CC chemokines and the receptors CCR3 and CCR5 are differentially expressed in the nonneoplastic leukocytic infiltrates of Hodgkin disease

Lymph nodes with Hodgkin disease (HD) harbor few neoplastic cells in a marked leukocytic infiltrate. Since chemokines are likely to be involved in the recruitment of these leukocytes, the expression of potentially relevant chemokines and chemokine receptors were studied in lymph nodes from 24 patients with HD and in 5 control lymph nodes. The expression of regulated on activation, normal T cell expressed and secreted (RANTES), monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta was analyzed by in situ hybridization and that of CCR3 and CCR5 by immunohistochemistry and flow cytometry. It was found that, overall, the expression of all 4 chemokines was markedly enhanced, but the cellular source was different. RANTES was expressed almost exclusively by T cells whereas the expression of MCP-1, MIP-1alpha, and MIP-1beta was confined largely to macrophages. In control lymph nodes, chemokine expression was low, with the exception of MIP-1alpha in macrophages. CCR3 and CCR5 were highly expressed in T cells of HD involved but not of control lymph nodes. CCR3 was equally distributed in CD4+ and CD8+ cells, but CCR5 was associated largely with CD4+ cells. In HD lymph nodes, CCR3 and CCR5 were also expressed in B cells, which normally do not express these receptors. All these chemokines and receptors studied, by contrast, were absent in the neoplastic cells. It was concluded that chemokines are involved in the formation of the HD nonneoplastic leukocytic infiltrate. Expression of CCR3 and CCR5 appears to be characteristic of HD, but the roles of these receptors' up-regulation for the disease process remain unclear.

Impact of volcanic stratospheric aerosols on diurnal temperature range in Europe over the past 200 years: Observations versus model simulations

We analyze the impact of stratospheric volcanic aerosols on the diurnal temperature range (DTR) over Europe using long-term subdaily station records. We compare the results with a 28-member ensemble of European Centre/Hamburg version 5.4 (ECHAM5.4) general circulation model simulations. Eight stratospheric volcanic eruptions during the instrumental period are investigated. Seasonal all- and clear-sky DTR anomalies are compared with contemporary (approximately 20 year) reference periods. Clear sky is used to eliminate cloud effects and better estimate the signal from the direct radiative forcing of the volcanic aerosols. We do not find a consistent effect of stratospheric aerosols on all-sky DTR. For clear skies, we find average DTR anomalies of −0.08°C (−0.13°C) in the observations (in the model), with the largest effect in the second winter after the eruption. Although the clear-sky DTR anomalies from different stations, volcanic eruptions, and seasons show heterogeneous signals in terms of order of magnitude and sign, the significantly negative DTR anomalies (e.g., after the Tambora eruption) are qualitatively consistent with other studies. Referencing with clear-sky DTR anomalies to the radiative forcing from stratospheric volcanic eruptions, we find the resulting sensitivity to be of the same order of magnitude as previously published estimates for tropospheric aerosols during the so-called “global dimming” period (i.e., 1950s to 1980s). Analyzing cloud cover changes after volcanic eruptions reveals an increase in clear-sky days in both data sets. Quantifying the impact of stratospheric volcanic eruptions on clear-sky DTR over Europe provides valuable information for the study of the radiative effect of stratospheric aerosols and for geo-engineering purposes.

Single-stranded DNA-binding proteins regulate the abundance of LIM domain and LIM domain-binding proteins.

The LIM domain-binding protein Ldb1 is an essential cofactor of LIM-homeodomain (LIM-HD) and LIM-only (LMO) proteins in development. The stoichiometry of Ldb1, LIM-HD, and LMO proteins is tightly controlled in the cell and is likely a critical determinant of their biological actions. Single-stranded DNA-binding proteins (SSBPs) were recently shown to interact with Ldb1 and are also important in developmental programs. We establish here that two mammalian SSBPs, SSBP2 and SSBP3, contribute to an erythroid DNA-binding complex that contains the transcription factors Tal1 and GATA-1, the LIM domain protein Lmo2, and Ldb1 and binds a bipartite E-box-GATA DNA sequence motif. In addition, SSBP2 was found to augment transcription of the Protein 4.2 (P4.2) gene, a direct target of the E-box-GATA-binding complex, in an Ldb1-dependent manner and to increase endogenous Ldb1 and Lmo2 protein levels, E-box-GATA DNA-binding activity, and P4.2 and beta-globin expression in erythroid progenitors. Finally, SSBP2 was demonstrated to inhibit Ldb1 and Lmo2 interaction with the E3 ubiquitin ligase RLIM, prevent RLIM-mediated Ldb1 ubiquitination, and protect Ldb1 and Lmo2 from proteasomal degradation. These results define a novel biochemical function for SSBPs in regulating the abundance of LIM domain and LIM domain-binding proteins.

