Allergen-induced IgE-dependent gut inflammation in a human PBMC-engrafted murine model of allergy.

BACKGROUND: Humanized murine models comprise a new tool to analyze novel therapeutic strategies for allergic diseases of the intestine.¦OBJECTIVE: In this study we developed a human PBMC-engrafted murine model of allergen-driven gut inflammation and analyzed the underlying immunologic mechanisms.¦METHODS: Nonobese diabetic (NOD)-scid-γc(-/-) mice were injected intraperitoneally with human PBMCs from allergic donors together with the respective allergen or not. Three weeks later, mice were challenged with the allergen orally or rectally, and gut inflammation was monitored with a high-resolution video miniendoscopic system, as well as histologically.¦RESULTS: Using the aeroallergens birch or grass pollen as model allergens and, for some donors, also hazelnut allergen, we show that allergen-specific human IgE in murine sera and allergen-specific proliferation and cytokine production of human CD4(+) T cells recovered from spleens after 3 weeks could only be measured in mice treated with PBMCs plus allergen. Importantly, these mice had the highest endoscopic scores evaluating translucent structure, granularity, fibrin, vascularity, and stool after oral or rectal allergen challenge and a strong histologic inflammation of the colon. Analyzing the underlying mechanisms, we demonstrate that allergen-associated colitis was dependent on IgE, human IgE receptor-expressing effector cells, and the mediators histamine and platelet-activating factor.¦CONCLUSION: These results demonstrate that allergic gut inflammation can be induced in human PBMC-engrafted mice, allowing the investigation of pathophysiologic mechanisms of allergic diseases of the intestine and evaluation of therapeutic interventions.

A cell-based model of extracellular-matrix-guided endothelial cell migration during angiogenesis.

Angiogenesis, the formation of new blood vessels sprouting from existing ones, occurs in several situations like wound healing, tissue remodeling, and near growing tumors. Under hypoxic conditions, tumor cells secrete growth factors, including VEGF. VEGF activates endothelial cells (ECs) in nearby vessels, leading to the migration of ECs out of the vessel and the formation of growing sprouts. A key process in angiogenesis is cellular self-organization, and previous modeling studies have identified mechanisms for producing networks and sprouts. Most theoretical studies of cellular self-organization during angiogenesis have ignored the interactions of ECs with the extra-cellular matrix (ECM), the jelly or hard materials that cells live in. Apart from providing structural support to cells, the ECM may play a key role in the coordination of cellular motility during angiogenesis. For example, by modifying the ECM, ECs can affect the motility of other ECs, long after they have left. Here, we present an explorative study of the cellular self-organization resulting from such ECM-coordinated cell migration. We show that a set of biologically-motivated, cell behavioral rules, including chemotaxis, haptotaxis, haptokinesis, and ECM-guided proliferation suffice for forming sprouts and branching vascular trees.

Differentially expressed gene profile in the 6-hydroxy-dopamine-induced cell culture model of Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons of the substantia nigra pars compacta with unknown aetiology. 6-Hydroxydopamine (6-OHDA) treatment of neuronal cells is an established in vivo model for mimicking the effect of oxidative stress found in PD brains. We examined the effects of 6-OHDA treatment on human neuroblastoma cells (SH-SY5Y) and primary mesencephalic cultures. Using a reverse arbitrarily primed polymerase chain reaction (RAP-PCR) approach we generated reproducible genetic fingerprints of differential expression levels in cell cultures treated with 6-OHDA. Of the resulting sequences, 23 showed considerable homology to known human coding sequences. The results of the RAP-PCR were validated by reverse transcription PCR, real-time PCR and, for selected genes, by Western blot analysis and immunofluorescence. In four cases, [tomoregulin-1 (TMEFF-1), collapsin response mediator protein 1 (CRMP-1), neurexin-1, and phosphoribosylaminoimidazole synthetase (GART)], a down-regulation of mRNA and protein levels was detected. Further studies will be necessary on the physiological role of the identified proteins and their impact on pathways leading to neurodegeneration in PD.

Molecular detection and identification of zygomycetes species from paraffin-embedded tissues in a murine model of disseminated zygomycosis: a collaborative European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) evaluation.

