Osteopathy for Endometriosis and Chronic Pelvic Pain - a Pilot Study.
Introduction: Pelvic pain is a common problem in gynaecological practice. It is often unclear whether definite causality exists between reported symptoms and objective clinical findings of the female genital tract, and medical or operative treatments do not always achieve long-term resolution of symptoms. Methods: This pilot study investigated 28 patients (age 20-65, median 36.5 years) from a gynaecology practice whose only clinical finding was painful pelvic floor muscle tightness. Following standardised gynaecological and physiotherapist examination, all patients received osteopathic treatment. Pain had been present for a median of 3 years (range 1 month to 20 years). 14 patients had previously confirmed endometriosis. Treatment success was evaluated on consultation with patients in person or in writing. Results: 22 of the 28 participants completed the treatment according to plan. Overall, 17 reported symptom improvement, while 10 of the 14 patients with endometriosis did. Conclusion: Osteopathy is well received by women with painful pelvic floor muscle tightness and appears to be an effective treatment option.


Neuroimaging Biomarkers of a History of Concussion Observed in Asymptomatic Young Athletes.
Participation in contact sports places athletes at elevated risk for repeated head injuries and is associated with negative mental health outcomes later in life. The current study identified changes observable on neuroimaging that persisted beyond the apparent resolution of acute symptoms of concussion. Sixteen young adult ice hockey players with a remote history of concussion but no subjective complaints were compared against 13 of their teammates with no history of concussion. Participants completed a detailed phenotypic assessment and a neuroimaging battery including diffusion kurtosis imaging and resting-state functional magnetic resonance imaging. Athletes with a history of concussion performed no differently from those without on phenotypic assessment, but showed significantly elevated fractional anisotropy (FA) in the left genu and anterior corona radiata relative to those without. Post hoc analyses revealed that elevated FA was associated with increased microstructural complexity perpendicular to the primary axon (radial kurtosis). Athletes with concussion history also showed significant differences in the organization of the default mode network (DMN) characterized by stronger temporal coherence in posterior DMN, decreased temporal coherence in anterior DMN, and increased functional connectivity outside the DMN. In the absence of deficits on detailed phenotypic assessment, athletes with a history of concussion displayed changes to the microstructural architecture of the cerebral white matter and to the functional connectivity of the brain at rest. Some of these changes are consistent with those previously associated with persisting deficits and complaints, but we also report novel, complementary changes that possibly represent compensatory mechanisms.


Continence for women: a test of AWHONN's evidence-based protocol in clinical practice. Association of Women's Health Obstetric and Neonatal Nurses.
To test the effectiveness of an evidence-based protocol for urinary incontinence in increasing identification of women with the condition and improving their outcomes. Prospective formative evaluation study. Twenty-one public, private, and other women's health care sites. Women in ambulatory care settings (N = 1,474) provided descriptive statistics. Clinical outcomes were tested in 132 cases for whom pre- and posttreatment data were available. Standardized screening and baseline follow-up forms were used to minimize time burden on clinicians; bladder and pelvic floor muscle training materials were provided to clinicians for distribution. Self-reported frequency, volume, and quality of life related to incontinence and cost of self-management were used to assess protocol effectiveness. Frequency of incontinence episodes, estimated volume lost per episode, and the cost of self-management decreased. Quality of life improved, as reflected in decreased bother attributed to incontinence and in the number of women avoiding activities such as shopping, exercising, or travel because of incontinence. This simple program of pelvic floor muscle and bladder training, as it has been systematically implemented in a variety of ambulatory women's health care settings, has benefited women's continence status. The results of this project strongly support widespread application.


Effect of short-term physical exercise on serum total testosterone levels in young adults.
The effect of short term (12 weeks) physical exercise on serum total testosterone level was evaluated in 30 young male adults, aged 18-27 years (mean age 21.67±2.26 years). These medical students, having sedentary life style underwent heavy exercise by attaining heart rate 125-150 beats/min on bicycle ergometer for 15 min on alternate day basis amounted to 670 kilopond metre per minute work done and percentage of VO2max was 71±3. Pre-exercise serum total testosterone levels (5.49±1.31) of students were compared with those obtained after 1 week and 12 weeks of initiation of exercise. The serum total testosterone was measured by DRG Testosterone ELISA kit. After 1 week of exercise, a statistically insignificant decrease (5.488±1.32; P>0.05) was found while after 12 weeks of exercise, a statistically significant increase (6.41±2.28 P<0.05) was noticed between the pre-and post-exercise serum total testosterone levels. We conclude that short-term exercise produces an elevation in serum testosterone levels in young adults.


RASSF1A is part of a complex similar to the Drosophila Hippo/Salvador/Lats tumor-suppressor network.
The Ras Association Domain Family 1A (RASSF1A) gene is one of the most frequently silenced genes in human cancer. RASSF1A has been shown to interact with the proapoptotic kinase MST1. Recent work in Drosophila has led to the discovery of a new tumor-suppressor pathway involving the Drosophila MST1 and MST2 ortholog, Hippo, as well as the Lats/Warts serine/threonine kinase and a protein named Salvador (Sav). Little is known about this pathway in mammalian cells. We report that complexes consisting of RASSF1A, MST2, WW45 (the human ortholog of Sav), and LATS1 exist in human cells. MST2 enhances the RASSF1A-WW45 interaction, which requires the C-terminal SARAH domain of both proteins. Components of this complex are localized at centrosomes and spindle poles from interphase to telophase and at the midbody during cytokinesis. Both RASSF1A and WW45 activate MST2 by promoting MST2 autophosphorylation and LATS1 phosphorylation. Mitosis is delayed in Rassf1a(-/-) mouse embryo fibroblasts and frequently results in cytokinesis failure, similar to what has been observed for LATS1-deficient cells. RASSF1A, MST2, or WW45 can rescue this defect. The complex of RASSF1A, MST2, WW45, and LATS1 consists of several tumor suppressors, is conserved in mammalian cells, and appears to be involved in controlling mitotic exit.


Intervertebral disk nutrition: a review of factors influencing concentrations of nutrients and metabolites.
The biomechanical behavior of the intervertebral disk ultimately depends on the viability and activity of a small population of resident cells that make and maintain the disk's extracellular matrix. Nutrients that support these cells are supplied by the blood vessels at the disks' margins and diffuse through the matrix of the avascular disk to the cells. This article reviews pathways of nutrient supply to these cells; examines factors that may interrupt these pathways, and discusses consequences for disk cell survival, disk degeneration, and disk repair.


A Review of Circulating Tumor DNA as a Biomarker Guide for Total Neoadjuvant Therapy in Patients with Locally Advanced Rectal Cancer.
Non-operative management of patients with locally advanced rectal cancer (LARC) is emerging as a popular approach for patients that have no evidence of disease following neoadjuvant therapy. However, high rates of local recurrence or distant metastases have highlighted the urgent need for robust biomarker strategies to aid clinical management of these patients. This review summarizes recent advances in the utility of cell-free (cf) and circulating tumor (ct) DNA as potential biomarkers to help guide individualized non-operative management strategies for LARC patients receiving neoadjuvant therapy. Liquid biopsies and the detection of cfDNA/ctDNA is an emerging technology with the potential to provide a non-invasive approach to monitor disease response and improve the identification of patients with LARC that would best benefit from non-operative management. Substantial work is still needed before cfDNA/ctDNA monitoring can be widely adopted in the clinical setting. Studies reviewed herein highlight several areas of opportunity for improving the effectiveness and utility of cfDNA/ctDNA for managing patients with LARC.


Development of self-feeding behavior in children with typical development and those with arm movement impairments.
Self-feeding is a critical self-care skill that unites motor abilities (e.g., grasping and transporting utensils/food to the mouth) and cognitive abilities (e.g., using a spoon as a tool). This cross-sectional study assessed self-feeding behavior in a sample of 38 children with typical development (TD) and compared it between 18 of those children and 18 age- and sex-matched peers with arm movement impairments (MI). Children were assessed with a bowl of cereal and two spoons presented in four different orientations. Results suggested that children with MI were less successful than their TD peers in both motor aspects (e.g., grasp and transport of food and utensils) and cognitive aspects (correct grasp across spoon orientations) of self-feeding. Novel findings highlight: (a) interesting differences in visual attention between children with TD or MI; (b) the role of hand-preference in the correct grasping of the spoon(s) and effective self-feeding; (c) the positive relation between motor and cognitive aspects of self-feeding; and (d) that greater variability of self-feeding behavior relates to improved performance of cognitive aspects of the task. These results identify challenging components of self-feeding for children with MI that should be targeted by early interventions and assistive technologies aimed at increasing self-feeding independence.


Distributional effects of climate change taxation: the case of the UK.
Current economic instruments aimed at climate change mitigation focus mainly on CO(2) emissions, but efficient climate mitigation needs to focus on other greenhouse gases as well as CO(2). This study investigates the distributional effects of climate change taxes on households belonging to different income and lifestyle groups; and it compares the effects of a CO(2) tax with a multiple GHG tax in the UK in terms of cost efficiency and distributional effects. Results show that a multi GHG tax is more efficient than a CO(2) tax due to lower marginal abatement costs, and that both taxes are regressive, with lower income households paying a relatively larger share of their income for the taxes than higher income households. A shift from a CO(2) tax to a GHG tax will reduce and shift the tax burden between consumption categories such as from energy-intensive products to food products. Consumers have different abilities to respond to the tax and change their behavior due to their own socio-economic attributes as well as the physical environment such as the age of the housing stock, location, and the availability of infrastructure. The housing-related carbon emissions are the largest component of the CO(2) tax payments for low income groups and arguments could be made for compensation of income losses and reduction of fuel poverty through further government intervention.