The HARPS search for southern extra-solar planets

The vast diversity of planetary systems detected to date is defying our capability of understanding their formation and evolution. Well-defined volume-limited surveys are the best tool at our disposal to tackle the problem, via the acquisition of robust statistics of the orbital elements. We are using the HARPS spectrograph to conduct our survey of ≈850 nearby solar-type stars, and in the course of the past nine years we have monitored the radial velocity of HD 103774, HD 109271, and BD-061339. In this work we present the detection of five planets orbiting these stars, with msin   (i) between 0.6 and 7 Neptune masses, four of which are in two multiple systems, comprising one super-Earth and one planet within the habitable zone of a late-type dwarf. Although for strategic reasons we chose efficiency over precision in this survey, we have the capability to detect planets down to the Neptune and super-Earth mass range as well as multiple systems, provided that enough data points are made available.

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the "REGISTRY" cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.

Suicidal ideation in a European Huntington's disease population.

BACKGROUND Previous studies indicate increased prevalences of suicidal ideation, suicide attempts, and completed suicide in Huntington's disease (HD) compared with the general population. This study investigates correlates and predictors of suicidal ideation in HD. METHODS The study cohort consisted of 2106 HD mutation carriers, all participating in the REGISTRY study of the European Huntington's Disease Network. Of the 1937 participants without suicidal ideation at baseline, 945 had one or more follow-up measurements. Participants were assessed for suicidal ideation by the behavioural subscale of the Unified Huntington's Disease Rating Scale (UHDRS). Correlates of suicidal ideation were analyzed using logistic regression analysis and predictors were analyzed using Cox regression analysis. RESULTS At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation. Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9-1.0), anxiety (OR=2.14; 95%CI: 1.4-3.3), aggression (OR=2.41; 95%CI: 1.5-3.8), a previous suicide attempt (OR=3.95; 95%CI: 2.4-6.6), and a depressed mood (OR=13.71; 95%CI: 6.7-28.0) were independently correlated to suicidal ideation at baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%. Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI: 1.1-4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2-5.0) at baseline were independent predictors of incident suicidal ideation, whereas a previous suicide attempt was not predictive. LIMITATIONS As suicidal ideation was assessed by only one item, and participants were a selection of all HD mutation carriers, the prevalence of suicidal ideation was likely underestimated. CONCLUSIONS Suicidal ideation in HD frequently occurs. Assessment of suicidal ideation is a priority in mutation carriers with a depressed mood and in those using benzodiazepines.

Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain

Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aβ42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.

Cognitive Interventions with Children with Special Needs - Transfer effects and multidisciplinary perspectives

Our last study with regularly developed children demonstrated a positive effect of working memory training on cognitive abilities. Building upon these findings, the aim of this multidisciplinary study is to investigate the effects of training of core functions with children who are suffering from different learning disabilities, like AD/HD, developmental dyslexia or specific language impairment. In addition to working memory training (BrainTwister), we apply a perceptual training, which concentrates on auditory-visual matching (Audilex), as well as an implicit concept learning task. We expect differential improvements of mental capacities, specifically of executive functions (working memory, attention, auditory and visual processing), scholastic abilities (language and mathematical skills), as well as of problem solving. With that, we hope to find further directions regarding helpful and individually adapted interventions in educational settings. Interested parties are invited to discuss and comment the design, the research question, and the possibilities in recruiting the subjects.

The biomechanics of the hip joint using new diagnostic aspects in the field of hip joint dysplasia. Constructive criticism of hip dysplasia diagnosis and present marketable breeding methods with an outlook on future perspectives and possibilities. Part I

In absence of basic canine hip biomechanics, a specific, consequent three dimensional concept to evaluate the coxofemoral joint was developed for the dog. With the help of a new method to radiologically demonstrate the hip in a physiological standing position several new clinically relevant aspects could be further investigated. For example the breed specific anatomical differences in the hip, and dynamics and the background on "iatrogenic luxations" in HD diagnostics could be shown. The caudal luxation and the growth abnormalities of the hip and their consequences on the whole leg (antetorsion syndrome) as a consequence of inadequate breeding could be demonstrated.

