Humoral and cytotoxic T cell immune responses to internal and external structural proteins of simian virus 5 induced by immunization with solid matrix-antibody-antigen complexes.
Monoclonal antibodies (MAbs) were complexed to solid matrices and used to purify virus proteins from simian virus 5 (SV5)-infected tissue culture cells, ideally in such a way as to bind equimolar amounts of antigen to antibody. The resulting solid matrix-antibody-antigen (SMAA) complexes were then used as immunogens and successfully induced specific humoral and cytotoxic T cell responses. By attaching more than one MAb to the solid matrix and using such complexes to purify the respective proteins multivalent immunization was achieved. Analysis of the cytotoxic T cell response of immunized animals indicated that both surface and internal SV5 structural proteins can act as target antigens. Immunization with SMAA complexes, in the absence of adjuvant, induced higher levels of antibody than the antigen alone precipitated on alum. However, immunization with SMAA complexes resulted in relatively less antibody being produced to the antigenic determinant through which the protein is coupled, via antibody, to the SMAA complex compared with the amount of antibody produced against other antigenic determinants on that protein. The particulate solid matrix used to form the SMAA complexes in most of the experiments was a 'fixed' and killed suspension of the Cowan A strain of Staphylococcus aureus, although preliminary results indicated that Protein A-Sepharose could also be used as a solid matrix. Prior immunization with S. aureus alone did not reduce the level of the immune response to the appropriate antigen on subsequent immunization with S. aureus-antibody-antigen complexes. In fact on immunization of mice with these complexes the level of antibody produced to the S. aureus matrix itself was less when S. aureus-antibody-antigen complexes were used as immunogens than when S. aureus or S. aureus-antibody complexes were used. Furthermore, rabbits immunized with S. aureus-mouse MAb-antigen complexes showed a vigorous immune response to the antigen.


Validation of the conceptual research utilization scale: an application of the standards for educational and psychological testing in healthcare.
There is a lack of acceptable, reliable, and valid survey instruments to measure conceptual research utilization (CRU). In this study, we investigated the psychometric properties of a newly developed scale (the CRU Scale). We used the Standards for Educational and Psychological Testing as a validation framework to assess four sources of validity evidence: content, response processes, internal structure, and relations to other variables. A panel of nine international research utilization experts performed a formal content validity assessment. To determine response process validity, we conducted a series of one-on-one scale administration sessions with 10 healthcare aides. Internal structure and relations to other variables validity was examined using CRU Scale response data from a sample of 707 healthcare aides working in 30 urban Canadian nursing homes. Principal components analysis and confirmatory factor analyses were conducted to determine internal structure. Relations to other variables were examined using: (1) bivariate correlations; (2) change in mean values of CRU with increasing levels of other kinds of research utilization; and (3) multivariate linear regression. Content validity index scores for the five items ranged from 0.55 to 1.00. The principal components analysis predicted a 5-item 1-factor model. This was inconsistent with the findings from the confirmatory factor analysis, which showed best fit for a 4-item 1-factor model. Bivariate associations between CRU and other kinds of research utilization were statistically significant (p < 0.01) for the latent CRU scale score and all five CRU items. The CRU scale score was also shown to be significant predictor of overall research utilization in multivariate linear regression. The CRU scale showed acceptable initial psychometric properties with respect to responses from healthcare aides in nursing homes. Based on our validity, reliability, and acceptability analyses, we recommend using a reduced (four-item) version of the CRU scale to yield sound assessments of CRU by healthcare aides. Refinement to the wording of one item is also needed. Planned future research will include: latent scale scoring, identification of variables that predict and are outcomes to conceptual research use, and longitudinal work to determine CRU Scale sensitivity to change.


Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities.
A mouse model for Down syndrome, Ts1Cje, has been developed. This model has made possible a step in the genetic dissection of the learning, behavioral, and neurological abnormalities associated with segmental trisomy for the region of mouse chromosome 16 homologous with the so-called "Down syndrome region" of human chromosome segment 21q22. Tests of learning in the Morris water maze and assessment of spontaneous locomotor activity reveal distinct learning and behavioral abnormalities, some of which are indicative of hippocampal dysfunction. The triplicated region in Ts1Cje, from Sod1 to Mx1, is smaller than that in Ts65Dn, another segmental trisomy 16 mouse, and the learning deficits in Ts1Cje are less severe than those in Ts65Dn. In addition, degeneration of basal forebrain cholinergic neurons, which was observed in Ts65Dn, was absent in Ts1Cje.


Dopamine decreases expression of type-1 angiotensin II receptors in renal proximal tubule.
Systemic and/or locally produced angiotensin II stimulates salt and water reabsorption in the renal proximal tubule. In vivo, dopamine (DA) may serve as a counterregulatory hormone to angiotensin II's acute actions on the proximal tubule. We examined whether dopamine modulates AT1 receptor expression in cultured proximal tubule cells (RPTC) expressing DA1 receptors. Dopamine decreased basal RPTC AT1 receptor mRNA levels by 67 +/- 7% (n = 10; P < 0.005) and decreased 125I-angiotensin II binding by 41 +/- 7% (n = 4; P < 0.05). The DA1-specific agonist, SKF38393 decreased basal AT1 receptor mRNA levels (65 +/- 5% inhibition; n = 5; P < 0.025), and the DA1-specific antagonist, SCH23390 reversed dopamine's inhibition of AT1 receptor mRNA expression (24 +/- 10% inhibition; n = 8; NS) and angiotensin II binding (5 +/- 15%; n = 4; NS). DA2-specific antagonists were ineffective. In rats given L-DOPA in the drinking water for 5 d, there were decreases in both proximal tubule AT1 receptor mRNA expression (80 +/- 5%; n = 6; P < 0.005) and specific [125I] Ang II binding (control: 0.74 +/- 0.13 fmol/mg pro vs. 0.40 +/- 0.63 fmol/mg pro; n = 5; P < 0.05). In summary, dopamine, acting through DA1 receptors, decreased AT1 receptor expression in proximal tubule, an effect likely mediated by increased intracellular cAMP levels. Local dopamine production also led to decreased AT1 receptor expression, suggesting dopamine may reset sensitivity of the proximal tubule to angiotensin II.


House dust mite avoidance measures for perennial allergic rhinitis: a systematic review of efficacy.
Perennial allergic rhinitis is a common chronic disorder that results most frequently from sensitivity to house dust mites. National and international guidelines for the management of allergic rhinitis recommend that house dust mite avoidance measures be considered in all patients with house dust mite-provoked rhinitis. To assess the benefit and harm of measures designed to reduce house dust mite exposure in the management of house dust mite-sensitive allergic rhinitis, published and unpublished randomised controlled trials were systematically searched. A methodological assessment of trial quality was conducted using the Cochrane approach. Four trials satisfied the inclusion criteria, all of which were small and judged to be of poor quality. The results indicate that, when compared with controls, significant reductions of allergen load can be achieved by physical and chemical means, but there is little evidence at present that these reductions translate into sustained improvements in clinical outcomes. No serious adverse effects were reported from the interventions.


Are we SHARP enough? The importance of adequate patient selection in sorafenib treatment for hepatocellular carcinoma.
Upon FDA/EMEA registration for hepatocellular carcinoma (HCC), sorafenib received a broader therapeutic indication than the eligibility criteria of the landmark SHARP trial. This allowed treatment of SHARP non-eligible patients in daily clinical practice. To assess sorafenib efficacy and safety in SHARP eligible and non-eligible patients, and determine the validity of the current therapeutic indication as described by the FDA/EMEA. Consecutive patients treated with sorafenib for advanced HCC at two Dutch tertiary referral centers between 2007 and 2016 were analyzed retrospectively. Primary outcome was overall survival (OS). Secondary outcomes were time to progression (TTP), response rate, adverse events and reasons for discontinuation. Outcomes were compared between SHARP eligible and non-eligible patients. One hundred and ninety-three of 257 (75%) patients were SHARP eligible. SHARP eligible patients (9.5 months, 95% CI 7.7-11.3) had a longer median OS than non-eligible patients (5.4 months, 95% CI 3.6-7.1) (log-rank p < .001). SHARP non-eligible patients were more often Child-Pugh B, had higher AST and ALT levels and developed more grade 3-4 liver dysfunction (44 versus 23%, p < .001) during treatment. SHARP ineligibility remained the strongest predictor of OS (HR 1.78, 95% CI 1.32-2.41) and an independent predictor of TTP (HR 1.45, 95% CI 1.05-2.00) in multivariable analysis. Landmark trial outcomes of sorafenib for HCC are reproducible in daily practice, provided that the SHARP eligibility criteria are respected. Based on the findings of this and previous studies, sorafenib usage should be restricted to Child-Pugh A patients.


ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth.
Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosine kinase that is expressed preferentially in neurons of the central and peripheral nervous systems at late embryonic stages. To elucidate the role of ALK in neurons, we developed an agonist monoclonal antibody (mAb) against the extracellular domain of ALK. Here we show that mAb16-39 elicits tyrosine phosphorylation of endogenously expressed ALK in human neuroblastoma (SK-N-SH) cells. Stimulation of these cells with mAb16-39 markedly induces the tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), Shc, and c-Cbl and also their interaction with ALK and activation of ERK1/2. Furthermore, we show that continuous incubation with mAb16-39 induces the cell growth and neurite outgrowth of SK-N-SH cells. These responses are completely blocked by MEK inhibitor PD98059 but not by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin, indicating an essential role of the mitogen-activated protein kinase (MAP kinase) signaling cascade in ALK-mediated growth and differentiation of neurons.


