Synaptic Plasticity at Intrathalamic Connections via CaV3.3 T-type Ca2+ Channels and GluN2B-Containing NMDA Receptors.

The T-type Ca(2+) channels encoded by the Ca(V)3 genes are well established electrogenic drivers for burst discharge. Here, using Ca(V)3.3(-/-) mice we found that Ca(V)3.3 channels trigger synaptic plasticity in reticular thalamic neurons. Burst discharge via Ca(V)3.3 channels induced long-term potentiation at thalamoreticular inputs when coactivated with GluN2B-containing NMDA receptors, which are the dominant subtype at these synapses. Notably, oscillatory burst discharge of reticular neurons is typical for sleep-related rhythms, suggesting that sleep contributes to strengthening intrathalamic circuits.

Dynamical properties of discrete breathers in curved chains with first and second neighbor interaction

We present the study of discrete breather dynamics in curved polymerlike chains consisting of masses connected via nonlinear springs. The polymer chains are one dimensional but not rectilinear and their motion takes place on a plane. After constructing breathers following numerically accurate procedures, we launch them in the chains and investigate properties of their propagation dynamics. We find that breather motion is strongly affected by the presence of curved regions of polymers, while the breathers themselves show a very strong resilience and remarkable stability in the presence of geometrical changes. For chains with strong angular rigidity we find that breathers either pass through bent regions or get reflected while retaining their frequency. Their motion is practically lossless and seems to be determined through local energy conservation. For less rigid chains modeled via second neighbor interactions, we find similarly that chain geometry typically does not destroy the localized breather states but, contrary to the angularly rigid chains, it induces some small but constant energy loss. Furthermore, we find that a curved segment acts as an active gate reflecting or refracting the incident breather and transforming its velocity to a value that depends on the discrete breathers frequency. We analyze the physical reasoning behind these seemingly general breather properties.

Interaction of a discrete breather with a lattice junction

We study the scattering of a moving discrete breather (DB) on a junction in a Fermi-Pasta-Ulam chain consisting of two segments with different masses of the particles. We consider four distinct cases: (i) a light-heavy (abrupt) junction in which the DB impinges on the junction from the segment with lighter mass, (ii) a heavy-light junction, (iii) an up mass ramp in which the mass in the heavier segment increases continuously as one moves away from the junction point, and (iv) a down mass ramp. Depending on the mass difference and DB characteristics (frequency and velocity), the DB can either reflect from, or transmit through, or get trapped at the junction or on the ramp. For the heavy-light junction, the DB can even split at the junction into a reflected and a transmitted DB. The latter is found to subsequently split into two or more DBs. For the down mass ramp the DB gets accelerated in several stages, with accompanying radiation (phonons). These results are rationalized by calculating the Peierls-Nabarro barrier for the various cases. We also point out implications of our results in realistic situations such as electron-phonon coupled chains.

Confinement of discrete breathers in inhomogeneously profiled nonlinear chains

We investigate numerically the scattering of a moving discrete breather on a pair of junctions in a Fermi-Pasta-Ulam chain. These junctions delimit an extended region with different masses of the particles. We consider (i) a rectangular trap, (ii) a wedge shaped trap, and (iii) a smoothly varying convex or concave mass profile. All three cases lead to DB confinement, with the ease of trapping depending on the profile of the trap. We also study the collision and trapping of two DBs within the profile as a function of trap width, shape, and approach time at the two junctions. The latter controls whether one or both DBs are trapped.

Universality in models for disorder induced phase transitions

We have systematically analyzed six different reticular models with quenched disorder and no thermal fluctuations exhibiting a field-driven first-order phase transition. We have studied the nonequilibrium transition, appearing when varying the amount of disorder, characterized by the change from a discontinuous hysteresis cycle (with one or more large avalanches) to a smooth one (with only tiny avalanches). We have computed critical exponents using finite size scaling techniques and shown that they are consistent with universal values depending only on the space dimensionality d.

