Defective homing and impaired induction of cytotoxic T cells by BCR/ABL-expressing dendritic cells

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease arising from a hematopoietic stem cell expressing the BCR/ABL fusion protein. Leukemic and dendritic cells (DCs) develop from the same transformed hematopoietic progenitors. How BCR/ABL interferes with the immunoregulatory function of DCs in vivo is unknown. We analyzed the function of BCR/ABL-expressing DCs in a retroviral-induced murine CML model using the glycoprotein of lymphocytic choriomeningitis virus as a model leukemia antigen. BCR/ABL-expressing DCs were found in bone marrow, thymus, spleen, lymph nodes, and blood of CML mice. They were characterized by a low maturation status and induced only limited expansion of naive and memory cytotoxic T lymphocytes (CTLs). In addition, immunization with in vitro-generated BCR/ABL-expressing DCs induced lower frequencies of specific CTLs than immunization with control DCs. BCR/ABL-expressing DCs preferentially homed to the thymus, whereas only few BCR/ABL-expressing DCs reached the spleen. Our results indicate that BCR/ABL-expressing DCs do not efficiently induce CML-specific T-cell responses resulting from low DC maturation and impaired homing to secondary lymphoid organs. In addition, BCR/ABL-expressing DCs in the thymus may contribute to CML-specific tolerance induction of specific CTLs.

Stent thrombosis is associated with an impaired response to antiplatelet therapy

OBJECTIVES: We sought to evaluate the response to antiplatelet therapy in patients with stent thrombosis (ST). BACKGROUND: Stent thrombosis is associated with considerable morbidity and mortality. An impaired response to antiplatelet therapy might be related to an increased risk for ST. METHODS: Eighty-two patients were included in the present study: 23 patients with previous ST, 50 matched controls (coronary stenting without ST), and 9 healthy volunteers. Platelet aggregation (PA) was studied (optical aggregometry) under monotherapy with acetylsalicylic acid (ASA) 100 mg daily for one month, followed by dual therapy with ASA 100 mg and clopidogrel 75 mg daily (loading dose 300 mg) for another month. RESULTS: Maximal (5 and 20 micromol) adenosine diphosphate-induced PA was significantly higher in patients with ST compared with controls (5 micromol, p < 0.005; 20 micromol, p < 0.05) and volunteers (5 micromol, p < 0.005; 20 micromol, p < 0.05). Resistance to ASA (>20% aggregation with 0.5 mg/ml arachidonic acid) was more prevalent in patients with ST (48%) compared with control patients (32%, p = ns) and volunteers (0%, p = 0.01). Clopidogrel significantly reduced PA in all three groups, but intergroup differences persisted. Clopidogrel resistance (<10% relative change) was similar in patients with ST, control patients, and volunteers (4%, 6%, and 11%, respectively, all p = NS). However, combined ASA and clopidogrel resistance was more prevalent in patients with ST (52%) compared with controls (38%, p = NS) and volunteers (11%, p < 0.05). CONCLUSIONS: Patients with previous ST show an impaired response to antiplatelet therapy with ASA compared with controls and volunteers. Additional treatment with clopidogrel is not able to overcome these differences in PA. Acetylsalicylic acid but not clopidogrel resistance appears to be associated with ST.

Impaired verbal memory in Parkinson disease: relationship to prefrontal dysfunction and somatosensory discrimination

OBJECTIVE: To study the neurocognitive profile and its relationship to prefrontal dysfunction in non-demented Parkinson's disease (PD) with deficient haptic perception. METHODS: Twelve right-handed patients with PD and 12 healthy control subjects underwent thorough neuropsychological testing including Rey complex figure, Rey auditory verbal and figural learning test, figural and verbal fluency, and Stroop test. Test scores reflecting significant differences between patients and healthy subjects were correlated with the individual expression coefficients of one principal component, obtained in a principal component analysis of an oxygen-15-labeled water PET study exploring somatosensory discrimination that differentiated between the two groups and involved prefrontal cortices. RESULTS: We found significantly decreased total scores for the verbal learning trials and verbal delayed free recall in PD patients compared with normal volunteers. Further analysis of these parameters using Spearman's ranking correlation showed a significantly negative correlation of deficient verbal recall with expression coefficients of the principal component whose image showed a subcortical-cortical network, including right dorsolateral-prefrontal cortex, in PD patients. CONCLUSION: PD patients with disrupted right dorsolateral prefrontal cortex function and associated diminished somatosensory discrimination are impaired also in verbal memory functions. A negative correlation between delayed verbal free recall and PET activation in a network including the prefrontal cortices suggests that verbal cues and accordingly declarative memory processes may be operative in PD during activities that demand sustained attention such as somatosensory discrimination. Verbal cues may be compensatory in nature and help to non-specifically enhance focused attention in the presence of a functionally disrupted prefrontal cortex.