Nonignorable censoring in randomized clinical trials.
In a clinical trial, survival may be censored by the end of the study, especially for subjects who enter later in the enrollment period. If there is a trend toward better survival over time then longer survivors experience shorter censoring times (heavier censoring). In such a case, the censoring and survival times are correlated, and thus the censoring is nonignorable in the sense that standard survival models that assume independent censoring could yield incorrect inferences. We will demonstrate a graphical method for analyzing sensitivity of estimates of survival model parameters to small departures from nonignorable censoring. We assume a parametric model of survival together with a scaled beta model for the censoring process that incorporates the dependence of censoring time on survival time. We assess sensitivity using an index of local sensitivity to nonignorability (Troxel et al.). High sensitivity indicates a large impact of nonignorable censoring on the parameter of interest and a need for additional modeling. A simulation study shows that the approach is valid for practical use. We apply our method to a clinical trial evaluating the survival benefit of a surgically implanted left ventricular assist device in subjects with end-stage heart failure. Sensitivity is somewhat larger in estimates of the mean survival in the device arm, where survival is better and the fraction censored is therefore larger. The degree of nonignorability required to substantially affect estimates is larger than seems plausible, however. Our results illustrate how one can apply sensitivity analysis to evaluate the reliability of survival parameter estimates in a clinical trial.


An immunodominant La/SSB autoantibody proteome derives from public clonotypes.
The La/SSB autoantigen is a major target of long-term humoral autoimmunity in primary Sjögren's Syndrome (SS) and systemic lupus erythematosus. A majority of patients with linked anti-Ro60/Ro52/La responses target an NH2-terminal epitope designated LaA that is expressed on Ro/La ribonucleoprotein complexes and the surface membrane of apoptotic cells. In this study, we used high-resolution Orbitrap mass spectrometry to determine the clonality, isotype and V-region sequences of LaA-specific autoantibodies in seven patients with primary SS. Anti-LaA immunoglobulin (Ig)Gs purified from polyclonal sera by epitope-specific affinity chromatography were analysed by combined database and de-novo mass spectrometric sequencing. Autoantibody responses comprised two heavily mutated IgG1 kappa-restricted monoclonal species that were shared (public) across unrelated patients; one clonotype was specified by an IGHV3-30 heavy chain paired with IGKV3-15 light chain and the second by an IGHV3-43/IGKV3-20 pairing. Shared amino acid replacement mutations were also seen within heavy and light chain complementarity-determining regions, consistent with a common breach of B cell tolerance followed by antigen-driven clonal selection. The discovery of public clonotypic autoantibodies directed against an immunodominant epitope on La, taken together with recent findings for the linked Ro52 and Ro60 autoantigens, supports a model of systemic autoimmunity in which humoral responses against protein-RNA complexes are mediated by public sets of autoreactive B cell clonotypes.


Aliskiren prevents and ameliorates metabolic syndrome in fructose-fed rats.
The renin-angiotensin system plays a major role in the pathogenesis of metabolic syndrome. The objective of this study was to examine the effects of aliskiren, a direct renin inhibitor, on the metabolic syndrome of fructose-fed rats. Male Sprague-Dawley rats were divided into 4 groups (n = 6 for each group). Group Con: rats were fed a standard chow diet for 8 weeks, group Fru: rats were fed a high fructose diet (60% fructose) for 8 weeks, group FruA: rats were fed a high fructose diet and were co-infused with aliskiren (100 mg/kg/day), and group FruB: rats were treated as group Fru, but aliskiren was administered 4 weeks later. Systolic blood pressure (SBP), homeostasis model assessment-insulin resistance (HOMA-IR), and blood profiles were measured. By the end of week 4 and 8 of a high fructose diet, SBP had increased significantly from 111 ±5 to 142 ±4 and 139 ±5 mmHg (p < 0.05), respectively. A high fructose diet significantly increased HOMA-IR from baseline (6.15 ±1.59) to 21.25 ±2.08 and 21.28 ±3.1 (p < 0.05) at week 4 and 8, respectively, and significantly induced metabolic syndrome. Concurrent aliskiren treatment prevented the development of hypertension and metabolic syndrome in fructose-fed rats. When fructose-induced hypertension was established, subsequent aliskiren treatment for 4 weeks reversed the elevated SBP and ameliorated metabolic syndrome. There were no significant differences in food, water intake, urine flow or body weight gain among groups. Aliskiren not only prevents but also ameliorates metabolic syndrome in fructose-fed rats.


Recent advances in understanding how rod-like bacteria stably maintain their cell shapes.
Cell shape and cell volume are important for many bacterial functions. In recent years, we have seen a range of experimental and theoretical work that led to a better understanding of the determinants of cell shape and size. The roles of different molecular machineries for cell-wall expansion have been detailed and partially redefined, mechanical forces have been shown to influence cell shape, and new connections between metabolism and cell shape have been proposed. Yet the fundamental determinants of the different cellular dimensions remain to be identified. Here, we highlight some of the recent developments and focus on the determinants of rod-like cell shape and size in the well-studied model organisms Escherichia coli and Bacillus subtilis.


Perceptions of pesticides exposure risks by operators, workers, residents and bystanders in Greece, Italy and the UK.
The EU Directive on the sustainable use of pesticides (EU128/2009/EC) requires European Member States to develop training activities targeting occupational exposure to pesticides, and communication material aimed at residents and bystanders. Risk perceptions, knowledge and attitudes associated with passive and occupational exposure to pesticide potentially influence the extent to which different stakeholders adopt self-protective behaviour. A methodology for assessing the link between attitudes, adoption of self-protective behaviours and exposure was developed and tested. A survey was implemented in the Greece, Italy and the UK, and targeted stakeholders associated with pesticide exposure linked to orchards, greenhouse crops and arable crops respectively. The results indicated that the adoption of protective measures is low for residents and bystanders, with the exception of residents in Greece, when compared to operators and workers, who tend to follow recommended safety practices. A regression analysis was used to examine the factors affecting the probability of adopting protective measures as well the as the level of exposure in the case of operators and workers where data are available. The results indicate that the likelihood of engaging in self-protective behaviour is not significantly affected by perceptions of own health being affected by pesticides for residents and bystanders. However, operators who perceive that their heath has been negatively affected by the use of pesticides are found to be more likely to adopt self-protective behaviours. Gender and country differences, in perceptions, attitudes and self-protection are also observed. Recommendations for improved communication, in particular for vulnerable groups, are provided.


The Risk of Fatigue and Sleepiness in the Ridesharing Industry: An American Academy of Sleep Medicine Position Statement.
The ridesharing-or ride-hailing-industry has grown exponentially in recent years, transforming quickly into a fee-for-service, unregulated taxi industry. While riders are experiencing the benefits of convenience and affordability, two key regulatory and safety issues deserve consideration. First, individuals who work as drivers in the ridesharing industry are often employed in a primary job, and they work as drivers during their "off" time. Such a schedule may lead to driving after extended periods of wakefulness or during nights, both of which are factors that increase the risk of drowsy driving accidents. Second, these drivers are often employed as "independent contractors," and therefore they are not screened for medical problems that can reduce alertness, such as obstructive sleep apnea. Some ridesharing companies now require a rest period after an extended driving shift. This measure is encouraging, but it is insufficient to impact driving safety appreciably, particularly since many of these drivers are already working extended hours and tend to drive at non-traditional times when sleepiness may peak. Therefore, it is the position of the American Academy of Sleep Medicine (AASM) that fatigue and sleepiness are inherent safety risks in the ridesharing industry. The AASM calls on ridesharing companies, government officials, medical professionals, and law enforcement officers to work together to address this public safety risk. A collaborative effort is necessary to understand and track the scope of the problem, provide relevant education, and mitigate the risk through thoughtful regulation and effective fatigue risk management systems.


The Care of Children With Congenital Heart Disease in Their Primary Medical Home.
Congenital heart disease (CHD) is the most common birth anomaly. With advances in repair and palliation of these complex lesions, more and more patients are surviving and are discharged from the hospital to return to their families. Patients with CHD have complex health care needs that often must be provided for or coordinated for by the primary care provider (PCP) and medical home. This policy statement aims to provide the PCP with general guidelines for the care of the child with congenital heart defects and outlines anticipated problems, serving as a repository of current knowledge in a practical, readily accessible format. A timeline approach is used, emphasizing the role of the PCP and medical home in the management of patients with CHD in their various life stages.


Noninvasive ventilation for acute respiratory failure. Quite low time consumption for nurses.
Methods of noninvasive pressure support ventilation (NIPSV) are not always easy to apply in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD). The assistance time spent by nurses in relation to ventilatory time was prospectively studied, when NIPSV was used, in a sequential mode, in COPD patients with either acute exacerbations (58 patients, group I) or postextubation hypercapnic respiratory insufficiency (42 patients, group II) in a medical intensive care unit. During the first 24 h after enrolment, NIPSV was used for 6.7+/-3.2 h (mean+/-SD) in group I and 5.6+/-3.1 h in group II; the duration of NIPSV sessions and the nurse time consumption per session were respectively 47+/-12 and 11+/-7 min in group 1, and 46+/-12 and 11+/-6 min in group II. After the first 24 h of the study, the duration of NIPSV was 4.7+/-3.2 h x day(-1) in group I and 4.9+/-3.5 h x day(-1) in group II, and the nurse time consumption dropped significantly: the duration of NIPSV sessions and the nurse time consumption per session were respectively 44+/-10 and 7+/-4 min in group I, and 47+/-14 and 7+/-3 min in group II. Between the first 24 h and the subsequent period of 24 h, the nursing time dropped significantly (98 versus 59 min in group I (p<0.05), and 85 versus 52 min in group II (p<0.05)). There was no difference in the duration of NIPSV sessions, or in the overall assistance time per session, between the two groups of patients. In conclusion, the study seems to favour a quite low assistance time spent by nurses in relation to ventilatory time when noninvasive pressure support ventilation is used in chronic obstructive pulmonary disease patients with either acute exacerbations or postextubation hypercapnic respiratory insufficiency.