Enhanced pulse propagation in non-linear arrays of oscillators

The propagation of a pulse in a nonlinear array of oscillators is influenced by the nature of the array and by its coupling to a thermal environment. For example, in some arrays a pulse can be speeded up while in others a pulse can be slowed down by raising the temperature. We begin by showing that an energy pulse (one dimension) or energy front (two dimensions) travels more rapidly and remains more localized over greater distances in an isolated array (microcanonical) of hard springs than in a harmonic array or in a soft-springed array. Increasing the pulse amplitude causes it to speed up in a hard chain, leaves the pulse speed unchanged in a harmonic system, and slows down the pulse in a soft chain. Connection of each site to a thermal environment (canonical) affects these results very differently in each type of array. In a hard chain the dissipative forces slow down the pulse while raising the temperature speeds it up. In a soft chain the opposite occurs: the dissipative forces actually speed up the pulse, while raising the temperature slows it down. In a harmonic chain neither dissipation nor temperature changes affect the pulse speed. These and other results are explained on the basis of the frequency vs energy relations in the various arrays

Lymphoid stroma in health and disease

Summary Secondary lymphoid organs (SLOB), such as lymph nodes and spleen, are the sites where primary immune responses are initiated. T lymphocytes patrol through the blood and SLOs on the search for pathogens which are presented to them as antigens by dendritic cells. Stromal cells in the Tzone - so called T zone fibroblastic reticular cells (TRCs) -are critical in organizing the migration of T cells and dendritic cells by producing the chemoattractants CCL19 and CCL21 and by forming a network which T cells use as a guidance system. They also form a system of small channels or conduits that allow rapid transport of small antigen molecules or cytokines from the subcapsular sinus to high endothelial venules. The phenotype and function of TRCs have otherwise remained largely unknown. We found a critical role for lymph node access in CD4+ and CD8+ T cell homeostasis and identified TRCs within these organs as the major source of interleukin-7 (IL-7). IL-7 is an essential survival factor for naïve T lymphocytes of which the cellular source in the periphery had been poorly defined. In vitro, TRC were able to prevent the death of naïve T but not of B lymphocytes by secreting IL-7 and the CCR7 ligand CCL 19. Using gene-targeted mice, we show anon-redundant function of CCL19 in T cell homeostasis. The data suggest that TRCs regulate T cell numbers by providing a limited reservoir of survival factors for which T cells have to compete. They help to maintain a diverse T cell repertoire granting full immunocompetence. To determine whether TRCs also play a role in pathology, we characterized so-called tertiary lymphoid organs (TLOs) that often develop at sites of chronic inflammation. We show that TLOs resemble lymph nodes or Peyer's patches not only with regard to lymphoid cells. TLOs formed extensive TRC networks and a functional conduit system in all three marine inflammation models tested. In one model we dissected the cells and signals leading to the formation of these structures. We showed that they critically depend on the presence of lymphotoxin and lymphoid tissue inducer cells. TRCs in TLOs also produce CCL19, GCL21 and possibly IL-7 which are all involved in the development of TLOs. Stromal cells therefore play a central role in the onset and perpetuation of chronic inflammatory diseases and could be an interesting target for therapy. Résumé Le système immunitaire est la défense de notre corps contre toutes sortes d'infections et de tumeurs. II est constitué de différentes populations de lymphocytes qui patrouillent constamment le corps à la recherche de pathogène. Parmi eux, les lymphocytes T et B passent régulièrement dans les organes lymphoïdes secondaires (SLO) qui sont les sites d'initiation de la réponse immunitaire. Les lymphocytes T sont recrutés du sang aux SLO où ils cherchent leur antigène respectif présenté par des cellules dendritiques. Des cellules stromales dans la zone T -nommées fibroblastic reticular cells' (TRC) -sécrètent des chimiokines CCL19 et CCL21 et ainsi facilitent les rencontres entre lymphocytes T et cellules dendritiques. De plus, elles forment un réseau que les lymphocytes T utilisent comme système de guidage. Ce réseau forme des petits canaux (ou conduits) qui permettent le transport rapide, d'antigène soluble ou de cytokines, de la lymphe aux veinules à endothelium épais (HEV). Le phénotype ainsi que les autres fonctions des TRCs demeurent encore à ce jour inconnus. Nous avons trouvé que l'accès des lymphocytes T CD4+ et CD8+ aux ganglions joue un rôle central pour l'homéostasie. Interleukin-7 (IL-7) est un facteur de survie essentiel pour les lymphocytes T naïfs dont la source cellulaire dans la périphérie était mal définie. Nous avons identifié les TRCs dans les ganglions comme source principale d'interleukin-7 (IL-7). In vitro, les TRCs étaient capable de prévenir la mort des lymphocytes T mais pas celle de lymphocytes B grâce à la sécrétion d'IL-7 et de CCL19. En utilisant des souris déficientes du gène CCL19, nous avons observé que l'homéostasie des lymphocytes T dépend aussi de CCL19 in vivo. Les données suggèrent que les TRCs aident à maintenir un répertoire large et diversifié de cellules T et ainsi l'immunocompétence. Pour déterminer si les TRCs pourraient jouer un rote également dans la pathologie, nous avons caractérisé des organes lymphoïdes tertiaires (TLOs) souvent associés avec l'inflammation chronique. Les TLOs ressemblent à des ganglions ou des plaques de Peyer pas seulement en ce qui concerne la présence de lymphocytes. Nous avons constaté que les TLOs forment des réseaux de TRC et un système fonctionnel de conduits. La formation de ces structures est fortement diminuée dans l'absence du signal lymphotoxin ou des cellules connues comme ymphoid tissue-inducer tells: Les TRCs dans les TLOs produisent les chimiokines CCL19, CCL21 et possiblement aussi IL-7 qui sont impliquées dans le développement des TLOs. Les cellules stromales jouent donc un rôle central dans l'initation et la perpétuation des maladies inflamatoires chroniques et pourraient être une cible intéressante pour la thérapie.

