De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.

Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing neurons.

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial.

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients.

Sefer ṭaʿame ha-miḳra seu institutiones Accentuationis Hebrææ, tabulis mnemonicis hinc inde illustratæ : [et] Variis Scripturæ S. Exemplis comprobatæ, Ad majorem lucem Verbo Divino conciliandam [et] Orthodoxiam nostram contra Heterodoxos inprimis contra Judæos facilius defendandam, methodo Wasmuthiana adornatæ

autore M. Henrico Opitio

Fungi novo-guineenses

Von P. Hennings

Fungi novo-guineenses II

Von P. Hennings

Characterization of tumor-associated Foxp3+ regulatory T cells and de-novo induction by the tumor microenvironment

Regulatory T cells expressing the fork-head box transcription factor 3 (Foxp3) play a central role in the dominant control of immunological tolerance. Compelling evidence obtained from both animal and clinical studies have now linked the expansion and accumulation of Foxp3+ regulatory T cells associated with tumor lesions to the failure of immune-mediated tumor rejection. However, further progress of the field is hampered by the gap of knowledge regarding their phenotypic, functional, and the developmental origins in which these tumor-associated Foxp3+ regulatory T cells are derived. Here, we have characterized the general properties of tumor-associated Foxp3+ regulatory T cells and addressed the issue of tumor microenvironment mediated de-novo induction by utilizing a well known murine tumor model MCA-205 in combination with our BAC Foxp3-GFP reporter mice and OT-II TCR transgenic mice on the RAG deficient background (RAG OT-II). De-novo induction defines a distinct mechanism of converting non-regulatory precursor cells to Foxp3+ regulatory T cells in the periphery as opposed to the expansion of pre-existing regulatory T cells formed naturally during thymic T cell development. This mechanism is of particularly importance to how tumors induce tumor-antigen-specific suppressor cells to subvert anti-tumor immune responses. Our study has found that tumor-associated Foxp3+ regulatory T cells are highly activated, undergo vigorous proliferation, are more potent by in-vitro suppression assays, and express higher levels of membrane-bound TGF-β1 than non-tumor regulatory T cells. With Foxp3-GFP reporter mice or RAG OT-II TCR transgenic mice, we show that tumor tissue can induce detectable de-novo generation of Foxp3+ regulatory T cells of both polyclonal or antigen specific naïve T cells. This process was not only limited for subcutaneous tumors but for lung tumors as well. Furthermore, this process required the inducing antigen to be co-localized within the tumor tissue. Examination of tumor tissue revealed an abundance of myeloid CD11b+ antigen-presenting cells that were capable of inducing Foxp3+ regulatory T cells. Taken together, these findings elucidate the general attributes and origins of tumor-associated Foxp3+ regulatory T cells in the tumor microenvironment and in their role in the negative regulation of tumor immunity.^

Evaluation of epidemiological and clinical factors in survival of patients with de novo myelodysplastic syndrome at the University of Texas MD Anderson cancer center

Little is known about epidemiological markers that are associated with survival of patients with myelodysplastic syndromes (MDS). We conducted a secondary case-based analysis of 465 de novo MDS patients from the University of Texas MD Anderson Cancer Center (UTMDACC). We investigated the association between demographic as well as occupational exposure markers and survival while incorporating known clinical markers of prognosis. In our patient population, 60.6% were men and the majority were white (93.1%). The distribution of MDS subtypes by the French–American–British (FAB) classification was 81 (19%) refractory anemia (RA), 46 (9.9%) refractory anemia with ringed sideroblasts (RARS), 57 (12.3%) chronic myelomonocytic leukemia (CMML), 173 (37.2%) RA with excess blasts (RAEB), and 86 (18.5%) RAEB in transformation (RAEBT). We found that those older at diagnosis (> 60 years of age) (HR = 1.68, CI = 1.26-2.25) were at a higher risk of dying compared to younger patients. Similarly, high pack years of smoking (>= 30 pack years of smoking) (HR = 1.34, CI = 1.02-1.74), and agricultural chemical exposure (HR = 1.61, CI = 1.05-2.46) were significantly associated with overall lower survival when compared to patients with none or medium exposures. Among clinical markers, greater than 5% bone marrow blasts (HR = 1.81 CI = 1.27-2.56), poor cytogenetics (HR = 3.20, CI = 2.37-4.33)), and platelet cytopenias (<100000/ul) (HR = 1.46, CI = 1.11-1.92) were also significantly associated with overall MDS survival.^ The identification of epidemiological markers could help physicians stratify patients and customize treatment strategies to improve the outcome of MDS based on patient lifestyle information such as smoking exposure and agrochemical exposure. We hope that this study highlights the impact of these exposures in MDS prognosis.^

