 14 and 17%, the FOA method may not be as accurate as the MCS method due to a discontinuity in the manure P loss component of APLE at a manure solid content of 15%. The estimated uncertainties in APLE predictions based on assumed errors in the input variables ranged from ±2 to 64% of the predicted value. Results from this study highlight the importance of including reasonable estimates of model uncertainty when using models to predict P loss.


Lipid content and fatty acid composition of Porosira glacialis and Attheya longicornis in response to carbon dioxide (CO2) aeration.
In the current study two novel psychrophilic diatoms Porosira glacialis and Attheya longicornis were tested for suitability to CO2 mitigation coupled with production of the physiologically requisite omega- 3 fatty acids. This study is in line with the worldwide conducted research aimed at applying biorefinery concept to heavy polluting industries. Since the production of algal high value compounds, i.e. essential fatty acids, relies on utilization of residual CO2 emissions coming from industry, the costs of such production maybe substantially reduced. Besides, the ecological benefits of the biorefinery concept being implemented are obvious, since CO2 is one of the major greenhouse gases. The current research has shown that one of the tested microalgal species, the diatom P. glacialis showed good tolerance to high (20-25%) levels of CO2 and maintained growth rates comparable to controls. The total lipid content in the CO2 aerated culture increased from 8.91 to 10.57% in cell dry mass. Additionally, the content of docosahexaenoic acid (DHA) increased from 3.90 to 5.75%, while the concentration of eicosapentaenoic acid (EPA) decreased from 26.59 to 23.66%. In contrast, A. longicornis did not demonstrate any significant increase in total lipid content. Besides, its growth was hampered by high levels of CO2 aeration.


Entropy production of a Brownian ellipsoid in the overdamped limit.
We analyze the translational and rotational motion of an ellipsoidal Brownian particle from the viewpoint of stochastic thermodynamics. The particle's Brownian motion is driven by external forces and torques and takes place in an heterogeneous thermal environment where friction coefficients and (local) temperature depend on space and time. Our analysis of the particle's stochastic thermodynamics is based on the entropy production associated with single particle trajectories. It is motivated by the recent discovery that the overdamped limit of vanishing inertia effects (as compared to viscous fricion) produces a so-called "anomalous" contribution to the entropy production, which has no counterpart in the overdamped approximation, when inertia effects are simply discarded. Here we show that rotational Brownian motion in the overdamped limit generates an additional contribution to the "anomalous" entropy. We calculate its specific form by performing a systematic singular perturbation analysis for the generating function of the entropy production. As a side result, we also obtain the (well-known) equations of motion in the overdamped limit. We furthermore investigate the effects of particle shape and give explicit expressions of the "anomalous entropy" for prolate and oblate spheroids and for near-spherical Brownian particles.


Cetuximab retargeting of adenovirus via the epidermal growth factor receptor for treatment of intraperitoneal ovarian cancer.
Gene and virotherapy of ovarian cancer, using type 5 adenovirus (Ad5), has demonstrated good activity in preclinical animal studies, particularly after intraperitoneal administration of virus; however, success in clinical trials has been limited by poor infectivity of ovarian cancer cells and inflammatory responses to Ad5. We previously demonstrated that covalent modification of Ad5 with reactive copolymers on the basis of poly(hydroxypropylmethacrylamide) can shield the virus, offering protection from neutralizing antibodies and enabling retargeting to cancer-upregulated receptors with peptide ligands (basic fibroblast growth factor [bFGF] and murine epidermal growth factor [EGF]). These ligands may be less than ideal for clinical use, however, because they are potential mitogens. Accordingly, in this study we investigated the use of an anti-EGF receptor (EGFR) antibody, cetuximab, to retarget adenoviral transduction of EGFR-positives in vitro and in vivo. Cetuximab retargeting altered the physicochemical characteristics of Ad5, although it did not cause particle aggregation. Although cetuximab stimulated internalization of EGFR, similarly to EGF, it inhibited EGFR phosphorylation. Adenoviral transduction was inhibited after polymer coating, but was rescued in EGFR-positive cells (and not in EGFR-negative cells) by cetuximab retargeting. Cetuximab retargeting of wild-type adenovirus serotype 5 (Ad5WT) prolonged survival in an animal model of human ovarian cancer, similar to unmodified Ad5WT, but polymer coating ameliorated stimulation of adhesion formation. We conclude that polymer coating and covalent attachment of cetuximab successfully retargeted adenovirus to EGFR-positive cells, retained in vivo efficacy of an oncolytic adenovirus, and ameliorated side effects caused by unmodified adenovirus.