Sclerotherapy of telangiectasias: a painless two-step technique.

BACKGROUND: Sclerotherapy of telangiectasias and reticular leg veins can be unpleasant and painful for some patients. OBJECTIVE: To determine pain level with two different sclerotherapy techniques in a prospective randomized trial. METHODS: Patients with symmetrical telangiectasias and reticular veins on both legs (C(1A) or (S)E(P)A(S)P(N1) were randomized to the standard (successive injections of chromated glycerin mixed with one-third lidocaine-epinephrine 1%) or two-step technique (first treating only reticular veins with a single injection at the base of each cluster of telangiectasias and then successively injecting all remaining telangiectasias a few minutes later. Pain was assessed using a 100-point visual analogue scale (0 = no pain, 100 = maximum pain). RESULTS: Data from 53 consecutive patients could be evaluated. The two-step technique was significantly less painful (28.2) than the standard technique (40.6, p < .001). CONCLUSION: The two-step technique with chromated glycerin mixed with one-third lidocaine-epinephrine 1% significantly reduces sclerotherapy pain. This may be a useful technique for patients who are particularly sensitive or afraid of sclerotherapy.

Role of lymph node fibroblasts in T cell priming

SummarySecondary lymphoid organs, such as lymph nodes or spleen, are the only places in our body where primary adaptive immune responses are efficiently elicited. These organs have distinct Β and Τ cell rich zones and Τ lymphocytes constantly migrate from the bloodstream into Τ zones to scan dendritic cells (DCs) for antigens they present. Specialized fibroblasts, the Τ zone reticular cells (HR.Cs), span the Τ zone in the form a three-dimensional network. lK.Cs guide incoming Τ cells in their migration, both chemically, by the secretion of the chemokines CCL19 and CCL21, and physically, by construction of a road system to which also DCs adhere. In this way TRCs are thought to facilitate encounters of Τ cells with antigen-bearing DCs and thereby accelerate the selection of rare antigen-specific Τ cells. The resulting Τ cell activation, proliferation and differentiation all take place within the TRC network. However, the influence of TRCs on Τ cell activation has so fer not been elucidated with the possible reasons being that TRCs represent a relative rare cell population and that mice devoid of TRCs have not been described.To circumvent these technical limitations, we established TRC clones and lines to have an abundant source to functionally characterize TRCs. Both the clones and lines show a fibroblastic phenotype, express a surface marker profile comparable to ex vivo TRCs and produce extracellular matrix molecules. However, expression of Ccl19, Ccl21 and ZL-7 is lost and could not be restored by cytokine stimulation. When these TRC clones or lines were cultured in a three-dimensional cell culture system, their morphology changed and resembled that of in vivo TRCs as they formed networks. By adding Τ cells and antigen-loaded DCs to these cultures we successfully reconstructed lymphoid Τ zones that allowed antigen-specific Τ cell activation.To characterize the role of TRCs in Τ cell priming, TRCs were co-cultured with antigen-specific Τ cells in the presence antigen-loaded DCs. Surprisingly, the presence of TRC lines and ex vivo TRCs inhibited rather than enhanced CD8+ Τ cell activation, proliferation and effector cell differentiation. TRCs shared this feature with fibroblasts from non-lymphoid tissues as well as mesenchymal stromal cells. TRCs were identified as a strong source of nitric oxide (NO) thereby directly dampening Τ cell expansion as well as reducing the Τ cell priming capacity of DCs. The expression of inducible NO synthase (iNOS) was up- regulated in a subset of TRCs by both DC-signals as well as interferon-γ produced by primed