Transposon Tn10-like tetracycline resistance determinants in Haemophilus parainfluenzae.
Tetracycline resistance (Tcr) determinants from three different strains of Haemophilus parainfluenzae expressed 10-fold higher levels of resistance when mated into Escherichia coli. No plasmid was found in any of the E. coli recipients, even in matings in which a plasmid was identified in the donor Haemophilus sp. The Tcr determinant from Haemophilus sp. caused instability of resident plasmids in the recipient E. coli: all plasmids were lost within 30 generations in antibiotic-free media. However, by serial subculture in antibiotics, stable resident plasmids were obtained which carried the Tcr determinant from Haemophilus sp. and were transferable by conjugation and transformation among E. coli strains. All Haemophilus determinants hybridized with a probe for the Tcr determinant on Tn10, which bears inducible Tcr. However, Haemophilus determinants were constitutively resistant to tetracycline in the Haemophilus donors and in the E. coli recipients. This constitutive expression was recessive to wild-type Tn10 in the same cell, indicating that the constitutive phenotype resulted from the absence of an active repressor. Restrictive enzyme analysis of various E. coli plasmid derivatives bearing a Tcr determinant from Haemophilus sp. demonstrated that the inserted DNA was of similar size (8.95 to 9.35 kilobases), close to that of Tn10. Heteroduplex analysis and DNA:DNA hybridization confirmed that the Tcr determinant from Haemophilus sp. had greater than 90% homology with the Tn10 determinant, including the DNA sequence for the repressor.


Development of a specimen-sparing multichannel bead assay to detect antiparasite IgG4 for the diagnosis of Schistosoma and Wuchereria infections on the coast of Kenya.
To better delineate the impact of parasitic coinfection in coastal Kenya, we developed a novel specimen-sparing bead assay using multiplex flow immunoassay (MFI) technology to simultaneously measure serum or plasma immunoglobulin G4 (IgG4) against Brugia malayi antigen (BMA) and Schistosoma haematobium soluble worm antigen (SWAP). Properties of the bead assay were estimated by latent class analysis using data from S. haematobium egg counts/filarial rapid diagnostic cards (RDTs), parasite-specific enzyme-linked immunosorbent assays (ELISAs), and the multichannel IgG4 assay. For schistosomiasis, the bead assay had an estimated sensitivity of 81% and a specificity of 45%, and it was more sensitive than ELISA or urine egg counts for diagnosing infection. For filariasis, it had a sensitivity of 86% and a specificity of 39%, and it was more sensitive than ELISA or RDT. Measuring antibody by MFI is feasible and may provide more accurate epidemiological information than current parasitological tests, especially in the setting of low-intensity infections.


Doppler Tissue Evaluation of Atrial Conduction Properties in Patients With Non-alcoholic Fatty-liver Disease.
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in clinical practice, and there is an increasing trend in its prevalence in the general population. Recent studies have demonstrated increased risk of atrial fibrillation (AF) in NAFLD. However, information on the mechanism of increased risk of AF in NAFLD is lacking. Impaired atrial conduction is an important factor in the pathophysiology of AF. We aimed to investigate atrial conduction properties in patients with NAFLD by tissue Doppler echocardiography. Fifty-nine ultrasound diagnosed NAFLD patients without clinical diagnosis of hypertension, diabetes mellitus, or cardiac disease and 22 normal subjects as controls were included in this study. Atrial conduction properties were assessed by electromechanical delay (EMD) derived from Doppler tissue echocardiography examination and P-wave dispersion (PWD) calculated from the 12-lead electrocardiogram. Inter-atrial and intra-atrial EMD intervals were significantly longer in NAFLD patients than in controls (inter-atrial EMD, 31.9 ± 8.5 ms vs. 23.4 ± 4.6 ms,p= 0.0001, and intra-atrial EMD, 14.3 ± 5.2 vs. 10.2 ± 4.0 ms,p= 0.001). Similarly, PWD was significantly higher in NAFLD patients compared with controls (49.2 ± 6.3 ms vs. 43.3 ± 4.2 ms,p= 0.0001). Maximum left atrial volume was also significantly higher in the NAFLD group than in controls (51 ± 11 mL vs. 34 ± 9 mL,p< 0.0001). This study demonstrated that atrial conduction is impaired in patients with NAFLD. Also, in a patient population of NAFLD without any clinical diagnosis of cardiac disease, diabetes, or hypertension, left atrial volume was increased compared with controls. These findings suggest impaired atrial conduction as a factor in increased risk of AF in NAFLD.


Solving problems in social-ecological systems: definition, practice and barriers of transdisciplinary research.
Translating policies about sustainable development as a social process and sustainability outcomes into the real world of social-ecological systems involves several challenges. Hence, research policies advocate improved innovative problem-solving capacity. One approach is transdisciplinary research that integrates research disciplines, as well as researchers and practitioners. Drawing upon 14 experiences of problem-solving, we used group modeling to map perceived barriers and bridges for researchers' and practitioners' joint knowledge production and learning towards transdisciplinary research. The analysis indicated that the transdisciplinary research process is influenced by (1) the amount of traditional disciplinary formal and informal control, (2) adaptation of project applications to fill the transdisciplinary research agenda, (3) stakeholder participation, and (4) functional team building/development based on self-reflection and experienced leadership. Focusing on implementation of green infrastructure policy as a common denominator for the delivery of ecosystem services and human well-being, we discuss how to diagnose social-ecological systems, and use knowledge production and collaborative learning as treatments.


Hemodynamic mechanisms underlying cerebral aneurysm pathogenesis.
Intracranial aneurysms and associated subarachnoid hemorrhage (SAH) are predominant cerebrovascular disorders that present a significant public health risk through high rates of morbidity and mortality. Unruptured aneurysms that become large enough compress cerebral tissue and manifest various neurological signs. But the largest danger presented by these cerebrovascular lesions is from the increased likelihood that the vessel will rupture, causing a SAH, a condition that creates higher risk of cerebral ischemia through reduced cerebral blood flow and vasospasm. The specific pathophysiological mechanisms that cause these lesions are not fully understood. The current literature focuses on understanding the effects of and links between hemodynamic forces, vascular remodeling and inflammation, and genetics in aneurysm formation, development, and rupture. The present study represents a survey of the complete hemodynamic pathogenesis of aneurysmal SAH detailing the many factors and their connections that contribute to the pathophysiology of this disorder.


People with dementia attending farm-based day care in Norway - Individual and farm characteristics associated with participants' quality of life.
Farm-based day care for people with dementia is supposed to improve the participants quality of life by using activities and resources of the farm environment to promote mental and physical health. In this paper, we describe the characteristics of those attending farm-based day care services in Norway and explore the association between individual and farm characteristics and the quality of life. A sample of 94 people with dementia who attended farm-based day care was recruited from 25 farms between January 2017 and January 2018. The data collection was performed using standardized instruments. Information about the farms was retrieved from a former study. The association between the participants' quality of life and their individual and/or farm characteristics was examined with a linear multilevel regression model. The participants had a mean age of 76 years, 62% were men, and 68% had additional education after primary school. Most of them had mild (54.3%) or questionable dementia (18.3%). A few participants used antipsychotics (3.7%), tranquilizers (9.9%) and painkillers (13.6%), while a higher number used antidepressants (30.9%). Quality of life was associated with the experience of having social support (p = .023), a low score on depressive symptoms (p < .001), and spending time outdoors at the farm (p < .001). The variation between the farm-based day care services in the participants' reported quality of life was related to time spent outdoors at the farm. In light of the present study, it seems as farm-based day care is addressing people with dementia in an early stage, dominated by men, with quite good physical and medical condition. The strong association between quality of life and spending time outdoors underscores that facilitation for outdoor activity should be prioritized in all types of dementia care.


Principal motives for toothbrushing in a population of South African adolescents: implications for oral health promotion.
Little is known of the motives for tooth-brushing among adolescents in resource-poor settings. To investigate the principal motive for tooth-brushing among a rural population of South African adolescents. The participants were high school students between the ages of 12 and 19 years who provided baseline data during 2005 as part of a tobacco use prevention trial (n = 2119). Information was obtained using a self-administered survey questionnaire, including demographic data, data on the employment status of the parents, oral health practices and risk behaviors. The main outcome measure was the principal reason for brushing. Data was analyzed using chi-square statistics and multiple logistic regression analysis. Of the study participants, only 27.2% had ever visited a dentist. For 28.9%, both parents are unemployed. The principal motive for brushing among most adolescents (84.9%), including those who reported frequent sugar intake, was related to cosmetic rather than preventive dental health reasons. Motives for brushing were not associated with brushing frequency. However, the socially disadvantaged, current smokers, and those who reported a past suicide attempt were significantly less likely to brush for cosmetic reasons. Motives for tooth-brushing among adolescents may reflect their psychosocial state rather than knowledge of the preventive effect of brushing.


Dickkopf Wnt signaling pathway inhibitor 1 regulates the differentiation of mouse embryonic stem cells in vitro and in vivo.
Embryonic stem cells (ESCs) are pluripotent stem cells derived from early stage embryos. It remains unclear whether inhibiting the Wnt/β‑catenin signaling pathway using dickkopf Wnt signaling pathway inhibitor 1 (DKK1) impacts on the differentiation potential of mouse ESCs in vitro and in vivo. In the present study, immunohistochemical staining was used to measure the expression of markers of the three germ layers in ESCs and teratomas derived from ESCs. The expression of markers for the Wnt/β‑catenin signaling pathway were detected by reverse transcription‑polymerase chain reaction (RT‑qPCR). Immunohistochemistry and western blotting indicated that the expression levels of octamer‑binding transcription factor 4 in the DKK1‑treated ESC group were significantly greater compared with the control ESCs. Reduced expression levels of NeuroD and bone morphogenetic protein 4 were observed in the DKK1‑treated ESCs and teratomas derived from DKK1‑treated ESCs compared with the control group. Increased expression levels of SOX17 were observed in the DKK1‑treated ESCs compared with the control group. RT‑qPCR indicated that β‑catenin expression was significantly reduced in DKK1‑treated ESCs and teratomas derived from DKK1‑treated ESCs compared with the control groups. Western blotting indicated no alterations in the expression of GSK‑3β, however, the levels of phosphorylated‑GSK‑3β were significantly greater in the DKK1 treatment groups, while cyclin D1 and c‑Myc expression levels were significantly reduced in the DKK1 treatment groups compared with the control groups. These results suggest that inhibiting Wnt signaling in ESCs using DKK1 may promote mouse ESCs to differentiate into endoderm in vitro and in vivo, and suppress the tumorigenicity of ESCs.


