La jeune danseuse du temps des anges. L'Histoire

She danced at a time when the world was changing. Still a young girl, she loved dancing and animals, but the rest of what she was living at her age often seemed tasteless to her. She dreamed sometimes of being a great lover, sometimes a saint, but her mother counted on her for something else. One evening she was dancing in front of her parents and their guest, and her dance was impressive. However, she still had to look for ideas that would move her dance from improvisation to a more elaborate art. Her mother felt threatened by a preacher who maybe had violent disciples. Considering a sort of preventive revenge, she became threatening herself. The guest presented himself as a possible second arbiter between her and the preacher. The first arbiter, the king, unwilling to release the preacher, exile him, or condemn him to death, was slow to make a decision. The theatre of their confrontation also includes the sequences of a strange oratorio, since a new religion began to convert a few people. New ways of thinking and living would soon prevail. Salomé’s story is our story. It is the beginning of the world that has been ours for two thousand years.She danced at a time when the world was changing. Still a young girl, she loved dancing and animals, but the rest of what she was living at her age often seemed tasteless to her. She dreamed sometimes of being a great lover, sometimes a saint, but her mother counted on her for something else. One evening she was dancing in front of her parents and their guest, and her dance was impressive. However, she still had to look for ideas that would move her dance from improvisation to a more elaborate art. Her mother felt threatened by a preacher who maybe had violent disciples. Considering a sort of preventive revenge, she became threatening herself. The guest presented himself as a possible second arbiter between her and the preacher. The first arbiter, the king, unwilling to release the preacher, exile him, or condemn him to death, was slow to make a decision. The theatre of their confrontation also includes the sequences of a strange oratorio, since a new religion began to convert a few people. New ways of thinking and living would soon prevail. Salomé’s story is our story. It is the beginning of the world that has been ours for two thousand years

Unexpected Divorce: a traumatic love breakup

Este artigo discute o sofrimento psicológico vivenciado em um caso de divórcio inesperado, forma específica de separação, e suas possibilidades de manejo clínico, com base na Gestalt-terapia e nos estudos de perdas ambíguas. Para tanto, definimos esta forma de rompimento amoroso como aquela em que há um término abrupto, o processo decisório é unilateral, há sensação de abandono e não existe percepção da possibilidade da quebra do relacionamento. Estes fatores combinados têm um alto potencial traumático, dificultando a elaboração por parte de quem foi deixado. No estudo de caso apresentado, ficam claros os impactos do divórcio na qualidade de vida da participante, sua capacidade financeira, assim como sobre sua saúde física e mental. As especificidades do enlutamento pela perda ambígua e não finita vivenciada são evidentes, permitindo discutir um manejo clínico específico, focado no awareness e ajustamento criativo, e que passam pelos seguintes pilares: dar sentido e significado ao vivido, encontrar equilíbrio, reconstruir a identidade, lidar com a ambivalência de sentimentos, rever os apegos e reencontrar esperança.This article discusses the psychological suffering experienced in an unexpected divorce case, specific form of separation, and its possibilities for clinical management, based on Gestalt therapy and ambiguous loss studies. Therefore, we define this form of love breakup as one in which there is an abrupt end, the decision-making process is unilateral, there is a feeling of abandonment and there is no perception of the possibility of breaking the relationship. These factors combined have a high traumatic potential, making it difficult for those left to elaborate it. In the case study presented, the impacts of divorce on the participant's quality of life, her financial capacity, as well as on her physical and mental health, are clear. The specifics of mourning due to the ambiguous and non-finite loss experienced are evident, allowing us to discuss a specific clinical management, focused on awareness and creative adjustment, and which include the following pillars: giving sense and meaning to the experience, finding balance, rebuilding identity, dealing with the ambivalence of feelings, reviewing attachments and finding hope again

A phase III, randomized, non-inferiority study comparing the efficacy and safety of biosimilar filgrastim versus originator filgrastim for chemotherapy-induced neutropenia in breast cancer patients