Community analysis of biting midges (Culicoides Latr.) on livestock farms in Denmark.
This study presents descriptive statistics and community analysis of adult biting midges trapped at 16 livestock farms by means of light traps on Zealand and Lolland-Falster, Denmark. A total of 9,047 male and female Culicoides divided into 24 species, were caught. Biotic and abiotic factors ranging from presence of different host species (cattle or sheep/goats), presence of small woody areas or wetlands in the surrounding landscape, and agricultural practice (organic or conventional) were included in the community analysis. Only differences in the Culicoides communities between conventional and organic practices were tested significantly different. Total numbers of Culicoides individuals were higher on the organic farms than on the conventional farms. The larger loads of biting midges on the organic farms may be due to free-ranging animals that attracted the midges on pastures and carried them to the stable environment (the cattle of the conventional farms were held inside the stables). Presence of deciduous trees within 500 m of the farms resulted in higher numbers of Culicoides obsoletus s.s., while presence of wetlands increased the numbers of Culicoides punctatus and Culicoides pulicaris. Furthermore, Culicoides riethi and Culicoides puncticollis (subgenus Monoculicoides) were recorded in high numbers on individual farms. C. puncticollis was found for the first time in Denmark and so far only recorded from Zealand.


Plasticity of intermediate filament subunits.
Intermediate filaments (IFs) assembled in vitro from recombinantly expressed proteins have a diameter of 8-12 nm and can reach several micrometers in length. IFs assemble from a soluble pool of subunits, tetramers in the case of vimentin. Upon salt addition, the subunits form first unit length filaments (ULFs) within seconds and then assembly proceeds further by end-to-end fusion of ULFs and short filaments. So far, IF subunits have mainly been observed by electron microscopy of glycerol sprayed and rotary metal shadowed specimens. Due to the shear forces during spraying the IF subunits appear generally as straight thin rods. In this study, we used atomic force microscopy (AFM), cryo-electron microscopy (cryo-EM) combined with molecular modeling to investigate the conformation of the subunits of vimentin, desmin and keratin K5/K14 IFs in various conditions. Due to their anisotropic shape the subunits are difficult to image at high resolution by cryo-EM. In order to enhance contrast we used a cryo-negative staining approach. The subunits were clearly identified as thin, slightly curved rods. However the staining agent also forced the subunits to aggregate into two-dimensional networks of dot-like structures. To test this conformational change further, we imaged dried unfixed subunits on mica by AFM revealing a mixture of extended and dot-like conformations. The use of divalent ions such as calcium and magnesium, as well as glutaraldehyde exposure favored compact conformations over elongated ones. These experimental results as well as coarse-grained molecular dynamics simulations of a vimentin tetramer highlight the plasticity of IF subunits.


In vivo biocompatibility of a new cyanine dye for ILM peeling.
To investigate the biocompatibility of the new cyanine dye: 3,3'-Di-(4-sulfobutyl)-1,1,1',1'-tetramethyl-di-1H-benz[e]indocarbocyanine (DSS) as a vital dye for intraocular application in an in vivo rat model and to evaluate the effects of this dye on retinal structure and function. DSS at a concentration of 0.5% was applied via intravitreal injections to adult Brown Norway rats with BSS serving as a control. Retinal toxicity was assessed 7 days later by means of retinal ganglion cell (RGC) counts, light microscopy, optical coherence tomography (OCT), and electroretinography (ERG). No significant decrease in RGC numbers was observed. No structural changes of the central retina were observed either in vivo (OCT) or under light microscopy. ERGs detected a temporary reduction of retinal function 7 days after injection; this was no longer evident 14 days after injection. DSS showed good biocompatibility in a well-established experimental in vivo setting and may be usable for intraocular surgery as an alternative to other cyanine dyes. In contrast to indocyanine green, it additionally offers fluorescence in the visual spectrum. Further studies with other animal models are needed before translation into clinical application.


[VEPs induced by binocular disparity stimulus of the retinal nasotemporal overlap].
The human visual evoked potentials (VEPs) elicited by retinal disparity stimulation of the nasotemporal overlap area of the fundus, where ipsilaterally and contralaterally projecting retinal ganglion cells intermingle, were recorded bilaterally at the cortical hemispheres, and the contribution of the nasotemporal overlap to the mechanism of stereopsis was studied. The stimulus was a slit of a stereogram or correlogram applied to the center of the fovea of the right eye, or 3 degrees or 6 degrees nasal or temporal to the fovea. The negative waves of the VEPs evoked by the stereogram were located at O1 and O2. The VEP amplitudes evoked by the stereogram markedly exceeded those by the correlogram. In comparing the VEP amplitude of O1 with that of O2, when the slit of the stereogram hit the nasal side of the nasotemporal overlap O1 exceeded O2, and on the temporal side, this was reversed. The difference between the amplitudes at O1 and O2 was significant at 3 degrees from the fovea. These results showed electrophysiologically that the width of the nasotemporal overlap in the human retina is more or less 4 degrees and that the activity from the overlap area converges to disparity selective neurons in the visual cortex, suggesting that the overlap area is the region where cues to depth perception are obtained in the front-posterior plane of the fixation point.


Vortex Motion Quantifies Strong Dissipation in a Holographic Superfluid.
Holographic duality provides a description of strongly coupled quantum systems in terms of weakly coupled gravitational theories in a higher-dimensional space. It is a challenge, however, to quantitatively determine the physical parameters of the quantum systems corresponding to generic holographic theories. Here, we address this problem for the two-dimensional holographic superfluid, known to exhibit strong dissipation. We numerically simulate the motion of a vortex dipole and perform a high-precision matching of the corresponding dynamics resulting from the dissipative Gross-Pitaevskii equation. Excellent agreement is found for the vortex core shape and the spatiotemporal trajectories. A further comparison to the Hall-Vinen-Iordanskii equations for point vortices interacting with the superfluid allows us to determine the friction parameters of the holographic superfluid. Our results suggest that holographic vortex dynamics can be applied to experimentally accessible superfluids like strongly coupled ultracold Bose gases or thin helium films with temperatures in the Kelvin range. This would make holographic far-from-equilibrium dynamics and turbulence amenable to experimental tests.


The where and when of T cell regulation in transplantation.
Multiple cell types contribute to the peripheral regulation of T cell alloresponses in haematopoieitc cell transplantation (HCT) and solid organ transplantation (SOT). Of these, regulatory T cells (Tregs) are the principal players and have shown the greatest success in the therapeutic control of detrimental immune responses. Investigations into the induction, location, and mechanism of suppression utilised by Tregs to control alloreactive responses are ongoing. The activation and homing characteristics of Tregs are important to their regulatory capabilities, with activation and homing occurring in the same time and space as conventional T cells. This review discusses these characteristics and recent advances in the field as we move closer to the ultimate goal of utilising Tregs as treatment for allograft rejection and graft-versus-host disease (GvHD).


The role of neuropeptides and neurohormones in neurogenic cardiac arrhythmias.
The functional significance of neuropeptides and neurohormones throughout the neuroaxis has been the focus of considerable research over the past 25 years. These "gut peptides" or "reproductive hormones" have been localized within nuclei responsible for the relay of visceral afferent information to the forebrain. The presence of peptides and hormones along the gut- or heart-brain continuum suggests that these neurochemicals do more than modulate the visceral processes of digestion and reproduction respectively. Numerous studies have shown that the exogenous administration of these neurochemicals directly into visceral afferent nuclei significantly alters blood pressure, heart rate, autonomic tone and the sensitivity of the baroreceptor reflex (an index of sympatho-vagal balance). A strong inverse correlation has been demonstrated between the sensitivity of the baroreceptor reflex and susceptibility to lethal cardiac arrhythmias which lead ultimately to sudden cardiac death. The differential effects of various neurochemicals on the sensitivity of the baroreceptor reflex suggests that some neurochemicals may act as preventatives while others may actually contribute to the pathogenesis of neurogenic cardiac arrhythmias. Hormones such as estrogen, in addition to their neuroprotective properties, may also play a role in modulating the cardiovascular consequences to neurogenic pathologies including stroke and epilepsy. This review will summarize the evidence available which suggests that neuropeptides and neurohormones can alter both neurogenic as well as visceral pathology-induced changes in autonomic function resulting in an increased risk of sudden cardiac death.


Requirement for an oxidant in Pd/Cu co-catalyzed terminal alkyne homocoupling to give symmetrical 1,4-disubstituted 1,3-diynes.
Palladium-catalyzed terminal alkyne dimerization, through oxidative homocoupling, is a useful approach to the synthesis of symmetrical 1,4-diynes. Recent investigations have suggested that this reaction might be accomplished in the absence of intentionally added stoichiometric oxidants (to reoxidize Pd(0) to Pd(II)). In this paper, we have fully addressed the question of whether oxygen (or added oxidant) is required to facilitate this process. The presence of a stoichiometric quantity of air (or added oxidant such as I2) is essential for alkyne dimerization. Excess PPh3 inhibits alkyne dimerization to enyne, which only occurs to a significant extent when the reaction is starved of oxidant. Theoretical studies shed more light on the requirement for an oxidant in the homocoupling reaction in order for the process to be theromodynamically favorable. The employment of I2 as the stoichiometric oxidant appears to be the method of choice. The dual role of Cu both in transmetalation of alkynyl units to Pd(II) and in assisting reoxidation of Pd(0) to Pd(II) is suggested.


Fade statistics of a ground-to-satellite optical link in the presence of lead-ahead and aperture mismatch.
In a recent publication [J. Opt. Soc. Am. A25, 1594-1608 (2008).JOAOD60740-323210.1364/JOSAA.25.001594] we developed expressions for the tilt errors that arise from the effects of lead-ahead and aperture mismatch when transmitting a laser beam from the ground to a satellite. We extend these results to examine the fade statistics of the irradiance at the satellite due to these tilt errors and turbulence induced scintillation. The system concept is that the light from a beacon on the satellite is received by the ground station and a derived signal is used to drive a tracking/pointing system for the uplink beam. However, the beam must be pointed ahead along the satellite track to intercept the satellite (lead-ahead), and physical constraints may require that the beam transmit aperture is different in size or location than the aperture receiving the beacon signal (aperture mismatch). These two issues cause the light entering the receiving aperture (tracker) and the beam exiting the transmit aperture (pointer) to traverse somewhat different turbulence volumes, which limits the ability of the tracking/pointing system to place the maximum flux on the satellite.