In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function

INTRODUCTION: The antiretroviral drug efavirenz (EFV) is extensively metabolized into three primary metabolites: 8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV. There is a wide interindividual variability in EFV plasma exposure, explained to a great extent by cytochrome P450 2B6 (CYP2B6), the main isoenzyme responsible for EFV metabolism and involved in the major metabolic pathway (8-hydroxylation) and to a lesser extent in 7-hydroxylation. When CYP2B6 function is impaired, the relevance of CYP2A6, the main isoenzyme responsible for 7-hydroxylation may increase. We hypothesize that genetic variability in this gene may contribute to the particularly high, unexplained variability in EFV exposure in individuals with limited CYP2B6 function. METHODS: This study characterized CYP2A6 variation (14 alleles) in individuals (N=169) previously characterized for functional variants in CYP2B6 (18 alleles). Plasma concentrations of EFV and its primary metabolites (8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV) were measured in different genetic backgrounds in vivo. RESULTS: The accessory metabolic pathway CYP2A6 has a critical role in limiting drug accumulation in individuals characterized as CYP2B6 slow metabolizers. CONCLUSION: Dual CYP2B6 and CYP2A6 slow metabolism occurs at significant frequency in various human populations, leading to extremely high EFV exposure.

Articulated Narrowcasting for Privacy and Awareness in Multimedia Conferencing Systems and Design for Implementation Within a SIP Framework

This article proposes a new focus of research for multimedia conferencing systems which allows a participant to flexibly select another participant or a group for media transmission. For example, in a traditional conference system, participants voices might by default be shared with all others, but one might want to select a subset of the conference members to send his/her media to or receive media from. We review the concept of narrowcasting, a model for limiting such information streams in a multimedia conference, and describe a design to use existing standard protocols (SIP and SDP) for controlling fine-grained narrowcasting sessions.

Proposed WIPO Treaty for Improved Access for Blind, Visually Impaired, and Other Reading Disabled Persons

Although the world’s attention has on several occasions been turned to the plight of the vision impaired, there has been no international copyright instrument that specifically provides for limitations or exceptions to copyright for their benefit. Such an instrument becomes imperative amidst the grow- ing number of persons in this category and the need to facilitate their access to information that will give them the opportunity to participate in public affairs. Brazil, Ecuador, Paraguay, and Mexico (Brazilian group) seek to fill this gap by submitting to the WIPO’s Standing Committee on Copyright and Related Rights a draft treaty for Improved Access for Blind, Visually Impaired and Other Reading Disabled Persons. How- ever, this proposal has generated a lot of reactions, resulting in three other such proposals being submit- ted to WIPO for deliberations. Copyright owners have also opposed the treaty. Amidst these reactions, this work seeks to analyze the compatibility of the Brazilian group’s proposal with the TRIPS three-step test, which has enjoyed a great deal of international recognition since its inclusion in the Berne Convention. It also seeks to find its compatibility with EU copyright law as harmonized in the Directive 2001/29/EC. In the end, we conclude that the proposed treaty is in harmony with the three-step test, and though it has some variations from the EU Copyright Directive, it nonetheless shares some underlying objectives with the Directive and does not radically depart from what prevails in several EU member states.

[Livestock owners with specifically increased disease awareness for Bluetongue: A new approach to disease surveillance]

For the first time in Switzerland, specifically trained livestock owners were included in a national disease surveillance program by the Federal Veterinary Office. A questionnaire on data about clinical and epidemiological aspects of Bluetongue Disease (BT) as well as on herd management was completed by 26 sheep owners three months after they had attended a training course about BT. The control group, consisted of 264 randomly selected sheep and cattle owners who had not visited a training course. Results showed that disease awareness for BT after attending the training course was considerably increased. This was especially evident in the better knowledge of the participants about the great number of possible symptoms. Training courses with the objective of increased disease awareness of livestock owners are an efficient, cost-effective instrument in control programs for exotic diseases.

Early- and delayed antipsychotic response and prediction of outcome in 528 severely impaired patients with schizophrenia treated with amisulpride

'Early-onset' studies have shown that symptomatic response often occurs early and that early symptomatic response is predictive for later outcome. Limiting factors of these studies include the restriction on symptomatic outcome, the inclusion of mostly moderately ill patients, and the use of various antipsychotics.