OBJECTIVES: To compare the efficacy and safety of two filgrastim formulations for controlling chemotherapy-induced neutropenia and to evaluate the non-inferiority of the test drug relative to the originator. METHODS: This phase III non-inferiority study had a randomized, multicenter, and open-label design. The patients were randomized at a ratio of 1:1 with a follow-up period of 6 weeks for each patient. In both study arms, filgrastim was administered subcutaneously at a daily dose of 5 mg/kg body weight. The primary endpoint was the rate of grade 4 neutropenia in the first treatment cycle. The secondary endpoints were the duration of grade 4 neutropenia, the generation of anti-filgrastim antibodies, and the rates of adverse events, laboratory abnormalities, febrile neutropenia, and neutropenia of any grade. RESULTS: The primary efficacy analysis demonstrated the non-inferiority of the test drug compared with the originator drug; the upper limit of the 90% confidence interval (CI) for the rate of neutropenia between the two groups (12.61%) was lower than the established margin of non-inferiority. The two treatments were similar with respect to the secondary endpoints and safety. CONCLUSION: The efficacy and safety profile of the test drug were similar to those of the originator product based on the rate of grade 4 neutropenia in the first treatment cycle. This study supports Anvisa’s approval of the first biosimilar drug manufactured by the Brazilian industry (Fiprima¯)

Balloon cells promote immune system activation in focal cortical dysplasia type 2b

AIMS: Focal cortical dysplasia (FCD) type 2 is an epileptogenic malformation of the neocortex associated with somatic mutations in the mammalian target of rapamycin (mTOR) pathway. Histopathologically, FCD 2 is subdivided into FCD 2a and FCD 2b, the only discriminator being the presence of balloon cells (BCs) in FCD 2b. While pro‐epileptogenic immune system activation and inflammatory responses are commonly detected in both subtypes, it is unknown what contextual role BCs play. METHODS: The present study employed RNA sequencing of surgically resected brain tissue from FCD 2a (n = 11) and FCD 2b (n = 20) patients compared to autopsy control (n = 9) focusing on three immune system processes: adaptive immunity, innate immunity and cytokine production. This analysis was followed by immunohistochemistry on a clinically well‐characterised FCD 2 cohort. RESULTS: Differential expression analysis revealed stronger expression of components of innate immunity, adaptive immunity and cytokine production in FCD 2b than in FCD 2a, particularly complement activation and antigen presentation. Immunohistochemical analysis confirmed these findings, with strong expression of leukocyte antigen I and II in FCD 2b as compared to FCD 2a. Moreover, T‐lymphocyte tissue infiltration was elevated in FCD 2b. Expression of markers of immune system activation in FCD 2b was concentrated in subcortical white matter. Lastly, antigen presentation was strongly correlated with BC load in FCD 2b lesions. CONCLUSION: We conclude that, next to mutation‐driven mTOR activation and seizure activity, BCs are crucial drivers of inflammation in FCD 2b. Our findings indicate that therapies targeting inflammation may be beneficial in FCD 2b

Mechanism of primitive duct formation in the pancreas and submandibular glands: a role for SDF-1