UNDERSTANDING TRENDS ASSOCIATED WITH CLOUDS IN IRRADIATED EXOPLANETS

Unlike previously explored relationships between the properties of hot Jovian atmospheres, the geometric albedo and the incident stellar flux do not exhibit a clear correlation, as revealed by our re-analysis of Q0-Q14 Kepler data. If the albedo is primarily associated with the presence of clouds in these irradiated atmospheres, a holistic modeling approach needs to relate the following properties: the strength of stellar irradiation (and hence the strength and depth of atmospheric circulation), the geometric albedo (which controls both the fraction of starlight absorbed and the pressure level at which it is predominantly absorbed), and the properties of the embedded cloud particles (which determine the albedo). The anticipated diversity in cloud properties renders any correlation between the geometric albedo and the stellar flux weak and characterized by considerable scatter. In the limit of vertically uniform populations of scatterers and absorbers, we use an analytical model and scaling relations to relate the temperature-pressure profile of an irradiated atmosphere and the photon deposition layer and to estimate whether a cloud particle will be lofted by atmospheric circulation. We derive an analytical formula for computing the albedo spectrum in terms of the cloud properties, which we compare to the measured albedo spectrum of HD 189733b by Evans et al. Furthermore, we show that whether an optical phase curve is flat or sinusoidal depends on whether the particles are small or large as defined by the Knudsen number. This may be an explanation for why Kepler-7b exhibits evidence for the longitudinal variation in abundance of condensates, while Kepler-12b shows no evidence for the presence of condensates despite the incident stellar flux being similar for both exoplanets. We include an "observer's cookbook" for deciphering various scenarios associated with the optical phase curve, the peak offset of the infrared phase curve, and the geometric albedo.

Veterinary hemodialysis: advances in management and technology.

Hemodialysis (HD) is a renal replacement therapy that can enable recovery of patients in acute kidney failure and prolong survival for patients with end-stage kidney failure. HD is also uniquely suited for management of refractory volume overload and removal of certain toxins from the bloodstream. Over the last decade, veterinary experience with HD has deepened and refined and its geographic availability has increased. As awareness of the usefulness and availability of dialytic therapy increases among veterinarians and pet owners and the number of veterinary dialysis facilities increases, dialytic management will become the standard of advanced care for animals with severe intractable uremia.

Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis.

BACKGROUND Exposure to food allergens through a disrupted skin barrier has been recognized as a potential factor in the increasing prevalence of food allergy. OBJECTIVE We sought to test the immunologic mechanisms by which epicutaneous sensitization to food allergens predisposes to intestinal food allergy. METHODS Mice were epicutaneously sensitized with ovalbumin or peanut on an atopic dermatitis-like skin lesion, followed by intragastric antigen challenge. Antigen-specific serum IgE levels and T(H)2 cytokine responses were measured by ELISA. Expression of type 2 cytokines and mast cell proteases in the intestine were measured by using real-time PCR. Accumulation of basophils in the skin and mast cells in the intestine was examined by using flow cytometry. In vivo basophil depletion was achieved by using diphtheria toxin treatment of Baso-DTR mice. For cell-transfer studies, the basophil population was expanded in vivo by means of hydrodynamic tail vein injection of thymic stromal lymphopoietin (TSLP) cDNA plasmid. RESULTS Sensitization to food allergens through an atopic dermatitis-like skin lesion is associated with an expansion of TSLP-elicited basophils in the skin that promote antigen-specific T(H)2 cytokine responses, increased antigen-specific serum IgE levels, and accumulation of mast cells in the intestine, promoting the development of intestinal food allergy. Critically, disruption of TSLP responses or depletion of basophils reduced the susceptibility to intestinal food allergy, whereas transfer of TSLP-elicited basophils into intact skin promoted disease. CONCLUSION Epicutaneous sensitization on a disrupted skin barrier is associated with accumulation of TSLP-elicited basophils, which are necessary and sufficient to promote antigen-induced intestinal food allergy.