Effectiveness of transaortic venting from a failing left ventricle during venoarterial bypass.
Insufficient unloading of the left ventricle (LV) is a limitation of percutaneous cardiopulumonary support (PCPS). We previously reported the unloading effect of transaortic catheter venting (TACV) during venoarterial bypass (VAB) in normal hearts. The aim of this study was to assess the effectiveness of TACV with VAB in a heart failure (HF) model. Seven adult mongrel dogs underwent TACV with VAB, and isolated LV failure was induced by multiple ligation of left coronary arteries. With standard hemodynamic monitoring, slope of the LV end-systolic pressure-volume relationship (Emax; mm Hg/ml), aortic elastance (Ea; mm Hg/ml), LV stroke work (SW; 10(-4)J), preload recruitable stroke work (PRSW; 10(-4)J/ ml), LV pressure-volume area (PVA; 10(-4)J), and potential energy (PE; 10(-4)J) were assessed using a micro-tip manometer and a conductance catheter. In addition to evaluation of LV function, myocardial adenosine 5'-triphosphate (ATP) was measured in each condition. The TACV combined support significantly reduced LV total energy (PVA) and LV work (SW). The LV energetic charge (PE/PVA, myocardial ATP) was significantly increased by TACV. These results suggest that TACV might be an effective technique for LV recovery during VAB or PCPS in patients with severe heart failure.


A Randomized, Double-blind, Placebo-controlled, Parallel-group, Pilot Study of Cannabidiol-rich Botanical Extract in the Symptomatic Treatment of Ulcerative Colitis.
Cannabidiol (CBD) exhibits anti-inflammatory properties that could improve disease activity in inflammatory bowel disease. This proof-of-concept study assessed efficacy, safety and tolerability of CBD-rich botanical extract in ulcerative colitis (UC) patients. Patients aged 18 years or older, with left-sided or extensive UC, Mayo scores of 4-10 (endoscopy scores ≥1), and on stable 5-aminosalicylic acid dosing, were randomized to 10-weeks' CBD-rich botanical extract or placebo capsules. The primary endpoint was the percentage of patients in remission after treatment. Statistical testing was 2-sided, using a 10% significance level. Patients were less tolerant of CBD-rich botanical extract compared with placebo, taking on average one-third fewer capsules, and having more compliance-related protocol deviations (principally insufficient exposure), prompting identification of a per protocol (PP) analysis set. The primary endpoint was negative; end of treatment remission rates were similar for CBD-rich botanical extract (28%) and placebo (26%). However, PP analysis of total and partial Mayo scores favoured CBD-rich botanical extract (P = 0.068 and P = 0.038, respectively). Additionally, PP analyses of the more subjective physician's global assessment of illness severity, subject global impression of change, and patient-reported quality-of-life outcomes were improved for patients taking CBD-rich botanical extract (P = 0.069, P = 0.003, and P = 0.065, respectively). Adverse events (AEs) were predominantly mild/moderate with many in the CBD-rich botanical extract group potentially attributable to the ∆9-tetrahydrocannabinol content. A greater proportion of gastrointestinal-related AEs, indicative of UC worsening, was seen on placebo. Although the primary endpoint was not reached, several signals suggest CBD-rich botanical extract may be beneficial for symptomatic treatment of UC.


A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer.
Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.


RECOGNITION AND AVOIDANCE OF ION SOURCE-GENERATED ARTIFACTS IN LIPIDOMICS ANALYSIS.
Lipid research is attracting more and more attention as various key roles and novel biological functions of lipids have been demonstrated and discovered in the organism. Mass spectrometry (MS)-based lipidomics approaches are the most powerful and effective tools for analysis of cellular lipidomes with very high sensitivity and specificity. However, the artifacts generated from in-source fragmentation are always present in all kinds of ion sources, even soft ionization techniques (i.e., electrospray ionization and matrix-assisted laser desorption/ionization [MALDI]). These artifacts can cause many problems for lipidomics, especially when the fragment ions correspond to/are isomeric species of other endogenous lipid species in complex biological samples. These commonly observed artifacts could lead to misannotation, false identification, and consequently, incorrect attribution of phenotypes, and will have negative impact on any MS-based lipidomics research including but not limited to biomarker discovery, drug development, etc. Liquid chromatography-MS, shotgun lipidomics, and MALDI-MS imaging are three representative lipidomics approaches in which ion source-generated artifacts are all manifested and are comprehensively summarized in this article. The strategies on how to avoid/reduce the artifacts of in-source fragmentation on lipidomics analysis are also discussed in detail. We believe that with the recognition and avoidance of ion source-generated artifacts, MS-based lipidomics approaches will provide better accuracy on comprehensive analysis of biological samples and will make greater contribution to the research on metabolism and translational/precision medicine (collectively termed functional lipidomics). © 2020 John Wiley & Sons Ltd. Mass Spec Rev.


Persistence of the Gypsy Moth Pheromone, Disparlure, in the Environment in Various Climates.
Mating disruption techniques are used in pest control for many species of insects, yet little is known regarding the environmental persistence of these pheromones following their application and if persistence is affected by climatic conditions. We first studied the persistent effect of ground applications of Luretape® GM in Lymantria dispar (L) mating disruption in VA, USA in 2006. The removal of Luretape® GM indicated that the strong persistent effect of disparlure in the environment reported by previous studies is produced by residual pheromone in the dispensers as opposed to environmental contamination. In 2010 and 2011, we evaluated the efficacy of two formulations, Disrupt® II and SPLAT GM(TM), in VA and WI, USA, which presented different climatic conditions. In plots treated in WI and VA, male moth catches in pheromone-baited traps were reduced in the year of treatment and one year after the pheromone applications relative to untreated controls. However, similar first- and second-year effects of pheromone treatments in VA and WI suggest that the release rate over one and two years was the same across markedly different climates. Future applications that use liquid or biodegradable formulations of synthetic pheromones could reduce the amount of persistence in the environment.


Host population diversity as a driver of viral infection cycle in wild populations of green sulfur bacteria with long standing virus-host interactions.
Temperate phages are viruses of bacteria that can establish two types of infection: a lysogenic infection in which the virus replicates with the host cell without producing virions, and a lytic infection where the host cell is eventually destroyed, and new virions are released. While both lytic and lysogenic infections are routinely observed in the environment, the ecological and evolutionary processes regulating these viral dynamics are still not well understood, especially for uncultivated virus-host pairs. Here, we characterized the long-term dynamics of uncultivated viruses infecting green sulfur bacteria (GSB) in a model freshwater lake (Trout Bog Lake, TBL). As no GSB virus has been formally described yet, we first used two complementary approaches to identify new GSB viruses from TBL; one in vitro based on flow cytometry cell sorting, the other in silico based on CRISPR spacer sequences. We then took advantage of existing TBL metagenomes covering the 2005-2018 period to examine the interactions between GSB and their viruses across years and seasons. From our data, GSB populations in TBL were constantly associated with at least 2-8 viruses each, including both lytic and temperate phages. The dominant GSB population in particular was consistently associated with two prophages with a nearly 100% infection rate for >10 years. We illustrate with a theoretical model that such an interaction can be stable given a low, but persistent, level of prophage induction in low-diversity host populations. Overall, our data suggest that lytic and lysogenic viruses can readily co-infect the same host population, and that host strain-level diversity might be an important factor controlling virus-host dynamics including lytic/lysogeny switch.


Habitat selection and home range in the Blanford's fox, Vulpes cana: compatibility with the resource dispersion hypothesis.
This paper presents analyses of habitat-use and home range size in the Blanford's fox. We predicted, from the resource dispersion hypothesis (RDH), that home ranges would encompass similar areas of combined fruitful habitats, but widely different areas of useless habitats, and thus that home ranges would be larger where such fruitful patches are fragmented and widely dispersed. Home range estimates of 0.5-2.0 km2 were calculated for 16 adult Blanford's foxes, using three different methods. There were no significant differences in home range size between sexes or study sites. One habitat, dry creekbed, was the most frequently visited in all home ranges. Dry creekbed provided abundant prey for the foxes and only sparse cover for their predators. Both the available area of creekbed in each range, and the area of creekbed patches that was used by the foxes, were independent of home range size. However, the variance in home range size was explained by the mean distance between the main denning area and the most frequently used patches of creekbed. These results are in accord with some predictions of the resource dispersion hypothesis.


A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part II. Management of patients.
During the outbreak of Crimean-Congo haemorrhagic fever (CCHF) at Tygerberg Hospital 8 patients were diagnosed positive. CCHF was diagnosed in another patient several months later. The treatment of these 9 cases is outlined. When it became evident that CCHF could present with a spectrum of severity, treatment was adjusted according to each patient's requirements. The essential components consisted of correction of haematological abnormalities combined with hyperimmune serum; the latter is particularly important for the severely ill patient with no antibodies to CCHF. The antiviral agents ribavirin and interferon were used but evidence to substantiate their application in future cases was inconclusive. Interferon was discontinued because of severe side-effects, many of which simulated the clinical features of CCHF. Objective improvement after corticosteroid treatment was noted in only 1 patient, but some of her symptoms could have been due to a transfusion reaction. Antibiotics were not routinely used. The 2 patients who died were diagnosed late, did not receive hyperimmune serum, and eventually developed multi-organ failure. The course of CCHF can probably be modified if the diagnosis is made early, if antiserum is given, and if the haematological abnormalities are promptly corrected.