The present study was performed to assess the interlaboratory reproducibility of the molecular detection and identification of species of Zygomycetes from formalin-fixed paraffin-embedded kidney and brain tissues obtained from experimentally infected mice. Animals were infected with one of five species (Rhizopus oryzae, Rhizopus microsporus, Lichtheimia corymbifera, Rhizomucor pusillus, and Mucor circinelloides). Samples with 1, 10, or 30 slide cuts of the tissues were prepared from each paraffin block, the sample identities were blinded for analysis, and the samples were mailed to each of seven laboratories for the assessment of sensitivity. A protocol describing the extraction method and the PCR amplification procedure was provided. The internal transcribed spacer 1 (ITS1) region was amplified by PCR with the fungal universal primers ITS1 and ITS2 and sequenced. As negative results were obtained for 93% of the tissue specimens infected by M. circinelloides, the data for this species were excluded from the analysis. Positive PCR results were obtained for 93% (52/56), 89% (50/56), and 27% (15/56) of the samples with 30, 10, and 1 slide cuts, respectively. There were minor differences, depending on the organ tissue, fungal species, and laboratory. Correct species identification was possible for 100% (30 cuts), 98% (10 cuts), and 93% (1 cut) of the cases. With the protocol used in the present study, the interlaboratory reproducibility of ITS sequencing for the identification of major Zygomycetes species from formalin-fixed paraffin-embedded tissues can reach 100%, when enough material is available.

The Hindu Model of Social Organization and the bhakti Movement : the Example of Vallabha's sampradāya

(Résumé de l'ouvrage) This volume addresses research topics within the field of Bhakti literature, the devotional poetry and other compositions of devotional character in the earlier literature of the modern South Asian languages. Its papers range from the roots of the Bhakti tradition in the early history of Krsna to its modern adaptations in nineteenth- and twentieth-century culture. Geographically, they span Bengal to Sind, Panjab to Maharashtra. Contemporary study of the modern Indian languages has broadened the scope of scholarship to consider today's Hindu attitudes, and those of a mixed society, against the background of ancient culture. Here, materials in six modern Asian languages are discussed: Bengali, Gujarati, Hindi in its main literary forms, Marathi, Panjabi and Sindhi; with assessment also of material in Sanskrit, Arabic and Chinese. In addition to studies of literary (and orally transmitted) works in the Krsna or Rama traditions, and of Sufi compositions and their interpretation, there are papers on the early history of sacred sites, the emergence of the religion of Rama, later religious formulations throughout the subcontinent, and the interaction of the Islamic and the Hindu.

Bringing actors and violent conflict into forced migration literature. A model of the decision to return

Populations displaced as a result of mass violent conflict have become one of the most pressing humanitarian concerns of the last decades. They have also become one salient political issue as a perceived burden (in economic and security terms) and as an important piece in the shift towards a more interventionist paradigm in the international system, based on both humanitarian and security grounds. The saliency of these aspects has detracted attention from the analysis of the interactions between relocation processes and violent conflict. Violent conflict studies have also largely ignored those interactions as a result of the consideration of these processes as mere reaction movements determined by structural conditions. This article takes the view that individual’s agency is retained during such processes, and that it is consequential, calling for the need to introduce a micro perspective. Based on this, a model for the individual’s decision of return is presented. The model has the potential to account for the dynamics of return at both the individual and the aggregate level. And it further helps to grasp fundamental interconnections with violent conflict. Some relevant conclusions are derived for the case of Bosnia-Herzegovina and about the implications of the politicization of return.

A qualitative response model of thermal comfort

A sound statistical methodology is presented for modelling the correspondence between the characteristics of individuals, their thermal environment, and their thermal sensation. The proposed methodology substantially improves that developed by P.O. Fanger, by formulating a more general and precise model of thermal comfort. It enables us to estimate the model from a sample of data where all the parameters of comfort vary at the same time, which is not possible with that adopted by Fanger. Moreover, the present model is still valid when thermal conditions are far from optimum. (C) 1997 Elsevier Science Ltd.

Potassium channel alterations mediate peripheral nerve hyperexcitability in a mouse model of type 2 diabetes mellitus

Diabetes mellitus (DM) is a major cause of peripheral neuropathy. More than 220 million people worldwide suffer from type 2 DM, which will, in approximately half of them, lead to the development of diabetic peripheral neuropathy. While of significant medical importance, the pathophysiological changes present in DPN are still poorly understood. To get more insight into DPN associated with type 2 DM, we decided to use the rodent model of this form of diabetes, the db/db mice. During the in-vivo conduction velocity studies on these animals, we observed the presence of multiple spiking followed by a single stimulation. This prompted us to evaluate the excitability properties of db/db peripheral nerves. Ex-vivo electrophysiological evaluation revealed a significant increase in the excitability of db/db sciatic nerves. While the shape and kinetics of the compound action potential of db/db nerves were the same as for control nerves, we observed an increase in the after-hyperpolarization phase (AHP) under diabetic conditions. Using pharmacological inhibitors we demonstrated that both the peripheral nerve hyperexcitability (PNH) and the increased AHP were mostly mediated by the decreased activity of Kv1-channels. Importantly, we corroborated these data at the molecular level. We observed a strong reduction of Kv1.2 channel presence in the juxtaparanodal regions of teased fibers in db/db mice as compared to control mice. Quantification of the amount of both Kv1.2 isoforms in DRG neurons and in the endoneurial compartment of peripheral nerve by Western blotting revealed that less mature Kv1.2 was integrated into the axonal membranes at the juxtaparanodes. Our observation that peripheral nerve hyperexcitability present in db/db mice is at least in part a consequence of changes in potassium channel distribution suggests that the same mechanism also mediates PNH in diabetic patients. ∗Current address: Department of Physiology, UCSF, San Francisco, CA, USA.