CD8+ Τ cells. Importantly, iNOS expression was induced during viral infection in vivo in both lymph node TRCs and DCs. Consistent with a role for NO as a negative regulator, the primary Τ cell response was exaggerated in iNOS-/- mice. Our findings highlight that in addition to their established positive roles in Τ cell responses TRCs and DCs cooperate in a negative feedback loop to attenuate Τ cell expansion during acute inflammation.RésuméLes organes lymphoïdes secondaires, comme les ganglions lymphoïdes ou la rate, sont les seuls sites dans notre corps où la réponse primaire des lymphocytes Β et Τ est initiée efficacement. Ces organes ont des zones différentes, riches en cellules Β ou T. Des lymphocytes Τ circulent constamment du sang vers les zones T, où ils échantillonent la surface des cellules dendritiques (DCs) pour identifier les antigènes qu'ils présentent. Des fibroblastes spécialisés - nommés Τ zone reticular cells (TRCs)' forment un réseau tridimensionnel dans la zone T. Les TRCs guident la migration des cellules Τ par deux moyens: chimiquement, par la sécrétion des chimiokines CCL19 et CCL21 et physiquement, par la construction d'un réseau routier en trois dimensions, auquel adhèrent aussi des DCs. Dans ce? cas, on pense que la présence des TRCs facilite les rencontres entre les cellules Τ et les DCs chargées de l'antigène et accélère la sélection des rares cellules Τ spécifiques. Ensuite, l'activation de cellules T, ainsi que la prolifération et la différenciation se produisent toutes à l'intérieur du réseau des TRCs. L'influence des TRCs sur l'activation des cellules T n'est que très peu caractérisée, en partie parce que les TRCs représentent une population rare et que les souris déficientes dans les TRCs n'ont pas encore été découvertes.Pour contourner ces limitations techniques, nous avons établi des clones et des lignées cellulaires de TRC pour obtenir une source indéfinie de ces cellules permettant leur caractérisation fonctionnelle. Les clones et lignées établis ont un phénotype de fibroblaste, ils expriment des molécules de surface similaires aux TRCs ex vivo et produisent de la matrice extracellulaire. Mais l'expression de Ccl19, Ccl21 et 11-7 est perdue et ne peut pas être rétablie par stimulation avec différentes cytokines. Les clones TRC ou les lignées cultivées en un système tridimensionnel de culture cellulaire, montrent une morphologie changée, qui ressemble à celle de TRC ex vivo inclus la construction de réseaux tridimensionnels.Pour caractériser le rôle des TRC dans l'activation des cellules T, nous avons cultivé des TRCs avec des cellules T spécifiques et des DCs chargées avec l'antigène. Etonnamment, la présence des TRC (lignées et ex vivo) inhibait plutôt qu'elle améliorait l'activation, la prolifération et la différenciation des lymphocytes T CDS+. Les TRCs partageaient cette fonction avec des fibr-oblastes des organes non lymphoïdes et des cellules souches du type mésenchymateux. Dans ces conditions, les TRCs sont une source importante d'oxyde nitrique (NO) et par ce fait limitent directement l'expansion des cellules T et réduisent aussi la capacité des DCs à activer les cellules T. L'expression de l'enzyme NO synthase inductible (ïNOS) est régulée à la hausse par des signaux dérivés des DCs et par l'interféron-γ produit par des cellules T de type CD8+ activées. Plus important, l'expression d'iNOS est induite pendant une infection virale in vivo, dans les TRCs et dans les DCs. Par conséquent, la réponse primaire de cellules T est exagérée dans des souris iNOS-/-. Nos résultats mettent en évidence qu'en plus de leur rôle positif bien établi dans la réponse immunitaire, les TRCs et les DCs coopèrent dans une boucle de rétroaction négative pour atténuer l'expansion des cellules T pendant l'inflammation aigiie pour protéger l'intégrité et la fonctionnalité des organes lymphoïdes secondaires.