Essential and selective role of SNX12 in transport of endocytic and retrograde cargo.
The endosomal protein-sorting machineries play vital roles in diverse physiologically important cellular processes. Much of the core membrane-sorting apparatus is conserved in evolution, such as retromer, which is involved in the recycling of a diverse set of cargoes via the retrograde trafficking route. Here, in an RNAi-based loss-of-function study, we identified that suppression of SNX12 leads to a severe blockage in CIM6PR (also known as IGF2R) transport and alters the morphology of the endocytic compartments. We demonstrate that SNX12 is involved in the early phase of CIM6PR transport, and mediates receptor recycling upstream of the other well-established SNX components of retromer. Ultra-structural analysis revealed that SNX12 resides on tubulo-vesicular structures, despite it lacking a BAR domain. Furthermore, we illustrate that SNX12 plays a key role in intraluminal vesicle formation and in the maturation of a subpopulation of early endosomes into late endosomes, thereby regulating selective endocytic transport of cargo for degradation. This study therefore provides evidence for the existence of early endosomal subpopulations that have differential roles in the sorting of the cargoes along endocytic degradative pathways.


Experimental Legionnaires' disease in SCID-Beige mice reconstituted with human leucocytes.
A new small animal model of experimental Legionnaires' disease is described in which the reconstitution of SCID-Beige mice with human peripheral blood leucocytes permits the in-vivo growth of Legionella pneumophila in the lungs of aerosol-challenged mice. Following infection, viable bacterial counts within the lungs of mice increased from 10(5) cfu/lung at the time of inoculation to a maximum of 10(10) cfu/lung by 48 h post-inoculation. Two types of disease were detected in the lungs of infected SCID-Beige mice. An acute exudative bronchiolitis and bronchopneumonia were seen in the most severely affected mice and, in the less severely affected mice, lesions of subacute or chronic disease were seen with thickening of alveolar walls and consolidation of lung tissue. Human cells did not appear to be involved directly in the pathology but were required for the establishment of infection. Immunohistological staining of lung tissue revealed substantial amounts of bacterial antigen distributed in a pattern similar to that seen in human Legionnaires' disease.


Mowat-Wilson syndrome.
Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype (high forehead, frontal bossing, large eyebrows, medially flaring and sparse in the middle part, hypertelorism, deep set but large eyes, large and uplifted ear lobes, with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth, with M-shaped upper lip, frequent smiling, and a prominent but narrow and triangular pointed chin), moderate-to-severe intellectual deficiency, epilepsy and variable congenital malformations including Hirschsprung disease (HSCR), genitourinary anomalies (in particular hypospadias in males), congenital heart defects, agenesis of the corpus callosum and eye anomalies. The prevalence of MWS is currently unknown, but 171 patients have been reported so far. It seems probable that MWS is under-diagnosed, particularly in patients without HSCR. MWS is caused by heterozygous mutations or deletions in the Zinc finger E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1). To date, over 100 deletions/mutations have been reported in patients with a typical phenotype; they are frequently whole gene deletions or truncating mutations, suggesting that haploinsufficiency is the main pathological mechanism. Studies of genotype-phenotype analysis show that facial gestalt and delayed psychomotor development are constant clinical features, while the frequent and severe congenital malformations are variable. In a small number of patients, unusual mutations can lead to an atypical phenotype. The facial phenotype is particularly important for the initial clinical diagnosis and provides the hallmark warranting ZEB2 mutational analysis, even in the absence of HSCR. The majority of MWS cases reported so far were sporadic, therefore the recurrence risk is low. Nevertheless, rare cases of sibling recurrence have been observed. Congenital malformations and seizures require precocious clinical investigation with intervention of several specialists (including neonatologists and pediatricians). Psychomotor development is delayed in all patients, therefore rehabilitation (physical therapy, psychomotor and speech therapy) should be started as soon as possible.


The effect of adverse information and positive promotion on women's preferences for prescribed contraceptive products.
Recent rapid growth in the range of contraceptive products has given women more choice, but also adds complexity to the resultant decision of which product to choose. This paper uses a discrete choice experiment (DCE) to investigate the effect of adverse information and positive promotion on women's stated preferences for prescribed contraceptive products. In November 2007, 527 Australian women aged 18-49 years were recruited from an online panel. Each was randomly allocated to one of three information conditions. The control group only received basic information on contraceptive products. One treatment group also received adverse information on the risks of the combined oral pill. The other group received basic information and promotional material on the vaginal ring, newly introduced into Australia and on the transdermal patch, which is unavailable in Australia. Respondents completed 32 choice sets with 3 product options where each option was described by a product label: either combined pill, minipill, injection, implant, hormonal IUD, hormonal vaginal ring, hormonal transdermal patch or copper IUD; and by the attributes: effect on acne, effect on weight, frequency of administration, contraceptive effectiveness, doctor's recommendation, effect on periods and cost. Women's choices were analysed using a generalized multinomial logit model (G-MNL) and model estimates were used to predict product shares for each information condition. The predictions indicated that adverse information did not affect women's preferences for products relative to only receiving basic information. The promotional material increased women's preferences for the transdermal patch. Women in all groups had a low preference for the vaginal ring which was not improved by promotion. The findings highlight the need for researchers to pay attention to setting the context when conducting DCEs as this can significantly affect results.


Histone chaperone specificity in Rtt109 activation.
Rtt109 is a histone acetyltransferase that requires a histone chaperone for the acetylation of histone 3 at lysine 56 (H3K56). Rtt109 forms a complex with the chaperone Vps75 in vivo and is implicated in DNA replication and repair. Here we show that both Rtt109 and Vps75 bind histones with high affinity, but only the complex is efficient for catalysis. The C-terminal acidic domain of Vps75 contributes to activation of Rtt109 and is necessary for in vivo functionality of Vps75, but it is not required for interaction with either Rtt109 or histones. We demonstrate that Vps75 is a structural homolog of yeast Nap1 by solving its crystal structure. Nap1 and Vps75 interact with histones and Rtt109 with comparable affinities. However, only Vps75 stimulates Rtt109 enzymatic activity. Our data highlight the functional specificity of Vps75 in Rtt109 activation.


X-ray structure and mutational analysis of the atrazine Chlorohydrolase TrzN.
Atrazine chlorohydrolase, TrzN (triazine hydrolase or atrazine chlorohydrolase 2), initiates bacterial metabolism of the herbicide atrazine by hydrolytic displacement of a chlorine substituent from the s-triazine ring. The present study describes crystal structures and reactivity of wild-type and active site mutant TrzN enzymes. The homodimer native enzyme structure, solved to 1.40 Å resolution, is a (βα)(8) barrel, characteristic of members of the amidohydrolase superfamily. TrzN uniquely positions threonine 325 in place of a conserved aspartate that ligates the metal in most mononuclear amidohydrolases superfamily members. The threonine side chain oxygen atom is 3.3 Å from the zinc atom and 2.6 Å from the oxygen atom of zinc-coordinated water. Mutation of the threonine to a serine resulted in a 12-fold decrease in k(cat)/K(m), largely due to k(cat), whereas the T325D and T325E mutants had immeasurable activity. The structure and kinetics of TrzN are reminiscent of carbonic anhydrase, which uses a threonine to assist in positioning water for reaction with carbon dioxide. An isosteric substitution in the active site glutamate, E241Q, showed a large diminution in activity with ametryn, no detectable activity with atratone, and a 10-fold decrease with atrazine, when compared with wild-type TrzN. Activity with the E241Q mutant was nearly constant from pH 6.0 to 10.0, consistent with the loss of a proton-donating group. Structures for TrzN-E241Q were solved with bound ametryn and atratone to 1.93 and 1.64 Å resolution, respectively. Both structure and kinetic determinations suggest that the Glu(241) side chain provides a proton to N-1 of the s-triazine substrate to facilitate nucleophilic displacement at the adjacent C-2.


Functional classification of memory CD8(+) T cells by CX3CR1 expression.
Localization of memory CD8(+) T cells to lymphoid or peripheral tissues is believed to correlate with proliferative capacity or effector function. Here we demonstrate that the fractalkine-receptor/CX3CR1 distinguishes memory CD8(+) T cells with cytotoxic effector function from those with proliferative capacity, independent of tissue-homing properties. CX3CR1-based transcriptome and proteome-profiling defines a core signature of memory CD8(+) T cells with effector function. We find CD62L(hi)CX3CR1(+) memory T cells that reside within lymph nodes. This population shows distinct migration patterns and positioning in proximity to pathogen entry sites. Virus-specific CX3CR1(+) memory CD8(+) T cells are scarce during chronic infection in humans and mice but increase when infection is controlled spontaneously or by therapeutic intervention. This CX3CR1-based functional classification will help to resolve the principles of protective CD8(+) T-cell memory.


Noninvasive Ultrasound of the Tibial Muscle for Longitudinal Analysis of Nerve Regeneration in Rats.
Today's criterion standards for measuring functional recovery after nerve trauma in experimental studies are the muscle mass ratio and the isometric tetanic force; both tests are invasive and require a sacrificial procedure. The authors propose ultrasound as a noninvasive method to determine muscle atrophy, and evaluate its validity and reliability by comparing it to muscle mass ratio, isometric tetanic force, and histology. Fifty rats sustained a 10-mm autograft sciatic nerve reconstruction. With a 2-week interval, five animals were tested with a total follow-up of 20 weeks. The functional recovery of the hind-limb muscles was measured with ultrasound, muscle mass ratio, and isometric tetanic force. In addition, neuromuscular junctions were analyzed histologically. The different evaluation techniques were compared and the reliability of the ultrasound was determined. Four weeks after denervation, extensive muscle atrophy resulted in a decrease of muscle mass up to 30 percent. Ultrasound showed good correlations with muscle mass ratio for both tibial (r = 0.85) and gastrocnemius muscles (r = 0.89). Both intrarater reliability (r = 0.97) and interrater reliability (r = 0.88) of the ultrasound were high. The correlation with force was lower (0.62) but still statistically significant. Ultrasound measurement of muscle atrophy was highly correlated with the criterion standard muscle mass ratio and was also significantly correlated with isometric tetanic force. Histologic evaluation confirmed the regeneration pattern observed with ultrasound. The authors propose that ultrasound can be used as a valid alternative to muscle mass ratio to study muscle atrophy after nerve injury in a less-invasive and more animal-friendly manner.