Tunable quasi-two-dimensional electron gases in oxide heterostructures.
We report on a large electric-field response of quasi-two-dimensional electron gases generated at interfaces in epitaxial heterostructures grown from insulating oxides. These device structures are characterized by doping layers that are spatially separated from high-mobility quasi-two-dimensional electron gases and therefore present an oxide analog to semiconducting high-electron mobility transistors. By applying a gate voltage, the conductivity of the electron gases can be modulated through a quantum phase transition from an insulating to a metallic state.


Short-term impact of Experience Corps participation on children and schools: results from a pilot randomized trial.
This article reports on the short-term impact of a school-based program using older adult volunteers and aimed at improved academic achievement and reduced disruptive classroom behavior in urban elementary school students. The Experience Corps Baltimore (Maryland) program places a critical mass of older adult volunteers, serving 15 hours or more per week, in public schools to perform meaningful and important roles to improve the educational outcomes of children and the health and well-being of the volunteers. This article reports on the preliminary impact of the program on children in grades K-3. A total of 1,194 children in grades K-3 from six urban elementary schools participated in this pilot trial. At follow-up, third grade children whose schools were randomly selected for the program had significantly higher scores on a standardized reading test than children in the control schools, and there was a nonsignificant trend for improvement in alphabet recognition and vocabulary ability among kindergarten children in the program. Office referrals for classroom misbehavior decreased by about half in the Experience Corps schools, but remained the same in the control schools. Teachers had somewhat more favorable attitudes toward senior volunteers as a result of having older volunteers in the classroom, although the difference between the intervention and control schools was not statistically significant. In this pilot trial, the Experience Corps program led to selective improvements in student reading/academic achievement and classroom behavior while not burdening the school staff.


Does the addition of visceral manipulation alter outcomes for patients with low back pain? A randomized placebo controlled trial.
This study aimed to investigate whether the addition of visceral manipulation, to a standard physiotherapy algorithm, improved outcomes in patients with low back pain. Sixty-four patients with low back pain who presented for treatment at a private physiotherapy clinic were randomized to one of two groups: standard physiotherapy plus visceral manipulation (n = 32) or standard physiotherapy plus placebo visceral manipulation (n = 32). The primary outcome was pain (measured with the 0-10 Numerical Pain Rating Scale) at 6 weeks. Secondary outcomes were pain at 2 and 52 weeks, disability (measured with the Roland-Morris Disability Questionnaire) at 2, 6 and 52 weeks and function (measured with the Patient-Specific Functional Scale) at 2, 6 and 52 weeks. This trial was registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12611000757910). The addition of visceral manipulation did not affect the primary outcome of pain at 6 weeks (-0.12, 95% CI = -1.45 to 1.21). There were no significant between-group differences for the secondary outcomes of pain at 2 weeks or disability and function at 2, 6 or 52 weeks. The group receiving addition of visceral manipulation had less pain than the placebo group at 52 weeks (mean 1.57, 95% CI = 0.32 to 2.82). Participants were adequately blinded to group status and there were no adverse effects reported in either group. Our study suggests that visceral manipulation in addition to standard care is not effective in changing short-term outcomes but may produce clinically worthwhile improvements in pain at 1 year.


Effects of anti-smoking advertising on youth smoking: a review.
This paper reviews empirical studies, encompassing community trials and field experiments, and evaluates government-funded anti-smoking campaigns, ecologic studies of population impact of anti-smoking advertising, and qualitative studies that have examined the effects of anti-smoking advertising on teenagers. We conclude that anti-smoking advertising appears to have more reliable positive effects on those in pre-adolescence or early adolescence by preventing commencement of smoking. It is unclear whether this is due to developmental differences, or is a reflection of smoking experience, or a combination of the two. In addition, it is evident that social group interactions, through family, peer and cultural contexts, can play an important role in reinforcing, denying, or neutralizing potential effects of anti-smoking advertising. Although there is some research to suggest that advertising genres that graphically depict the health effects of smoking, emphasize social norms against smoking, and portray the tobacco industry as manipulative can positively influence teenagers, these findings are far from consistent. Finally, the effects of anti-smoking advertising on youth smoking can be enhanced by the use of other tobacco control strategies, and may be dampened by tobacco advertising and marketing. Overall, the findings of this review indicate that there is no single "recipe" for anti-smoking advertising that leads to reductions in youth smoking. Anti-smoking advertising can influence youth smoking, but whether it does in the context of individual anti-smoking campaigns needs to be the subject of careful evaluation.


Structure-function analysis of the integrin beta 7 subunit: identification of domains involved in adhesion to MAdCAM-1.
Beta 7 integrins serve special roles in mucosal immunity. Alpha 4 beta 7-mediated adhesion to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) directs lymphocyte homing to the gut, and alpha E beta 7 mediates binding of lymphocytes to E-cadherin on epithelial cells. Since alpha 4 beta 7 mediates adhesion to MAdCAM-1 but alpha 4 beta 1 does not, we used beta 7/beta 1 chimeras to directly assess the importance of specific regions of beta 7 in MAdCAM-1 binding. We found a region of beta 7 (residues 46-386) that accounts for specificity of alpha 4 beta 7 binding to MAdCAM-1. We also used human/mouse and human/rat chimeric beta 7 subunits to map epitopes recognized by fifteen anti-beta 7 mAbs. Six of seven Abs that block adhesion to MAdCAM-1 and E-cadherin (Fib 21, 22, 27, 30, 504; Act-1) mapped to amino acid residues 176-250. Residues 176-250 lie within the region of beta 7 that specifies MAdCAM-1 binding and also within a region that has a predicted structure homologous to the metal ion-dependent adhesion site (MIDAS) domains of the integrin subunits alpha L and alpha M. Three new Abs that recognize beta 7 in the presence of Mn2+, but not Ca2+, and promote adhesion to MAdCAM-1, mapped to amino acids 46-149. One blocking and five other Abs mapped to other regions (amino acids 387-725). We conclude that a MIDAS-like domain serves a critical role in beta 7 integrin-mediated adhesion.


Sensitivity to communicative relevance tells young children what to imitate.
How do children decide which elements of an action demonstration are important to reproduce in the context of an imitation game? We tested whether selective imitation of a demonstrator's actions may be based on the same search for relevance that drives adult interpretation of ostensive communication. Three groups of 18-month-old infants were shown a toy animal either hopping or sliding (action style) into a toy house (action outcome), but the communicative relevance of the action style differed depending on the group. For the no prior information group, all the information in the demonstration was new and so equally relevant. However, for infants in the ostensive prior information group, the potential action outcome was already communicated to the infant prior to the main demonstration, rendering the action style more relevant. Infants in the ostensive prior information group imitated the action style significantly more than infants in the no prior information group, suggesting that the relevance manipulation modulated their interpretation of the action demonstration. A further condition (non-ostensive prior information) confirmed that this sensitivity to new information is only present when the 'old' information had been communicated, and not when infants discovered this information for themselves. These results indicate that, like adults, human infants expect communication to contain relevant content, and imitate action elements that, relative to their current knowledge state or to the common ground with the demonstrator, is identified as most relevant.


Experimental and First-Principles NMR Analysis of Pt(II) Complexes With O,O'-Dialkyldithiophosphate Ligands.
Polycrystalline bis(dialkyldithiophosphato)Pt(II) complexes of the form [Pt{S2P(OR)2}2] (R = ethyl, iso-propyl, iso-butyl, sec-butyl or cyclo-hexyl group) were studied using solid-state 31P and 195Pt NMR spectroscopy, to determine the influence of R to the structure of the central chromophore. The measured anisotropic chemical shift (CS) parameters for 31P and 195Pt afford more detailed chemical and structural information, as compared to isotropic CS and J couplings alone. Advanced theoretical modeling at the hybrid DFT level, including both crystal lattice and the important relativistic spin-orbit effects qualitatively reproduced the measured CS tensors, supported the experimental analysis, and provided extensive orientational information. A particular correction model for the non-negligible lattice effects was adopted, allowing one to avoid a severe deterioration of the 195Pt anisotropic parameters due to the high requirements posed on the pseudopotential quality in such calculations. Though negligible differences were found between the 195Pt CS tensors with different substituents R, the 31P CS parameters differed significantly between the complexes, implying the potential to distinguish between them. The presented approach enables good resolution and a detailed analysis of heavy-element compounds by solid-state NMR, thus widening the understanding of such systems.


Antioxidant intake from diet and supplements and risk of digestive cancers in middle-aged adults: results from the prospective NutriNet-Santé cohort.
Experimental studies suggest beneficial effects of antioxidants in digestive cancer prevention. However, epidemiological results are contrasting and few studies quantitatively assessed supplemental intake. This study aimed at investigating the associations between antioxidant intakes (dietary, supplemental and total) and digestive cancer risk. This prospective study included 38 812 middle-aged subjects (≥45 years) from the NutriNet-Santé cohort (2009-2016). Dietary data were collected using repeated 24 h records. A specific questionnaire assessed dietary supplement use over a 12-month period. A composition database of about 8000 dietary supplements was developed. Associations between continuous and sex-specific quartiles of vitamins C and E, β-carotene and Se intakes and digestive cancer risk were characterised using multivariable Cox proportional hazard models. A total of 167 incident digestive cancers (120 colorectal, twenty-six pancreatic, nine oesophagus, seven stomach and five liver) were diagnosed during follow-up investigation. Dietary (hazard ratios (HR)Q4 v. Q1=0·56; 95 % CI 0·34, 0·91, P trend=0·01) and total (HRQ4 v. Q1=0·51; 95 % CI 0·30, 0·84, P trend=0·008) vitamin C intakes, dietary (HRQ4 v. Q1=0·56; 95 % CI 0·34, 0·92, P trend=0·005) and total (HRQ4 v. Q1=0·58; 95 % CI 0·36, 0·94, P trend=0·003) vitamin E intakes, and dietary (HRfor an increment of 10 µg/d=0·92; 95 % CI 0·85, 1·00, P=0·04) and total (HRfor an increment of 10 µg/d=0·92; 95 % CI 0·86, 0·99, P=0·03) Se intakes were associated with a decreased digestive cancer risk. Statistically significant interactions were observed between dietary and total Se intakes and alcohol consumption as well as between total vitamin E intake and smoking status. This prospective cohort study with quantitative assessment of supplemental intakes suggests a potential protective effect of several antioxidants (vitamins C and E and Se) on digestive cancer risk, and a modulation of some of these relationships by alcohol consumption and smoking status.