Hepatitis B virus infection is associated with impaired immunological recovery during antiretroviral therapy in the Swiss HIV cohort study

Hepatitis B virus (HBV) infection is a major cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients worldwide. It is unclear whether HIV-related outcomes are affected by HBV coinfection. We compared virological suppression and immunological recovery during antiretroviral therapy (ART) of patients of different HBV serological status in the Swiss HIV Cohort Study. CD4 cell recovery during ART was significantly impaired in hepatitis B surface antigen-positive patients and in those with anti-hepatitis B core antigen alone compared with HBV-uninfected patients, despite similar virological efficacy of ART. CD4 increase in patients with resolved HBV infection was similar to that in HBV-uninfected individuals.

Monitoring the Time Course of Perception without Awareness: A Comparison of Mirror Masked Words and Nonwords

Mirror masked words are embedded into a context that makes them appear as senseless patterns or as strings of unfamiliar letters. Thus, mirror masked words can be shown for several hundreds of milliseconds without being recognised as words. We sought to further investigate effects of nonsconscious reading by monitoring event-related brain potentials (ERPs) while participants observed mirror masked letter strings. ERPs were recorded while participants observed mirror masked words and nonwords. Data of 15 participants was segmented into periods of quasi-stable field topography (microstates). Microstates for masked words and nonwords were compared using randomization tests, statistical parametric scalp maps and Low Resolution Electromagnetic Tomography (LORETA). ERPs to masked words and nonwords showed significant topographic differences between 136 and 256 ms, indicating that stimuli were nonconsciously discriminated. A LORETA model localised sources of activation discriminating between masked words and nonwords in left operculum, the right superior parietal lobe and right superior temporal gyrus indicating higher current density for nonwords than for words in these areas. ERPs of mirror masked stimuli can indicate unconscious discrimination even in cases where behavioural priming is unreliable. This approach might be useful for investigating differences in early, nonconscious stages of word perception.

Impaired gesture performance in schizophrenia: particular vulnerability of meaningless pantomimes

Schizophrenia patients frequently present with subtle motor impairments, including higher order motor function such as hand gesture performance. Using cut off scores from a standardized gesture test, we previously reported gesture deficits in 40% of schizophrenia patients irrespective of the gesture content. However, these findings were based on normative data from an older control group. Hence, we now aimed at determining cut-off scores in an age and gender matched control group. Furthermore, we wanted to explore whether gesture categories are differentially affected in Schizophrenia. Gesture performance data of 30 schizophrenia patients and data from 30 matched controls were compared. Categories included meaningless, intransitive (communicative) and transitive (object related) hand gestures, which were either imitated or pantomimed, i.e. produced on verbal command. Cut-off scores of the age matched control group were higher than the previous cut-off scores in an older control group. An ANOVA tested effects of group, domain (imitation or pantomime), and semantic category (meaningless, transitive or intransitive), as well as their interaction. According to the new cut-off scores, 67% of the schizophrenia patients demonstrated gestural deficits. Patients performed worse in all gesture categories, however meaningless gestures on verbal command were particularly impaired (p = 0.008). This category correlated with poor frontal lobe function (p < 0.001). In conclusion, gestural deficits in schizophrenia are even more frequent than previously reported. Gesture categories that pose higher demands on planning and selection such as pantomime of meaningless gestures are predominantly affected and associated with the well-known frontal lobe dysfunction.

Design and Impact of Awareness Functions – A Study about Social Media in Virtual Teams

The usage of social media in leisure time settings has become a prominent research topic. However, less research has been done on the design of social media in collaboration settings. In this study, we investigate how social media can support asynchronous collaboration in virtual teams and specifically how they can increase activity awareness. On the basis of an open source social networking platform, we present two prototype designs: a standard platform with basic support for information processing, communication and process – as suggested by Zigurs and Buckland (1998) – and an advanced platform with additional support for activity awareness via specialfeed functions. We argue that the standard platform already conveys activity awareness to a certain extent, however, that this awareness can be increased even more by the feeds in the advanced platform. Both prototypes are tested in a field experiment and evaluated with respect to their impact on perceived activity awareness, coordination and satisfaction. We show that the advanced design increases coordination and satisfaction through increased perceived activity awareness.

Failure cue priming and impaired cognitive performance—analyses of avoidance motivation as a mediator and fear of failure as a moderator.

The present research investigates whether and how learned symbols for failure reduce task performance. We tested the effect of number priming in two countries with different learning histories for numbers. Priming numbers associated with failure (6 in Germany and 1 in Switzerland) were hypothesized to reduce performance. As expected, in Switzerland, priming with the failure number 1 reduced performance (Study 1), whereas in Germany, priming with the failure number 6 impaired performance in analogy tasks (Study 2). Study 2 additionally analyzed the mechanism and showed that the relationship between failure number priming and performance was mediated by evoked avoidance motivation and that dispositional fear of failure moderated this mediation.