Energy relaxation in nonlinear one-dimensional lattices

We study energy relaxation in thermalized one-dimensional nonlinear arrays of the Fermi-Pasta-Ulam type. The ends of the thermalized systems are placed in contact with a zero-temperature reservoir via damping forces. Harmonic arrays relax by sequential phonon decay into the cold reservoir, the lower-frequency modes relaxing first. The relaxation pathway for purely anharmonic arrays involves the degradation of higher-energy nonlinear modes into lower-energy ones. The lowest-energy modes are absorbed by the cold reservoir, but a small amount of energy is persistently left behind in the array in the form of almost stationary low-frequency localized modes. Arrays with interactions that contain both a harmonic and an anharmonic contribution exhibit behavior that involves the interplay of phonon modes and breather modes. At long times relaxation is extremely slow due to the spontaneous appearance and persistence of energetic high-frequency stationary breathers. Breather behavior is further ascertained by explicitly injecting a localized excitation into the thermalized arrays and observing the relaxation behavior.

Avaliação da tomografia de alta resolução versus radiografia de tórax na doença intersticial pulmonar na esclerose sistêmica

OBJETIVO: Avaliar a acurácia da tomografia de alta resolução (TCAR) do tórax em relação à radiografia simples (RX) do tórax no diagnóstico de doença intersticial pulmonar relacionada à esclerose sistêmica (ES). MATERIAIS E MÉTODOS: Foram realizados TCAR e RX de tórax em póstero-anterior e perfil em 34 pacientes com diagnóstico de ES, segundo critérios do Colégio Americano de Reumatologia, e feita comparação entre as prevalências dos achados radiológicos sugestivos de doença intersticial pulmonar encontradas com estes dois métodos de imagem. RESULTADOS: Foram observadas alterações em 31 (91%) das TCAR, enquanto 16 (47%) dos RX de tórax se apresentavam alterados. Os achados mais freqüentes à TCAR foram: linhas septais (74%), faveolamento (56%) e bandas parenquimatosas (26%), localizados predominantemente nas bases pulmonares. Os RX de tórax demonstraram áreas de infiltrado reticular em 32% dos casos e distorção parenquimatosa em 12% dos pacientes. Em 18 (53%) pacientes com RX de tórax normal a TCAR revelou espessamento septal em 55%, vidro fosco em 44%, faveolamento em 38,5% e cistos em 33%. CONCLUSÃO: A TCAR é mais sensível que o RX de tórax para a investigação de envolvimento intersticial pulmonar inicial em pacientes com ES, justificando, em casos incipientes, tratamento com terapia imunossupressora.

Modelo de interpretação da tomografia computadorizada de alta resolução do diagnóstico diferencial das doenças intersticiais crônicas

O reconhecimento e o diagnóstico diferencial dos diversos padrões da tomografia computadorizada de alta resolução (TCAR) são de fundamental importância na avaliação das doenças pulmonares difusas. Existem vários padrões de TCAR descritos na literatura, sendo alguns deles superponíveis. A interpretação desses padrões pode ser uma tarefa difícil, particularmente para residentes e radiologistas não especializados em tórax. Os autores ilustram os achados característicos da TCAR nas doenças pulmonares intersticiais crônicas e propõem um modelo simplificado de interpretação desses achados, baseado no padrão e na distribuição da doença. O algoritmo inclui os seis principais padrões de anormalidade identificados na TCAR: septal, reticular, cístico, nodular, de atenuação em vidro fosco e consolidação parenquimatosa.