Public health over private wealth: rebalancing public and private interests in international trade and investment agreements.
The emerging global trade and investment regime is a site of ongoing contestation between states, powerful industry actors and civil society organisations seeking to influence the formation of legal rules, principles, practices and institutions. The inclusion of major transnational tobacco, alcohol and ultraprocessed food companies seeking to influence governments in these processes has resulted in the expanded distribution and consumption of unhealthy commodities across the globe, overshadowing many of the positive impacts for health hypothesised from liberalised trade. The growing number of pathways for market actors to exert undue influence over national and international regulatory environments provided by agreements, such as the Comprehensive and Progressive Agreement for Trans-Pacific Partnership, has given many cause to be concerned. In the context of continued commitment by states to international trade and investment negotiations, we present several avenues for public health scholars, advocates and practitioners to explore to rebalance public and private interests in these deals.


Technology-assisted patient access to clinical information: an evaluation framework for blue button.
Patient access to clinical information represents a means to improve the transparency and delivery of health care as well as interactions between patients and health care providers. We examine the movement toward augmenting patient access to clinical information using technology. Our analysis focuses on "Blue Button," a tool that many health care organizations are implementing as part of their Web-based patient portals. We present a framework for evaluating the effects that technology-assisted access to clinical information may have on stakeholder experiences, processes of care, and health outcomes. A case study of the United States Department of Veterans Affairs' (VA) efforts to make increasing amounts of clinical information available to patients through Blue Button. Drawing on established collaborative relationships with researchers, clinicians, and operational partners who are engaged in the VA's ongoing implementation and evaluation efforts related to Blue Button, we assessed existing evidence and organizational practices through key informant interviews, review of documents and other available materials, and an environmental scan of published literature and the websites of other health care organizations. Technology-assisted access to clinical information represents a significant advance for VA patients and marks a significant change for the VA as an organization. Evaluations of Blue Button should (1) consider both processes of care and outcomes, (2) clearly define constructs of focus, (3) examine influencing factors related to the patient population and clinical context, and (4) identify potential unintended consequences. The proposed framework can serve as a roadmap to guide subsequent research and evaluation of technology-assisted patient access to clinical information. To that end, we offer a series of related recommendations.


On the energy balance closure and net radiation in complex terrain.
In complex, sloping terrain, horizontal measurements of net radiation are not reflective of the radiative energy available for the conductive and convective heat exchange of the underlying surface. Using data from a grassland site on a mountain slope characterised by spatial heterogeneity in inclination and aspect, we tested the hypothesis that a correction of the horizontal net radiation measurements which accounts for the individual footprint contributions of the various surfaces to the measured sensible and latent heat eddy covariance fluxes will yield more realistic slope-parallel net radiation estimates compared to a correction based on the average inclination and aspect of the footprint. Our main result is that both approaches led to clear, but very similar improvements in the phase between available energy and the sum of the latent and sensible heat fluxes. As a consequence the variance in the sum of latent and sensible heat flux explained by available radiation improved by >10 %, while energy balance closure improved only slightly. This is shown to be mainly due to the average inclination and aspect corresponding largely with the inclination and aspect of the main flux source area in combination with a limited sensitivity of the slope correction to small angular differences in, particularly, inclination and aspect. We conclude with a discussion of limitations of the present approach and future research directions.


Quantum chemical study of the initial surface reactions in atomic layer deposition of TiN on the SiO(2) surface.
Cluster calculations employing hybrid density functional theory have been carried out to examine the initial surface reactions in atomic layer deposition (ALD) of TiN thin films on the SiO(2) surface using TiCl(4) and NH(3) as precursors. The potential energy surface (PES) of both half-reactions at different temperatures is presented. The first half-reaction between TiCl(4) with the SiO(2) surface is activated with an activation barrier of 0.78 eV and an exothermicity of 0.38 eV, suggesting that it is thermodynamically favourable. Also, the NH(3) half-reaction begins with the formation of amido complexes by the replacement of Cl atoms by NH(2), which is endothermic by 0.58 eV with a physisorbed HCl state (HCl-PS1). Formation of the amido complexes can be followed by an elimination reaction to form imido complexes, which has a relatively high activation barrier of 2.51 eV. In addition, the effect of the reaction temperature on the Cl impurity concentrations and film growth rate in the ALD process is also discussed.


[Organized physical activity in the elderly, a tool to improve physical fitness during ageing].
An adequate level of fitness is critical to achieving healthy ageing. The aim of this study was to evaluate the impact of organized physical activity (PA) and the number of hours of practice on the fitness levels of the elderly. A total of 3104 people over 65 years old from Spain, belonging to the EXERNET Multicenter Project (722 men and 2382 women, mean age: 72.1 ± 5.3 years) participated in the study. Fitness was evaluated by 8 specific tests for this population. Participation in organized PA was recorded through a questionnaire. Differences in fitness values depending on the participation in PA and the number of hours were measured with ANCOVA adjusting for age, hours of walking and sitting time. Those who did not participate in this type of activity increased their risk of having a low level of fitness in most variables evaluated, with some differences between sexes (OR: from 1.6 to 2.6 in men and from 1.4 to 2.2 in women). In men, no significant differences were observed between practicing less than 2, 2-4 or more than 4 hours (P grater than 0,05), with an exception in the strength of the left arm. However, women who performed more than 2 hours a week in organized PA had better balance, strength of lower and upper extremities, flexibility of lower extremities, walking speed and aerobic capacity than those who performed less than 2 hours of PA a week (P less than 0,05). The practice of organized PA produces a beneficial effect on the fitness of the elderly regardless of age, hours of walking and time sitting per day.


Osteomimicry of mammary adenocarcinoma cells in vitro; increased expression of bone matrix proteins and proliferation within a 3D collagen environment.
Bone is the most common site of metastasis for breast cancer, however the reasons for this remain unclear. We hypothesise that under certain conditions mammary cells possess osteomimetic capabilities that may allow them to adapt to, and flourish within, the bone microenvironment. Mammary cells are known to calcify within breast tissue and we have recently reported a novel in vitro model of mammary mineralization using murine mammary adenocarcinoma 4T1 cells. In this study, the osteomimetic properties of the mammary adenocarcinoma cell line and the conditions required to induce mineralization were characterized extensively. It was found that exogenous organic phosphate and inorganic phosphate induce mineralization in a dose dependent manner in 4T1 cells. Ascorbic acid and dexamethasone alone have no effect. 4T1 cells also show enhanced mineralization in response to bone morphogenetic protein 2 in the presence of phosphate supplemented media. The expression of several bone matrix proteins were monitored throughout the process of mineralization and increased expression of collagen type 1 and bone sialoprotein were detected, as determined by real-time RT-PCR. In addition, we have shown for the first time that 3D collagen glycosaminoglycan scaffolds, bioengineered to represent the bone microenvironment, are capable of supporting the growth and mineralization of 4T1 adenocarcinoma cells. These 3D scaffolds represent a novel model system for the study of mammary mineralization and bone metastasis. This work demonstrates that mammary cells are capable of osteomimicry, which may ultimately contribute to their ability to preferentially metastasize to, survive within and colonize the bone microenvironment.


Amplification by host cell factors of a sequence contained within the herpes simplex virus 1 genome.
We report that a cloned 1620-base-pair (bp) DNA fragment mapping in the BamHI O fragment of herpes simplex virus 1 DNA is amplified after transfection into uninfected cells. The DNA fragment maps entirely within a portion of the open reading frame encoding the large subunit of the viral ribonucleotide reductase and does not contain any of the known lytic origins of viral DNA synthesis. Amplification of this sequence in transfected cells results in accumulation of full-sized Dpn I-resistant plasmids containing the sequence in Hirt extracts of low molecular weight DNA. Subfragments of the 1620-bp fragment were not amplified, whereas larger fragments containing the intact 1620-bp fragment were amplified. The amplification of the fragment in MCF7 cells, which express steroid receptors, was stimulated by the addition of estrogen to the medium. Addition of progesterone, dexamethasone, or testosterone was ineffective. The viral genome therefore contains at least one origin of DNA synthesis capable of supporting replication of viral DNA by cellular factors. The existence of such a host origin of DNA replication in the viral genome was predicted by the hypothesis that viral DNA is amplified by cellular enzymes in sensory neurons harboring latent virus; the link between these sequences and amplification of viral DNA during latency remains to be proven.