Method for Bacterial Growth and Ammonia Production and Effect of Inhibitory Substances in Disposable Absorbent Hygiene Products.
The purpose of this study was to evaluate a pragmatic laboratory method to provide a technique for developing incontinence products better able to reduce malodor when used in the clinical setting. Bacterial growth and bacterially formed ammonia in disposable absorbent incontinence products was measured by adding synthetic urine inoculated with bacteria to test samples cut from the crotch area of the product. The inhibitory effect's of low pH (4.5 and 4.9) and 3 antimicrobial substances-chlorhexidine, polyhexamethylene biguanide (PHMB), and thymol-at 2 concentrations each, were studied. From the initial inocula of 3.3 log colony-forming units per milliliter (cfu/mL) at baseline, the bacterial growth of the references increased to 5.0 to 6.0 log cfu/mL at 6 hours for Escherichia coli, Proteus mirabilis, and Enterococcus faecalis. At 12 hours there was a further increase to 7.0 to 8.9 log cfu/mL. Adjusting the pH of the superabsorbent in the incontinence product from 6.0 to pH 4.5 and pH 4.9 significantly (P < .05) inhibited the bacterial growth rates, in most cases, both at 6 and 12 hours. The effect was most pronounced at pH 4.5. Chlorhexidine had significant (P < .05) inhibitory effect on E. coli and E. faecalis, and at 12 hours also on P. mirabilis. For PHMB and thymol the results varied. At 6 hours, the ammonia concentration in the references (pH 6.0) was 200 to 300 ppm and it was 1500 to 1600 ppm at 8 hours. At pH 4.5, no or little ammonia production was measured at 6 and 8 hours. At pH 4.9, there was a significant reduction (P < .01). Chlorhexidine and PHMB exerted a significant (P < .01 or P < .001) inhibitory effect on ammonia production at both concentrations and at 6 and 8 hours. Thymol 0.003% and 0.03% showed inhibitory effect at both 6 hours (P < .01 or P < .001) and at 8 hours (P < .05 or P < .001). The method described in this study can be used to compare the ability of various disposable absorbent products to inhibit bacterial growth and ammonia production. This technique, we describe, provides a pragmatic method for assessing the odor-inhibiting capacity of specific incontinence products.


Stability of toxin gene proportion in red-pigmented populations of the cyanobacterium Planktothrix during 29 years of re-oligotrophication of Lake Zürich.
Harmful algal blooms deteriorate the services of aquatic ecosystems. They are often formed by cyanobacteria composed of genotypes able to produce a certain toxin, for example, the hepatotoxin microcystin (MC), but also of nontoxic genotypes that either carry mutations in the genes encoding toxin synthesis or that lost those genes during evolution. In general, cyanobacterial blooms are favored by eutrophication. Very little is known about the stability of the toxic/nontoxic genotype composition during trophic change. Archived samples of preserved phytoplankton on filters from aquatic ecosystems that underwent changes in the trophic state provide a so far unrealized possibility to analyze the response of toxic/nontoxic genotype composition to the environment. During a period of 29 years of re-oligotrophication of the deep, physically stratified Lake Zürich (1980 to 2008), the population of the stratifying cyanobacterium Planktothrix was at a minimum during the most eutrophic years (1980 to 1984), but increased and dominated the phytoplankton during the past two decades. Quantitative polymerase chain reaction revealed that during the whole observation period the proportion of the toxic genotype was strikingly stable, that is, close to 100%. Inactive MC genotypes carrying mutations within the MC synthesis genes never became abundant. Unexpectedly, a nontoxic genotype, which lost its MC genes during evolution, and which could be shown to be dominant under eutrophic conditions in shallow polymictic lakes, also co-occurred in Lake Zürich but was never abundant. As it is most likely that this nontoxic genotype contains relatively weak gas vesicles unable to withstand the high water pressure in deep lakes, it is concluded that regular deep mixing selectively reduced its abundance through the destruction of gas vesicles. The stability in toxic genotype dominance gives evidence for the adaptation to deep mixing of a genotype that retained the MC gene cluster during evolution. Such a long-term dominance of a toxic genotype draws attention to the need to integrate phylogenetics into ecological research as well as ecosystem management.


