Rivalry of homeostatic and sensory-evoked emotions: dehydration attenuates olfactory disgust and its neural correlates

Neural correlates have been described for emotions evoked by states of homeostatic imbalance (e.g. thirst, hunger, and breathlessness) and for emotions induced by external sensory stimulation (such as fear and disgust). However, the neurobiological mechanisms of their interaction, when they are experienced simultaneously, are still unknown. We investigated the interaction on the neurobiological and the perceptional level using subjective ratings, serum parameters, and functional magnetic resonance imaging (fMRI) in a situation of emotional rivalry, when both a homeostatic and a sensory-evoked emotion were experienced at the same time. Twenty highly dehydrated male subjects rated a disgusting odor as significantly less repulsive when they were thirsty. On the neurobiological level, we found that this reduction in subjective disgust during thirst was accompanied by a significantly reduced neural activity in the insular cortex, a brain area known to be considerably involved in processing of disgust. Furthermore, during the experience of disgust in the satiated condition, we observed a significant functional connectivity between brain areas responding to the disgusting odor, which was absent during the stimulation in the thirsty condition. These results suggest interference of conflicting emotions: An acute homeostatic imbalance can attenuate the experience of another emotion evoked by the sensory perception of a potentially harmful external agent. This finding offers novel insights with regard to the behavioral relevance of biologically different types of emotions, indicating that some types of emotions are more imperative for behavior than others. As a general principle, this modulatory effect during the conflict of homeostatic and sensory-evoked emotions may function to safeguard survival.

Dimensions of Global Change in African Mountains: The Example of Mount Kenya

This paper discusses the effects of global change in African mountains, with the example of Mount Kenya. The geographical focus is the northwestern, semi-arid foot zone of the mountain (Laikipia District). Over the past 50 years, this area has experienced rapid and profound transformation, the respective processes of which are all linked to global change. The main driving forces behind these processes have been political and economic in nature. To these an environmental change factor has been added in recent years – climate change. After introducing the area of research, the paper presents three dimensions of global change that are manifested in the region and largely shape its development: Socio-political change, economic change, environmental change. For the regions northwest of Mount Kenya, climate models predict important changes in rainfall distribution that will have a profound impact on freshwater availability and management. The results presented here are based on research undertaken northwest of Mount Kenya within the framework of a series of long-term Kenyan-Swiss research programmes that began in the early 1980s.

Dysfunction of Cortical Dendritic Integration in Neuropathic Pain Reversed by Serotoninergic Neuromodulation

Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target.

Depletion of regulatory T cells augments a vaccine-induced T effector cell response against the liver-stage of malaria but fails to increase memory

Regulatory T cells (T(reg)) have been shown to restrict vaccine-induced T cell responses in different experimental models. In these studies CD4(+)CD25(+) T(reg) were depleted using monoclonal antibodies against CD25, which might also interfere with CD25 on non-regulatory T cell populations and would have no effect on Foxp3(+)CD25(-) T(reg). To obtain more insights in the specific function of T(reg) during vaccination we used mice that are transgenic for a bacterial artificial chromosome expressing a diphtheria toxin (DT) receptor-eGFP fusion protein under the control of the foxp3 gene locus (depletion of regulatory T cell mice; DEREG). As an experimental vaccine-carrier recombinant Bordetella adenylate cyclase toxoid fused with a MHC-class I-restricted epitope of the circumsporozoite protein (ACT-CSP) of Plasmodium berghei (Pb) was used. ACT-CSP was shown by us previously to introduce the CD8+ epitope of Pb-CSP into the MHC class I presentation pathway of professional antigen-presenting cells (APC). Using this system we demonstrate here that the number of CSP-specific T cells increases when T(reg) are depleted during prime but also during boost immunization. Importantly, despite this increase of T effector cells no difference in the number of antigen-specific memory cells was observed.