Dietary lipids modify redox homeostasis and steroidogenic status in rat testis.
The present study explored the effect of dietary oils on lipid composition, antioxidant status, and the activity of the main steroidogenic enzymes in the testis. Forty Wistar rats were randomly assigned to one of four groups (n = 10) fed for 60 d on the same basal diet plus different lipid sources as commercial oils: soybean, olive, coconut, or grapeseed. After sacrifice, testicular lipids and fatty acid composition, free radical biomarkers, antioxidant levels, hormones, and steroidogenic enzymes were determined. The lipid composition of diets produced significant changes in neutral/phospholipids, free/esterified cholesterol, and plasmalogen proportion. Fatty acid patterns of these lipids were also strongly modified, influencing the double bond index. We also found a close correlation between the type of diet and the generation of free radicals. The oxidative stress in testes was higher with the grapeseed oil-supplemented diet and decreased with the other diets in this order: soybean oil > olive oil > coconut oil. Animals fed with the olive oil and coconut oil diets showed the highest testicular levels of antioxidants in addition to significantly high levels of testosterone and 3beta- or 17beta-hydroxysteroid dehydrogenase enzymes. Different oils in the diets strongly modified the homeostasis of the testicular antioxidant defense system and, in consequence, affected steroidogenic function, showing a clear correlation with the damage induced. According to our results, an appropriate mixture of olive and soybean oils could be a healthy recommendation.


Intercultural Training in Tense Times: Cultural Identities and Lived Experiences Within a Community of Practice of Youth Mental Health Care in Montréal.
This article presents an analysis of the lived experiences of youth mental health practitioners taking part in Transcultural Interinstitutional and Interdisciplinary Case Discussion Seminars (TIICDS), an intercultural training initiative developed in Montréal (Québec, Canada), while considering the current context of increasing social polarizations. Using insights from the community of practice (CoP) framework and drawing on the analysis of 21 seminar sessions and 26 semi-structured individual interviews, this article examines the relation between the local sociopolitical context, the participants' verbalization about their identities, and the affect and cognition evoked by the training. Results indicate that TIICDSs present several features of a CoP and that intercultural training needs to build on both theoretical and experiential knowledge, while considering local contextual elements. These include historical and contemporary social representations and power differentials between groups, the cultural identities of trainees, and the institutions and sociopolitical structures in which clinical practices take place. These elements, we argue, are sensitive and potentially conflictual but can be addressed through supportive and reflexive group-based initiatives such as CoPs that bring together practitioners on a regular basis and provide them with a 'culturally safe enough' space in which they can learn to complexify their understanding of clinical situations.


An exploratory study of seasonality and preschoolers' physical activity engagement.
While there is an emerging body of literature showing variations in physical activity between seasons, further investigation is needed to better understand this association in preschool-age children. This study was designed to examine seasonal variation from fall to winter in physical activity among preschoolers. Forty-six preschool children from 2 preschools in a large Midwestern Metropolitan area completed weekly habitual physical activity measures in both fall and following winter. The habitual physical activity was quantified with the GT1M Actigraph uniaxial accelerometer. To determine seasonal differences in physical activity, a series of paired sample t tests were conducted. Although overall physical activity level declined in winter, the magnitude of seasonality effects seem varied in terms of contexts. Compared with the decline during after-school time and during weekends, the differences in physical activity across the 2 seasons were much less evident during the time attending preschool and during weekdays. Seasonality in physical activity can be moderated by other contextual factors, such as preschool policies and curriculum. Preschools may serve as a major battlefield for fighting against physical inactivity and obesity during childhood due to their practical controllability.


microRNA profiling in Epstein-Barr virus-associated B-cell lymphoma.
The Epstein-Barr virus (EBV) is an oncogenic human Herpes virus found in ∼15% of diffuse large B-cell lymphoma (DLBCL). EBV encodes miRNAs and induces changes in the cellular miRNA profile of infected cells. MiRNAs are small, non-coding RNAs of ∼19-26 nt which suppress protein synthesis by inducing translational arrest or mRNA degradation. Here, we report a comprehensive miRNA-profiling study and show that hsa-miR-424, -223, -199a-3p, -199a-5p, -27b, -378, -26b, -23a, -23b were upregulated and hsa-miR-155, -20b, -221, -151-3p, -222, -29b/c, -106a were downregulated more than 2-fold due to EBV-infection of DLBCL. All known EBV miRNAs with the exception of the BHRF1 cluster as well as EBV-miR-BART15 and -20 were present. A computational analysis indicated potential targets such as c-MYB, LATS2, c-SKI and SIAH1. We show that c-MYB is targeted by miR-155 and miR-424, that the tumor suppressor SIAH1 is targeted by miR-424, and that c-SKI is potentially regulated by miR-155. Downregulation of SIAH1 protein in DLBCL was demonstrated by immunohistochemistry. The inhibition of SIAH1 is in line with the notion that EBV impedes various pro-apoptotic pathways during tumorigenesis. The down-modulation of the oncogenic c-MYB protein, although counter-intuitive, might be explained by its tight regulation in developmental processes.


Solid bioneedle-delivered influenza vaccines are highly thermostable and induce both humoral and cellular immune responses.
The potential of bioneedles to deliver influenza vaccines was investigated. Four influenza vaccine formulations were screened to determine the optimal formulation for use with bioneedles. The stability of the formulations after freeze-drying was checked to predict the stability of the influenza vaccines in the bioneedles. Subunit, split, virosomal and whole inactivated influenza (WIV) vaccine were formulated and lyophilized in bioneedles, and subsequently administered to C57BL/6 mice. Humoral and cellular immune responses were assessed after vaccination. The thermostability of lyophilized vaccines was determined after one-month storage at elevated temperatures. Bioneedle influenza vaccines induced HI titers that are comparable to those induced by intramuscular WIV vaccination. Delivery by bioneedles did not alter the type of immune response induced by the influenza vaccines. Stability studies showed that lyophilized influenza vaccines have superior thermostability compared to conventional liquid vaccines, and remained stable after one-month storage at 60°C. Influenza vaccines delivered by bioneedles are a viable alternative to conventional liquid influenza vaccines. WIV was determined to be the most potent vaccine formulation for administration by bioneedles. Lyophilized influenza vaccines in bioneedles are independent of a cold-chain, due to their increased thermostability, which makes distribution and stockpiling easier.


Depression, disability days, and days lost from work in a prospective epidemiologic survey.
We describe the relationship of depression and depressive symptoms to disability days and days lost from work in 2980 participants in the Epidemiologic Catchment Area Study in North Carolina after 1 year of follow-up. Compared with asymptomatic individuals, persons with major depression had a 4.78 times greater risk of disability (95% confidence interval, 1.64 to 13.88), and persons with minor depression with mood disturbance, but not major depression, had a 1.55 times greater risk (95% confidence interval, 1.00 to 2.40). Because of its prevalence, individuals with minor depression were associated with 51% more disability days in the community than persons with major depression. This group was also at increased risk of having a concomitant anxiety disorder or developing major depression within 1 year. We conclude that the threshold for identifying clinically significant depression may need to be reevaluated to include persons with fewer symptoms but measurable morbidity. Only by changing our nosology can the societal impact of depression be adequately addressed.


Effect of GABAergic compounds on gonadotropin-releasing hormone receptor gene expression in the rat.
Using a competitive reverse transcription-polymerase chain reaction (RT-PCR), the amounts of GnRH receptor (GnRHR) transcript in a discrete nucleus micropunched from rat brain slices were determined. GnRHR transcript was highly expressed in anterior pituitary >> median eminence > posterior mediobasal hypothalamus (pMBH) > preoptic area (POA) but not in cortex and posterior pituitary, which were used as control tissues. To examine the effect of GABA on GnRHR transcript level, 10 nmol of muscimol, a GABA-A receptor agonist, or baclofen, a GABA-B receptor agonist, was microinjected into the lateral ventricle of ovariectomized rats. Two hours after an intraventricular injection, rats were decapitated. Blood was collected 1 h before and after drug administration and used for LH determination. Serum LH levels were significantly reduced by muscimol but not by baclofen within 2 h. The activation of GABA-A receptors with muscimol resulted in a significant inhibition in GnRHR transcript level in both the pMBH and POA but not in the pituitary. The activation of GABA-B receptors with baclofen, however, did not produce any effect on GnRHR transcript level in the pMBH and POA, as well as the pituitary. This experiment demonstrates for the first time that GABAergic neurotransmission, through GABA-A receptors, is involved in the regulation of GnRHR transcript level in the rat hypothalamus. This suggests that GABAergic neurotransmission regulates GnRHR gene expression in a coordinated, yet complex, fashion in the control of the neuroendocrine function of GnRH-LH axis.


Young Women's Ratings of Three Placebo Multipurpose Prevention Technologies for HIV and Pregnancy Prevention in a Randomized, Cross-Over Study in Kenya and South Africa.
End-user input is critical to inform development of multipurpose prevention technology (MPT) products that prevent HIV and pregnancy. The TRIO Study, conducted in Kenya and South Africa, enrolled 277 HIV-negative women aged 18-30 in a randomized cross-over study to use each placebo MPT (daily oral tablets, monthly injections, and monthly vaginal ring) for one month. At the end of each month, participants rated how much they liked using the product on a 5-point Likert scale (5 = liked very much). We compared mean ratings using paired t-tests and examined sociodemographic-, attribute-, and behavior-related characteristics associated with ratings using multivariable linear regression and data from in-depth interviews. After use, mean ratings were significantly higher for injections [4.3 (SD = 1.0)] compared with tablets [3.0 (SD = 1.3)] and rings [3.3 (SD = 1.4)] (p < 0.001); mean ratings for rings were significantly higher than for tablets (p = 0.013). Mean ratings of a hypothetical active MPT increased for all products after the one-month period of use, with the greatest increase for rings, the least familiar product. In multivariable analysis, acceptability of key product attributes (e.g., product look) were associated with a significant increase of ≥ 1 point in the mean rating across all three products (p ≤ 0.001). Perceived ability to use the product without partner knowledge was associated with a higher mean rating for rings (b = 0.50; p = 0.006). The acceptability of product attributes contributed significantly to the rating of all products, highlighting the value of choice in pregnancy and HIV prevention to accommodate diverse users.