[Treatment with sulbactam/cefoperazone of severe infections in patients with hematological disorders].
Infectious episodes in 90 patients with hematological disorders were treated with sulbactam/cefoperazone (SBT/CPZ), a new combination drug of a potent beta-lactamase inhibitor, sodium sulbactam, and a third generation cephalosporin, sodium cefoperazone. Clinical responses to the SBT/CPZ regimen were excellent in 23 cases, good in 30 cases, fair in 11 cases, and poor in 26 cases. The overall efficacy rate (percentage of cases showing excellent or good responses) was 58.9%. Efficacy rates classified according to different infections were: 80% in documented sepsis, 57.6% in suspected sepsis, 61.1% in pneumonia and 50% in other infections. One episode of side effect was encountered with redness and itching of skin. Hepatic disorders were observed in 3 cases. These adverse reactions, however, were not serious. These results indicate that SBT/CPZ has a high therapeutic efficacy to severe infections in patients with hematological disorders.


Significance of CT in head injury: correlation with intracranial pressure.
The authors correlated the computed tomographic (CT) findings and intracranial pressure (ICP) in 150 consecutive comatose head injury patients to determine if noninvasive CT can help identify the patients not requiring ICP monitoring. The study reveals that a majority of patients (55%) with hemorrhagic lesions shown by CT suffer from intracranial hypertension and require ICP monitoring for proper management. Of the patients with normal initial CT, 98% had normal ICP during the first 24 hr. Of the patients with normal CT, 15% developed intracranial hypertension later, irrespective of the initial Glasgow coma scale score or age. More than half of the patients who developed intracranial hypertension subsequently had normal ICP through the first 48 hr. The study indicates that ICP monitoring need not routinely be performed on admission on severe head injury patients with a normal CT. However, repeat CT at 24--48 hr before ICP monitoring in patients with initially normal CT may be valuable, particularly if their clinical status deteriorates.


A practical guide to the selection of independent components of the electroencephalogram for artifact correction.
Electroencephalographic data are easily contaminated by signals of non-neural origin. Independent component analysis (ICA) can help correct EEG data for such artifacts. Artifact independent components (ICs) can be identified by experts via visual inspection. But artifact features are sometimes ambiguous or difficult to notice, and even experts may disagree about how to categorise a particular component. It is therefore important to inform users on artifact properties, and give them the opportunity to intervene. Here we first describe artifacts captured by ICA. We review current methods to automatically select artifactual components for rejection, and introduce the SASICA software, implementing several novel selection algorithms as well as two previously described automated methods (ADJUST, Mognon et al. Psychophysiology 2011;48(2):229; and FASTER, Nolan et al. J Neurosci Methods 2010;48(1):152). We evaluate these algorithms by comparing selections suggested by SASICA and other methods to manual rejections by experts. The results show that these methods can inform observers to improve rejections. However, no automated method can accurately isolate artifacts without supervision. The comprehensive and interactive plots produced by SASICA therefore constitute a helpful guide for human users for making final decisions. Rejecting ICs before EEG data analysis unavoidably requires some level of supervision. SASICA offers observers detailed information to guide selection of artifact ICs. Because it uses quantitative parameters and thresholds, it improves objectivity and reproducibility in reporting pre-processing procedures. SASICA is also a didactic tool that allows users to quickly understand what signal features captured by ICs make them likely to reflect artifacts.