Why do educated mothers matter? A model of parental help

The paper investigates the role of mothers in affecting childrens' performance at school. It develops a theoretical model in which household is treated as an individual, whose utility depends on the performance at school of the student and on consumption. The model focuses on the possibilities through which mother’s help may affect pupil's performance in terms of time devoted to supervision and spillover effects. Empirical evidence, using Italian PISA 2006, shows that highly educated mothers have a positive impact on students' score only when they are highly qualified in the job market.

CD4+CD25-mTGFbeta+ T cells induced by nasal application of ovalbumin transfer tolerance in a therapeutic model of asthma.

Background: Intranasal administration of high amount of allergen was shown to induce tolerance and to reverse the allergic phenotype. However, mechanisms of tolerance induction via the mucosal route are still unclear. Objectives: To characterize the therapeutic effects of intranasal application of ovalbumin (OVA) in a mouse model of bronchial inflammation as well as the cellular and molecular mechanisms leading to protection upon re-exposure to allergen. Methods: After induction of bronchial inflammation, mice were treated intranasally with OVA and re-exposed to OVA aerosols 10 days later. Bronchoalveolar lavage fluid (BALF), T cell proliferation and cytokine secretion were examined. The respective role of CD4(+)CD25(+) and CD4(+)CD25(-) T cells in the induction of tolerance was analysed. Results: Intranasal treatment with OVA drastically reduced inflammatory cell recruitment into BALF and bronchial hyperresponsiveness upon re-exposure to allergen. Both OVA- specific-proliferation of T cells, T(h)1 and T(h)2 cytokine production from lung and bronchial lymph nodes were inhibited. Transfer of CD4(+)CD25(-) T cells, which strongly expressed membrane-bound transforming growth factor beta (mTGF beta), from tolerized mice protected asthmatic recipient mice from subsequent aerosol challenges. The presence of CD4(+)CD25(+)(Foxp3(+)) T cells during the process of tolerization was indispensable to CD4(+)CD25(-) T cells to acquire regulatory properties. Whereas the presence of IL-10 appeared dispensable in this model, the suppression of CD4(+)CD25(-)mTGF beta(+) T cells in transfer experiments significantly impaired the down-regulation of airways inflammation. Conclusion: Nasal application of OVA in established asthma led to the induction of CD4(+)CD25(-)mTGF beta(+) T cells with regulatory properties, able to confer protection upon allergen re-exposure.

Early broncoconstriction in anesthetized sheep: a simplified experimental model of asthma

Résumé Cette étude décrit un modèle expérimental de bronchoconstriction précoce induite par aérosolisation d'un extrait d'Ascaris suum chez des moutons anesthésiés par de l'isoflurane et ventilés mécaniquement. Dix moutons adultes ont été anesthésiés et ventilés mécaniquement puis ont été exposés à un stimulus bronchoconstrictif sous forme d'un aérosol d'extrait d'Ascaris suum durant 25 minutes. Tous les moutons ont été exposés deux fois à huit semaines d'intervalle à ce même stimulus. Les échanges gazeux ainsi que les paramètres respiratoires ont été mesurés régulièrement durant la période d'aérosolisation ainsi que durant les 60 minutes suivantes. A la fin de la période d'aérosolisation, une augmentation significative (p<0.05) des pressions de crête (+114%) et de plateau (+148%), de la résistance expiratoire (+93%) et de la pression partielle artérielle de gaz carbonique PaCO2 (+25%) a été constatée, de même qu'une diminution significative (p<0.05) de la compliance respiratoire (-41 %) et de la pression partielle artérielle d'oxygène PaO2 (-49%). Ces modifications sont restées stables durant toute la période d'observation. Ce modèle expérimental animal de bronchoconstriction offre de nombreux avantages : la stabilité hémodynamique et le confort de l'animal sont améliorés et la réaction de stress est inhibée. Il permet de plus une distribution optimale de l'antigène respiratoire et finalement évite l'utilisation d'un pléthysmographe corporel. Abstract This study describes a simplified experimental model of early bronchoconstriction induced by aerosolization of Ascaris suum extract in isoflurane-anesthetized and mechanically ventilated sheep. Ten adult sheep were anesthetized, mechanically ventilated and then challenged with an aerosol of Ascaris suum extract during 25 minutes. All of them were challenged twice at eight weeks intervals. During the bronchoconstrictive challenges and the following sixty minutes, gas exchange was measured and respiratory mechanics parameters computed from a lung mechanics calculator. At the end of the challenge, a significant increase (p<0.05) was observed in peak (+114%) and plateau (+148%) pressures, expiratory resistance (+93%) and PaCO2 (+25%) along with a significant decrease (p<0.05) in respiratory compliance (-41 %) and PaO2 (-49%). These changes remained stable throughout the 60 minutes study period. This model offers several advantages: hemodynamic stability and animal welfare are improved and the stress response is blunted. It allows an optimal distribution of the antigen and finally avoids the need of a body plethysmograph.

