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.

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.

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.

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.

Role of diuretics, blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study

OBJECTIVE To examine the degree to which use of β blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset diabetes. DESIGN Reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. SETTING NAVIGATOR trial. PARTICIPANTS Patients who at baseline (enrolment) were treatment naïve to β blockers (n=5640), diuretics (n=6346), statins (n=6146), and calcium channel blockers (n=6294). Use of calcium channel blocker was used as a metabolically neutral control. MAIN OUTCOME MEASURES Development of new onset diabetes diagnosed by standard plasma glucose level in all participants and confirmed with glucose tolerance testing within 12 weeks after the increased glucose value was recorded. The relation between each treatment and new onset diabetes was evaluated using marginal structural models for causal inference, to account for time dependent confounding in treatment assignment. RESULTS During the median five years of follow-up, β blockers were started in 915 (16.2%) patients, diuretics in 1316 (20.7%), statins in 1353 (22.0%), and calcium channel blockers in 1171 (18.6%). After adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new onset diabetes (hazard ratio 1.23, 95% confidence interval 1.06 to 1.44, and 1.32, 1.14 to 1.48, respectively), whereas β blockers and calcium channel blockers were not associated with new onset diabetes (1.10, 0.92 to 1.31, and 0.95, 0.79 to 1.13, respectively). CONCLUSIONS Among people with impaired glucose tolerance and other cardiovascular risk factors and with serial glucose measurements, diuretics and statins were associated with an increased risk of new onset diabetes, whereas the effect of β blockers was non-significant.

Disentangling multiple drivers of pollination in a landscape-scale experiment

Animal pollination is essential for the reproductive success of many wild and crop plants. Loss and isolation of (semi-)natural habitats in agricultural landscapes can cause declines of plants and pollinators and endanger pollination services.We investigated the independent effects of these drivers on pollination of young cherry trees in a landscape-scale experiment. We included (i) isolation of study trees from other cherry trees (up to 350 m), (ii) the amount of cherry trees in the landscape, (iii) the isolation from other woody habitats (up to 200 m) and (iv) the amount of woody habitats providing nesting and floral resources for pollinators. At the local scale, we considered effects of (v) cherry flower density and (vi) heterospecific flower density. Pollinators visited flowers more often in landscapes with high amount of woody habitat and at sites with lower isolation from the next cherry tree. Fruit set was reduced by isolation from the next cherry tree and by a high local density of heterospecific flowers but did not directly depend on pollinator visitation. These results reveal the importance of considering the plant’s need for con-specific pollen and its pollen competition with co-flowering species rather than focusing only on pollinators’ habitat requirements and flower visita-tion. It proved to be important to disentangle habitat isolation from habitat loss, local from landscape-scale effects, and direct effects of pollen availability on fruit set from indirect effects via pollinator visitation to understand the delivery of an agriculturally important ecosystem service.

Drivers of RFID adoption in the automotive industry

The automotive industry is confronted with increasing competition, leading to higher cost pressures and the demand to optimize production processes and value chains. Here the RFID technology promises to improve a range of processes in logistics and manufacturing. Despite its promising potential in the automotive industry, RFID has not yet made a decisive step from pilots to real-life implementations in the supply chain. Building on existing models of technology adoption, we analyze RFID adoption dynamics in the automotive industry. Building on existing IOS adoption models tailored to RFID specifics and based on ten semi-structured interviews with OEMs and suppliers, we evaluate main drivers of RFID adoption in the automotive industry. Our key findings are that the use of a coercive approach by the OEM could be redundant because of the market-driven RFID adoption among many suppliers. Furthermore, suppliers implementing RFID can now gain an early mover competitive advantage by developing higher trust in their relationship with the OEM as well as accumulating unique expertise in this area.

A novel computer test to assess driving-relevant cognitive functions - a pilot study

BACKGROUND: The assessment of driving-relevant cognitive functions in older drivers is a difficult challenge as there is no clear-cut dividing line between normal cognition and impaired cognition and not all cognitive functions are equally important for driving. METHODS: To support decision makers, the Bern Cognitive Screening Test (BCST) for older drivers was designed. It is a computer-assisted test battery assessing visuo-spatial attention, executive functions, eye-hand coordination, distance judgment, and speed regulation. Here we compare the performance in BCST with the performance in paper and pencil cognitive screening tests and the performance in the driving simulator testing of 41 safe drivers (without crash history) and 14 unsafe drivers (with crash history). RESULTS: Safe drivers performed better than unsafe drivers in BCST (Mann-Whitney U test: U = 125.5; p = 0.001) and in the driving simulator (Student's t-test: t(44) = -2.64, p = 0.006). No clear group differences were found in paper and pencil screening tests (p > 0.05; ns). BCST was best at identifying older unsafe drivers (sensitivity 86%; specificity 61%) and was also better tolerated than the driving simulator test with fewer dropouts. CONCLUSIONS: BCST is more accurate than paper and pencil screening tests, and better tolerated than driving simulator testing when assessing driving-relevant cognition in older drivers.

Unraveling environmental drivers of a recent increase in Swiss fungi fruiting

Disentangling biotic and abiotic drivers of wild mushroom fruiting is fraught with difficulties because mycelial growth is hidden belowground, symbiotic and saprotrophic supply strategies may interact, and myco-ecological observations are often either discontinuous or too short. Here, we compiled and analyzed 115 417 weekly fungal fruit body counts from permanent Swiss inventories between 1975 and 2006. Mushroom fruiting exhibited an average autumnal delay of 12 days after 1991 compared with before, the annual number of fruit bodies increased from 1801 to 5414 and the mean species richness doubled from 10 to 20. Intra- and interannual coherency of symbiotic and saprotrophic mushroom fruiting, together with little agreement between mycorrhizal yield and tree growth suggests direct climate controls on fruit body formation of both nutritional modes. Our results contradict a previously reported declining of mushroom harvests and propose rethinking the conceptual role of symbiotic pathways in fungi-host interaction. Moreover, this conceptual advancement may foster new cross-disciplinary research avenues, and stimulate questions about possible amplifications of the global carbon cycle, as enhanced fungal production in moist mid-latitude forests rises carbon cycling and thus increases greenhouse gas exchanges between terrestrial ecosystems and the atmosphere.