Whole slide images for primary diagnostics of paediatric pathology specimens: a feasibility study.
Whole slide images (WSI) have been used in many pathology applications such as teleconsultation, teaching and research, but not in primary diagnostics. The aim of this study was to test the feasibility of using WSI in primary diagnostics of paediatric pathology specimens and placental tissue. Eighty consecutive tissues biopsies and resections from patients under 18 years old were selected, as well as 20 placentas. These cases had been diagnosed in the year 2009 by a single pathologist. The same pathologist who had performed the original diagnosis based on light microscopy was asked to rediagnose these 100 cases on WSI scanned at 20× magnification as well as by light microscopy having the original clinical information available, but blinded to the original light microscopic diagnoses. The original diagnoses were compared with WSI based diagnoses and rediagnoses by light microscopy and classified as concordant, mildly discordant (without clinical consequences) and discordant (with clinical consequences). The original diagnoses were concordant with WSI and light microscopic diagnoses in 90% and 93% of cases respectively, which was not significantly different. Digital reassessment yielded eight mild discrepancies and two discrepant cases (2%) where the difference in diagnoses could have clinical implications for the patient. Light microscopic reassessment showed seven mild discrepancies. It turned out to be difficult to identify nucleated red blood cells on WSI, even when scanned at 40×. Primary diagnostics of paediatric tissue biopsies and resections can generally well be done on WSI. However, some difficulties were encountered in examining placenta tissue where the identification of nucleated red blood cells may need higher resolution or even scanning at multiple focus depths, which is well possible on most current slide scanners.


Characterization of the native C-reactive protein (cCRP) and the corresponding liver mRNA in dogs.
C-reactive protein (CRP) plays an important role in the acute phase reaction in humans and dogs. For the canine CRP (cCRP) only an in silico deduced preliminary transcript and amino acid sequence is available. The objective of this study was to further characterize the native cCRP protein and its corresponding liver mRNA. Furthermore, immunological similarities of serum CRP in related animal species were investigated. Native cCRP protein was isolated from dog-sera by affinity chromatography and further analyzed by immunodetection, protein sequencing (mass spectrometry and N-terminal Edman sequencing), 2D-gel electrophoresis, and glycoprotein analysis. Furthermore, cCRP cDNA sequence was determined from dog liver total RNA by RT-PCR. Gel electrophoresis, immunodetection and glycoprotein detection revealed two cCRP isotypes with different molecular weights (22 and 25kDa) with the upper band being glycosylated. Selective glycoprotein analysis showed sialic acid terminally linked (2-6) to galactose or N-acetylgalactosamine and subsequent PNGase F treatment identified N-terminal linkage. Mass spectrometry confirmed approximately 45% of the cCRP predicted amino acid sequence and N-terminal amino acid sequencing revealed a shorter native cCRP than expected (204 amino acids). The new canine CRP mRNA sequence confirms 100% of the formerly deduced sequence. Immunological homologies to the canine CRP protein were found in selected dog-related species. This study contributes major molecular details to the knowledge about canine CRP. Such structural information may assist in developing new diagnostic tools for inflammatory-based diseases in dogs as well as other dog-related species.


ATP synthase F1 subunits recruited to centromeres by CENP-A are required for male meiosis.
The histone H3 variant CENP-A epigenetically defines the centromere and is critical for chromosome segregation. Here we report an interaction between CENP-A and subunits of the mitochondrial ATP synthase complex in the germline of male Drosophila. Furthermore, we report that knockdown of CENP-A, as well as subunits ATPsyn-α, -βlike (a testis-specific paralogue of ATPsyn-β) and -γ disrupts sister centromere cohesion in meiotic prophase I. We find that this disruption is likely independent of reduced ATP levels. We identify that ATPsyn-α and -βlike localise to meiotic centromeres and that this localisation is dependent on the presence of CENP-A. We show that ATPsyn-α directly interacts with the N-terminus of CENP-A in vitro and that truncation of its N terminus perturbs sister centromere cohesion in prophase I. We propose that the CENP-A N-terminus recruits ATPsyn-α and -βlike to centromeres to promote sister centromere cohesion in a nuclear function that is independent of oxidative phosphorylation.