REPRESSOR OF ULTRAVIOLET-B PHOTOMORPHOGENESIS function allows efficient phototropin mediated ultraviolet-B phototropism in etiolated seedlings.
Ultraviolet B (UV-B) light is a part of the solar radiation which has significant effects on plant morphology, even at low doses. In Arabidopsis, many of these morphological changes have been attributed to a specific UV-B receptor, UV resistance locus 8 (UVR8). Recent findings showed that next to phototropin regulated phototropism, UVR8 mediated signaling is able of inducing directional bending towards UV-B light in etiolated seedlings of Arabidopsis, in a phototropin independent manner. In this study, kinetic analysis of phototropic bending was used to evaluate the relative contribution of each of these pathways in UV-B mediated phototropism. Diminishing UV-B light intensity favors the importance of phototropins. Molecular and genetic analyses suggest that UV-B is capable of inducing phototropin signaling relying on phototropin kinase activity and regulation of NPH3. Moreover, enhanced UVR8 responses in the UV-B hypersensitive rup1rup2 mutants interferes with the fast phototropin mediated phototropism. Together the data suggest that phototropins are the most important receptors for UV-B induced phototropism in etiolated seedlings, and a RUP mediated negative feedback pathway prevents UVR8 signaling to interfere with the phototropin dependent response.


Identification and characterization of poorly differentiated invasive carcinomas in a mouse model of pancreatic neuroendocrine tumorigenesis.
Pancreatic neuroendocrine tumors (PanNETs) are a relatively rare but clinically challenging tumor type. In particular, high grade, poorly-differentiated PanNETs have the worst patient prognosis, and the underlying mechanisms of disease are poorly understood. In this study we have identified and characterized a previously undescribed class of poorly differentiated PanNETs in the RIP1-Tag2 mouse model. We found that while the majority of tumors in the RIP1-Tag2 model are well-differentiated insulinomas, a subset of tumors had lost multiple markers of beta-cell differentiation and were highly invasive, leading us to term them poorly differentiated invasive carcinomas (PDICs). In addition, we found that these tumors exhibited a high mitotic index, resembling poorly differentiated (PD)-PanNETs in human patients. Interestingly, we identified expression of Id1, an inhibitor of DNA binding gene, and a regulator of differentiation, specifically in PDIC tumor cells by histological analysis. The identification of PDICs in this mouse model provides a unique opportunity to study the pathology and molecular characteristics of PD-PanNETs.


Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome.
Antibiotic administration is the standard treatment for the bacterium Helicobacter pylori, the main causative agent of peptic ulcer disease and gastric cancer. However, the long-term consequences of this treatment on the human indigenous microbiota are relatively unexplored. Here we studied short- and long-term effects of clarithromycin and metronidazole treatment, a commonly used therapy regimen against H. pylori, on the indigenous microbiota in the throat and in the lower intestine. The bacterial compositions in samples collected over a four-year period were monitored by analyzing the 16S rRNA gene using 454-based pyrosequencing and terminal-restriction fragment length polymorphism (T-RFLP). While the microbial communities of untreated control subjects were relatively stable over time, dramatic shifts were observed one week after antibiotic treatment with reduced bacterial diversity in all treated subjects in both locations. While the microbiota of the different subjects responded uniquely to the antibiotic treatment some general trends could be observed; such as a dramatic decline in Actinobacteria in both throat and feces immediately after treatment. Although the diversity of the microbiota subsequently recovered to resemble the pre treatment states, the microbiota remained perturbed in some cases for up to four years post treatment. In addition, four years after treatment high levels of the macrolide resistance gene erm(B) were found, indicating that antibiotic resistance, once selected for, can persist for longer periods of time than previously recognized. This highlights the importance of a restrictive antibiotic usage in order to prevent subsequent treatment failure and potential spread of antibiotic resistance.


Current opportunities to catalyze research in nutrition and cancer prevention - an interdisciplinary perspective.
Cancer Research UK and Ludwig Cancer Research convened an inaugural international Cancer Prevention and Nutrition Conference in London on December 3-4, 2018. Much of the discussion focused on the need for systematic, interdisciplinary approaches to better understand the relationships of nutrition, exercise, obesity and metabolic dysfunction with cancer development. Scientists at the meeting underscored the importance of studying the temporal natural history of exposures that may cumulatively impact cancer risk later in life.A robust dialogue identified obesity as a major risk for cancer, and the food environment, especially high energy and low nutrient processed foods, as strong and prevalent risk factors for obesity. Further engagement highlighted challenges in the post-diagnostic setting, where similar opportunities to understand the complex interplay of nutrition, physical activity, and weight will inform better health outcomes.Going forward, holistic research approaches, encompassing insights from multiple disciplines and perspectives, will catalyze progress urgently needed to prevent cancer and improve public health.


DARK Classics in Chemical Neuroscience: Methamphetamine.
Methamphetamine has the second highest prevalence of drug abuse after cannabis, with estimates of 35 million users worldwide. The ( S)-(+)-enantiomer is the illicit drug, active neurostimulant, and eutomer, while the ( R)-(-)-enantiomer is contained in over the counter decongestants. While designated a schedule II drug in 1970, ( S)-(+)-methamphetamine is available by prescription for the treatment of attention-deficit disorder and obesity. The illicit use of ( S)-(+)-methamphetamine results in the sudden "rush" of stimulation to the motivation, movement, pleasure, and reward centers in the brain, caused by rapid release of dopamine. In this review, we will provide an overview of the synthesis, pharmacology, adverse effects, and drug metabolism of this widely abused psychostimulant that distinguish it as a DARK classic in Chemical Neuroscience.


Long-term outcome of surgical treatment of intracavernous giant aneurysms.
A number of approaches have been proposed for the treatment of intracavernous giant aneurysms. In the present study, we have analyzed long-term surgical outcome of 27 consecutive cases of our experience. All the cases were unruptured and symptomatic, showing symptoms such as extraocular movement disorder or visual disturbances. Thirteen cases were male and 14 cases were female. The age of the patients ranged between 11 and 75 years (average 52.2 years) and follow-up periods were between 1 and 20 years (average 7.7 years). Abducens nerve was distributed in 20 cases, oculomotor nerve in 12 cases, optic nerve in six cases, trigeminal nerve in six cases, and trochlear nerve in five cases. In addition to conventional angiography, three-dimensional computed tomographic angiography, balloon test occlusion (BTO), slow injection angiography, aneurysmography, and single photon emission computed tomography with BTO were used to determine a method of treatment. Therapeutic modalities of the present series were as follows: four cases were unoperated, common carotid artery ligation was performed in eight cases, internal carotid artery (IC) ligation in three cases, IC ligation plus superficial temporal artery (STA)--middle cerebral artery (MCA) anastomosis in four cases, IC ligation plus high flow vein bypass in three cases, IC trapping plus STA-MCA anastomosis in three cases, and direct clipping in two cases. Although two cases showed early and late ischemic complications, other cases demonstrated improvement of cranial nerve dysfunction relatively soon after surgical treatment and long-term outcome was generally good. It is concluded that good long-term surgical outcome is obtained for intracavernous giant aneurysms by selecting adequate surgical treatment based upon careful preoperative evaluation of these aneurysms using sophisticated diagnostic methods.


Alterations in central neuropeptide expression, release, and receptor binding in rats bred for high anxiety: critical role of vasopressin.
To model aspects of trait anxiety/depression, Wistar rats were bred for extremes in either hyper (HAB)- or hypo(LAB)-anxiety as measured on the elevated plus-maze and in a variety of additional behavioral tests. Similar to psychiatric patients, HAB rats prefer passive stress-coping strategies, indicative of depression-like behavior, show hyper-reactivity of the hypothalamo-pituitary-adrenal axis, and a pathological response to the dexamethasone/corticotropin-releasing hormone (CRH) challenge test. Here we tested central mRNA expression, release patterns, and receptor binding of neuropeptides critically involved in the regulation of both anxiety-related behavior and the HPA axis. Thus, CRH, arginine-8-vasopressin (AVP), and oxytocin (OXT) were studied in brains of HAB and LAB males both under basal conditions and after exposure to a mild emotional stressor. In HAB rats, CRH mRNA was decreased in the bed nucleus of the stria terminalis only. While no significant difference in CRH1-receptor binding was found in any brain area, CRH2-receptor binding was elevated in the hypothalamic paraventricular nucleus (PVN), the ventromedial hypothalamus, and the central amygdala of HABs compared to LABs. AVP, but not OXT, mRNA expression as well as release of the neuropeptide, were higher in the PVN of HABs, whereas AVP V1a-receptor binding failed to show significant differences in any brain region studied. Remarkably, intra-PVN treatment of HABs with the AVP V1-receptor antagonist d (CH(2))(5) Tyr (Me) AVP resulted in a decrease in anxiety/depression-related behavior. The elevated expression and release of AVP within the PVN of HAB rats together with the behavioral effects of the AVP V1-receptor antagonist suggest a critical involvement of this neuropeptide in neuroendocrine and behavioral phenomena associated with trait anxiety/depression.


Genomic biomarkers of prenatal intrauterine inflammation in umbilical cord tissue predict later life neurological outcomes.
Preterm birth is a major risk factor for neurodevelopmental delays and disorders. This study aimed to identify genomic biomarkers of intrauterine inflammation in umbilical cord tissue in preterm neonates that predict cognitive impairment at 10 years of age. Genome-wide messenger RNA (mRNA) levels from umbilical cord tissue were obtained from 43 neonates born before 28 weeks of gestation. Genes that were differentially expressed across four indicators of intrauterine inflammation were identified and their functions examined. Exact logistic regression was used to test whether expression levels in umbilical cord tissue predicted neurocognitive function at 10 years of age. Placental indicators of inflammation were associated with changes in the mRNA expression of 445 genes in umbilical cord tissue. Transcripts with decreased expression showed significant enrichment for biological signaling processes related to neuronal development and growth. The altered expression of six genes was found to predict neurocognitive impairment when children were 10 years old These genes include two that encode for proteins involved in neuronal development. Prenatal intrauterine inflammation is associated with altered gene expression in umbilical cord tissue. A set of six of the differentially expressed genes predict cognitive impairment later in life, suggesting that the fetal environment is associated with significant adverse effects on neurodevelopment that persist into later childhood.