La asunción de lo popular el teatro didáctico anarquista de Alberto Ghiraldo y su programa poético de «dar al pueblo la palabra»

Este trabajo aborda la conexión entre prácticas de comunicación y movimientos sociales a través de la particular asunción de lo popular que realizó el anarquismo en nuestro país a principios del siglo XX. Tomamos como caso particular el teatro didáctico propuesto por Alberto Ghiraldo, para describir algunas de las estrategias comunicacionales puestas en función, en relación con la cultura popular, con el fin de concientizar a las masas de los aspectos ideológicos del anarquismo.

La especificidad de la voz como sensible y su presencia en la consideración del verbo del intelecto

Fil: Ramasco de Monzón, Ruth. Universidad Nacional de Tucumán

La poesía como intemperie : La experiencia de la nada en Oscar del Barco y Stéphane Mallarmé

Entre 1864 y 1869 Mallarmé atraviesa la llamada crisis metafísica. En su Correspondencia de esos años leemos reflexiones en torno a la cuestión de la nada que se pueden pensar en vinculación con Igitur o la locura de Elbehnon (1868-1879) y Notes sur le langage de 1869 (proyecto de tesis sobre el lenguaje posteriormente abandonado) donde se plantea una tensión entre Verbo, Palabra y Lenguaje. La cuestión de la nada lo llevará a repensar las posibilidades de representación poética (imágenes verbales, alegoría, símbolo, vínculo con la música, las constelaciones imprevistas y la noción de latencia o sugestión). De esa experiencia con el lenguaje resultan estrechamente ligadas la pregunta por la necesidad y potencia de lo poético y la pregunta por la forma (intento de des-limitar al lenguaje). En Exceso y donación, Oscar del Barco reflexiona sobre "El Dios sin Dios". Se trata de un desdoblamiento por el que salir de las idolatrías (la onto-teleo-logía) para alcanzar el valor vital del pensamiento filosófico o de la poesía como consistencia ante el hay de la creación, lo i- limitado, el puro verbo sin alguien que cree y sin algo creado, que es el hombre. Enfrentado a la impaciencia de la palabra, su excedencia y divinidad, su copertenencia en el estado de acontecimiento. En los vínculos entre poesía y filosofía, proponemos una lectura trasversal del pensamiento de Oscar del Barco "Sobre el problema de Dios" y las Correspondencias y Notes sur le langage e Mallarmé que gira en torno a la experiencia de a nada como experiencia de la intemperie (de lo abierto), excedencia del yo, del sujeto, del mundo. De allí trazaremos algunas consideraciones respecto del espacio de la poesía como campo abierto para vivir la intemperie, la experiencia en el mundo y en el lenguaje en las fronteras del sentido

Los Twist : Estrategias del humor en el universo poético-político del rock nacional

En la década del ochenta, y por varios factores, el universo de sentido (poético/político) del discurso del rock argentino entró en crisis: se difuminaron los límites de lo que había sido una cierta comunidad rockera, el género "conquistó" la masividad en el mercado discográfico y el campo se fragmentó en múltiples tendencias, con diversas estrategias de enunciación. Hacia 1983 se editó el primer disco del grupo Los Twist, La dicha en movimiento, y el objeto de este trabajo será medir su indudable novedad y el valor diferencial que adoptó respecto del contexto que reseñamos. Si bien algunos grupos habían usado ya el humor como recurso (en general, con intención satírica), Los Twist será la primer banda que lo asuma como un programa estético definido; mientras que, por otra parte, llegará incluso a proponer una parodia de su propia imagen "rockera": en este punto, la estrategia paródica no sólo permitirá una distancia irónica, sino que también enfatizará y terminará revelando las líneas centrales que identifican al discurso que se parodia: una actitud ideológica de "contestación", la configuración de un imaginario sobre la juventud como actor social, cierta relación, en fin, con el poder y el mercado de los medios de comunicación