Evaluation of protocol uniformity concerning laparoscopic cholecystectomy in the Netherlands.
Iatrogenic bile duct injury remains a current complication of laparoscopic cholecystectomy. One uniform and standardized protocol, based on the "critical view of safety" concept of Strasberg, should reduce the incidence of this complication. Furthermore, owing to the rapid development of minimally invasive surgery, technicians are becoming more frequently involved. To improve communication between the operating team and technicians, standardized actions should also be defined. The aim of this study was to compare existing protocols for laparoscopic cholecystectomy from various Dutch hospitals. Fifteen Dutch hospitals were contacted for evaluation of their protocols for laparoscopic cholecystectomy. All evaluated protocols were divided into six steps and were compared accordingly. In total, 13 hospitals responded--5 academic hospitals, 5 teaching hospitals, 3 community hospitals--of which 10 protocols were usable for comparison. Concerning the trocar positions, only minor differences were found. The concept of "critical view of safety" was represented in just one protocol. Furthermore, the order of clipping and cutting the cystic artery and duct differed. Descriptions of instruments and apparatus were also inconsistent. Present protocols differ too much to define a universal procedure among surgeons in The Netherlands. The authors propose one (inter)national standardized protocol, including standardized actions. This uniform standardized protocol has to be officially released and recommended by national scientific associations (e.g., the Dutch Society of Surgery) or international societies (e.g., European Association for Endoscopic Surgery and Society of American Gastrointestinal and Endoscopic Surgeons). The aim is to improve patient safety and professional communication, which are necessary for new developments.


A comparison of an anterior jaw lift manoeuvre with the Berman airway for assisting fibreoptic orotracheal intubation.
This study compared the efficacy of an anterior jaw lift manoeuvre with that of the Berman airway in clearing the upper airway during oral fibreoptic tracheal intubation in anaesthetised, paralysed patients. Fifty patients were randomly assigned to undergo fibreoptic-assisted intubation with one method, followed by crossover to the alternative method. The time taken to view the vocal cords was the primary endpoint, and we also noted the rate of failure to view the cords, i.e. cords not seen after 120 s of endoscopy. Anterior jaw lift yielded significantly shorter times to view the vocal cords (median [interquartile range; range]: 22 [17-46; 7-120] s vs 40 [29-67; 21-120] s, p = 0.001) and a higher success rate (49/50 vs 42/50, p = 0.014). We conclude that the anterior jaw lift is more effective than the Berman device for achieving airway clearance in this setting.


Polyadic Entropy, Synergy and Redundancy among Statistically Independent Processes in Nonlinear Statistical Physics with Microphysical Codependence.
The information shared among observables representing processes of interest is traditionally evaluated in terms of macroscale measures characterizing aggregate properties of the underlying processes and their interactions. Traditional information measures are grounded on the assumption that the observable represents a memoryless process without any interaction among microstates. Generalized entropy measures have been formulated in non-extensive statistical mechanics aiming to take microphysical codependence into account in entropy quantification. By taking them into consideration when formulating information measures, the question is raised on whether and if so how much information permeates across scales to impact on the macroscale information measures. The present study investigates and quantifies the emergence of macroscale information from microscale codependence among microphysics. In order to isolate the information emergence coming solely from the nonlinearly interacting microphysics, redundancy and synergy are evaluated among macroscale variables that are statistically independent from each other but not necessarily so within their own microphysics. Synergistic and redundant information are found when microphysical interactions take place, even if the statistical distributions are factorable. These findings stress the added value of nonlinear statistical physics to information theory in coevolutionary systems.


The vitamin D pathway: a new target for control of the skin's immune response?
The surface of our skin is constantly challenged by a wide variety of microbial pathogens, still cutaneous infections are relatively rare. Within cutaneous innate immunity the production of antimicrobial peptides (AMPs) is a primary system for protection against infection. Many AMPs can be found on the skin, and these include molecules that were discovered for their antimicrobial properties, and other peptides and proteins first known for activity as chemokines, enzymes, enzyme inhibitors and neuropeptides. Cathelicidins were among the first families of AMPs discovered on the skin. They are now known to have two distinct functions; they have direct antimicrobial activity and will initiate a host cellular response resulting in cytokine release, inflammation and angiogenesis. Dysfunction of cathelicidin is relevant in the pathogenesis of several cutaneous diseases including atopic dermatitis where cathelicidin induction is suppressed, rosacea, where cathelicidin peptides are abnormally processed to forms that induce cutaneous inflammation and a vascular response, and psoriasis, where a cathelicidin peptide can convert self-DNA to a potent stimulus of an autoinflammatory cascade. Recent work has unexpectedly identified vitamin D3 as a major factor involved in the regulation of cathelicidin expression. Therapies targeting the vitamin D3 pathway and thereby cathelicidin may provide new treatment modalities in the management of infectious and inflammatory skin diseases.