Esclerose sistêmica progressiva: aspectos na tomografia computadorizada de alta resolução

OBJETIVO: Descrever os achados de tomografia computadorizada de alta resolução de pacientes com esclerose sistêmica pulmonar, independentemente dos sintomas respiratórios. MATERIAIS E MÉTODOS: Foram revisados 73 exames de tomografia computadorizada de alta resolução de 44 pacientes com diagnóstico de esclerodermia estabelecido através de critérios clínicos e laboratoriais. Os exames foram revisados por dois radiologistas, que estabeleceram os achados por consenso. RESULTADOS: Em 91,8% (n = 67) dos exames observaram-se alterações. Os principais achados foram lesões de padrão reticular (90,4%), opacidades em vidro-fosco (63%), bronquiectasias e bronquiolectasias de tração (56,2%), dilatação esofagiana (46,6%), faveolamento (28,8%) e sinais de hipertensão pulmonar (15,6%). Na maioria dos casos as lesões eram bilaterais (89%) e simétricas (58,5%). Quanto à localização, houve predomínio de lesões basais (91,2%) e periféricas (92,2%). CONCLUSÃO: A esclerose sistêmica progressiva acarreta fibrose pulmonar na maioria dos pacientes, caracterizada principalmente por lesão reticular basal e periférica.

Revisão radiológica de 173 casos consecutivos de paracoccidioidomicose

OBJETIVO: Revisar e determinar a incidência dos achados radiológicos mais importantes da paracoccidioidomicose, e verificar as possíveis variantes de suas apresentações. MATERIAIS E MÉTODOS: Foram revistos 173 casos consecutivos de paracoccidioidomicose, atendidos no período de 1970 a 1980. Os estudos radiológicos direcionados a cada caso foram reanalisados por no mínimo dois radiologistas experientes. RESULTADOS: Foram encontrados 94 casos de acometimento pulmonar isolado e 38 de acometimento pulmonar associado a lesões ganglionares, viscerais, ósseas e à tuberculose. Sem envolvimento pulmonar foram encontrados 41 casos, com lesões intestinais, viscerais, ósseas ou combinadas. Os principais achados radiológicos da forma pulmonar foram opacidade intersticial reticular e nodular bilateral, seguida por consolidação, também bilateral. As formas visceral e intestinal apresentaram lesões predominantes no fígado, jejuno e íleo. Na forma ganglionar houve predominância do comprometimento difuso abdominal e periférico, e no ósseo, áreas de lise principalmente em ossos longos e clavícula. CONCLUSÃO: A paracoccidioidomicose é doença granulomatosa comum no Brasil, acometendo principalmente o pulmão, tendo como porta de entrada a inalação dos esporos do fungo. Outras formas desta doença, menos freqüentes ou raras, devem ser permanentemente lembradas no diagnóstico diferencial.

Comprometimento pulmonar na esclerose sistêmica: revisão de casos

OBJETIVO: Rever e avaliar os padrões de alterações encontrados em exames de imagem de pacientes com comprometimento pulmonar da esclerose sistêmica. MATERIAIS E MÉTODOS: Foram retrospectivamente estudados os exames de radiografia simples e tomografia computadorizada de alta resolução de 23 pacientes com esclerose sistêmica. RESULTADOS: Na radiografia simples, o padrão reticular em bases pulmonares foi predominante, tendo sido verificado em 18 pacientes (78,2%). A tomografia computadorizada de alta resolução evidenciou lesão pulmonar em todos os pacientes estudados, encontrando-se faveolamento em nove pacientes (39,1%), opacidades em vidro fosco associadas a opacidades reticulares em oito (34,7%), predomínio de opacidades reticulares em cinco (21,7%) e vidro fosco em um paciente (4,3%). CONCLUSÃO: O padrão de anormalidades tomográficas possui boa correlação com os achados histopatológicos, diferenciando padrões predominantemente inflamatórios de fibróticos, com os padrões inflamatórios estando associados a uma resposta superior ao tratamento. Dessa maneira, observou-se alteração sugestiva de fibrose na maior parte dos casos (faveolamento e opacidades reticulares somando 60,8%), porém com boa parte apresentando padrões sugestivos de processo inflamatório.