Reevaluation of the MASTER-2009 MLI and H-10 Debris Modeling

The current paper is an excerpt from the doctoral thesis ”Multi-Layer Insulation as Contribution to Orbital Debris”written at the Institute of Aerospace Systems of the Technische Universit ̈at of Braunschweig. The Multi-Layer In-sulation (MLI) population included in ESA’s MASTER-2009 (M eteoroid and Space-Debris Terrestrial Environment Reference) software is based on models for two mechanisms: One model simulates the release of MLI debris during fragmentation events while another estimates the continuo us release of larger MLI pieces due to aging related deterioration of the material. The aim of the thesis was to revise the MLI models from the base up followed by a re-validation of the simulated MLI debris population. The validation is based on comparison to measurement data of the GEO and GTO debris environment obtained by the Astronomical Institute of the University of Bern (AIUB) using ESA’s Space Debris Telescope (ESASDT), the 1-m Zeiss telescope located at the Optical Ground Station (OGS) at the Teide Observatory at Tenerife, Spain. The re-validation led to the conclusion that MLI may cover a much smaller portion of the observed objects than previously published. Further investigation of the resulting discrepancy revealed that the contribution of altogether nine known Ariane H-10 upper stage explosion events which occurred between 1984 and 2002 has very likely been underestimated in past simulations.

Optimization of Optical Follow-up Strategies Based on Covariance Analysis

An in-depth study, using simulations and covariance analysis, is performed to identify the optimal sequence of observations to obtain the most accurate orbit propagation. The accuracy of the results of an orbit determination/ improvement process depends on: tracklet length, number of observations, type of orbit, astrometric error, time interval between tracklets and observation geometry. The latter depends on the position of the object along its orbit and the location of the observing station. This covariance analysis aims to optimize the observation strategy taking into account the influence of the orbit shape, of the relative object-observer geometry and the interval between observations.

Inactivation of the p53-KLF4-CEBPA Axis in Acute Myeloid Leukemia.

PURPOSE In acute myeloid leukemia (AML), the transcription factors CEBPA and KLF4 as well as the universal tumor suppressor p53 are frequently deregulated. Here, we investigated the extent of dysregulation, the molecular interactions, and the mechanisms involved. EXPERIMENTAL DESIGN One hundred ten AML patient samples were analyzed for protein levels of CEBPA, KLF4, p53, and p53 modulators. Regulation of CEBPA gene expression by KLF4 and p53 or by chemical p53 activators was characterized in AML cell lines. RESULTS We found that CEBPA gene transcription can be directly activated by p53 and KLF4, suggesting a p53-KLF4-CEBPA axis. In AML patient cells, we observed a prominent loss of p53 function and concomitant reduction of KLF4 and CEBPA protein levels. Assessment of cellular p53 modulator proteins indicated that p53 inactivation in leukemic cells correlated with elevated levels of the nuclear export protein XPO1/CRM1 and increase of the p53 inhibitors MDM2 and CUL9/PARC in the cytoplasm. Finally, restoring p53 function following treatment with cytotoxic chemotherapy compounds and p53 restoring non-genotoxic agents induced CEBPA gene expression, myeloid differentiation, and cell-cycle arrest in AML cells. CONCLUSIONS The p53-KLF4-CEBPA axis is deregulated in AML but can be functionally restored by conventional chemotherapy and novel p53 activating treatments. Clin Cancer Res; 22(3); 746-56. ©2015 AACR.

Neurotoxicity of stem cell mobilization chemotherapy with vinorelbine in myeloma patients after bortezomib treatment.

Vinorelbine chemotherapy with G-CSF stimulation is the standard mobilization regimen in Switzerland for multiple myeloma patients. However, with the increasing use of bortezomib during induction treatment, adding the neurotoxic compound vinorelbine for mobilization may aggravate bortezomib-induced polyneuropathy. In this retrospective single-center study, we aimed to explore vinorelbine mediated neuropathy in 106 consecutive bortezomib pretreated myeloma patients. We confirmed that vinorelbine with G-CSF represents a reliable and effective regimen for mobilization of autologous stem cells. However, the single administration of 35 mg/m(2) vinorelbine added significant neurotoxicity. We found that 24 patients (24%) reported vinorelbine mediated neurotoxicity: Aggravation of bortezomib-induced neuropathy was observed in 17 patients (17%), and vinorelbine mobilization induced first occurrence of polyneuropathy in additional 7 patients (7%). We observed that development of polyneuropathy was not associated with differing survival rates. Finally, affected patients reported polyneuropathy associated disease burden as "very high" in 13% and "high" in 50%. Our data indicate that a single administration of vinorelbine to mobilize autologous stem cells is associated with significant additional polyneuropathy in bortezomib pretreated myeloma patients. The efficacy of vinorelbine mobilization should be balanced against its neurotoxic potential.