Forecasting seizures in dogs with naturally occurring epilepsy.
Seizure forecasting has the potential to create new therapeutic strategies for epilepsy, such as providing patient warnings and delivering preemptive therapy. Progress on seizure forecasting, however, has been hindered by lack of sufficient data to rigorously evaluate the hypothesis that seizures are preceded by physiological changes, and are not simply random events. We investigated seizure forecasting in three dogs with naturally occurring focal epilepsy implanted with a device recording continuous intracranial EEG (iEEG). The iEEG spectral power in six frequency bands: delta (0.1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), low-gamma (30-70 Hz), and high-gamma (70-180 Hz), were used as features. Logistic regression classifiers were trained to discriminate labeled pre-ictal and inter-ictal data segments using combinations of the band spectral power features. Performance was assessed on separate test data sets via 10-fold cross-validation. A total of 125 spontaneous seizures were detected in continuous iEEG recordings spanning 6.5 to 15 months from 3 dogs. When considering all seizures, the seizure forecasting algorithm performed significantly better than a Poisson-model chance predictor constrained to have the same time in warning for all 3 dogs over a range of total warning times. Seizure clusters were observed in all 3 dogs, and when the effect of seizure clusters was decreased by considering the subset of seizures separated by at least 4 hours, the forecasting performance remained better than chance for a subset of algorithm parameters. These results demonstrate that seizures in canine epilepsy are not randomly occurring events, and highlight the feasibility of long-term seizure forecasting using iEEG monitoring.


Verapamil treatment after coronary angioplasty in patients at high risk of recurrent stenosis.
To evaluate the efficacy of high-dose verapamil treatment (240 mg twice daily) in the prevention of angiographic restenosis after primary successful coronary angioplasty in patients at high risk of recurrent obstruction. A placebo controlled, double blind trial in which patients with stable angina pectoris and patients with unstable angina or non-Q wave infarction treated with 330 mg aspirin and 75 mg dipyridamole twice daily were randomised to a verapamil group or a control group. Follow up angiography was performed 6 months after angioplasty or sooner if signs of recurrent ischaemia developed. University department of cardiology. 196 consecutive patients undergoing coronary angioplasty from the beginning of April 1987 to the end of March 1989 and meeting the selection criteria that included the presence of at least one of six predefined risk factors for restenosis. At the time of coronary angioplasty 113 patients had unstable angina or non-Q wave infarction and 83 had stable angina pectoris. In 89 (91%) patients in the verapamil group and in 83 (85%) control patients follow up angiograms were available. The restenosis rate was lower in the verapamil group (48.3%) than in the placebo group (62.7%) (odds ratio 0.56, 95% confidence interval (CI) 0.303 to 1.025 p = 0.059). Of the 172 patients in whom follow up angiograms were available, 24 (13 taking verapamil and 11 taking placebo) did not comply with the trial for more than 40 (34) days (mean (1 SD)). For the remaining 148 patients the restenosis rate was 47.4% in the verapamil group and 63.9% in the placebo group (odds ratio 0.52, 95% CI 0.271 to 0.993, p = 0.046). In the 97 patients with unstable angina or non-Q wave infarction the restenosis rate was not significantly influenced by verapamil (55.8% with verapamil v 62.2% with placebo, odds ratio 0.77, 95% CI 0.339 to 1.728, p = 0.520). In the 75 patients with stable angina pectoris the restenosis rate dropped from 63.2% with placebo to 37.8% with verapamil (odds ratio 0.36, 95% CI 0.137 to 0.917, p = 0.038). The observed beneficial effect of high-dose verapamil treatment on the angiographic restenosis rate in patients with stable angina pectoris and at increased risk of recurrent obstruction requires confirmation in further prospective studies.


Changes in Albuminuria Predict Cardiovascular and Renal Outcomes in Type 2 Diabetes: A Post Hoc Analysis of the LEADER Trial.
A post hoc analysis to investigate the association between 1-year changes in albuminuria and subsequent risk of cardiovascular and renal events. LEADER was a randomized trial of liraglutide up to 1.8 mg/day versus placebo added to standard care for 3.5-5 years in 9,340 participants with type 2 diabetes and high cardiovascular risk. We calculated change in urinary albumin-to-creatinine ratio (UACR) from baseline to 1 year in participants with >30% reduction (n = 2,928), 30-0% reduction (n = 1,218), or any increase in UACR (n = 4,124), irrespective of treatment. Using Cox regression, risks of major adverse cardiovascular events (MACE) and a composite nephropathy outcome (from 1 year to end of trial in subgroups by baseline UACR [<30 mg/g, 30-300 mg/g, or ≥300 mg/g]) were assessed. The analysis was adjusted for treatment allocation alone as a fixed factor and for baseline variables associated with cardiovascular and renal outcomes. For MACE, hazard ratios (HRs) for those with >30% and 30-0% UACR reduction were 0.82 (95% CI 0.71, 0.94; P = 0.006) and 0.99 (0.82, 1.19; P = 0.912), respectively, compared with any increase in UACR (reference). For the composite nephropathy outcome, respective HRs were 0.67 (0.49, 0.93; P = 0.02) and 0.97 (0.66, 1.43; P = 0.881). Results were independent of baseline UACR and consistent in both treatment groups. After adjustment, HRs were significant and consistent in >30% reduction subgroups with baseline micro- or macroalbuminuria. A reduction in albuminuria during the 1st year was associated with fewer cardiovascular and renal outcomes, independent of treatment. Albuminuria monitoring remains an important part of diabetes care, with great unused potential.


Embryonic stem cell differentiation requires full length Chd1.
The modulation of chromatin dynamics by ATP-dependent chromatin remodeling factors has been recognized as an important mechanism to regulate the balancing of self-renewal and pluripotency in embryonic stem cells (ESCs). Here we have studied the effects of a partial deletion of the gene encoding the chromatin remodeling factor Chd1 that generates an N-terminally truncated version of Chd1 in mouse ESCs in vitro as well as in vivo. We found that a previously uncharacterized serine-rich region (SRR) at the N-terminus is not required for chromatin assembly activity of Chd1 but that it is subject to phosphorylation. Expression of Chd1 lacking this region in ESCs resulted in aberrant differentiation properties of these cells. The self-renewal capacity and ESC chromatin structure, however, were not affected. Notably, we found that newly established ESCs derived from Chd1(Δ2/Δ2) mutant mice exhibited similar differentiation defects as in vitro generated mutant ESCs, even though the N-terminal truncation of Chd1 was fully compatible with embryogenesis and post-natal life in the mouse. These results underscore the importance of Chd1 for the regulation of pluripotency in ESCs and provide evidence for a hitherto unrecognized critical role of the phosphorylated N-terminal SRR for full functionality of Chd1.


[Gender identity disorders as a symptom of psychosis, schizophrenia in particular].
In the Netherlands it has recently become possible for transsexual patients to receive hormonal treatment from the onset of puberty. Until the age of 16, pubertal development can be prevented with luteinizing hormone-releasing hormone (LHRH) agonists. From 16 years of age onwards, gender adjustment can be initiated by administration of hormones of the opposite sex. Surgical treatment can be offered once the patient reaches 18 years of age. Although such treatment will only be initiated with reticence and after a long phase of intense diagnostic screening, the question arises whether a clear differentiation can be made between pure gender identity disorders and secondary transsexual feelings that are part of an ongoing psychopathological development, such as schizophrenia. The potential diagnostic confusion is illustrated by a case history of a male schizophrenic patient. This patient had been treated hormonally for transsexualism for years before acute psychotic decompensation occurred. Neuroleptic treatment of the psychosis rapidly reduced the psychotic symptoms. In retrospect, the patient regards his transsexual period as a 'mistake'. Delusions about one's physical appearance and the urge to drastically change the way one looks appear to be relatively common in patients suffering from schizophrenia.


Antibody response of cattle to vaccination with commercial modified live rabies vaccines in Guatemala.
Vampire bat rabies is a public and animal health concern throughout Latin America. As part of an ecological study of vampire bat depredation on cattle in southern Guatemala, we conducted a vaccine seroconversion study among three dairy farms. The main objectives of this cross sectional and cohort study were to understand factors associated with bat bites among cattle, to determine whether unvaccinated cattle had evidence of rabies virus exposure and evaluate whether exposure was related to bat bite prevalence, and to assess whether cattle demonstrate adequate seroconversion to two commercial vaccines used in Guatemala. In 2012, baseline blood samples were collected immediately prior to intramuscular inoculation of cattle with one of two modified live rabies vaccines. Post vaccination blood samples were collected 13 and 393 days later. Sera were tested for rabies virus neutralizing antibodies (rVNA) by the rapid fluorescent focus inhibition test (RFFIT). Across two years of study, 36% (254/702) of inspected cattle presented gross evidence of vampire bat bites. Individual cattle with a bat bite in 2012 were more likely have a bat bite in 2013. Prior to vaccination, 12% (42/350) of cattle sera demonstrated rVNA, but bite status in 2012 was not associated with presence of rVNA. Vaccine brand was the only factor associated with adequate rVNA response of cattle by day 13. However, vaccine brand and rVNA status at day 13 were associated with an adequate rVNA titer on day 393, with animals demonstrating an adequate titer at day 13 more likely to have an adequate titer at day 393. Our findings support stable levels of vampire bat depredation and evidence of rVNA in unvaccinated cattle. Brand of vaccine may be an important consideration impacting adequate rVNA response and long-term maintenance of rVNA in cattle. Further, the results demonstrate that initial response to vaccination is associated with rVNA status over one year following vaccination.


Ecological linkages between aboveground and belowground biota.
All terrestrial ecosystems consist of aboveground and belowground components that interact to influence community- and ecosystem-level processes and properties. Here we show how these components are closely interlinked at the community level, reinforced by a greater degree of specificity between plants and soil organisms than has been previously supposed. As such, aboveground and belowground communities can be powerful mutual drivers, with both positive and negative feedbacks. A combined aboveground-belowground approach to community and ecosystem ecology is enhancing our understanding of the regulation and functional significance of biodiversity and of the environmental impacts of human-induced global change phenomena.