Adverse drug reactions reporting : Knowledge and opinion of general public in Penang, Malaysia.
The objective of this study was to explore the knowledge of the general population towards ADR and their reporting system. An anonymous, self-administered questionnaire (15 items) was designed. The questionnaire was subjected to face validity and content validity. The reliability coefficient was found to be 0.71. This study recruited proportionately large convenience sample of the general public in Penang. Interviews using a structured questionnaire were conducted over a week period in August 2009. The recommended sample size was calculated to be 368. Three hundred thirty-four responses were received. Slightly more than half of the respondents were in the age group of 18-25 years (53.6%; n = 179). When asked about the sources of their medication majority of them reported medical doctor (85.6%), whereas small number (34.7%) reported community pharmacists as sources of medications. Three-quarter of the respondents (77.2%) get their information about the side-effects of drugs from physicians, followed by pharmacist (44.6%). More than half of the respondents (65.6%, n = 219) reported unawareness about the existence of ADR center set up by the Ministry of Health. Respondents reflected inadequate knowledge on ADR reporting. This needs to be corrected as the trend of future pharmacovigilance is toward the patient. Moreover, the new trend seems to be more appropriate as the patient is the group of the people who are directly affected from the ADR of a particular drug and not the health-care providers. Furthermore, the patient will be informed about the economic implications of not reporting ADR. It is recommended that government agencies, like MADRAC needs to find ways to increase patient- reported ADR cases.


A genome-wide association analysis reveals a potential role for recombination in the evolution of antimicrobial resistance in Burkholderia multivorans.
Cystic fibrosis (CF) lung infections caused by members of the Burkholderia cepacia complex, such as Burkholderia multivorans, are associated with high rates of mortality and morbidity. We performed a population genomics study of 111 B. multivorans sputum isolates from one CF patient through three stages of infection including an early incident isolate, deep sampling of a one-year period of chronic infection occurring weeks before a lung transplant, and deep sampling of a post-transplant infection. We reconstructed the evolutionary history of the population and used a lineage-controlled genome-wide association study (GWAS) approach to identify genetic variants associated with antibiotic resistance. We found the incident isolate was basally related to the rest of the strains and more susceptible to antibiotics from three classes (β-lactams, aminoglycosides, quinolones). The chronic infection isolates diversified into multiple, distinct genetic lineages and showed reduced antimicrobial susceptibility to the same antibiotics. The post-transplant reinfection isolates derived from the same source as the incident isolate and were genetically distinct from the chronic isolates. They also had a level of susceptibility in between that of the incident and chronic isolates. We identified numerous examples of potential parallel pathoadaptation, in which multiple mutations were found in the same locus or even codon. The set of parallel pathoadaptive loci was enriched for functions associated with virulence and resistance. Our GWAS analysis identified statistical associations between a polymorphism in the ampD locus with resistance to β-lactams, and polymorphisms in an araC transcriptional regulator and an outer membrane porin with resistance to both aminoglycosides and quinolones. Additionally, these three loci were independently mutated four, three and two times, respectively, providing further support for parallel pathoadaptation. Finally, we identified a minimum of 14 recombination events, and observed that loci carrying putative parallel pathoadaptations and polymorphisms statistically associated with β-lactam resistance were over-represented in these recombinogenic regions.


Coherent and dynamic beam splitting based on light storage in cold atoms.
We demonstrate a coherent and dynamic beam splitter based on light storage in cold atoms. An input weak laser pulse is first stored in a cold atom ensemble via electromagnetically-induced transparency (EIT). A set of counter-propagating control fields, applied at a later time, retrieves the stored pulse into two output spatial modes. The high visibility interference between the two output pulses clearly demonstrates that the beam splitting process is coherent. Furthermore, by manipulating the control lasers, it is possible to dynamically control the storage time, the power splitting ratio, the relative phase, and the optical frequencies of the output pulses. With further improvements, the active beam splitter demonstrated in this work might have applications in photonic photonic quantum information and in all-optical information processing.


The Gradience of Multilingualism in Typical and Impaired Language Development: Positioning Bilectalism within Comparative Bilingualism.
A multitude of factors characterizes bi- and multilingual compared to monolingual language acquisition. Two of the most prominent viewpoints have recently been put in perspective and enriched by a third (Tsimpli, 2014): age of onset of children's exposure to their native languages, the role of the input they receive, and the timing in monolingual first language development of the phenomena examined in bi- and multilingual children's performance. This article picks up a fourth potential factor (Grohmann, 2014b): language proximity, that is, the closeness between the two or more grammars a multilingual child acquires. It is a first attempt to flesh out the proposed gradient scale of multilingualism within the approach dubbed "comparative bilingualism." The empirical part of this project comes from three types of research: (i) the acquisition and subsequent development of pronominal object clitic placement in two closely related varieties of Greek by bilectal, binational, bilingual, and multilingual children; (ii) the performance on executive control tasks by monolingual, bilectal, and bi- or multilingual children; and (iii) the role of comparative bilingualism in children with a developmental language impairment for both the diagnosis and subsequent treatment as well as the possible avoidance or weakening of how language impairment presents.


Defining influenza A virus hemagglutinin antigenic drift by sequential monoclonal antibody selection.
Human influenza A virus (IAV) vaccination is limited by "antigenic drift," rapid antibody-driven escape reflecting amino acid substitutions in the globular domain of hemagglutinin (HA), the viral attachment protein. To better understand drift, we used anti-hemagglutinin monoclonal Abs (mAbs) to sequentially select IAV escape mutants. Twelve selection steps, each resulting in a single amino acid substitution in the hemagglutinin globular domain, were required to eliminate antigenicity defined by monoclonal or polyclonal Abs. Sequential mutants grow robustly, showing the structural plasticity of HA, although several hemagglutinin substitutions required an epistatic substitution in the neuraminidase glycoprotein to maximize growth. Selecting escape mutants from parental versus sequential variants with the same mAb revealed distinct escape repertoires, attributed to contextual changes in antigenicity and the mutation landscape. Since each hemagglutinin mutation potentially sculpts future mutation space, drift can follow many stochastic paths, undermining its unpredictability and underscoring the need for drift-insensitive vaccines.


Role of shear rate and platelets in promoting fibrin formation on rabbit subendothelium. Studies utilizing patients with quantitative and qualitative platelet defects.
The deposition of platelets on subendothelium of rabbit aortic segments exposed to non-anticoagulated human blood increased progressively with increasing wall shear rates (50-2,600 s-1), whereas fibrin deposition decreased. Studies in normal subjects and patients with platelet disorders suggested that, under the conditions used, platelets were essential for fibrin deposition at intermediate (650 s-1) but not low (50 s-1) shear rates. Fibrin deposition was markedly diminished in a patient with Scott syndrome whose platelets have a diminished capacity to bind Factor Xa and activate Factors IX and II. In glycoprotein IIb-IIIa deficiency, fibrin deposition was normal (or somewhat increased), whereas in glycoprotein Ib deficiency the association of fibrin with platelets, but not subendothelium, was decreased. The findings indicate that platelets, perhaps through surface localization of coagulation proteins, promote fibrin deposition on subendothelium at arterial shear rates and suggest that agents directed against platelet coagulant properties could be antithrombotic.


Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism.
Case-fatality rates are important for assessing the risks and benefits of anticoagulation in patients with venous thromboembolism (VTE). To summarize case-fatality rates of recurrent VTE and major bleeding events during anticoagulation and recurrent VTE after anticoagulation. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and all evidence-based medicine reviews in the Ovid interface through the second quarter of 2008. 69 articles (13 prospective cohort studies and 56 randomized, controlled trials) that reported on patients with symptomatic VTE who received anticoagulation therapy for at least 3 months and on the rate of fatal recurrent VTE and fatal major bleeding. Two reviewers independently extracted data onto standardized forms. During the initial 3 months of anticoagulation, the rate of recurrent fatal VTE was 0.4% (95% CI, 0.3% to 0.6%), with a case-fatality rate of 11.3% (CI, 8.0% to 15.2%). The rate of fatal major bleeding events was 0.2% (CI, 0.1% to 0.3%), with a case-fatality rate of 11.3% (CI, 7.5% to 15.9%). After anticoagulation, the rate of fatal recurrent VTE was 0.3 per 100 patient-years (CI, 0.1% to 0.4%), with a case-fatality rate of 3.6% (CI, 1.9% to 5.7%). Estimates come from heterogeneous trial and cohort populations and are not derived from patient-level longitudinal data. Differences in case-fatality rates during and after anticoagulation may be attributable to unmeasured patient characteristics. The case-fatality rates of recurrent VTE and major bleeding events are similar during the initial period of VTE treatment. The case-fatality rate of recurrent VTE decreases after completion of the initial period of anticoagulation. When combined with absolute rates of recurrent VTE and major bleeding events, case-fatality rates provide clinicians with a surrogate measure of mortality to balance the risks and benefits of anticoagulant therapy in patients with VTE. Canadian Institute for Health Research and Heart and Stroke Foundation of Ontario.


Degree of differentiation in colorectal adenocarcinomas: a multivariate analysis of the influence on survival.
Three hundred and sixty eight resected colorectal adenocarcinomas were graded (WHO) retrospectively and the results correlated with estimated length of patient survival. In 30 (82%) of the tumours more than one degree of differentiation was found. Histological grade significantly influenced survival time when other explanatory variables such as tumour site and stage, age, and sex were adjusted for. The results suggested that three degrees of differentiation (well, moderate, and poor) are sufficient for the grading of colorectal carcinomas, and that grading should be based on the predominating degree of differentiation represented in the primary tumour.