Prevalence of Subclinical Rheumatic Heart Disease in Eastern Nepal

Importance: Although rheumatic heart disease has been nearly eradicated in high-income countries, 3 in 4 children grow up in parts of the world where it is still endemic. Objectives: To determine the prevalence of clinically silent and manifest rheumatic heart disease as a function of age, sex, and socioeconomic status and to estimate age-specific incidence. Design, Setting, and Participants: In this school-based cross-sectional study with cluster sampling, 26 schools in the Sunsari district in Eastern Nepal with 5467 eligible children 5 to 15 years of age were randomly selected from 595 registered schools. After exclusion of 289 children, 5178 children were enrolled in the present study from December 12, 2012, through September 12, 2014. Data analysis was performed from October 1, 2014, to April 15, 2015. Exposures: Demographic and socioeconomic characteristics were acquired in a standardized interview by means of a questionnaire customized to the age of the children. A focused medical history was followed by a brief physical examination. Cardiac auscultation and transthoracic echocardiography were performed by 2 independent physicians. Main Outcomes and Measures: Rheumatic heart disease according to the World Heart Federation criteria. Results: The median age of the 5178 children enrolled in the study was 10 years (interquartile range, 8-13 years), and 2503 (48.3%) were female. The prevalence of borderline or definite rheumatic heart disease was 10.2 (95% CI, 7.5-13.0) per 1000 children and increased with advancing age from 5.5 (95% CI, 3.5-7.5) per 1000 children 5 years of age to 16.0 (95% CI, 14.9-17.0) in children 15 years of age, whereas the mean incidence remained stable at 1.1 per 1000 children per year. Children with rheumatic heart disease were older than children without rheumatic heart disease (median age [interquartile range], 11 [9-14] years vs 10 [8-13] years; P = .03), more commonly female (34 [64.2%] vs 2469 [48.2%]; P = .02), and more frequently went to governmental schools (40 [75.5%] vs 2792 [54.5%]; P = .002). Silent disease (n = 44) was 5 times more common than manifest disease (n = 9). Conclusions and Relevance: Rheumatic heart disease affects 1 in 100 schoolchildren in Eastern Nepal, is primarily clinically silent, and may be more common among girls. The overall prevalence and the ratio of manifest to subclinical disease increase with advancing age, whereas the incidence remains stable at 1.1 per 1000 children per year. Early detection of silent disease may help prevent progression to severe valvular damage.

Disturbances of agency and ownership in schizophrenia: An auditory verbal event related potentials study

A ‘sense of self’ is essentially the ability to distinguish between self-generated and external stimuli. It consists of at least two very basic senses: a sense of agency and a sense of ownership. Disturbances seem to provide a basic deficit in many psychiatric diseases. The aim of our study was to manipulate those qualities separately in 28 patients with schizophrenia (14 auditory hallucinators and 14 non-hallucinators) and 28 healthy controls (HC) and to investigate the effects on the topographies and the power of the event-related potential (ERP). We performed a 76-channel EEG while the participants performed the task as in our previous paper. We computed ERPs and difference maps for the conditions and compared the amount of agency and ownership between the HC and the patients. Furthermore, we compared the global field power and the topographies of these effects. Our data showed effects of agency and ownership in the healthy controls and the hallucinator group and to a lesser degree in the non-hallucinator group. We found a reduction of the N100 during the presence of agency, and a bilateral temporal negativity related to the presence of ownership. For the agency effects, we found significant differences between HC and the patients. Contrary to the expectations, our findings were more pronounced in non-hallucinators, suggesting a more profoundly disturbed sense of agency compared to hallucinators. A contemporary increase of global field power in both patient groups indicates a compensatory recruitment of other mechanisms not normally associated with the processing of agency and ownership.