The c-Abl-MST1 signaling pathway mediates oxidative stress-induced neuronal cell death.
Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. The protein kinase MST1 (mammalian Ste20-like kinase 1) plays a major role in oxidative stress-induced cell death in primary mammalian neurons. However, the mechanisms that regulate MST1 in oxidative stress responses remain largely unknown. In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1. Inhibition of c-Abl promotes the degradation of MST1 through C terminus of Hsc70-interacting protein (CHIP)-mediated ubiquitination, and thereby attenuates cell death. Oxidative stress induces the c-Abl-dependent tyrosine phosphorylation of MST1 and increases the interaction between MST1 and FOXO3 (Forkhead box O3), thereby activating the MST1-FOXO signaling pathway, leading to cell death in both primary culture neurons and rat hippocampal neurons. The identification of the c-Abl tyrosine kinase as a novel upstream activator of MST1 suggests that the c-Abl-MST1 signaling cascade plays an important role in cellular responses to oxidative stress.


Constitutive formation of caveolae in a bacterium.
Caveolin plays an essential role in the formation of characteristic surface pits, caveolae, which cover the surface of many animal cells. The fundamental principles of caveola formation are only slowly emerging. Here we show that caveolin expression in a prokaryotic host lacking any intracellular membrane system drives the formation of cytoplasmic vesicles containing polymeric caveolin. Vesicle formation is induced by expression of wild-type caveolins, but not caveolin mutants defective in caveola formation in mammalian systems. In addition, cryoelectron tomography shows that the induced membrane domains are equivalent in size and caveolin density to native caveolae and reveals a possible polyhedral arrangement of caveolin oligomers. The caveolin-induced vesicles or heterologous caveolae (h-caveolae) form by budding in from the cytoplasmic membrane, generating a membrane domain with distinct lipid composition. Periplasmic solutes are encapsulated in the budding h-caveola, and purified h-caveolae can be tailored to be targeted to specific cells of interest.


Ultra-low-loss high-aspect-ratio Si3N4 waveguides.
We characterize an approach to make ultra-low-loss waveguides using stable and reproducible stoichiometric Si3N4 deposited with low-pressure chemical vapor deposition. Using a high-aspect-ratio core geometry, record low losses of 8-9 dB/m for a 0.5 mm bend radius down to 3 dB/m for a 2 mm bend radius are measured with ring resonator and optical frequency domain reflectometry techniques. From a waveguide loss model that agrees well with experimental results, we project that 0.1 dB/m total propagation loss is achievable at a 7 mm bend radius with this approach.


Pathogenesis II: fungal responses to host responses: interaction of host cells with fungi.
Most of our knowledge concerning the virulence determinants of pathogenic fungi comes from the infected host, mainly from animal models and more recently from in vitro studies with cell cultures. The fungi usually present intra- and/or extracellular host-parasite interfaces, with the parasitism phenomenon dependent on complementary surface molecules. Among living organisms, this has been characterized as a cohabitation event, where the fungus is able to recognize specific host tissues acting as an attractant, creating stable conditions for its survival. Several fungi pathogenic for humans and animals have evolved special strategies to deliver elements to their cellular targets that may be relevant to their pathogenicity. Most of these pathogens express surface factors that mediate binding to host cells either directly or indirectly, in the latter case binding to host adhesion components such as extracellular matrix (ECM) proteins, which act as 'interlinking' molecules. The entry of the pathogen into the host cell is initiated by fungal adherence to the cell surface, which generates an uptake signal that may induce its cytoplasmic internalization. Once this is accomplished, some fungi are able to alter the host cytoskeletal architecture, as manifested by a rearrangement of microtubule and microfilament proteins, and this can also induce epithelial host cells to become apoptotic. It is possible that fungal pathogens induce modulation of different host cell pathways in order to evade host defences and to foster their own proliferation. For a number of pathogens, the ability to bind ECM glycoproteins, the capability of internalization and the induction of apoptosis are considered important factors in virulence. Furthermore, specific recognition between fungal parasites and their host cell targets may be mediated by the interaction of carbohydrate-binding proteins, e.g., lectins on the surface of one type of cell, probably a parasite, that combine with complementary sugars on the surface of host-cell. These interactions supply precise models to study putative adhesins and receptor-containing molecules in the context of the fungus-host interface. The recognition of the host molecules by fungi such as Aspergillus fumigatus, Paracoccidioides brasiliensis and Histoplasma capsulatum, and their molecular mechanisms of adhesion and invasion, are reviewed in this paper.


Italian Guidelines in Patch Testing - adapted from the European Society of Contact Dermatitis (ESCD).
Patch testing is the standard procedure used to diagnose allergic contact dermatitis. It is an in-vivo test, which reproduces the reaction to a contact allergen. This in-vivo test aims to reproduce the elicitation phase of allergic contact dermatitis and is performed applying allergens under occlusion on the skin under standardized conditions. These guidelines for the best practice in performing patch test have been developed by an Italian group of experts taking in account the Italian legislation and local pharmacological governance. Guidelines are adapted from the original article under the guidance of the European Society of Contact Dermatitis (ESCD) and on the basis of the SIDAPA guidelines.


An analysis of the association between older recipient age and outcomes after whole-organ pancreas transplantation - a single-centre, retrospective study.
Older people are increasingly being referred for consideration for pancreas transplantation (PT). We investigated the outcomes after PT in our older recipient cohort. A prospectively maintained database was interrogated. The cohort was analysed for associations between outcome and older recipient age. A total of 444 transplants were performed in patients aged 23-54 years and 83 transplants in patients aged 55-67 years. There was no difference in death-censored pancreas or kidney graft survival between the groups. Patient death was associated with older recipient age (HR 1.63 per 10-year increase). In multivariate Cox regression, risk of mortality was also associated with post-transplant myocardial infarction (HR 7.25, P = 0.006), pancreas failure (HR 1.91, P = 0.003) and kidney failure (HR 3.55, P < 0.001). About 40% of recipients who died in the first year post-transplant suffered early graft loss. Those alive at a year post-transplant had inferior survival if they had lost their kidney graft (P < 0.001). Mortality is higher in older patients and is strongly associated with pancreas and kidney graft failure. This suggests that pancreas transplantation is feasible in older recipients, and careful selection of donor organs is important to optimize survival.


Inhibition of angiogenesis mediated by extremely low-frequency magnetic fields (ELF-MFs).
The formation of new blood vessels is an essential therapeutic target in many diseases such as cancer, ischemic diseases, and chronic inflammation. In this regard, extremely low-frequency (ELF) electromagnetic fields (EMFs) seem able to inhibit vessel growth when used in a specific window of amplitude. To investigate the mechanism of anti-angiogenic action of ELF-EMFs we tested the effect of a sinusoidal magnetic field (MF) of 2 mT intensity and frequency of 50 Hz on endothelial cell models HUVEC and MS-1 measuring cell status and proliferation, motility and tubule formation ability. MS-1 cells when injected in mice determined a rapid tumor-like growth that was significantly reduced in mice inoculated with MF-exposed cells. In particular, histological analysis of tumors derived from mice inoculated with MF-exposed MS-1 cells indicated a reduction of hemangioma size, of blood-filled spaces, and in hemorrhage. In parallel, in vitro proliferation of MS-1 treated with MF was significantly inhibited. We also found that the MF-exposure down-regulated the process of proliferation, migration and formation of tubule-like structures in HUVECs. Using western blotting and immunofluorescence analysis, we collected data about the possible influence of MF on the signalling pathway activated by the vascular endothelial growth factor (VEGF). In particular, MF exposure significantly reduced the expression and activation levels of VEGFR2, suggesting a direct or indirect influence of MF on VEGF receptors placed on cellular membrane. In conclusion MF reduced, in vitro and in vivo, the ability of endothelial cells to form new vessels, most probably affecting VEGF signal transduction pathway that was less responsive to activation. These findings could not only explain the mechanism of anti-angiogenic action exerted by MFs, but also promote the possible development of new therapeutic applications for treatment of those diseases where excessive angiogenesis is involved.


Effect of bacterial endotoxin and interleukin-1 beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: an in vivo microdialysis study.
In this study the effect of immune system stimulation and intracerebroventricular (i.c.v.) administration of interleukin-1 beta (IL-1 beta) on hippocampal serotonergic neurotransmission, behavioral activity, and the hypothalamic-pituitary-adrenocortical (HPA) axis is described. An in vivo microdialysis method was used to measure hippocampal extracellular concentrations of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in conscious, freely moving rats. In addition, we established a method to continuously monitor free corticosterone levels in dialysates. Behavioral activity was scored by measuring the time during which rats were active (locomotion, grooming, eating, drinking). We found a significant, positive relationship between behavioral activity and hippocampal extracellular concentrations of 5-HT. Intraperitoneal (i.p.) administration of the bacterial endotoxin lipopolysaccharide (LPS; 30, 100, and 300 micrograms/kg body weight) produced an increase in the extracellular concentrations of 5-HT and 5-HIAA in the hippocampus, which was paralleled by a significant decline in behavioral activity and a marked increase in extracellular corticosterone levels. Thus, the close correlation between hippocampal extracellular 5-HT levels and behavioral activity observed in control rats was disrupted in the LPS-treated animals. The effects of i.p. LPS could be mimicked by i.c.v. application of recombinant human IL-1 beta (hIL-1 beta; 100 ng). i.c.v. pretreatment with the IL-1 receptor antagonist (IL-1ra; 10 micrograms) antagonized the hIL-1 beta-induced effects. IL-1ra showed no intrinsic effects. Furthermore, it was found that i.c.v. pretreatment with IL-1ra (10 micrograms) significantly attenuated the i.p. LPS-induced (100 micrograms/kg body weight) rise in hippocampal extracellular 5-HT levels.(ABSTRACT TRUNCATED AT 250 WORDS)


Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis.
The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10-8 to 5 x 10-10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1*0103 (odds ratio [OR] = 6.941, p = 1.92*10-13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1*1301 (OR = 2.25, p = 7.92*10-9) and another SNP rs17188113 (OR = 0.48, p = 7.56*10-9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1*0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10-10) and female gender (OR = 8.85, p = 4.82x10-13). In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.