Risk of heart disease in relation to radiotherapy and chemotherapy with anthracyclines among 19,464 breast cancer patients in Denmark, 1977-2005.
The risk of heart disease subsequent to breast cancer radiotherapy was examined with particular focus on women receiving anthracycline-containing chemotherapy. Women diagnosed with early-stage breast cancer in Denmark, 1977-2005, were identified from the register of the Danish Breast Cancer Cooperative Group, as was information on cancer-directed treatment. Information on heart disease was sought from the Danish National Patient and Cause of Death Registries. Incidence rate ratios were estimated comparing left-sided with right-sided cancer (IRR, LvR), stratified by calendar year, age, and time since breast cancer radiotherapy. Among 19,464 women receiving radiotherapy, the IRR, LvR, was 1.11 (95% CI 1.03-1.20, p=0.005) for all heart disease and among those also receiving anthracyclines the IRR, LvR, was 1.32 (95% CI 1.02-1.70, p=0.03). This risk was highest if the treatment was given before the age of 50years (IRR, LvR, 1.44, (95% CI 1.04-2.01) but there was no significant trend with age or time since treatment. Radiotherapy for left-sided breast cancer is associated with a higher risk of heart disease than for right-sided with the largest increases seen in women who also received anthracycline-containing chemotherapy.


Diallyl disulfide-induced apoptosis in a breast-cancer cell line (MCF-7) may be caused by inhibition of histone deacetylation.
The health benefits of garlic have been proven by epidemiological and experimental studies. Diallyl disulphide (DADS), the major organosulfur compound found in garlic oil, is known to lower the incidence of breast cancer both in vitro and in vivo. The studies reported here demonstrate that DADS induces apoptosis in the MCF-7 breast-cancer cell line through interfering with cell-cycle growth phases in a way that increases the sub-G(0) population and substantially halts DNA synthesis. DADS also induces phosphatidylserine translocation from the inner to the outer leaflet of the plasma membrane and activates caspase-3. Further studies revealed that DADS modulates the cellular levels of Bax, Bcl-2, Bcl-xL, and Bcl-w in a dose-dependent manner, suggesting the involvement of Bcl-2 family proteins in DADS induced apoptosis. Histone deacetylation inhibitors (HDACi) are known to suppress cancer growth and induce apoptosis in cancer cells. Here it is shown that DADS has HDACi properties in MCF-7 cells as it lowers the removal of an acetyl group from an acetylated substrate and induces histone-4 (H4) hyper-acetylation. The data thus indicate that the HDACi properties of DADS may be responsible for the induction of apoptosis in breast cancer cells.


(-)-Epicatechin gallate (ECG) stimulates osteoblast differentiation via Runt-related transcription factor 2 (RUNX2) and transcriptional coactivator with PDZ-binding motif (TAZ)-mediated transcriptional activation.
Osteoporosis is a degenerative bone disease characterized by low bone mass and is caused by an imbalance between osteoblastic bone formation and osteoclastic bone resorption. It is known that the bioactive compounds present in green tea increase osteogenic activity and decrease the risk of fracture by improving bone mineral density. However, the detailed mechanism underlying these beneficial effects has yet to be elucidated. In this study, we investigated the osteogenic effect of (-)-epicatechin gallate (ECG), a major bioactive compound found in green tea. We found that ECG effectively stimulates osteoblast differentiation, indicated by the increased expression of osteoblastic marker genes. Up-regulation of osteoblast marker genes is mediated by increased expression and interaction of the transcriptional coactivator with PDZ-binding motif (TAZ) and Runt-related transcription factor 2 (RUNX2). ECG facilitates nuclear localization of TAZ through PP1A. PP1A is essential for osteoblast differentiation because inhibition of PP1A activity was shown to suppress ECG-mediated osteogenic differentiation. Taken together, the results showed that ECG stimulates osteoblast differentiation through the activation of TAZ and RUNX2, revealing a novel mechanism for green tea-stimulated osteoblast differentiation.


Single vs multiple-spore inoculum effect on growth kinetic parameters and modeled probabilities of growth and aflatoxin B1 production of Aspergillus flavus on pistachio extract agar.
The objective of the present study was to assess the differences in modeled growth/AFB1 production probability and kinetic growth parameters for Aspergillus flavus inoculated as single spores or in a concentrated inoculation point (~500 spores). The experiment was carried out at 25°C and at two water activities (0.85 and 0.87) on pistachio extract agar (3%). Binary data obtained from growth and AFB1 studies were modeled using linear logistic regression analysis. The radial growth curve for each colony was fitted to a linear model for the estimation of the lag phase for growth and the mycelial growth rate. In general, radial growth rate and lag phase for growth were not normally distributed and both of them were affected by the inoculation type, with the lag phase for growth being more affected. Changing from the multiple spore to the single spore inoculation led to a delay of approximately 3-5days on the lag phase and higher growth rates for the multiple spore experiment were found. The same trend was observed on the probability models, with lower predicted probabilities when colonies came up from single spores, for both growth and AFB1 production probabilities. Comparing both types of models, it was concluded that a clear overestimation of the lag phase for growth occurred using the linear model, but only in the multiple spore experiment. Multiple spore inoculum gave very similar estimated time to reach some set probabilities (t10, t50 and t100) for growth or AFB1 production due to the abruptness of the logistic curve developed. The observed differences suggest that inoculum concentration greatly affects the outcome of the predictive models, the estimated times to growth/AFB1 production being much earlier for the concentrated inoculum than for a single spore colony (up to 9days). Thus the number of spores used to generate data in predictive mycology experiments should be carefully controlled in order to predict as accurately as possible the fungal behavior in a foodstuff.


Spanish guidelines for the management of autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6-10% of patients on renal replacement therapy (RRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a consensus statement presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence found were C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) and RRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are not provided since no drug has regulatory approval for this indication.


Monetary incentives enhance processing in brain regions mediating top-down control of attention.
To evaluate the effect of an abstract motivational incentive on top-down mechanisms of visual spatial attention, 10 subjects engaged in a target detection task and responded to targets preceded by spatially valid (predictive), invalid (misleading) or neutral central cues under three different incentive conditions: win money (WIN), lose money (LOSE), and neutral (neither gain nor lose). Activation in the posterior cingulate cortex was correlated with visual spatial expectancy, defined as the degree to which the valid cue benefited performance as evidenced by faster reaction times compared to non-directional cues. Winning and losing money enhanced this relationship via overlapping but independent limbic mechanisms. In addition, activity in the inferior parietal lobule was correlated with disengagement (the degree to which invalid cues diminished performance). This relationship was also enhanced by monetary incentives. Finally, incentive enhanced the relationship of activation in the visual cortex to visual spatial expectancy and disengagement for both types of incentive (WIN and LOSE). These results show that abstract incentives enhance neural processing within the attention network in a process- and valence-selective manner. They also show that different cognitive and motivational mechanisms may produce a common effect upon unimodal cortices in order to enhance processing to serve the current behavioral goal.


Trifluoperazine inhibits hippocampal long-term potentiation and the phosphorylation of a 40,000 dalton protein.
Brief high frequency stimulation induces long-term potentiation (LTP) and changes in the endogenous phosphorylation of a 40,000 dalton protein in the hippocampus in a calcium-dependent manner. In the present paper we report that 40 microM trifluoperazine (TFP), a phenothiazine that binds calmodulin and blocks its activity, inhibits LTP in the hippocampal slice. In addition, calmodulin stimulates and TFP inhibits the phosphorylation of the 40,000 dalton protein (as well as that of several other proteins) in a dose-dependent fashion.


Effects of hazelnuts and cocoa on vascular reactivity in healthy subjects: a randomised study.
Cocoa helps maintain endothelium-dependent vasodilation; consumption of hazelnuts has been associated with reduced cardiovascular disease risk. This study assesses the effects of hazelnuts and cocoa on vascular reactivity and metabolic profile. Sixty-one healthy volunteers, examined in a randomised, controlled, two-week intervention, received one of six breakfast integrations containing either hazelnuts, cocoa, both or none. Consumption of unpeeled hazelnuts improved HDL-cholesterol (+7.3%, p = .01 vs. baseline, p = .02 vs. control). Brachial artery peak systolic velocities (PSV) at rest increased with hazelnut integrations by 43.4% (p = .04 vs. control) and hazelnut-cocoa integrations by 26.4% (p = .01 vs. control). PSV after 3-min cuff occlusion increased by 60.7% (p = .002 vs. control) with a peeled hazelnut snack and by 64.7% with a hazelnut-cocoa integration (p = .04 vs. control). The combination hazelnut-cocoa may act in a synergic and protective way on cardiovascular system.


Investing Early: Taking Stock of Outcomes and Economic Returns from Early Childhood Programs.
The past two decades have been characterized by a growing body of research from diverse disciplines-child development, psychology, neuroscience, and economics, among others-demonstrating the importance of establishing a strong foundation in the early years of life. The research evidence has served to document the range of early childhood services that can successfully put children and families on the path toward lifelong health and well-being, especially those at greatest risk of poor outcomes. As early childhood interventions have proliferated, researchers have evaluated whether the programs improve children's outcomes and, when they do, whether the improved outcomes generate benefits that can outweigh the program costs. This study examines a set of evaluations that meet criteria for scientific rigor and synthesizes their results to better understand the outcomes, costs, and benefits of early childhood programs. The authors focus on evaluations of 115 early childhood programs serving children or parents of children from the prenatal period to age 5. Although preschool is perhaps the best-known early childhood intervention, the study also reviewed such programs as home visiting, parent education, government transfers providing cash and in-kind benefits, and those that use a combination of approaches. The findings demonstrate that most of the reviewed programs have favorable effects on at least one child outcome and those with an economic evaluation tend to show positive economic returns. With this expanded evidence base, policymakers can be highly confident that well-designed and -implemented early childhood programs can improve the lives of children and their families.


Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina.
Optic nerve formation requires precise retinal ganglion cell (RGC) axon pathfinding within the retina to the optic disc, the molecular basis of which is not well understood. At CNS targets, interactions between Eph receptor tyrosine kinases on RGC axons and ephrin ligands on target cells have been implicated in formation of topographic maps. However, studies in chick and mouse have shown that both Eph receptors and ephrins are also expressed within the retina itself, raising the possibility that this receptor-ligand family mediates aspects of retinal development. Here, we more fully document the presence of specific EphB receptors and B-ephrins in embryonic mouse retina and provide evidence that EphB receptors are involved in RGC axon pathfinding to the optic disc. We find that as RGC axons begin this pathfinding process, EphB receptors are uniformly expressed along the dorsal-ventral retinal axis. This is in contrast to the previously reported high ventral-low dorsal gradient of EphB receptors later in development when RGC axons map to CNS targets. We show that mice lacking both EphB2 and EphB3 receptor tyrosine kinases, but not each alone, exhibit increased frequency of RGC axon guidance errors to the optic disc. In these animals, major aspects of retinal development and cellular organization appear normal, as do the expression of other RGC guidance cues netrin, DCC, and L1. Unexpectedly, errors occur in dorsal but not ventral retina despite early uniform or later high ventral expression of EphB2 and EphB3. Furthermore, embryos lacking EphB3 and the kinase domain of EphB2 do not show increased errors, consistent with a guidance role for the EphB2 extracellular domain. Thus, while Eph kinase function is involved in RGC axon mapping in the brain, RGC axon pathfinding within the retina is partially mediated by EphB receptors acting in a kinase-independent manner.


Using Cloud-Based Physical Activity Data from Google Fit and Apple Healthkit to Expand Recording of Physical Activity Data in a Population Study.
Large population studies are important sources for medical research. These studies are well planned, well organized, and costly. However, people record health data themselves using different sensors, which are mostly unplanned, unorganized and inexpensive. Nevertheless, self-recorded data might be an important supplement to population studies. The question is how to access and use this data. In the seventh survey of the Tromsøcohort study, questionnaires and accelerometers were used to collect data on physical activity (PA). We now plan to collect historical PA data from these participants, using mobile sensor data already stored in the cloud. We will examine the feasibility of this approach and the quality of this data. Objectively measured historical data will provide valuable insights in the potential and limitations of mobile sensors as new data collection tools in medical research.


Hypothesis-independent pathway analysis implicates GABA and acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma.
Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p < 0.001. In addition, the human leukocyte antigen (HLA) gene family was significantly associated with POAG (p < 0.001). In the POAG subset with normal-pressure glaucoma (NPG), the butanoate metabolism pathway was also significantly associated (p < 0.001) as well as the MAPK and Hedgehog signaling pathways (hsa04010 and hsa04340), glycosaminoglycan biosynthesis-heparan sulfate pathway (hsa00534) and the phenylalanine, tyrosine and tryptophan biosynthesis pathway (hsa0400). The butanoate metabolism pathway overall, and specifically the aspects of the pathway that contribute to GABA and acetyl-CoA metabolism, was the only pathway significantly associated with both POAG and NPG. Collectively these results implicate GABA and acetyl-CoA metabolism in glaucoma pathogenesis, and suggest new potential therapeutic targets.


Programmed Multiple C-H Bond Functionalization of the Privileged 4-hydroxyquinoline Template.
The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C-H functionalization. However, such methods have only occasionally been used, in an iterative manner, to decorate various positions of a medicinal scaffold to build chemical libraries. We herein report the multiple, site selective, metal-catalyzed C-H functionalization of a "programmed" 4-hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity-oriented functionalization, of which four were targeted. The C-2 and C-8 decorations were directed by an N-oxide, before taking benefit of an O-carbamoyl protection at C-4 to perform a Fries rearrangement and install a carboxamide at C-3. This also released the carbonyl group of 4-quinolones, the ultimate directing group to functionalize position 5. Our study highlights the power of multiple C-H functionalization to generate diversity in a biologically relevant library, after showing its strong antimalarial potential.


Prevention and management of acute reactions to intravenous iron in surgical patients.
Absolute or functional iron deficiency is the most prevalent cause of anaemia in surgical patients, and its correction is a fundamental strategy within "Patient Blood Management" programmes. Offering perioperative oral iron for treating iron deficiency anaemia is still recommended, but intravenous iron has been demonstrated to be superior in most cases. However, the long-standing prejudice against intravenous iron administration, which is thought to induce anaphylaxis, hypotension and shock, still persists. With currently available intravenous iron formulations, minor infusion reactions are not common. These self-limited reactions are due to labile iron and not hypersensitivity. Aggressively treating infusion reactions with H1-antihistamines or vasopressors should be avoided. Self-limited hypotension during intravenous iron infusion could be considered to be due to hypersensitivity or vascular reaction to labile iron. Acute hypersensitivity reactions to current intravenous iron formulation are believed to be caused by complement activation-related pseudo-allergy. However, though exceedingly rare (<1:250,000 administrations), they should not be ignored, and intravenous iron should be administered only at facilities where staff is trained to evaluate and manage these reactions. As preventive measures, prior to the infusion, staff should inform all patients about infusion reactions and identify those patients with increased risk of hypersensitivity or contraindications for intravenous iron. Infusion should be started at a low rate for a few minutes. In the event of a reaction, the very first intervention should be the immediate cessation of the infusion, followed by evaluation of severity and treatment. An algorithm to scale the intensity of treatment to the clinical picture and/or response to therapy is presented.


Applications of Text Messaging, and Bibliotherapy for Treatment of Patients Affected by Depressive Symptoms.
Intensity of depressive symptoms could be exacerbated due to the paucity of appropriate treatments. We assessed the effectiveness of bibliotherapy and text messaging, which aimed at amelioration of patient's behavior and consciousness, which could lead to suicide prevention. This was a randomized clinical trial implemented in rural health centers of Isfahan district (Iran). Health centers were assigned in three trials consisting of the booklet, text messaging, and control groups. Each group consisted of 70 patients. Inclusion criteria were being affected by depressive symptom, <18 years, and cell phone accessibility. Mental retardation, drug and alcohol abuse, visual disability, dementia, suicide attempt history, electrotherapy, and receiving psychological interventions were our not met criteria. Our patient outcomes comprised intensity of depressive symptom and treatment compliance. The first two trials were requested to study instructive booklets in 30 days while the second cohort was demanded to study the booklet in accordance with the daily delivered text messaging. Out of 210 individuals, 198 patients finished this study. The intensity of depressive symptom was significantly affected through time and group factors as well as time-group interaction (F = 12.30, P < 0.001). Based on treatment compliance, the interactive effect of group factor and the time factor was statistically significant. It seems that bibliotherapy could efficiently decrease the intensity of depressive symptoms. Nevertheless, in comparison with our booklet trial, the text messaging group achieved neither durable nor significant success; thus, bibliotherapy could be utilized as a complementary methodology aiming depression treatment.


Changes in intrusive memories associated with imaginal reliving in posttraumatic stress disorder.
The study investigated changes in intrusive memories associated with imaginal reliving of traumatic events in posttraumatic stress disorder (PTSD). The study population comprised 44 patients treated with imaginal reliving in the context of cognitive therapy for PTSD [Behav. Res. Ther. 38 (2000) 319-345]. For most patients, imaginal reliving did not lead to exacerbations in intrusion frequency. The decrease in intrusion frequency after reliving was gradual, as was the decrease in their distress, vividness, and perceived "nowness." Poorer outcome, i.e., a smaller reduction in residual gain scores for intrusion frequency with reliving, was associated with greater initial PTSD severity, greater anger, greater perceived "nowness" of intrusive memories, and more negative interpretations of PTSD symptoms. The patient's anxiety, depression, self-blame, and dissociation were not predictive of response to reliving.


Acute myocardial infarction with cardiogenic shock in a young physically active physician concurrently using the anabolic steroid sustanon: A case report.
The association between ischemic heart disease (IHD) and the concurrent use of anabolic androgenic steroids (AASs) is underestimated in clinical settings. The tendency of patients to not disclose AASs use may explain this underestimation. In the present case report, the clinical case of a 26-year-old physically active male, who was a physician, without any classical coronary risk factors, who presented with chest pain that was misdiagnosed by the peripheral care unit as skeletal muscle pain is described. Later, the patient was brought to our central hospital (King Abdullah University Hospital) suffering from a massive acute myocardial infarction with marked ECG changes and cardiogenic shock. Following stabilization of his condition, a detailed history of the patient was taken, during which the patient admitted that he was a chronic user of the anabolic steroid sustanon (250 mg, once/week for 6 months) and amino acid supplements (whey protein isolate, 6 tabs every day for 1 year). Specific cardiac markers were increased and the patient exhibited dynamic ischemic changes in his electrocardiogram. Notably, the coronary angiogram of the patient demonstrated ostial occlusion of the left anterior descending artery, which was associated with mid-right coronary artery embolic obstruction. Other than the anabolic steroids and protein supplementation use, the patient history, examination and lab evaluation were normal. During follow up, the patient continued to suffer heart failure with low ejection fraction. In addition, he developed apical thrombus 2 months after primary admission. The patient developed tachycardia in spite of optimal medical treatment and finally received an implantable cardioverter defibrillator. Physicians should always be aware of the possibility of AASs use in young physically active patients. IHD should always be suspected and investigated with typical chest pain in healthy young patients, even if regular risk factors are not present. Medical professionals should not be excluded as potential AASs users/abusers.