Science behind the cardio-metabolic benefits of omega-3 polyunsaturated fatty acids: biochemical effects vs. clinical outcomes.
Lower incidence of cardiovascular disease (CVD) in the Greenland Inuit, Northern Canada and Japan has been attributed to their consumption of seafood rich in long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA). While a large majority of pre-clinical and intervention trials have demonstrated heart health benefits of LCn-3PUFA, some studies have shown no effects or even negative effects. LCn-3PUFA have been shown to favourably modulate blood lipid levels, particularly a reduction in circulating levels of triglycerides. High density lipoprotein-cholesterol (HDL-C) levels are elevated following dietary supplementation with LCn-3PUFA. Although LCn-3PUFA have been shown to increase low-density lipoprotein-cholesterol (LDL-C) levels, the increase is primarily in the large-buoyant particles that are less atherogenic than small-dense LDL particles. The anti-inflammatory effects of LCn-3PUFA have been clearly outlined with inhibition of NFkB mediated cytokine production being the main mechanism. In addition, reduction in adhesion molecules (intercellular adhesion molecule, ICAM and vascular cell adhesion molecule 1, VCAM-1) and leukotriene production have also been demonstrated following LCn-3PUFA supplementation. Anti-aggregatory effects of LCn-3PUFA have been a subject of controversy, however, recent studies showing sex-specific effects on platelet aggregation have helped resolve the effects on hyperactive platelets. Improvements in endothelium function, blood flow and blood pressure after LCn-3PUFA supplementation add to the mechanistic explanation on their cardio-protective effects. Modulation of adipose tissue secretions including pro-inflammatory mediators and adipokines by LCn-3PUFA has re-ignited interest in their cardiovascular health benefits. The aim of this narrative review is to filter out the reasons for possible disparity between cohort, mechanistic, pre-clinical and clinical studies. The focus of the article is to provide possible explanation for the observed controversies surrounding heart health benefits of LCn-3PUFA.


Compressed-sensing motion compensation (CosMo): a joint prospective-retrospective respiratory navigator for coronary MRI.
Prospective right hemidiaphragm navigator (NAV) is commonly used in free-breathing coronary MRI. The NAV results in an increase in acquisition time to allow for resampling of the motion-corrupted k-space data. In this study, we are presenting a joint prospective-retrospective NAV motion compensation algorithm called compressed-sensing motion compensation (CosMo). The inner k-space region is acquired using a prospective NAV; for the outer k-space, a NAV is only used to reject the motion-corrupted data without reacquiring them. Subsequently, those unfilled k-space lines are retrospectively estimated using compressed sensing reconstruction. We imaged right coronary artery in nine healthy adult subjects. An undersampling probability map and sidelobe-to-peak ratio were calculated to study the pattern of undersampling, generated by NAV. Right coronary artery images were then retrospectively reconstructed using compressed-sensing motion compensation for gating windows between 3 and 10 mm and compared with the ones fully acquired within the gating windows. Qualitative imaging score and quantitative vessel sharpness were calculated for each reconstruction. The probability map and sidelobe-to-peak ratio show that the NAV generates a random undersampling k-space pattern. There were no statistically significant differences between the vessel sharpness and subjective score of the two reconstructions. Compressed-sensing motion compensation could be an alternative motion compensation technique for free-breathing coronary MRI that can be used to reduce scan time.


Acute kidney injury.
Acute kidney injury (formerly known as acute renal failure) is a syndrome characterised by the rapid loss of the kidney's excretory function and is typically diagnosed by the accumulation of end products of nitrogen metabolism (urea and creatinine) or decreased urine output, or both. It is the clinical manifestation of several disorders that affect the kidney acutely. Acute kidney injury is common in hospital patients and very common in critically ill patients. In these patients, it is most often secondary to extrarenal events. How such events cause acute kidney injury is controversial. No specific therapies have emerged that can attenuate acute kidney injury or expedite recovery; thus, treatment is supportive. New diagnostic techniques (eg, renal biomarkers) might help with early diagnosis. Patients are given renal replacement therapy if acute kidney injury is severe and biochemical or volume-related, or if uraemic-toxaemia-related complications are of concern. If patients survive their illness and do not have premorbid chronic kidney disease, they typically recover to dialysis independence. However, evidence suggests that patients who have had acute kidney injury are at increased risk of subsequent chronic kidney disease.


Fast switching characteristics of a microlens array using the electroclinic effect of SmA* liquid crystals.
We present a microlens array characterized by the electroclinic effect of chiral smectic A (SmA(*)) liquid crystals, which show the very fast dynamic switching characteristics required in high-speed optical devices. In order to easily control the intensity at the focal length of the proposed dynamic microlens structure, we adopt a solid-type liquid crystal polymer with optical anisotropy, which can split the beam intensity into two directions, depending on the vectorial portion of the polarization state of the light. The proposed microlens shows a focal intensity tunable by controlling the polarization of light at the SmA(*) liquid crystal. The lens has a very fast switching time of about 24 micros, which is several times faster than conventional microlens arrays with surface-stabilized ferroelectric liquid crystals.


Predicting intervention effect for COVID-19 in Japan: state space modeling approach.
Japan has observed a surge in the number of confirmed cases of the coronavirus disease (COVID-19) that has caused a serious impact on the society especially after the declaration of the state of emergency on April 7, 2020. This study analyzes the real time data from March 1 to April 22, 2020 by adopting a sophisticated statistical modeling based on the state space model combined with the well-known susceptible-infected-recovered (SIR) model. The model estimation and forecasting are conducted using the Bayesian methodology. The present study provides the parameter estimates of the unknown parameters that critically determine the epidemic process derived from the SIR model and prediction of the future transition of the infectious proportion including the size and timing of the epidemic peak with the prediction intervals that naturally accounts for the uncertainty. Even though the epidemic appears to be settling down during this intervention period, the prediction results under various scenarios using the data up to May 18 reveal that the temporary reduction in the infection rate would still result in a delayed the epidemic peak unless the long-term reproduction number is controlled.


Adverse event assessment of antimuscarinics for treating overactive bladder: a network meta-analytic approach.
Overactive bladder (OAB) affects the lives of millions of people worldwide and antimuscarinics are the pharmacological treatment of choice. Meta-analyses of all currently used antimuscarinics for treating OAB found similar efficacy, making the choice dependent on their adverse event profiles. However, conventional meta-analyses often fail to quantify and compare adverse events across different drugs, dosages, formulations, and routes of administration. In addition, the assessment of the broad variety of adverse events is dissatisfying. Our aim was to compare adverse events of antimuscarinics using a network meta-analytic approach that overcomes shortcomings of conventional analyses. Cochrane Incontinence Group Specialized Trials Register, previous systematic reviews, conference abstracts, book chapters, and reference lists of relevant articles were searched. Eligible studies included randomized controlled trials comparing at least one antimuscarinic for treating OAB with placebo or with another antimuscarinic, and adverse events as outcome measures. Two authors independently extracted data. A network meta-analytic approach was applied allowing for joint assessment of all adverse events of all currently used antimuscarinics while fully maintaining randomization. 69 trials enrolling 26'229 patients were included. Similar overall adverse event profiles were found for darifenacin, fesoterodine, transdermal oxybutynin, propiverine, solifenacin, tolterodine, and trospium chloride but not for oxybutynin orally administered when currently used starting dosages were compared. The proposed generally applicable transparent network meta-analytic approach summarizes adverse events in an easy to grasp way allowing straightforward benchmarking of antimuscarinics for treating OAB in clinical practice. Most currently used antimuscarinics seem to be equivalent first choice drugs to start the treatment of OAB except for oral oxybutynin dosages of ≥ 10 mg/d which may have more unfavorable adverse event profiles.


Reduced Pain Sensation and Reduced BOLD Signal in Parietofrontal Networks during Religious Prayer.
Previous studies suggest that religious prayer can alter the experience of pain via expectation mechanisms. While brain processes related to other types of top-down modulation of pain have been studied extensively, no research has been conducted on the potential effects of active religious coping. Here, we aimed at investigating the neural mechanisms during pain modulation by prayer and their dependency on the opioidergic system. Twenty-eight devout Protestants performed religious prayer and a secular contrast prayer during painful electrical stimulation in two fMRI sessions. Naloxone or saline was administered prior to scanning. Results show that pain intensity was reduced by 11% and pain unpleasantness by 26% during religious prayer compared to secular prayer. Expectancy predicted large amounts (70-89%) of the variance in pain intensity. Neuroimaging results revealed reduced neural activity during religious prayer in a large parietofrontal network relative to the secular condition. Naloxone had no significant effect on ratings or neural activity. Our results thus indicate that, under these conditions, pain modulation by prayer is not opioid-dependent. Further studies should employ an optimized design to explore whether reduced engagement of the frontoparietal system could indicate that prayer may attenuate pain through a reduction in processing of pain stimulus saliency and prefrontal control rather than through known descending pain inhibitory systems.


The influence of self-generated emotions on physical performance: an investigation of happiness, anger, anxiety, and sadness.
The present study examined the relationship between self-generated emotions and physical performance. All participants took part in five emotion induction conditions (happiness, anger, anxiety, sadness, and an emotion-neutral state) and we investigated their influence on the force of the finger musculature (Experiment 1), the jump height of a counter-movement jump (Experiment 2), and the velocity of a thrown ball (Experiment 3). All experiments showed that participants could produce significantly better physical performances when recalling anger or happiness emotions in contrast to the emotion-neutral state. Experiments 1 and 2 also revealed that physical performance in the anger and the happiness conditions was significantly enhanced compared with the anxiety and the sadness conditions. Results are discussed in relation to the Lazarus (1991, 2000a) cognitive-motivational-relational (CMR) theory framework.