Risk Factors and Clinical Features in Cashew Nut Oral Food Challenges.
Cashew nuts (CN) are capable of causing severe allergic reactions. However, little has been reported about the details of CN oral food challenges (OFC). CN-specific IgE (sIgE) levels were measured for 1 year in 66 patients who underwent an OFC with >3 g CN for diagnosis or confirmation of tolerance acquisition between June 2006 and August 2014. We retrospectively analyzed the OFC and patient background. The median (IQR) age of the 66 patients (48 boys/men and 18 girls/women) was 7.0 years (5.7-8.8). Twelve patients (18.2%) had a positive OFC result; 6 of 8 (75%) patients with a history of an immediate reaction to CN failed the OFC. Anaphylaxis was experienced by 5 of these 12 (42%) patients. A history of an immediate reaction to CN and the CN sIgE levels were significantly different for patients with a positive or negative OFC result (p < 0.01). Among patients without a previous immediate reaction to CN, the 95% positive predictive value (PPV) for the CN sIgE level for a positive OFC result was 66.1 kUA/L. A history of an immediate reaction to CN and high CN sIgE were risk factors for a positive OFC result. The number of positive OFC results was relatively low, but there was a high probability of anaphylaxis. We should consider the indication of OFC carefully for patients with a history of immediate reactions to CN and avoid OFC for patients without such a history whose CN sIgE values are >66.1 kUA/L (95% PPV).


IFN-gamma activates the C3G/Rap1 signaling pathway.
IFN-gamma transduces signals by activating the IFN-gamma receptor-associated Jak-1 and Jak-2 kinases and by inducing tyrosine phosphorylation and activation of the Stat-1 transcriptional activator. We report that IFN-gamma activates a distinct signaling cascade involving the c-cbl protooncogene product, CrkL adapter, and small G protein Rap1. During treatment of NB-4 human cells with IFN-gamma, c-cbl protooncogene product is rapidly phosphorylated on tyrosine and provides a docking site for the src homology 2 domain of CrkL, which also undergoes IFN-gamma-dependent tyrosine phosphorylation. CrkL then regulates activation of the guanine exchange factor C3G, with which it interacts constitutively via its N terminus src homology 3 domain. This results in the IFN-gamma-dependent activation of Rap1, a protein known to exhibit tumor suppressor activity and mediate growth inhibitory responses. In a similar manner, Rap1 is also activated in response to treatment of cells with type I IFNs (IFN-alpha, IFN-beta), which also engage CrkL in their signaling pathways. On the other hand, IFN-gamma does not induce formation of nuclear CrkL-Stat5 DNA-binding complexes, which are induced by IFN-alpha and IFN-beta, indicating that pathways downstream of CrkL are differentially regulated by different IFN subtypes. Taken altogether, our data demonstrate that, in addition to activating the Stat pathway, IFN-gamma activates a distinct signaling cascade that may play an important role in the generation of its growth inhibitory effects on target cells.


Life history tactics shape amphibians' demographic responses to the North Atlantic Oscillation.
Over the last three decades, climate abnormalities have been reported to be involved in biodiversity decline by affecting population dynamics. A growing number of studies have shown that the North Atlantic Oscillation (NAO) influences the demographic parameters of a wide range of plant and animal taxa in different ways. Life history theory could help to understand these different demographic responses to the NAO. Indeed, theory states that the impact of weather variation on a species' demographic traits should depend on its position along the fast-slow continuum. In particular, it is expected that NAO would have a higher impact on recruitment than on adult survival in slow species, while the opposite pattern is expected occur in fast species. To test these predictions, we used long-term capture-recapture datasets (more than 15,000 individuals marked from 1965 to 2015) on different surveyed populations of three amphibian species in Western Europe: Triturus cristatus, Bombina variegata, and Salamandra salamandra. Despite substantial intraspecific variation, our study revealed that these three species differ in their position on a slow-fast gradient of pace of life. Our results also suggest that the differences in life history tactics influence amphibian responses to NAO fluctuations: Adult survival was most affected by the NAO in the species with the fastest pace of life (T. cristatus), whereas recruitment was most impacted in species with a slower pace of life (B. variegata and S. salamandra). In the context of climate change, our findings suggest that the capacity of organisms to deal with future changes in NAO values could be closely linked to their position on the fast-slow continuum.


Dose prescription and optimisation based on tumour hypoxia.
INTRODUCTION. Tumour hypoxia is an important factor that confers radioresistance to the affected cells and could thus decrease the tumour response to radiotherapy. The development of advanced imaging methods that quantify both the extent and the spatial distribution of the hypoxic regions has created the premises to devise therapies that target the hypoxic regions in the tumour. MATERIALS AND METHODS. The present study proposes an original method to prescribe objectively dose distributions that focus the radiation dose to the radioresistant tumour regions and could therefore spare adjacent normal tissues. The effectiveness of the method was tested for clinically relevant simulations of tumour hypoxia that take into consideration dynamics and heterogeneity of oxygenation. RESULTS AND DISCUSSION. The results have shown that highly heterogeneous dose distributions may lead to significant improvements of the outcome only for static oxygenations. In contrast, the proposed method that involves the segmentation of the dose distributions and the optimisation of the dose prescribed to each segment to account for local heterogeneity may lead to significantly improved local control for clinically-relevant patterns of oxygenation. The clinical applicability of the method is warranted by its relatively easy adaptation to functional imaging of tumour hypoxia obtained with markers with known uptake properties.


Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.
The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .).


Immunophenotyping of peripheral eosinophils demonstrates activation in eosinophilic esophagitis.
Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by upper gastrointestinal symptoms and the presence of high numbers of eosinophils in the esophagus. Although eosinophils in the esophagus have been found to be activated in subjects with EoE, detailed studies of intracellular signaling pathways involved in the mechanism of activation of eosinophils in EoE have heretofore been limited. The aim of the study was to assess whether any surface molecules or transcription factors are activated in peripheral eosinophils in subjects with EoE. Eosinophils and CD3+ lymphocytes were identified directly from 50 μL of whole blood of EoE and control subjects. Using Hi-FACS, levels of surface activation markers, including CD66b, and intracellular phosphoepitopes, including phosphorylated forms of signal transducer and activator of transcription (phospho-STAT) 1 and 6, were measured within each cell subset. Levels of surface CD66b as well as levels of intracellular phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were significantly higher for untreated subjects with EoE vs healthy controls (P < 0.05). Levels of phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were lower in subjects with EoE on therapy versus untreated subjects with EoE (P < 0.05). Levels of phospho-STAT1 and phospho-STAT6, transcription factors involved in inflammatory processes, were both significantly higher in peripheral eosinophils from untreated (ie, newly diagnosed) subjects with EoE versus subjects with EoE on therapy, healthy controls. Blood-based measurements of CD66b and phospho-STAT levels in peripheral eosinophils may be beneficial for identifying EoE.


Effect of prophylactic topical brimonidine (0.15%) administration on the development of subconjunctival hemorrhage after intravitreal injection.
Brimonidine (0.15%), which is used to lower intraocular pressure, is an α-2-adrenergic agonist that has vasoconstrictive effects. This study examined whether the administration of brimonidine (0.15%) before intravitreal injection prevents subconjunctival hemorrhage. A prospective, randomized, double-masked single-center study. Two hundred and forty-four patients (244 eyes) who underwent intravitreal injection were prospectively examined. The control group (118 eyes) was given normal saline, while the experimental group received 0.15% brimonidine (126 eyes) 30 minutes before the intravitreal injection. On Days 1 and 7, the treatment outcome was assessed using slit-lamp microscopy. The severity of subconjunctival hemorrhage was scored on a scale of 1 (mild) to 3 (severe). To determine the size of the affected area, the lengths of the short and long axes of the subconjunctival hemorrhage were measured in millimeters and then multiplied. To consider both the severity and the size of subconjunctival hemorrhage, the severity score was multiplied by the size of the subconjunctival hemorrhage. Subconjunctival hemorrhage occurred as a result of intravitreal injection in 13.5% (17 eyes) of the brimonidine group and in 29.7% (35 eyes) of the control group (P = 0.003). On Days 1 and 7, the severity and size of the subconjunctival hemorrhage and the product of these 2 parameters were significantly lower in the brimonidine group. The administration of 0.15% brimonidine before an intravitreal injection decreased the incidence, severity, and size of subconjunctival hemorrhage.


New instrumentation system for cementless mobile-bearing unicompartmental knee arthroplasty improves surgical performance particularly for trainees.
Mobile-bearing medial-unicompartmental knee arthroplasty (mUKA) has a documented learning curve. New instrumentation has been designed with the aim of reducing the technical challenges of this procedure. The primary aim of this study was to evaluate the technical performance of mUKA using new (Microplasty) versus older (Phase III) instrumentation, performed by expert surgeons and trainees. Secondary aims were to evaluate functional outcome and mid-term survivorship. A time-based comparative cohort study was performed between 2009 and 2015 at a high-volume centre. 273 patients (273 knees, 49.5% female) of mean age 67.8 (standard deviation 10.1) years underwent mUKA. 153 (56.0%) procedures used Microplasty instruments and 120 procedures (44.0%) used Phase III instruments. Non-optimal bearing usage was less frequent with Microplasty than Phase III instruments (24 knees [15.7%] versus 33 knees [27.5%], p = 0.024), with differences due to improved trainee performance. Femoral component sagittal alignment outliers were less frequent with Microplasty, but this was not statistically significant (9 knees [5.9%] versus 13 knees [10.8%], p = 0.18). Post-operative Oxford Knee Scores (OKS) were better with Microplasty (median 42 points [interquartile range 38-44]) compared to Phase III (median 39.5 points [IQR 33-44]), which was statistically significant (p = 0.023), but not clinically meaningful. The overall 5-year Kaplan-Meier (KM) survival estimate was 99.3% (95% CI 97.0-99.8%), with no differences between Microplasty and Phase III instrumentation. New instrumentation improved the reliability of the proximal tibial resection in trainees. Further research is warranted to investigate whether Microplasty instrumentation shortens the learning curve for medial UKA.