Low-Power Hardware Implementation of a Support Vector Machine Training and Classification for Neural Seizure Detection.
In this paper, a low power support vector machine (SVM) training, feature extraction, and classification algorithm are hardware implemented in a neural seizure detection application. The training algorithm used is the sequential minimal optimization (SMO) algorithm. The system is implemented on different platforms: such as field programmable gate array (FPGA), Xilinx Virtex-7 and application specific integrated circuit (ASIC) using hardware-calibrated UMC 65 nm CMOS technology. The implemented training hardware is introduced as an accelerator intellectual property (IP), especially in the case of large number of training sets, such as neural seizure detection. Feature extraction and classification blocks are implemented to achieve the best trade-off between sensitivity and power consumption. The proposed seizure detection system achieves a sensitivity around 96.77% when tested with the implemented linear kernel classifier. A power consumption evaluation is performed on both the ASIC and FPGA platforms showing that the ASIC power consumption is improved by a factor of 2X when compared with the FPGA counterpart.


Changes in Murine Subbasal Corneal Nerves After Scopolamine-Induced Dry Eye Stress Exposure.
To evaluate the morphologic changes in the corneal subbasal nerve (CSN) plexus in wild-type (WT) mice after exposure to scopolamine-induced dry eye stress (DES) by using in vivo confocal microscopy. Twenty right eyes of twenty (n = 20) 8-week-old WT BALB/c male mice were investigated. The mice were divided into two experimental groups; 10 eyes of 10 mice exposed to DES for 28 days and 10 eyes of 10 mice were used as a control group. All mice underwent examinations for aqueous tear secretion quantity, tear film breakup time (TBUT), corneal vital staining. and corneal sensitivity thrice (pre-experiment, 2nd week, and 4th week). CSN density, tortuosity, reflectivity, and dendritic cell (DC) densities were examined. The mean aqueous tear secretion (P < 0.0001) and TBUTs (P < 0.0001) were significantly decreased after DES. The mean corneal vital staining scores were significantly higher (fluorescein, P < 0.0001; lissamine, P < 0.0001), the mean TBUTs were significantly shorter (P < 0.0001), and the corneal sensitivities (P < 0.0001) were significantly lower in the dry eye-induced mice than the control mice. The mean CSN fiber density (P < 0.0001) and the reflectivity (P < 0.001) were significantly lower; the mean tortuosity and the mean DC density were significantly higher (P < 0.0001) in the dry eye mice. Our data demonstrated that prolonged exposure to DES resulted in alterations of CSN density; DC intensity, reflectivity, and tortuosity as well as in tear volume; TBUT; fluorescein and lissamine green staining scores; and the corneal sensitivity in WT mice.


Calcium signalling: mitofusins promote interorganellar crosstalk.
Juxtaposition of the endoplasmic reticulum with mitochondria facilitates Ca(2+) fluxes between the organelles. However, the molecular basis of interorganellar tethering remains unknown. A recent report has identified a fundamental role for the dynamin-related mitofusins in the tethering mechanism, thereby ensuring rapid and high fidelity Ca(2+) signalling between the organelles.