A propensity score matched comparative study between paclitaxel-coated balloon and everolimus-eluting stents for the treatment of small coronary vessels.
To compare the long-term clinical outcomes of paclitaxel drug-coated-balloons (DCB) and everolimus-eluting-stents (EES) following the treatment of de novo small vessel coronary artery disease. It is currently unclear whether treatment of de novo small vessel coronary disease with DCB is comparable to second generation drug-eluting stents, which are the current standard of care. The present study enrolled 90 patients with small vessel coronary disease from the DCB treatment arm of the BELLO (Balloon Elution and Late Loss Optimization) trial and 2,000 patients treated with EES at the San Raffaele Scientific Institute. Propensity score matching was performed to adjust for differences in baseline clinical and angiographic characteristics, yielding a total of 181 patients: 90 patients with 94 lesions receiving DCB and 91 patients with 94 lesions receiving EES. Major adverse cardiac events (MACE) were defined as the composite of cardiac death, recurrent non-fatal myocardial infarction, and target vessel revascularization. After propensity score matching, baseline clinical and angiographic characteristics were similar between the two groups. The cumulative MACE rate at 1-year was 12.2% with DCB and 15.4% with EES (P = 0.538). Patients in the DCB group had similar TLR rates as compared to EES over the same interval (4.4% vs. 5.6%; P = 0.720). There were no cases of definite or probable stent or vessel thrombosis. The use of paclitaxel-DCB appears to be associated with similar clinical outcomes when compared to second-generation-EES in small coronary artery disease. The findings of this study should be confirmed with larger prospective randomized studies with longer follow-up. © 2017 Wiley Periodicals, Inc.


Pathophysiology, Diagnosis, and Treatment of Radiation Necrosis in the Brain.
New radiation modalities have made it possible to prolong the survival of individuals with malignant brain tumors, but symptomatic radiation necrosis becomes a serious problem that can negatively affect a patient's quality of life through severe and lifelong effects. Here we review the relevant literature and introduce our original concept of the pathophysiology of brain radiation necrosis following the treatment of brain, head, and neck tumors. Regarding the pathophysiology of radiation necrosis, we introduce two major hypotheses: glial cell damage or vascular damage. For the differential diagnosis of radiation necrosis and tumor recurrence, we focus on the role of positron emission tomography. Finally, in accord with our hypothesis regarding the pathophysiology, we describe the promising effects of the anti-vascular endothelial growth factor antibody bevacizumab on symptomatic radiation necrosis in the brain.


Intravenous Infusion Administration: A Comparative Study of Practices and Errors Between the United States and England and Their Implications for Patient Safety.
Intravenous medication administration is widely reported to be error prone. Technologies such as smart pumps have been introduced with a view to reducing these errors. An international comparison could provide evidence of their effectiveness, including consideration of contextual factors such as regulatory systems and local cultures. The aim of this study was to investigate similarities and differences in practices and error types involving intravenous medication administration in the United States and England, and summarise methodological differences necessary to perform these parallel studies. We drew on findings of separate point prevalence studies conducted across hospitals in each country. In these, we compared what was being administered at the time of observation with the prescription and relevant policies, errors were classified by type and severity, and proportions of infusions featuring each error type were calculated. We also reviewed what adaptations to the US protocol were needed for England. Authors independently reviewed findings from both studies and proposed themes for comparison. In online meetings, each country's research team clarified assumptions and explained their findings. Key themes included commonalities and contrasts in methods, findings, practices and policies. Although US sites made greater use of smart infusion devices, and had more precisely defined requirements around infusion device use, patterns of errors were similar. Differences among clinical contexts within each country were as marked as differences across countries. Regulatory and quality control systems shape practices, but causal relationships are complex. Infusion administration is a complex adaptive system with multiple interacting agents (professionals, patients, software systems, etc.) that respond in rich ways to their environments; safety depends on complex, interrelated factors.


The neutral sphingomyelinase pathway regulates packaging of the prion protein into exosomes.
Prion diseases are a group of transmissible, fatal neurodegenerative disorders associated with the misfolding of the host-encoded prion protein, PrP(C), into a disease-associated form, PrP(Sc). The transmissible prion agent is principally formed of PrP(Sc) itself and is associated with extracellular vesicles known as exosomes. Exosomes are released from cells both in vitro and in vivo, and have been proposed as a mechanism by which prions spread intercellularly. The biogenesis of exosomes occurs within the endosomal system, through formation of intraluminal vesicles (ILVs), which are subsequently released from cells as exosomes. ILV formation is known to be regulated by the endosomal sorting complexes required for transport (ESCRT) machinery, although an alternative neutral sphingomyelinase (nSMase) pathway has been suggested to also regulate this process. Here, we investigate a role for the nSMase pathway in exosome biogenesis and packaging of PrP into these vesicles. Inhibition of the nSMase pathway using GW4869 revealed a role for the nSMase pathway in both exosome formation and PrP packaging. In agreement, targeted knockdown of nSMase1 and nSMase2 in mouse neurons using lentivirus-mediated RNAi also decreases exosome release, demonstrating the nSMase pathway regulates the biogenesis and release of exosomes. We also demonstrate that PrP(C) packaging is dependent on nSMase2, whereas the packaging of disease-associated PrP(Sc) into exosomes occurs independently of nSMase2. These findings provide further insight into prion transmission and identify a pathway which directly assists exosome-mediated transmission of prions.


Application of a novel SSFBG-based single-input multiple-output encoder/decoder to optical packet switching.
We propose a novel superstructured fiber Bragg grating (SSFBG) based single-input multiple-output (SIMO) en/decoder, which can simultaneously process a group of independent optical codes with a specific permutation and combination of code patterns and spatially separate encoded and decoded signals into different optical paths. The number of optical codes processed by the SIMO en/decoder can be flexibly changed. We theoretically and experimentally investigate the coding performance of the SIMO en/decoder and discuss the unique features of the proposed device. In the experiment, we employ the SIMO en/decoder for optical label processing in an optical-code based optical packet switching system with the data rate of 10 Gbit/s and the packet rate of 312.5 MHz. The four-SSFBG based SIMO en/decoder are capable of simultaneously generating/recognizing four 31-chip 640 Gchip/s optical code based labels and distribute the labels into four designated destinations.


Selective Oxidation of HMF via Catalytic and Photocatalytic Processes Using Metal-Supported Catalysts.
In this study, 5-hydroxymethylfurfural (HMF) oxidation was carried out via both the catalytic and the photocatalytic approach. Special attention was devoted to the preparation of the TiO₂-based catalysts, since this oxide has been widely used for catalytic and photocatalytic application in alcohol oxidation reactions. Thus, in the catalytic process, the colloidal heterocoagulation of very stable sols, followed by the spray-freeze-drying (SFD) approach, was successfully applied for the preparation of nanostructured porous TiO₂-SiO₂ mixed-oxides with high surface areas. The versatility of the process made it possible to encapsulate Pt particles and use this material in the liquid-phase oxidation of HMF. The photocatalytic activity of a commercial titania and a homemade oxide prepared with the microemulsion technique was then compared. The influence of gold, base addition, and oxygen content on product distribution in the photocatalytic process was evaluated.


Impact of antiretroviral therapy on the incidence of tuberculosis: the Brazilian experience, 1995-2001.
The human immunodeficiency virus (HIV) fuels tuberculosis (TB) epidemics. In controlled clinical trials, antiretroviral therapy (ART) reduces TB incidence in HIV-infected patients. In this study we determine if, under programmatic conditions, Brazil's policy of universal ART access has impacted TB incidence among HIV-infected patients. We abstracted clinical information from records of HIV-infected patients managed in the public sector in 11 Brazilian states between 1/1/1995 and 12/31/2001. Case ascertainment (TB and HIV) utilized guidelines (with added stringency) published by Brazil's Ministry of Health. We determined TB incidence and hazards ratio (HR) for ART-naïve and ART-treated [including highly active ART (HAART)] patients employing Cox proportional hazards analysis. Information from 463 HIV-infected patients met study criteria. The median age of the study population was 34 years, 70% were male, and mean follow-up to primary endpoints--TB, death, and last clinic visit--was 330, 1059, and 1125 days, respectively. Of the 463 patients, 76 (16%) remained ART-naïve. Of the patients who never received HAART (n = 157) 81 were treated with ART non-HAART. Of the patients who received any ART (n = 387), 306 were treated with HAART (includes those patients who later switched from ART non-HAART to HAART). Tuberculosis developed in 39/463 (8%) patients. Compared to HAART- and ART non-HAART-treated patient groups, TB incidence was 10- (p<0.001) and 2.5-fold (p = 0.03) higher in ART-naïve patients, respectively. The median baseline absolute CD4+ T-lymphocyte count for patients who developed TB was not significantly different from that of patients who remained TB free. In multivariate analysis, the incidence of TB was statistically significantly lower in HAART-treated [HR 0.2; 95% (CI 0.1, 0.6); p<0.01] compared to ART naïve patients. A baseline CD4+ T-lymphocyte count <200 cells/mm(3) [HR 2.5; (95% CI 1.2, 5.4); p<0.01], prior hospitalization [HR 4.2; (95% CI 2.0, 8.8); p<0.001], prior incarceration [HR 4.1; 95% CI 1.6, 10.3); p<0.01], and a positive tuberculin skin test [HR 3.1; (95% CI 1.1, 9.0); p = 0.04] were independently and positively associated with incident TB. In this population-based study we demonstrate an 80% reduction in incident TB, under programmatic conditions, in HAART-treated HIV-infected patients compared to ART-naïve patients.


Optical interconnections for massively parallel architectures.
This paper presents a study of board-level interconnection requirements for highly parallel and massively parallel computing. Analytical models of the I/O bandwidth of popular interconnection networks have been developed and show that current electronic technologies are poor in supporting the necessary I/O density and bandwidth. Optical interconnects appear to offer greater potential in meeting these I/O requirements. Several possible optical implementations of interconnecting a network of electronic processors are compared. The use of polymer waveguides appears to offer the best solution compatible with existing multiboard system architectures.