BACKGROUND: The exocrine pancreas is composed of a branched network of ducts connected to acini. They are lined by a monolayered epithelium that derives from the endoderm and is surrounded by mesoderm-derived mesenchyme. The morphogenic mechanisms by which the ductal network is established as well as the signaling pathways involved in this process are poorly understood. RESULTS: By morphological analyzis of wild-type and mutant mouse embryos and using cultured embryonic explants we investigated how epithelial morphogenesis takes place and is regulated by chemokine signaling. Pancreas ontogenesis displayed a sequence of two opposite epithelial transitions. During the first transition, the monolayered and polarized endodermal cells give rise to tissue buds composed of a mass of non polarized epithelial cells. During the second transition the buds reorganize into branched and polarized epithelial monolayers that further differentiate into tubulo-acinar glands. We found that the second epithelial transition is controlled by the chemokine Stromal cell-Derived Factor (SDF)-1. The latter is expressed by the mesenchyme, whereas its receptor CXCR4 is expressed by the epithelium. Reorganization of cultured pancreatic buds into monolayered epithelia was blocked in the presence of AMD3100, a SDF-1 antagonist. Analyzis of sdf1 and cxcr4 knockout embryos at the stage of the second epithelial transition revealed transient defective morphogenesis of the ventral and dorsal pancreas. Reorganization of a globular mass of epithelial cells in polarized monolayers is also observed during submandibular glands development. We found that SDF-1 and CXCR4 are expressed in this organ and that AMD3100 treatment of submandibular gland explants blocks its branching morphogenesis. CONCLUSION: In conclusion, our data show that the primitive pancreatic ductal network, which is lined by a monolayered and polarized epithelium, forms by remodeling of a globular mass of non polarized epithelial cells. Our data also suggest that SDF-1 controls the branching morphogenesis of several exocrine tissues.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Seizure-mediated iron accumulation and dysregulated iron metabolism after status epilepticus and in temporal lobe epilepsy

Neuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat model of TLE. Magnetic susceptibility of the presumed seizure-onset zone from three patients with focal epilepsy was compared during and after seizure activity. Finally, the cellular effects of iron overload were studied in vitro using an acute mouse hippocampal slice preparation and cultured human fetal astrocytes. While iron-accumulating neurons had a pyknotic morphology, astrocytes appeared to acquire iron-sequestrating capacity as indicated by prominent ferritin expression and iron retention in the hippocampus of patients with SE or TLE. Interictal to postictal comparison revealed increased magnetic susceptibility in the seizure-onset zone of epilepsy patients. Post-SE rats had consistently higher hippocampal iron levels during the acute and chronic phase (when spontaneous recurrent seizures are evident). In vitro, in acute slices that were exposed to iron, neurons readily took up iron, which was exacerbated by induced epileptiform activity. Human astrocyte cultures challenged with iron and ROS increased their antioxidant and iron-binding capacity, but simultaneously developed a pro-inflammatory phenotype upon chronic exposure. These data suggest that seizure-mediated, chronic neuronal iron uptake might play a role in neuronal dysfunction/loss in TLE-HS. On the other hand, astrocytes sequester iron, specifically in chronic epilepsy. This function might transform astrocytes into a highly resistant, pro-inflammatory phenotype potentially contributing to pro-epileptogenic inflammatory processes

A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target

The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning (“Causal Reasoning Analytical Framework for Target discovery”—CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in three pre-clinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. CRAFT is applicable to disease settings other than epilepsy

The regions within the N-terminus critical for human glucagon like peptide-1 receptor (hGLP-1R) cell Surface expression

The hGLP-1R is a target for the treatment of type 2 diabetes and belongs to the class B family of GPCRs. Like other class B GPCRs, the GLP-1R contains an N-terminal signal peptide (SP) and undergoes N-linked glycosylation, which are important for its trafficking and maturation. This study analysed the role of the SP, the hydrophobic region after the SP (HRASP), glycosylation and the conserved residues within the N-terminus in GLP-1R trafficking. HGLP-1R targeted to the cell surface showed no SP, and the SP deleted mutant, but not the mutants defective in SP cleavage, showed cell surface expression, demonstrating the importance of SP cleavage for hGLP-1R cell surface expression. The N-terminal deletions of hGLP-1R revealed that the HRASP, not the SP, is essential for cell surface expression of GLP-1R. Further, inhibition of hGLP-1R glycosylation prevented cell surface expression of the receptor. Mutation of Trp39, Tyr69 and Tyr88, which are required for agonist binding, in the GLP-1R abolished cell surface expression of the receptor independent of the SP cleavage or N-linked glycosylation. In conclusion, the N-terminus of hGLP-1R regulates receptor trafficking and maturation. Therefore this study provides insight into the role of hGLP-1R N-terminus on the receptor cell surface expression