Imaging in prostate cancer diagnosis: present role and future perspectives.
Prostate cancer (PCa) remains a major health concern for the male population. Detection and primary diagnosis of PCa are based on digital rectal examination, serum prostate-specific antigen levels, and transrectal ultrasound (TRUS)-guided random biopsy. Moreover, the gold standard for detecting PCa, systematic biopsy, lacks sensitivity as well as grading accuracy. This review summarizes recent developments of ultrasonography modalities and functional magnetic resonance imaging (MRI) in the diagnosis of PCa. A comparison between the different methods is presented, including their clinical value and usefulness. It is concluded that innovative ultrasound techniques (including ultrasound contrast agents, 3-D and 4-D sonography, elastography and harmonic sonography) promise benefits in comparison to standard TRUS to accurately diagnose PCa. Promising advances have been made in the detection of PCa with multiparametric MRI. The combination of conventional and functional MRI techniques (including diffusion-weighted imaging, dynamic contrast-enhanced MRI, and MR spectroscopy) can provide information for differentiating PCa from noncancerous tissue and can be used for MRI-guided biopsies, especially in patients with persistent elevation of serum prostate-specific antigen and previous negative TRUS-guided biopsies. However, functional MRI technique and MRI-guided biopsy remain expensive and complex tools presenting inherent challenges.


Feasibility and acceptability of web-based enhanced relapse prevention for bipolar disorder (ERPonline): trial protocol.
Relapse prevention interventions for Bipolar Disorder are effective but implementation in routine clinical services is poor. Web-based approaches offer a way to offer easily accessible access to evidence based interventions at low cost, and have been shown to be effective for other mood disorders. This protocol describes the development and feasibility testing of the ERPonline web-based intervention using a single blind randomised controlled trial. Data will include the extent to which the site was used, detailed feedback from users about their experiences of the site, reported benefits and costs to mental health and wellbeing of users, and costs and savings to health services. We will gain an estimate of the likely effect size of ERPonline on a range of important outcomes including mood, functioning, quality of life and recovery. We will explore potential mechanisms of change, giving us a greater understanding of the underlying processes of change, and consequently how the site could be made more effective. We will be able to determine rates of recruitment and retention, and identify what factors could improve these rates. The findings will be used to improve the site in accordance with user needs, and inform the design of a large scale evaluation of the clinical and cost effectiveness of ERPonline. They will further contribute to the growing evidence base for web-based interventions designed to support people with mental health problems.


Memory T cells constitute a subset of the human CD8+CD45RA+ pool with distinct phenotypic and migratory characteristics.
Using HLA class I-viral epitope tetramers to monitor herpes virus-specific CD8(+) T cell responses in humans, we have shown that a significant fraction of responding cells revert from a CD45RO(+) to a CD45RA(+) state after priming. All tetramer-binding CD45RA(+) cells, regardless of epitope specificity, expressed a phenotype LFA-1(high)CCR7(low) that was stable for at least 10 years in infectious mononucleosis patients and indefinitely in asymptomatic carriers. CD8(+)CD45RA(+)LFA-1(high) cells were not present in cord blood but in adults account for up to 50% of CD8(+)CD45RA(+) cells. These CD45RA(+)LFA-1(high) cells have significantly shorter telomeres than CD45RA(+)LFA-1(low) cells, suggesting that the latter represent a naive population, while the former are memory cells. CD45RA(+) memory cells are a stable population of noncycling cells, but on stimulation they are potent producers of IFN-gamma, while naive CD8(+) cells produce only IL-2. The chemokine receptor profile and migratory potential of CD45RA(+) memory cells is very similar to CD45RO(+) cells but different to naive CD8 cells. In accord with this, CD45RA(+) memory cells were significantly underrepresented in lymph nodes, but account for virtually all CD8(+)CD45RA(+) T cells in peripheral tissues of the same individuals.


Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3.
In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine analogues which are inhibitors of human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes to explore a wide variety of substitution patterns and convergently access a diverse array of analogues. Compound 1 (CHIR-911, CT-99021, or CHIR-73911) emerged from an exploration of heterocycles at the C-5 position, phenyl groups at C-4, and a variety of differently substituted linker and aminopyridine moieties attached at the C-2 position. These compounds exhibited GSK3 IC50s in the low nanomolar range and excellent selectivity. They activate glycogen synthase in insulin receptor-expressing CHO-IR cells and primary rat hepatocytes. Evaluation of lead compounds 1 and 2 (CHIR-611 or CT-98014) in rodent models of type 2 diabetes revealed that single oral doses lowered hyperglycemia within 60 min, enhanced insulin-stimulated glucose transport, and improved glucose disposal without increasing insulin levels.


Reemergence of yellow fever: detection of transmission in the State of São Paulo, Brazil, 2008.
Following yellow fever virus (YFV) isolation in monkeys from the São José do Rio Preto region and two fatal human autochthonous cases from the Ribeirão Preto region, State of São Paulo, Brazil, two expeditions for entomological research and eco-epidemiological evaluation were conducted. A total of 577 samples from humans, 108 from monkeys and 3,049 mosquitoes were analyzed by one or more methods: virus isolation, ELISA-IgM, RT-PCR, histopathology and immunohistochemical. Of the 577 human samples, 531 were tested by ELISA-IgM, with 3 positives, and 235 were inoculated into mice and 199 in cell culture, resulting in one virus isolation. One sample was positive by histopathology and immunohistochemical. Using RT-PCR, 25 samples were processed with 4 positive reactions. A total of 108 specimens of monkeys were examined, 108 were inoculated into mice and 45 in cell culture. Four virus strains were isolated from Alouatta caraya. A total of 931 mosquitoes were captured in Sao Jose do Rio Preto and 2,118 in Ribeirão Preto and separated into batches. A single isolation of YFV was derived from a batch of 9 mosquitoes Psorophora ferox, collected in Urupês, Ribeirão Preto region. A serological survey was conducted with 128 samples from the municipalities of São Carlos, Rincão and Ribeirão Preto and 10 samples from contacts of patients from Ribeirão Preto. All samples were negative by ELISA-IgM for YFV. The results confirm the circulation of yellow fever, even though sporadic, in the Sao Paulo State and reinforce the importance of vaccination against yellow fever in areas considered at risk.


Electronic and structural properties of fluorene-thiophene copolymers as function of the composition ratio between the moieties: a theoretical study.
Through theoretical analysis, we study relevant properties of some molecular structures formed by oligothiophenes (T) and dioctylfluorenes (F) units, commonly employed in the fabrication of different kinds of optical and electronic devices. For so, we first consider F-(T)n-F molecules with different numbers of thiophene rings (n). Among other characteristics, we calculate the dipole moment change between the ground and excited state (Δμge), a quantity that greatly influences the exciton dissociation and charge carrier mobility. We show that the planarity of the ground state geometry correlates Δμge to the exciton binding energy (Eb), with higher Δμge's corresponding to lower Eb's when n > 3. We also unveil a relevant dependence of Δμge with the odd-even parity of n and that Δμge assumes higher values when the molecule is composed by bithiophene (instead of simple thiophenes) moieties in the syn-conformation (with the two heteroatoms pointing in the same direction). From molecules results, we then address larger systems, formed by different oligomers of F-T copolymers containing blocks of dioctylfluorenes and bithiophenes (T2). We systematic investigate their electronic and structural properties as function of the composition ratio between the T2 and F moieties. Similar to the molecules, we deduce that the magnitude of Δμge is higher for the syn conformer of the T2 unit. Moreover, the highest values of Δμge are achieved when the number of the T2 increases relative to a fixed number of the F units in the mer. Such behaviors are in agreement and actually can qualitative explain measurements in the literature on the quantum efficiency of charge carrier generation in F-T copolymers. The present findings can be helpful in designing novel materials with improved photoelectric responses.


Evaluation of a train-the-trainer workshop on sickle cell disease for ED providers.
(1) Determine the difference in pre-test and post-test knowledge scores for attendees of a train-the-trainer workshop and (2) determine the number of attendees who disseminated the content within 6 months of attending the workshop. A 1-day, train-the-trainer workshop focusing on sickle cell disease (SCD) was developed. ED nurses and physicians from the emergency departments with the highest number of patients with SCD were invited to participate at no cost. A panel consisting of 6 SCD and ED experts planned the workshop and developed 20 items for pre-test and post-test knowledge evaluation. The pre-test and post-test were administered at the beginning and end of the workshop, respectively. All attendees received a flash drive with all conference materials and were asked to disseminate workshop content to other ED colleagues. After 6 months, a brief survey was sent to the participants using Survey Monkey asking the number and type of providers trained. Fifty-five participants attended the workshop. The mean (SD) pre-test score for the entire cohort was 13 (2) and the post-test score was 16 (2); mean difference (95% CI) 2.96 (2.36, 3.57). Items that scored low included questions dealing with pathophysiologic complications, addiction, or ED utilization. Eighteen participants completed the 6-month follow-up survey. Seven participants reported disseminating workshop content to a total of 99 providers. A train-the-trainer workshop specifically designed for emergency physicians and nurses that discussed the broad spectrum of SCD was well attended, and 6 months later, 99 additional providers received training.