Urinary Mitochondrial DNA Copy Number Identifies Chronic Renal Injury in Hypertensive Patients.
Mitochondrial injury contributes to renal dysfunction in several models of renal disease, but its involvement in human hypertension remains unknown. Fragments of the mitochondrial genome released from dying cells are considered surrogate markers of mitochondrial injury. We hypothesized that hypertension would be associated with increased urine mitochondrial DNA (mtDNA) copy numbers. We prospectively measured systemic and urinary copy number of the mtDNA genes cytochrome-c oxidase-3 and NADH dehydrogenase subunit-1 by quantitative polymerase chain reaction in essential (n=25) and renovascular (RVH, n=34) hypertensive patients and compared them with healthy volunteers (n=22). Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin served as indices of renal injury. Renal blood flow and oxygenation were assessed by multidetector computed tomography and blood oxygen level-dependent magnetic resonance imaging. Blood pressure, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 were similarly elevated in essential hypertension and RVH, and estimated glomerular filtration rate was lower in RVH versus healthy volunteers and essential hypertension. Renal blood flow was lower in RVH compared with essential hypertension. Urinary mtDNA copy number was higher in hypertension compared with healthy volunteers, directly correlated with urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 and inversely with estimated glomerular filtration rate. In RVH, urinary mtDNA copy number correlated directly with intrarenal hypoxia. Furthermore, in an additional validation cohort, urinary mtDNA copy number was higher in RVH compared with healthy volunteers (n=10 each). The change in serum creatinine levels and estimated glomerular filtration rate 3 months after medical therapy without or with revascularization correlated with the change in urinary mtDNA. Therefore, elevated urinary mtDNA copy numbers in hypertensive patients correlated with markers of renal injury and dysfunction, implicating mitochondrial injury in kidney damage in human hypertension.


Postnatal blocking of interferon-gamma function prevented atherosclerotic plaque formation in apolipoprotein E-knockout mice.
It is unknown whether interferon-gamma has a positive or negative impact on atherosclerotic plaque formation. Thus, we examined the effects of postnatal interferon-gamma function blocking on plaque formation in apolipoprotein E-knockout (apoEKO) mice by overexpressing a soluble mutant of interferon-gamma receptor (sIFNgammaR), an interferon-gamma inhibitory protein. Mice were fed a Western-type diet from 8 weeks of age. sIFNgammaR or mock plasmid (control) was injected into the thigh muscle at 8 and 10 weeks' age, because serum sIFNgammaR protein was transiently increased with a peak at 2 days after a single sIFNgammaR gene transfer and remained elevated for 2 weeks. At 12 weeks' age, control apoEKO mice showed marked atherosclerotic plaques from the ascending aorta to the aortic arch. The plaques in the aortic root had massive lipid cores and macrophage infiltration with thin fibrous cap and few smooth muscle cells, demonstrating low plaque stability. In contrast, the luminal plaque area was remarkably reduced in sIFNgammaR-treated apoEKO mice. sIFNgammaR treatment not only reduced lipid core areas and macrophage infiltration but also increased smooth muscle cell count and fibrotic area, suggesting improved plaque stability. In controls, interleukin-1beta, monocyte chemoattractant protein-1, and vascular cell adhesion molecules-1 were remarkably upregulated in the aortic wall. These changes were significantly reversed by sIFNgammaR. sIFNgammaR treatment had no effects on serum cholesterol levels. In conclusion, sIFNgammaR treatment prevented plaque formation in apoEKO mice by inhibiting inflammatory changes in the arterial wall. The present study provides insight into a new strategy for preventing atherosclerosis.


Effects of Bone Marrow Mesenchymal Stem Cells on Plasminogen Activator Inhibitor-1 and Renal Fibrosis in Rats with Diabetic Nephropathy.
We undertook this study to observe the effects of bone marrow mesenchymal stem cells (BMSCs) on plasminogen activator inhibitor-1 (PAI-1) and renal fibrosis in rats with diabetic nephropathy and to explore its main mechanism. Thirty male Sprague Dawley rats were randomly divided into three groups: normal control group (NC group, n = 10), diabetic nephropathy group (DN group, n = 10), stem cell transplantation group (MSC group, n = 10). BMSCs were transplanted to rats in the MSC group via caudal vein infusion (2 × 10(6)/mL). At the end of 12 weeks, blood glucose, 24-h urinary protein, serum creatinine and renal mass index were measured. Morphology and collagen deposition in rat kidney were observed by HE and Masson staining, respectively. Expressions of PAI-1, transforming growth factor β1 (TGF-β1) and Smad3 in rat kidney were detected by immunohistochemistry and Western blot. Compared with DN group, 24-h protein, serum creatinine and renal mass index decreased significantly in MSC group. No significant changes in blood glucose (p >0.05) were shown. Immunohistochemistry and Western blot showed that expressions of PAI-1, TGF-β1 and Smad3 in NC group were lower than DN group. Expression of each protein in MSC group was between two groups (p <0.05). Correlation analysis revealed that PAI-1 and TGF-β1 (r = 0.987, p <0.05) and Smad3 (r = 0.974, p <0.05) showed a significant positive correlation. TGF-β1 and Smad3 (r = 0.962, p <0.05) were positively correlated. BMSCs significantly inhibited renal fibrosis in rats with DN. The mechanism may be related to inhibition of TGF-β1/Smad3 pathway, decreasing the expression of PAI-1 protein and reducing the accumulation of extracellular matrix, thereby balancing the fibrinolytic system.


Regulated changes in material properties underlie centrosome disassembly during mitotic exit.
Centrosomes must resist microtubule-mediated forces for mitotic chromosome segregation. During mitotic exit, however, centrosomes are deformed and fractured by those same forces, which is a key step in centrosome disassembly. How the functional material properties of centrosomes change throughout the cell cycle, and how they are molecularly tuned, remain unknown. Here, we used optically induced flow perturbations to determine the molecular basis of centrosome strength and ductility in C. elegans embryos. We found that both properties declined sharply at anaphase onset, long before natural disassembly. This mechanical transition required PP2A phosphatase and correlated with inactivation of PLK-1 (Polo kinase) and SPD-2 (Cep192). In vitro, PLK-1 and SPD-2 directly protected centrosome scaffolds from force-induced disassembly. Our results suggest that, before anaphase, PLK-1 and SPD-2 respectively confer strength and ductility to the centrosome scaffold so that it can resist microtubule-pulling forces. In anaphase, centrosomes lose PLK-1 and SPD-2 and transition to a weak, brittle state that enables force-mediated centrosome disassembly.


Positive selection of B cells expressing low densities of self-reactive BCRs.
B cell tolerance or autoimmunity is determined by selective events. Negative selection of self-reactive B cells is well documented and proven. In contrast, positive selection of conventional B cells is yet to be firmly established. Here, we demonstrate that developing self-reactive B cells are not always highly sensitive to the deletion mechanisms imposed by membrane-bound self-antigens. At low amounts, membrane-bound antigens allow survival of B cells bearing a single high affinity self-reactive B cell receptor (BCR). More importantly, we show that forced allelic inclusion modifies B cell fate; low quantities of self-antigen induce the selection and accumulation of increased numbers of self-reactive B cells with decreased expression of antigen-specific BCRs. By directly measuring antigen binding by intact B cells, we show that the low amounts of self-antigen select self-reactive B cells with a lower association constant. A fraction of these B cells is activated and secretes autoantibodies that form circulating immune complexes with self-antigen. These findings demonstrate that conventional B cells can undergo positive selection and that the fate of a self-reactive B cell depends on the quantity of self-antigen, the number of BCRs engaged, and on its overall antigen-binding avidity, rather than on the affinity of individual BCRs.


Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.
Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation. Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. We aimed to establish efficacy, safety, and patient characteristics associated with the response to mepolizumab. We undertook a multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries between Nov 9, 2009, and Dec 5, 2011. Eligible patients were aged 12-74 years, had a history of recurrent severe asthma exacerbations, and had signs of eosinophilic inflammation. They were randomly assigned (in a 1:1:1:1 ratio) to receive one of three doses of intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo (100 mL 0·9% NaCl) with a central telephone-based system and computer-generated randomly permuted block schedule stratified by whether treatment with oral corticosteroids was required. Patients received 13 infusions at 4-week intervals. The primary outcome was the rate of clinically significant asthma exacerbations, which were defined as validated episodes of acute asthma requiring treatment with oral corticosteroids, admission, or a visit to an emergency department. Patients, clinicians, and data analysts were masked to treatment assignment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01000506. 621 patients were randomised: 159 were assigned to placebo, 154 to 75 mg mepolizumab, 152 to 250 mg mepolizumab, and 156 to 750 mg mepolizumab. 776 exacerbations were deemed to be clinically significant. The rate of clinically significant exacerbations was 2·40 per patient per year in the placebo group, 1·24 in the 75 mg mepolizumab group (48% reduction, 95% CI 31-61%; p<0·0001), 1·46 in the 250 mg mepolizumab group (39% reduction, 19-54%; p=0·0005), and 1·15 in the 750 mg mepolizumab group (52% reduction, 36-64%; p<0·0001). Three patients died during the study, but the deaths were not deemed to be related to treatment. Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma. GlaxoSmithKline.


Reproducibility of serum sex steroid assays in men by RIA and mass spectrometry.
There is an increasing trend to apply gas chromatography combined with mass spectrometry (GC-MS) or liquid chromatography tandem mass spectrometry (LC-MS/MS) assay methods to large-scale epidemiologic studies for the measurement of serum sex steroids. These methods are generally considered the gold standard for sex steroid measurements because of their accuracy, sensitivity, turnaround time, and ability to assess a more complete panel of steroid metabolites in the same run. In this report, we evaluated the precision, including within-batch (intra) and between-batch (inter) reproducibility, of steroid hormone measurements determined by GC-MS and LC-MS/MS assays and RIA and compared measurements among these methods. Specifically, 282 overnight fasting serum samples from 20 male volunteers were analyzed for 12 steroid metabolites by GC-MS or LC-MS/MS in one lab over a 4-month period. Six of the analytes were also measured by RIA in another lab. Unconjugated hormones, including testosterone, dihydrotestosterone, dehydroepiandrosterone, androstenedione, androst-5-ene-3beta,17beta-diol, estrone, and estradiol, were measured by GC-MS, whereas conjugated hormones, including DHEA sulfate, androsterone glucuronide, 5alpha-androstane-3alpha,17beta-diol 3-glucuronide, 5alpha-androstane-3alpha,17beta-diol 17-glucuronide, and estrone sulfate, were measured by LC-MS/MS. A subset of these hormones, including testosterone, dihydrotestosterone, androstenedione, 5alpha-androstane-3alpha,17beta-diol 17-glucuronide, estrone, and estradiol, were also measured by RIA following extraction and chromatography. We used the coefficient of variation (CV) and the intraclass correlation coefficient (ICC) to assess within- and between-batch assay variations. For the 12 analytes measured by GC-MS or LC-MS/MS, CVs and ICCs for within- and between-batch measurements were similar, with CVs ranging from 6.1% to 21.4% and ICCs ranging from 87.6% to 99.2%. The six analytes measured by RIA had good CVs and ICCs, with CVs <10% and ICCs >70% (range, 71.7-99.7%). For the six metabolites that were measured by both methods, the CVs were similar, whereas the ICCs were generally higher with the GC-MS method. The absolute values for each analyte measured by RIA and GC-MS differed, with RIAs usually yielding markedly higher levels than GC-MS, although the Pearson and Spearman correlation coefficients for these six analytes were near one and all were significant (P < 0.001). Our results show that RIA, GC-MS, and LC-MS/MS assays for androgens and estrogens in the two labs included in the study have good reproducibility, as measured by small CVs (<15%) and high ICCs (>80%), with the exception of estradiol (71.7%) when measured by RIA. Despite substantial differences in absolute measurements of sex steroid hormones by RIA and MS methods, correlations between the two assays for the six sex steroids measured in the two labs were high (>0.9). However, it is important for future large epidemiologic studies to incorporate MS with high reproducibility and specificity to measure a more complete profile of androgen and estrogen metabolites to clarify the role of sex steroids in prostate cancer.


Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction of treatment response with viral immunity.
It remains challenging to predict the outcomes of therapy in patients with rheumatoid arthritis (RA). The objective of this study was to identify immune response signatures that correlate with clinical treatment outcomes in patients with RA. A cohort of 71 consecutive patients with early RA starting treatment with disease-modifying antirheumatic drugs (DMARDs) was recruited. Disease activity at baseline and after 21 to 24 weeks of follow-up was measured using the Disease Activity Score in 28 joints (DAS28). Immune response profiling was performed by analyzing multi-cytokine production from peripheral blood cells following incubation with a panel of stimuli, including a mixture of human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) lysates. Profiles identified via principal components analysis (PCA) for each stimulus were then correlated with the ΔDAS28 from baseline to follow-up. A clinically meaningful improvement in the DAS28 was defined as a decrease of ≥1.2. A profile of T-cell cytokines (IL-13, IL-4, IL-5, IL-2, IL-12, and IFN-γ) produced in response to CMV/EBV was found to correlate with the ΔDAS28 from baseline to follow-up. At baseline, a higher magnitude of the CMV/EBV immune response profile predicted inadequate DAS28 improvement (mean PCA-1 scores: 65.6 versus 50.2; P = 0.029). The baseline CMV/EBV response was particularly driven by IFN-γ (P = 0.039) and IL-4 (P = 0.027). Among patients who attained clinically meaningful DAS28 improvement, the CMV/EBV PCA-1 score increased from baseline to follow-up (mean +11.6, SD 25.5), whereas among patients who responded inadequately to DMARD therapy, the CMV/EBV PCA-1 score decreased (mean -12.8, SD 25.4; P = 0.002). Irrespective of the ΔDAS28, methotrexate use was associated with up-regulation of the CMV/EBV response. The CMV/EBV profile was associated with positive CMV IgG (P <0.001), but not EBV IgG (P = 0.32), suggesting this response was related to CMV exposure. A profile of T-cell immunity associated with CMV exposure influences the clinical response to DMARD therapy in patients with early RA. Because CMV latency is associated with greater joint destruction, our findings suggest that changes in T-cell immunity mediated by viral persistence may affect treatment response and possibly long-term outcomes of RA.


Bistable Photoswitching of Hemithioindigo with Green and Red Light: Entry Point to Advanced Molecular Digital Information Processing.
Photoswitches reacting to visible light instead of harmful UV irradiation are of very high interest due to the mild and broadly compatible conditions of their operation. Shifting the absorption into the red region of the electromagnetic spectrum usually comes at the cost of losing thermal stability of the metastable state-the switch switches off by itself. Only recently have photoswitches become available that combine visible light responsiveness with high bistability. However, shifting the wavelengths for bistable photoswitching beyond 600 nm is still a great challenge without involving secondary processes such as two-photon absorption or sensitization. We present a simple hemithioindigo photoswitch that can efficiently be photoisomerized using green and red light while maintaining a high thermal barrier of the metastable state. This highly sought after properties allow for selective switching in a mixture of hemithioindigo dyes. In addition, protonation can be used as second independent input altering the light response of the switch and allowing construction of advanced molecular digital information processing devices. This is demonstrated by realizing a broad variety of logical operations covering combinational and sequential logic behavior. By making use of the protonation-induced loss of thermal bistability, a high security keypad lock could be realized, which distinguishes the sequences of three different inputs and additionally erases its unlocked state after a short time.


Determination of β-lactam antibiotics in milk based on magnetic molecularly imprinted polymer extraction coupled with liquid chromatography-tandem mass spectrometry.
In this work, a rapid and selective method was successfully developed using the magnetic molecularly imprinted polymer (MMIP) as sorbent for the extraction of β-lactam antibiotics (BLAs) from milk samples. The MMIP has been prepared using penicillin V potassium (PENV) as template molecule, methacrylic acid as functional monomer, ethylene glycol dimethacrylate as crosslinking agent and Fe(3)O(4) magnetite as magnetic component. The experimental results showed that the MMIP had high affinity and selectivity toward PENV and other structurally related BLAs. The extraction process was carried out in a single step by mixing the extraction solvent, MMIPs and milk samples under ultrasonic action. When the extraction was completed, the MMIPs adsorbing the analytes were separated from the sample matrix by an external magnet. The analytes eluted from the MMIP were analyzed by liquid chromatography-tandem mass spectrometry. For achieving optimal preconcentration and reducing non-specific interactions, various parameters affecting the extraction efficiency such as extraction mode, extraction solvent, the amount of MMIPs, extraction time, washing solution and eluting solution were comprehensively evaluated. Under the optimal conditions, the detection limits of BLAs are in the range of 1.6-2.8 ng mL(-1). The relative standard deviations of intra- and inter-day ranging from 3.2% to 8.3% and from 3.6% to 9.8% are obtained, respectively. The method was applied to determine BLAs including PENV, amoxicillin and oxacillin in five milk samples from different provenances. The recoveries of BLAs in these samples from 71.6% to 90.7% are obtained.


Influence of boundary conditions on photon diffusion through an interface between two turbid media with different refractive indices.
The photon migration in two semi-infinite highly scattering media with different refractive indices is studied in the diffusion approximation for two sets of boundary conditions at the interface. In commonly used boundary conditions, the ratio of the intensity (fluence rate) to the squared refractive index is assumed continuous across an interface and the normal component of flux is required to be continuous. However, a more rigorous approach shows that the boundary condition for the intensity may be different. As was shown by Aronson [J. Opt. Soc. Am. A12, 2532 (1995)], the ratio of the intensity to the squared refractive index undergoes a jump across an interface that is proportional to the diffuse flux. A diffusion model with an instantaneous point source that can be solved analytically for both sets of boundary conditions is considered. The analytical solutions are derived and compared with the results of Monte Carlo simulations that take into account the reflections and refractions at the interface according to Fresnel's formulas. It is shown that the analytical solutions with the Aronson boundary condition for intensity match the Monte Carlo results better than the solutions with a continuous ratio of the intensity to the squared refractive index.


Comparing the range of musculoskeletal therapies applied by physical therapists with postgraduate qualifications in manual therapy in patients with non-specific neck pain with international guidelines and recommendations: An observational study.
The aim of this study is to compare Dutch usual care musculoskeletal therapy in patients with non-specific neck pain with recommendations from international clinical practice guidelines. Physical therapy is diverse, as it may consist of exercise, massage, advice, and other modalities. Physical therapists with post graduate qualifications in manual therapy (MT) may additionally apply spinal thrust manipulation or non-thrust mobilization techniques to treat neck pain. It is important that, in the absence of a Dutch clinical guideline for the treatment of patients with neck pain, musculoskeletal therapists use the available recommendations from international clinical practice guidelines when treating patients with neck pain. One updated clinical practice guideline was identified (Blanpied, 2017), a report from the Task Force on Neck Pain (Guzman et al., 2008) and the IFOMPT International Framework for Examination of the Cervical Region for potential of Cervical Arterial Dysfunction prior to Orthopaedic Manual Therapy Intervention (Rushton et al., 2014). At baseline 1193 patients are included and data with regard to pain, disability, fear avoidance, expectations and applied treatment modalities are gathered. Outcome is measured using the Global Perceived Effect questionnaire. Results show that patients with acute neck pain are treated significantly more often with manipulation compared to patients with sub-acute or chronic neck pain (p < .000) and younger patients are treated with manipulation more often than older patients (p < .000). In the presence of comorbidity, the preference of spinal manipulation seems to diminish, in favour of mobilization and exercise. Almost every patient receives multimodal therapy (94.3%) and spinal manipulation and mobilization are rarely used as a stand-alone treatment (4.5% and 0.8%). Dutch musculoskeletal therapists choose treatment strategies that correspond with recommendations from international guidelines.


Stakeholder research on biospecimen needs and reactions to the development of a national cancer human biobank by the National Cancer Institute.
An initial survey conducted by the National Cancer Institute (NCI) in October 2008 with cancer researchers around the country revealed both a need and support for the development of a national cancer HUman Biobank (caHUB). NCI sought additional feedback from decision makers whose organizations are potential users of a caHUB and who would have a direct influence on whether or not their organizations would participate in a caHUB. NCI commissioned online discussion groups with executive-level decision makers at academic institutions with cancer research programs and pharmaceutical/biotechnology organizations. Across both groups, a clear need for a national caHUB was uniformly expressed. While having a broad range of biospecimens--especially those hard to obtain--in one location was important, stakeholders agreed that the level of standardization the caHUB could offer was the most important benefit. Stakeholders believed the development of standard operating procedures around collection, storage, and quality assessment of biospecimens would be the greatest contribution of the caHUB, allowing more collaboration and higher confidence in research results. Barriers to contribution and/or use of the caHUB focused on funding and resources required of participants, concerns over standard operating procedures, and impositions on their organizations' intellectual property. Findings from the qualitative research are consistent with previous research and point to an overwhelming need for a solution that will address growing concerns about access and availability of quality biospecimens to conduct cancer research and ultimately expedite future discoveries to treat and cure cancer.