A two-compartment mathematical model of neuroglial metabolism using [1-(11)C] acetate.

The purpose of this study was to develop a two-compartment metabolic model of brain metabolism to assess oxidative metabolism from [1-(11)C] acetate radiotracer experiments, using an approach previously applied in (13)C magnetic resonance spectroscopy (MRS), and compared with an one-tissue compartment model previously used in brain [1-(11)C] acetate studies. Compared with (13)C MRS studies, (11)C radiotracer measurements provide a single uptake curve representing the sum of all labeled metabolites, without chemical differentiation, but with higher temporal resolution. The reliability of the adjusted metabolic fluxes was analyzed with Monte-Carlo simulations using synthetic (11)C uptake curves, based on a typical arterial input function and previously published values of the neuroglial fluxes V(tca)(g), V(x), V(nt), and V(tca)(n) measured in dynamic (13)C MRS experiments. Assuming V(x)(g)=10 × V(tca)(g) and V(x)(n)=V(tca)(n), it was possible to assess the composite glial tricarboxylic acid (TCA) cycle flux V(gt)(g) (V(gt)(g)=V(x)(g) × V(tca)(g)/(V(x)(g)+V(tca)(g))) and the neurotransmission flux V(nt) from (11)C tissue-activity curves obtained within 30 minutes in the rat cortex with a beta-probe after a bolus infusion of [1-(11)C] acetate (n=9), resulting in V(gt)(g)=0.136±0.042 and V(nt)=0.170±0.103 μmol/g per minute (mean±s.d. of the group), in good agreement with (13)C MRS measurements.

Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease.

Presenilin 1 (PS1) mutations are responsible for a majority of early onset familial Alzheimer's disease (FAD) cases, in part by increasing the production of Abeta peptides. However, emerging evidence suggests other possible effects of PS1 on synaptic dysfunction where PS1 might contribute to the pathology independent of Abeta. We chose to study the L286V mutation, an aggressive FAD mutation which has never been analyzed at the electrophysiological and morphological levels. In addition, we analyzed for the first time the long term effects of wild-type human PS1 overexpression. We investigated the consequences of the overexpression of either wild-type human PS1 (hPS1) or the L286V mutated PS1 variant (mutPS1) on synaptic functions by analyzing synaptic plasticity and associated spine density changes from 3 to 15 months of age. We found that mutPS1 induces a transient increase observed only in 4- to 5-month-old mutPS1 animals in NMDA receptor (NMDA-R)-mediated responses and LTP compared with hPS1 mice and nontransgenic littermates. The increase in synaptic functions is concomitant with an increase in spine density. With increasing age, however, we found that the overexpression of human wild-type PS1 progressively decreased NMDA-R-mediated synaptic transmission and LTP, without neurodegeneration. These results identify for the first time a transient increase in synaptic function associated with L286V mutated PS1 variant in an age-dependent manner. In addition, they support the view that the PS1 overexpression promotes synaptic dysfunction in an Abeta-independent manner and underline the crucial role of PS1 during both normal and pathological aging.

A Political Agency Model of Coattail Voting

In this paper, I provide a formal justi…cation for a well-established coattail effect, when a popular candidate at one branch of government attracts votes to candidates from the same political party for other branches of government. A political agency frame- work with moral hazard is applied to analyze coattails in simultaneous presidential and congressional elections. I show that coattail voting is a natural outcome of the optimal reelection scheme adopted by a representative voter to motivate politicians' efforts in a retrospective voting environment. I assume that an office-motivated politician (executive or congressman) prefers her counterpart to be affiliated with the same political party. This correlation of incentives leads the voter to adopt a joint performance evaluation rule, which is conditioned on the politicians belonging to the same party or different parties. The two-sided coattail effects then arise. On the one hand, the executive's suc- cess/failure props up/drags down her partisan ally in congressional election, which implies presidential coattails. On the other hand, the executive's reelection itself is affected by the congressman's performance, which results in reverse coattails. JEL classi…fication: D72, D86. Keywords: Coattail voting; Presidential coattails; Reverse coattails; Simultaneous elections; Political Agency; Retrospective voting.