Fiber Typing of the Erector Spinae and Multifidus Muscles in Healthy Controls and Back Pain Patients: A Systematic Literature Review.
Understanding the changes in muscle fiber typing is relevant in the context of muscle disorders because it provides information on the metabolic profile and functional capacity. The aim of this study was to systematically review the literature comparing muscle fiber typing in the back muscles of healthy subjects with low back pain (LBP) patients. Predefined keywords regarding muscle fiber typing and back muscles were combined in PubMed and Web of Science electronic search engines from inception to August 2014. Full-text articles were independently screened by 2 independent, blinded researchers. Full texts fulfilling the predefined inclusion criteria were assessed on risk of bias by 2 independent researchers, and relative data were extracted. Data were not pooled because of heterogeneity in biopsy locations and population. From the 214 articles that were identified, 18 met the inclusion criteria. These articles evaluated the muscle fiber type distribution or proportional fiber type area between muscles, muscle layers, men, and women or healthy subjects and LBP patients. Regarding muscle fiber type distribution, findings in healthy subjects and LBP patients show no or inconclusive evidence for intermuscular and interindividual differentiation. Studies evaluating the proportional fiber type area also suggest little intermuscular differentiation but provide plausible evidence that the proportional area occupied by type I fibers is higher in women compared to men. The evidence for differentiation based on the presence of low back pain is conflicting. This study found that the evidence regarding muscle fiber typing in back muscles is either inconclusive or shows little differences. The most plausible evidence exists for differentiation in proportional fiber type area depending on sex.


Incidence of cardiovascular events in white-coat, masked and sustained hypertension versus true normotension: a meta-analysis.
To perform a meta-analysis on the incidence of cardiovascular events in white-coat hypertension (WCHT), masked and sustained hypertension in comparison with true normotension. We searched for individual studies, in which the adjusted relative risk of incident cardiovascular events was assessed in patients with WCHT, masked and sustained hypertension versus normotension in the same study population. For each type of hypertension, the weighted overall hazard ratio (HR) and 95% confidence intervals (CI) were calculated. Seven studies were identified, involving a total of 11 502 participants. Four studies were performed in the population, two in primary care and one in specialist care. Two studies were exclusively on treated hypertensive patients; individuals on antihypertensive treatment were included in all the other studies except one. Cut-off blood pressure was 140/90 mmHg for office blood pressure in all studies and 135/85 mmHg (83 in one study) for out-of-office blood pressure. The average age of the study populations was 63 years; 53% were men. The endpoint consisted of cardiovascular death in one study and of various aggregates of fatal and non-fatal cardiovascular events in the others. During an average follow-up of 8.0 years, there were 912 first cardiovascular events. The overall adjusted HR versus normotension was 1.12 (95% CI 0.84-1.50) for WCHT (P = 0.59), 2.00 (1.58-2.52) for masked hypertension (P < 0.001), and 2.28 (1.87-2.78) for sustained hypertension (P < 0.001). The meta-analysis indicates that the incidence of cardiovascular events is not significantly different between WCHT and true normotension, whereas the outcome is worse in patients with masked or sustained hypertension.


Acute pulmonary vasoreactivity test with sildenafil or nitric monoxide before left ventricular assist device implantation.
There has been no established medical therapy to ameliorate pulmonary hypertension (PH) owing to left heart disease (LHD-PH). It has recently been shown that the left ventricular assist device (LVAD) can improve LHD-PH and therefore has the potential to become a major bridge tool for heart transplantation (HTx). However, some patients still have persistent PH even after LVAD treatment. It is essential to demonstrate the reversibility of end-organ dysfunction, including PH, prior to implantable LVAD treatment, especially in Japan, because implantable LVAD treatment is indicated only as bridge to transplantation. Here we report a patient with LHD-PH whose PH was demonstrated to be reversible by the acute pulmonary vasoreactivity test (APVT) with nitrogen monoxide (NO) and the phosphodiesterase-5 inhibitor sildenafil. Both inhaled NO and sildenafil reduced pulmonary vascular resistance, but pulmonary capillary wedge pressure was increased by NO, which was conversely decreased under increased cardiac output by sildenafil. After the patient was listed as an HTx recipient, pulmonary vascular resistance recovered down to an acceptable range with LVAD treatment. Based on these findings, we suggest that the APVT with sildenafil may be a useful and safe tool to predict improvement of PH after LVAD treatment.


Interactions of gaseous molecules with X-ray photons and photoelectrons in AP-XPS study of solid surface in gas phase.
Studies of the surface of a catalyst in the gas phase via photoelectron spectroscopy is an important approach to establish a correlation between the surface of a catalyst under reaction conditions or during catalysis and its corresponding catalytic performance. Unlike the well understood interactions between photoelectrons and the atomic layers of a surface in ultrahigh vacuum (UHV) and the well-developed method of quantitative analysis of a solid surface in UHV, a fundamental understanding of the interactions between X-ray photons and gaseous molecules and between photoelectrons and molecules of the gas phase in ambient pressure X-ray photoelectron spectroscopy (AP-XPS) is lacking. Through well designed experiments, here the impact of the interactions between photoelectrons and gaseous molecules and interactions between X-ray photons and gaseous molecules on the intensity of the collected photoelectrons have been explored. How the changes in photoelectron intensity resulting from these interactions influence measurement of the authentic atomic ratio of element M to A of a solid surface has been discussed herein, and methods to correct the measured nominal atomic ratio of two elements of a solid surface upon travelling through a gas phase to its authentic atomic ratio have been developed.


Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells.
Malignant pleural mesothelioma (MPM) is an incurable malignant disease, which results from chronic exposition to asbestos in at least 70% of the cases. Fibroblast activation protein (FAP) is predominantly expressed on the surface of reactive tumor-associated fibroblasts as well as on particular cancer types. Because of its expression on the cell surface, FAP is an attractive target for adoptive T cell therapy. T cells can be re-directed by retroviral transfer of chimeric antigen receptors (CAR) against tumor-associated antigens (TAA) and therefore represent a therapeutic strategy of adoptive immunotherapy. To evaluate FAP expression immunohistochemistry was performed in tumor tissue from MPM patients. CD8+ human T cells were retrovirally transduced with an anti-FAP-F19-∆CD28/CD3ζ-CAR. T cell function was evaluated in vitro by cytokine release and cytotoxicity assays. In vivo function was tested with an intraperitoneal xenograft tumor model in immunodeficient mice. FAP was found to be expressed in all subtypes of MPM. Additionally, FAP expression was evaluated in healthy adult tissue samples and was only detected in specific areas in the pancreas, the placenta and very weakly for cervix and uterus. Expression of the anti-FAP-F19-∆CD28/CD3ζ-CAR in CD8+ T cells resulted in antigen-specific IFNγ release. Additionally, FAP-specific re-directed T cells lysed FAP positive mesothelioma cells and inflammatory fibroblasts in an antigen-specific manner in vitro. Furthermore, FAP-specific re-directed T cells inhibited the growth of FAP positive human tumor cells in the peritoneal cavity of mice and significantly prolonged survival of mice. FAP re-directed CD8+ T cells showed antigen-specific functionality in vitro and in vivo. Furthermore, FAP expression was verified in all MPM histotypes. Therefore, our data support performing a phase I clinical trial in which MPM patients are treated with adoptively transferred FAP-specific re-directed T cells.


VESPA ASL: VElocity and SPAtially Selective Arterial Spin Labeling.
Spatially selective arterial spin labeling (ASL) perfusion MRI is sensitive to arterial transit times (ATT) that can result in inaccurate perfusion quantification when ATTs are long. Velocity-selective ASL is robust to this effect because blood is labeled within the imaging region, allowing immediate label delivery. However, velocity-selective ASL cannot characterize ATTs, which can provide important clinical information. Here, we introduce a novel pulse sequence, called VESPA ASL, that combines velocity-selective and pseudo-continuous ASL to simultaneously label different pools of arterial blood for robust cerebral blood flow (CBF) and ATT measurement. The VESPA ASL sequence is similar to velocity-selective ASL, but the velocity-selective labeling is made spatially selective, and pseudo-continuous ASL is added to fill the inflow time. The choice of inflow time and other sequence settings were explored. VESPA ASL was compared to multi-delay pseudo-continuous ASL and velocity-selective ASL through simulations and test-retest experiments in healthy volunteers. VESPA ASL is shown to accurately measure CBF in the presence of long ATTs, and ATTs < TI can also be measured. Measurements were similar to established ASL techniques when ATT was short. When ATT was long, VESPA ASL measured CBF more accurately than multi-delay pseudo-continuous ASL, which tended to underestimate CBF. VESPA ASL is a novel and robust approach to simultaneously measure CBF and ATT and offers important advantages over existing methods. It fills an important clinical need for noninvasive perfusion and transit time imaging in vascular diseases with delayed arterial transit.


Metapopulation dynamics override local limits on long-term parasite persistence.
A simple null model, particularly germane to small and vulnerable organisms such as parasites, is that local conditions set a stage upon which larger-scale dynamics play out. Soil moisture strongly influences survival of entomopathogenic nematodes (EPN), which in turn drive trophic cascades by protecting vegetation from root-feeding herbivores. In this study, we examine the mechanisms responsible for patchy occurrence of an entomopathogenic nematode, Heterorhabditis marelatus, in a California coastal prairie. One hypothesis proposes that biotic factors such as competition and natural enemies could regulate occurrence of EPN populations. We found that fungi and other enemies of EPN, although locally potent, did not explain the patterns of incidence across sites. Abiotic factors also have strong effects on EPN persistence, especially for vulnerable free-living stages. Thus, we tested the hypothesis that patchy occurrence of EPN on a large landscape was driven by differences in soil moisture. Our research uses long-term data on nematode incidence in combination with a landscape-level experiment to demonstrate the lack of a correlation between soil moisture and long-term persistence. A year-long experiment showed EPN mortality was weakly correlated with soil moisture among our study sites. Thirteen years of data, however, showed that colonization rates were highly correlated with long-term persistence. Sites with highest long-term persistence experienced the highest rates of rhizosphere colonization, extinction, and turnover. As a result, we concluded that metapopulation dynamics override limitations set by local and short-term abiotic conditions to determine long-term persistence in this parasite-driven trophic cascade.