Use of the painDETECT tool in rheumatoid arthritis suggests neuropathic and sensitization components in pain reporting.
Rheumatoid arthritis (RA) is an inflammatory autoimmune condition typified by systemic inflammation targeted toward synovial joints. Inhibition of proinflammatory networks by disease-modifying antirheumatic drugs, eg, methotrexate and biologic therapies, including tumor necrosis factor-α inhibitors, often leads to suppression of disease activity observed at the clinical level. However, despite the era of widespread use of disease-modifying treatments, there remain significant groups of patients who continue to experience pain. Our study formulated a pain assessment tool in the arthritis clinic to assess feasibility of measurements including the visual analog scale (VAS) and painDETECT to assess multimodal features of pain in people with established RA (n=100). Clinical measures of disease activity (Disease Activity Score in 28 Joints [DAS28]) were also recorded. Our data showed that despite the majority of subjects on at least one disease-modifying agent, the majority of patients reported severe pain (54%) by VAS, despite well-controlled clinical disease, with mean DAS28 2.07±0.9. Using the painDETECT questionnaire, 67% of patients had unlikely neuropathic pain. A significant proportion of subjects (28%) had possible neuropathic pain and 5% had features of likely neuropathic pain by painDETECT scoring. We found a positive correlation between VAS and painDETECT (R (2)=0.757). Of note, the group who had likely or probable neuropathic pain also showed significantly increased pain reporting by VAS (P<0.01). Subjects who were clinically obese (body mass index >30) also had statistically higher proportions of pain reporting (VAS 89.0±0.7 mm) compared with subjects who had a normal body mass index (VAS 45.2±21.8 mm), P<0.05. Our findings suggest that multimodal features of pain perception exist in RA, including neuropathic and sensitization elements, perhaps explaining why a subgroup of people with RA continue to experience ongoing pain, despite their apparent suppression of inflammation.


Influence of glaucomatous visual field loss on health-related quality of life.
We examined the influence of glaucomatous visual field defects on vision-targeted and generic health-related quality of life. Vision-targeted and generic health status were assessed across 5 glaucoma treatment categories and a normal reference group from 5 tertiary care ophthalmology practices during regularly scheduled eye care visits. The sample consisted of 147 patients who were members of specific glaucoma treatment categories and 44 reference group patients. For patients with glaucoma, eligibility included a diagnosis of glaucoma at least 1 year prior to enrollment and no evidence of other eye disease. Participants completed 2 vision-targeted surveys, the National Eye Institute Visual Functioning Questionnaire and the VF-14, and a generic health-related quality of life measure, the Medical Outcomes Study 36-Item Short Form. Data from automated perimetry (Humphrey Field Analyzer 24-2, Humphrey Instruments, San Leandro, Calif) were used to generate Advanced Glaucoma Intervention Study scores for all participants. The Medical Outcomes Study 36-Item Short Form scores from glaucoma and reference group participants collected on a random half of the sample were similar. However, comparisons of the vision-targeted surveys demonstrated significant mean differences on 7 of 11 National Eye Institute Visual Functioning Questionnaire scales, and a trend toward significant differences for the VF-14 (P < .07 by linear regression). Greater visual field defects in the better eye were significantly associated with poorer National Eye Institute Visual Functioning Questionnaire scores (P < .05), as well as with worse VF-14 scores. These findings were most dramatic for patients with the most severe field loss in the better eye. Vision-targeted questionnaires were more sensitive than a generic health-related quality of life measure to differences between glaucoma and normal reference participants. Our findings indicate that self-reports of vision-targeted health-related quality of life are sensitive to visual field loss and may be useful in tandem with the clinical examination to fully understand outcomes of treatment for glaucoma.


Bovine tuberculosis in cattle: reduced risk on wildlife-friendly farms.
The associations between habitat and other factors that lead to the risk of bovine tuberculosis (bTB) in diary cattle were examined in an unmatched case-control study. Data from 60 herds with recent history of bTB and 60 controls were analysed using logistic regression. The predictors included farmland habitat, topography, indices of badger density and herd size. Information-theoretic approaches were used to identify those predictor variables explaining the greatest variation in cattle herd bTB breakdowns. Reduced risk of bTB was associated with the management of farmland in ways favourable to wildlife conservation, as encouraged by recent (2005) European Common Agricultural Policy reforms.


Periodic alternating nystagmus.
A typical case of periodic alternating nystagmus is described. Periodic alternating nystagmus is a form of horizontal or horizontal-rotary jerk nystagmus of which the most characteristic feature is an alternation in direction at regular intervals. The condition appears to be not as rare as has been believed previously and may indicate a lesion in the upper part of the medulla.