Cancer epidemiology in the pacific islands - past, present and future.
The Pacific Ocean contains approximately 25,000 islands, stretching from Papua New Guinea to Easter Island, populated by mixtures of Melanesians, Micronesians and Polynesians, as well as migrant groups from Asia and Europe. The region encompasses a third of the surface of the earth although it is sparsely populated at a total of around 9 million. With the exception of some of the more populated islands, such as New Zealand and Hawaii, few surveys of chronic diseases have been conducted, but it is increasingly recognized that obesity, diabetes and associated conditions are emerging public health problems and clearly there is a need for cooperation to optimize control. Here we focus on cancer registry and epidemiological findings for Papua New Guinea, the Solomons, Vanuatu, Samoa, New Caledonia, Fiji, Polynesia, French Polynesia, Maori in New Zealand, Native Hawaiians, Micronesia, including Guam, and Aboriginal populations in Australia as assessed by PubMed searches and perusal of the International Agency for Cancer Research descriptive epidemiology database. Overall, the major cancers in males are oral and liver in Papua New Guinea and the Solomon Islands, and lung and prostate elsewhere (Fiji being exceptional in demonstrating a predominance of esophageal cancer), whereas in females it is breast and either cervix or lung, depending largely on whether cervical cancer screening program is active. In certain locations thyroid cancer is also very prevalent in females. The similarities and variation point to advantages for collaborative research to provide the evidence-base for effective cancer control programs in the region.


Liver Microvascular Injury and Thrombocytopenia of Antibody-Calicheamicin Conjugates in Cynomolgus Monkeys-Mechanism and Monitoring.
Purpose: Adverse reactions reported in patients treated with antibody-calicheamicin conjugates such as gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin include thrombocytopenia and sinusoidal obstruction syndrome (SOS). The objective of this experimental work was to investigate the mechanism for thrombocytopenia, characterize the liver injury, and identify potential safety biomarkers.Experimental Design: Cynomolgus monkeys were dosed intravenously at 6 mg/m2/dose once every 3 weeks with a nonbinding antibody-calicheamicin conjugate (PF-0259) containing the same linker-payload as gemtuzumab ozogamicin and inotuzumab ozogamicin. Monkeys were necropsied 48 hours after the first administration (day 3) or 3 weeks after the third administration (day 63).Results: PF-0259 induced acute thrombocytopenia (up to 86% platelet reduction) with nadirs on days 3 to 4. There was no indication of effects on megakaryocytes in bone marrow or activation of platelets in peripheral blood. Microscopic evaluation of liver from animals necropsied on day 3 demonstrated midzonal degeneration and loss of sinusoidal endothelial cells (SECs) associated with marked platelet accumulation in sinusoids. Liver histopathology on day 63 showed variable endothelial recovery and progression to a combination of sinusoidal capillarization and sinusoidal dilation/hepatocellular atrophy, consistent with early SOS. Among biomarkers evaluated, there were early and sustained increases in serum hyaluronic acid (HA) that correlated well with serum aspartate aminotransferase and liver microscopic changes, suggesting that HA may be a sensitive diagnostic marker of the liver microvascular injury.Conclusions: These data support the conclusion that target-independent damage to liver SECs may be responsible for acute thrombocytopenia (through platelet sequestration in liver sinusoids) and development of SOS. Clin Cancer Res; 23(7); 1760-70. ©2016 AACR.


Spinal neoplasms in small animals.
Tumors arising from or involving the spinal cord are important considerations in animals presented for pain and limb dysfunction. Clinical signs of spinal cord dysfunction, however, are not pathognomic for neoplastic disease in most instances. Advanced magnetic resonance imaging (MRI) often accurately identifies the location and extent of abnormalities. Although some spinal neoplasms have a characteristic appearance with MRI, in other instances the abnormalities may not be readily discernable as neoplastic. Histologic diagnosis, therefore, is imperative to provide information regarding potential treatment modalities and prognosis. Histologic diagnosis is most commonly performed following surgical biopsy and is often performed in combination with surgical removal.


Connectivity, pharmacology, and computation: toward a mechanistic understanding of neural system dysfunction in schizophrenia.
Neuropsychiatric diseases such as schizophrenia and bipolar illness alter the structure and function of distributed neural networks. Functional neuroimaging tools have evolved sufficiently to reliably detect system-level disturbances in neural networks. This review focuses on recent findings in schizophrenia and bipolar illness using resting-state neuroimaging, an advantageous approach for biomarker development given its ease of data collection and lack of task-based confounds. These benefits notwithstanding, neuroimaging does not yet allow the evaluation of individual neurons within local circuits, where pharmacological treatments ultimately exert their effects. This limitation constitutes an important obstacle in translating findings from animal research to humans and from healthy humans to patient populations. Integrating new neuroscientific tools may help to bridge some of these gaps. We specifically discuss two complementary approaches. The first is pharmacological manipulations in healthy volunteers, which transiently mimic some cardinal features of psychiatric conditions. We specifically focus on recent neuroimaging studies using the NMDA receptor antagonist, ketamine, to probe glutamate synaptic dysfunction associated with schizophrenia. Second, we discuss the combination of human pharmacological imaging with biophysically informed computational models developed to guide the interpretation of functional imaging studies and to inform the development of pathophysiologic hypotheses. To illustrate this approach, we review clinical investigations in addition to recent findings of how computational modeling has guided inferences drawn from our studies involving ketamine administration to healthy subjects. Thus, this review asserts that linking experimental studies in humans with computational models will advance to effort to bridge cellular, systems, and clinical neuroscience approaches to psychiatric disorders.


Pterostilbene, a bioactive component of blueberries, alleviates renal fibrosis in a severe mouse model of hyperuricemic nephropathy.
Accumulating evidences indicated that hyperuricemia was an independent risk factor for kidney diseases and contributed to kidney fibrosis. Preventing and treating renal fibrosis was an optimal treatment for hyperuricemia-induced kidney diseases. In the study, pterostilbene (PTE) as a bioactive component of blueberries was confirmed to possess lowering serum uric acid and renal protective functions by the decrease of serum creatinine, BUN, urine albumin, and urine albumin-to-creatinine ratio (uACR) in a mouse model of hyperuricemic nephropathy (HN). Importantly, PTE treatment remarkably alleviated renal fibrosis of HN mice indicated by the downregulation of fibronectin, collagen I and α-SMA production. Furthermore, PTE could suppress the fibrosis-related protein expressions of TGF-β1/Smad3, Src and STAT3 in the kidneys of HN mice. In conclusion, PTE suppressed the activation of TGF-β1/Smad3, Src and STAT3 signaling pathway to alleviate renal fibrosis of HN mice, highlighting that PTE was a potential antifibrotic strategy for hyperuricemic nephropathy.


Efficacy and safety of apixaban compared with warfarin for stroke prevention in patients with atrial fibrillation from East Asia: a subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.
The perceived risk of serious bleeding is an obstacle to the use of oral anticoagulation in East Asia. The efficacy and safety of apixaban in East Asian patients with atrial fibrillation are unknown. ARISTOTLE included 18,201 patients with nonvalvular atrial fibrillation randomized to apixaban 5mg twice daily or warfarin. The efficacy and safety of apixaban and warfarin among patients recruited from East Asia (n = 1,993) were compared with those recruited from outside East Asia (n = 16,208). Compared with warfarin, apixaban resulted in a consistent reduction in stroke or systemic embolism in East Asian (hazard ratio [HR] 0.74, 95% CI 0.50-1.10) and non-East Asian (HR 0.81, 95% CI 0.66-0.99) patients (interaction P = .70). Consistent benefits of apixaban over warfarin were also seen for major bleeding in East Asian (HR 0.53, 95% CI 0.35-0.80) and non-East Asian (HR 0.72, 95% CI 0.62-0.83) patients (interaction P = .17). There was a greater reduction in major or clinically relevant nonmajor bleeding with apixaban compared with warfarin in East Asian (HR 0.49, 95% CI 0.35-0.67) than in non-East Asian (HR 0.71, 95% CI 0.63-0.79) patients (interaction P = .03). Numerically higher rates of intracranial bleeding were seen in East Asian patients with warfarin but not with apixaban. Apixaban resulted in similar reductions in stroke or systemic embolism and major bleeding and greater reductions in major or clinically relevant nonmajor bleeding in patients from East Asia. Warfarin is associated with more intracranial bleeding, particularly in patients from East Asia.


Developmental activities that contribute to high or low performance by elite cricket batters when recognizing type of delivery from bowlers' advanced postural cues.
We examined the developmental activities that contribute to the development of superior anticipation skill among elite cricket batters. The batters viewed 36 video clips involving deliveries from bowlers that were occluded at ball release and were required to predict delivery type. Accuracy scores were used to create two subgroups: high-performing and low-performing anticipators. Questionnaires were used to record the participation history profiles of the groups. In the early stages of development, hours accumulated in cricket and other sports, as well as milestones achieved, did not differentiate groups. Significant between-group differences in activity profiles were found between 13 and 15 years of age, with high-performing anticipators accumulating more hours in structured cricket activity, and specifically in batting, compared with their low-performing counterparts.