Management of floating thrombus in the aortic arch

OBJECTIVE Floating aortic thrombus is an underrecognized source of systemic emboli and carries a life-threatening risk of stroke when located in the aortic arch. Optimal treatment is not established in available guidelines. We report our experience in managing floating thrombi in the aortic arch. METHODS Consecutive patients diagnosed with a floating aortic arch thrombus at a tertiary referral center between January 2008 and December 2014 were reviewed. Perioperative and midterm outcomes were assessed. RESULTS Ten patients (8 female) with a median age of 56 years (range, 47-82 years) were identified. Eight patients presented with a symptomatic embolic event, and 2 patients were asymptomatic. One patient presenting with stroke due to embolic occlusion of all supra-aortic vessels died 2 days after admission. Three patients (2 asymptomatic and 1 unfit for surgery) were treated conservatively by anticoagulation, leading to thrombus resolution in 2 patients. In the third patient, the thrombus persisted despite anticoagulation, resulting in recurrent embolic events. The remaining 6 patients underwent open thrombectomy of the aortic arch during deep hypothermic circulatory arrest. All patients treated by surgery had an uneventful postoperative course with no recurrent thrombus or embolic event during follow-up. Median follow-up of all patients was 17 months (range, 11-89 months). CONCLUSIONS Floating aortic arch thrombus is a dangerous source of systemic emboli. Surgical removal of the thrombus is easy to perform and followed by good clinical results. Conservative treatment with anticoagulation may be considered in asymptomatic, inoperable or high-risk patients.

Core networks for visual-concrete and abstract thought content: a brain electric microstate analysis

Commonality of activation of spontaneously forming and stimulus-induced mental representations is an often made but rarely tested assumption in neuroscience. In a conjunction analysis of two earlier studies, brain electric activity during visual-concrete and abstract thoughts was studied. The conditions were: in study 1, spontaneous stimulus-independent thinking (post-hoc, visual imagery or abstract thought were identified); in study 2, reading of single nouns ranking high or low on a visual imagery scale. In both studies, subjects' tasks were similar: when prompted, they had to recall the last thought (study 1) or the last word (study 2). In both studies, subjects had no instruction to classify or to visually imagine their thoughts, and accordingly were not aware of the studies' aim. Brain electric data were analyzed into functional topographic brain images (using LORETA) of the last microstate before the prompt (study 1) and of the word-type discriminating event-related microstate after word onset (study 2). Conjunction analysis across the two studies yielded commonality of activation of core networks for abstract thought content in left anterior superior regions, and for visual-concrete thought content in right temporal-posterior inferior regions. The results suggest that two different core networks are automatedly activated when abstract or visual-concrete information, respectively, enters working memory, without a subject task or instruction about the two classes of information, and regardless of internal or external origin, and of input modality. These core machineries of working memory thus are invariant to source or modality of input when treating the two types of information.

Protein disulfide isomerase blocks CEBPA translation and is up-regulated during the unfolded protein response in AML

Deregulation of the myeloid key transcription factor CEBPA is a common event in acute myeloid leukemia (AML). We previously reported that the chaperone calreticulin is activated in subgroups of AML patients and that calreticulin binds to the stem loop region of the CEBPA mRNA, thereby blocking CEBPA translation. In this study, we screened for additional CEBPA mRNA binding proteins and we identified protein disulfide isomerase (PDI), an endoplasmic reticulum (ER) resident protein, to bind to the CEBPA mRNA stem loop region. We found that forced PDI expression in myeloid leukemic cells in fact blocked CEBPA translation, but not transcription, whereas abolishing PDI function restored CEBPA protein. In addition, PDI protein displayed direct physical interaction with calreticulin. Induction of ER stress in leukemic HL60 and U937 cells activated PDI expression, thereby decreasing CEBPA protein levels. Finally, leukemic cells from 25.4% of all AML patients displayed activation of the unfolded protein response as a marker for ER stress, and these patients also expressed significantly higher PDI levels. Our results indicate a novel role of PDI as a member of the ER stress-associated complex mediating blocked CEBPA translation and thereby suppressing myeloid differentiation in AML patients with activated unfolded protein response (UPR).