Cost-effectiveness of using CYP2C19 genotype to guide selection of clopidogrel or ticagrelor in Australia.
This study aims to assess the cost-effectiveness in Australia of screening CYP2C19 loss-of-function (LoF) alleles to guide selection of clopidogrel or ticagrelor for individuals with acute coronary syndrome who are likely to undergo coronary stenting. Three treatment strategies were compared: universal clopidogrel therapy, universal ticagrelor therapy and genotyping CYP2C19 with use of ticagrelor for individuals with a LoF allele and clopidogrel for individuals without a LoF allele. Lifetime costs and quality-adjusted life years for each treatment strategy were estimated using a Markov model. The risks of events were primarily derived from the genetic substudy of the pivotal randomized controlled trial. CYP2C19 genotyping resulted in greater effectiveness and was cost-effective when compared with universal use of clopidogrel. However, universal use of ticagrelor was the most effective strategy overall and the incremental cost-effectiveness compared with the genotyping strategy was generally within what is considered acceptable. Ticagrelor is likely to be cost-effective even for individuals not carrying a CYP2C19 LoF allele.


Pancreatic cancer surgery in elderly patients: Balancing between short-term harm and long-term benefit. A population-based study in the Netherlands.
At a national level, it is unknown to what degree elderly patients with pancreatic or periampullary carcinoma benefit from surgical treatment compared to their younger counterparts. We investigated resection rates and outcomes after surgical treatment among elderly patients. From the Netherlands Cancer Registry, 20 005 patients diagnosed with primary pancreatic or periampullary cancer in 2005-2013 were selected. The associations between age (<70, 70-74, 75-79, ≥80 years) and resection rates were investigated using χ(2) tests, and surgical outcomes (30-, 90-day mortality) were evaluated using logistic regression analysis. Overall survival after resection was investigated by means of Kaplan-Meier and Cox proportional hazard regression analysis. During the study period, resection rates increased in all age groups (<70 years: 20-30%, p < 0.001; ≥80 years: 2-8%, p < 0.001). Of 3845 patients who underwent tumour resection for pancreatic or periampullary carcinoma, the proportion of octogenarians increased from 3.5% to 5.5% (p = 0.03), whereas postoperative mortality did not increase (30-day: 6-3%, p = 0.06; 90-day: 9-8%, p = 0.21). With rising age, 30-day postoperative mortality increased (4-5-7-8%, respectively, p < 0.001), while 90-day mortality was 6-10-13-12% (p < 0.001) and three-year overall survival rates after surgery were 35-33-28-31%, respectively (p < 0.001). After adjustment for confounding factors, octogenarians who survived 90 days postoperative exhibited an overall survival close to younger patients [hazard ratio (≥80 vs. <70 years) = 1.21, 95% confidence interval (0.99-1.47), p = 0.07]. Despite higher short-term mortality, octogenarians who underwent pancreatic resection showed long-term survival similar to younger patients. With careful patient screening and counselling of elderly patients, a further increase of resection rates may be combined with improved outcomes.


Distribution, differentiation, and survival of intravenously administered neural stem cells in a rat model of amyotrophic lateral sclerosis.
The transplantation of neural stem cells (NSCs) is a challenging therapeutic strategy for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). To provide insight into the potential of the intravenous delivery of NSCs, we evaluated the delivery of NSCs marked with green fluorescent protein to the central nervous system (CNS) via intravenous tail vein injections in an ALS model. The injected cell fates were followed 1, 3, and 7 days after transplantation. The highest efficiency of cell delivery to the CNS was found in symptomatic ALS (up to 13%), moderate in presymptomatic ALS (up to 6%), and the lowest in wild-type animals (up to 0.3%). NSCs injected into ALS animals preferentially colonized the motor cortex, hippocampus, and spinal cord, and their differentiation was characterized by a decrease of nestin expression and the appearance of MAP2-, GFAP-, O4-, and CD68-positive cells. Tumor necrosis factor (TNF) administration increased the CNS delivery of transplanted cells in wild-type and presymptomatic, but not ALS symptomatic animals. Moreover, a TNF-related increase in NSC differentiation and survival was detected. Apoptosis was detected as the main cause of the loss of transplanted cells and it was influenced by TNF. Although 3 days after TNF treatment cell death was accelerated, TNF slowed down apoptosis after 7 days. This study provides elementary facts about the process occurring after NSCs leave the blood stream and enter the nervous tissue affected by inflammation/degeneration, which should help facilitate the planning of future bench-to-bedside translational projects.