Bargaining for power and information : an experimental and theoretical analysis of the interaction between institutions, externalities and adverse selection

Bargaining is the building block of many economic interactions, ranging from bilateral to multilateral encounters and from situations in which the actors are individuals to negotiations between firms or countries. In all these settings, economists have been intrigued for a long time by the fact that some projects, trades or agreements are not realized even though they are mutually beneficial. On the one hand, this has been explained by incomplete information. A firm may not be willing to offer a wage that is acceptable to a qualified worker, because it knows that there are also unqualified workers and cannot distinguish between the two types. This phenomenon is known as adverse selection. On the other hand, it has been argued that even with complete information, the presence of externalities may impede efficient outcomes. To see this, consider the example of climate change. If a subset of countries agrees to curb emissions, non-participant regions benefit from the signatories’ efforts without incurring costs. These free riding opportunities give rise to incentives to strategically improve ones bargaining power that work against the formation of a global agreement. This thesis is concerned with extending our understanding of both factors, adverse selection and externalities. The findings are based on empirical evidence from original laboratory experiments as well as game theoretic modeling. On a very general note, it is demonstrated that the institutions through which agents interact matter to a large extent. Insights are provided about which institutions we should expect to perform better than others, at least in terms of aggregate welfare. Chapters 1 and 2 focus on the problem of adverse selection. Effective operation of markets and other institutions often depends on good information transmission properties. In terms of the example introduced above, a firm is only willing to offer high wages if it receives enough positive signals about the worker’s quality during the application and wage bargaining process. In Chapter 1, it will be shown that repeated interaction coupled with time costs facilitates information transmission. By making the wage bargaining process costly for the worker, the firm is able to obtain more accurate information about the worker’s type. The cost could be pure time cost from delaying agreement or cost of effort arising from a multi-step interviewing process. In Chapter 2, I abstract from time cost and show that communication can play a similar role. The simple fact that a worker states to be of high quality may be informative. In Chapter 3, the focus is on a different source of inefficiency. Agents strive for bargaining power and thus may be motivated by incentives that are at odds with the socially efficient outcome. I have already mentioned the example of climate change. Other examples are coalitions within committees that are formed to secure voting power to block outcomes or groups that commit to different technological standards although a single standard would be optimal (e.g. the format war between HD and BlueRay). It will be shown that such inefficiencies are directly linked to the presence of externalities and a certain degree of irreversibility in actions. I now discuss the three articles in more detail. In Chapter 1, Olivier Bochet and I study a simple bilateral bargaining institution that eliminates trade failures arising from incomplete information. In this setting, a buyer makes offers to a seller in order to acquire a good. Whenever an offer is rejected by the seller, the buyer may submit a further offer. Bargaining is costly, because both parties suffer a (small) time cost after any rejection. The difficulties arise, because the good can be of low or high quality and the quality of the good is only known to the seller. Indeed, without the possibility to make repeated offers, it is too risky for the buyer to offer prices that allow for trade of high quality goods. When allowing for repeated offers, however, at equilibrium both types of goods trade with probability one. We provide an experimental test of these predictions. Buyers gather information about sellers using specific price offers and rates of trade are high, much as the model’s qualitative predictions. We also observe a persistent over-delay before trade occurs, and this mitigates efficiency substantially. Possible channels for over-delay are identified in the form of two behavioral assumptions missing from the standard model, loss aversion (buyers) and haggling (sellers), which reconcile the data with the theoretical predictions. Chapter 2 also studies adverse selection, but interaction between buyers and sellers now takes place within a market rather than isolated pairs. Remarkably, in a market it suffices to let agents communicate in a very simple manner to mitigate trade failures. The key insight is that better informed agents (sellers) are willing to truthfully reveal their private information, because by doing so they are able to reduce search frictions and attract more buyers. Behavior observed in the experimental sessions closely follows the theoretical predictions. As a consequence, costless and non-binding communication (cheap talk) significantly raises rates of trade and welfare. Previous experiments have documented that cheap talk alleviates inefficiencies due to asymmetric information. These findings are explained by pro-social preferences and lie aversion. I use appropriate control treatments to show that such consideration play only a minor role in our market. Instead, the experiment highlights the ability to organize markets as a new channel through which communication can facilitate trade in the presence of private information. In Chapter 3, I theoretically explore coalition formation via multilateral bargaining under complete information. The environment studied is extremely rich in the sense that the model allows for all kinds of externalities. This is achieved by using so-called partition functions, which pin down a coalitional worth for each possible coalition in each possible coalition structure. It is found that although binding agreements can be written, efficiency is not guaranteed, because the negotiation process is inherently non-cooperative. The prospects of cooperation are shown to crucially depend on i) the degree to which players can renegotiate and gradually build up agreements and ii) the absence of a certain type of externalities that can loosely be described as incentives to free ride. Moreover, the willingness to concede bargaining power is identified as a novel reason for gradualism. Another key contribution of the study is that it identifies a strong connection between the Core, one of the most important concepts in cooperative game theory, and the set of environments for which efficiency is attained even without renegotiation.