Ictal activity is sustained by the estrogen receptor ß during the estrous cycle.

Catamenial epilepsy, defined as a periodicity of seizure exacerbation during the menstrual cycle, affects up to 70 % of epileptic women. Seizures in these patients are often non-responsive to medication; however, our understanding of the relation between menstrual cycle and seizure generation (i.e. ictogenesis) remains limited. We employed here field potential recordings in the in vitro 4-aminopyridine model of epileptiform synchronization in female mice (P60-P130) and found that: (i) the estrous phase favors ictal activity in the entorhinal cortex; (ii) these ictal discharges display an onset pattern characterised by the presence of chirps that are thought to mirror synchronous interneuron firing; and (iii) blocking estrogen receptor ß-mediated signaling reduces ictal discharge duration. Our findings indicate that the duration of 4AP-induced ictal discharges, in vitro, increases during the estrous phase, which corresponds to the human peri-ovulatory period. We propose that these effects are caused by the presumptive enhancement of interneuron excitability due to increased estrogen receptor ß-mediated signaling.

The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2.

Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence.

The p75 Neurotrophin Receptor in Preadolescent Prefrontal Parvalbumin Interneurons Promotes Cognitive Flexibility in Adult Mice.

BACKGROUND: Parvalbumin (PV)-positive GABAergic (gamma-aminobutyric acidergic) cells provide robust perisomatic inhibition to neighboring pyramidal neurons and regulate brain oscillations. Alterations in PV interneuron connectivity and function in the medial prefrontal cortex have been consistently reported in psychiatric disorders associated with cognitive rigidity, suggesting that PV cell deficits could be a core cellular phenotype in these disorders. The p75 neurotrophin receptor (p75NTR) regulates the time course of PV cell maturation in a cell-autonomous fashion. Whether p75NTR expression during postnatal development affects adult prefrontal PV cell connectivity and cognitive function is unknown. METHODS: We generated transgenic mice with conditional knockout of p75NTR in postnatal PV cells. We analyzed PV cell connectivity and recruitment following a tail pinch by immunolabeling and confocal imaging in naïve mice or following p75NTR re-expression in preadolescent or postadolescent mice using Cre-dependent viral vectors. Cognitive flexibility was evaluated using behavioral tests. RESULTS: PV cell-specific p75NTR deletion increased both PV cell synapse density and proportion of PV cells surrounded by perineuronal nets, a marker of mature PV cells, in adult medial prefrontal cortex, but not visual cortex. Both phenotypes were rescued by viral-mediated reintroduction of p75NTR in preadolescent, but not postadolescent, medial prefrontal cortex. Prefrontal cortical PV cells failed to upregulate c-Fos following a tail-pinch stimulation in adult conditional knockout mice. Finally, conditional knockout mice showed impaired fear memory extinction learning as well as deficits in an attention set-shifting task. CONCLUSIONS: These findings suggest that p75NTR expression in adolescent PV cells contributes to the fine-tuning of their connectivity and promotes cognitive flexibility in adulthood.

Detecting fine and elaborate movements with piezo sensors provides non-invasive access to overlooked behavioral components.

Behavioral phenotyping devices have been successfully used to build ethograms, but many aspects of behavior remain out of reach of available phenotyping systems. We now report on a novel device, which consists in an open-field platform resting on highly sensitive piezoelectric (electromechanical) pressure-sensors, with which we could detect the slightest movements (up to individual heart beats during rest) from freely moving rats and mice. The combination with video recordings and signal analysis based on time-frequency decomposition, clustering, and machine learning algorithms provided non-invasive access to previously overlooked behavioral components. The detection of shaking/shivering provided an original readout of fear, distinct from but complementary to behavioral freezing. Analyzing the dynamics of momentum in locomotion and grooming allowed to identify the signature of gait and neurodevelopmental pathological phenotypes. We believe that this device represents a significant progress and offers new opportunities for the awaited advance of behavioral phenotyping.

Sensory processing dysregulations as reliable translational biomarkers in SYNGAP1 haploinsufficiency.

Amongst the numerous genes associated with intellectual disability, SYNGAP1 stands out for its frequency and penetrance of loss-of-function variants found in patients, as well as the wide range of co-morbid disorders associated with its mutation. Most studies exploring the pathophysiological alterations caused by Syngap1 haploinsufficiency in mouse models have focused on cognitive problems and epilepsy; however, whether and to what extent sensory perception and processing are altered by Syngap1 haploinsufficiency is less clear. By performing EEG recordings in awake mice, we identified specific alterations in multiple aspects of auditory and visual processing, including increased baseline gamma oscillation power, increased theta/gamma phase amplitude coupling following stimulus presentation and abnormal neural entrainment in response to different sensory modality-specific frequencies. We also report lack of habituation to repetitive auditory stimuli and abnormal deviant sound detection. Interestingly, we found that most of these alterations are present in human patients as well, thus making them strong candidates as translational biomarkers of sensory-processing alterations associated with SYNGAP1/Syngap1 haploinsufficiency.

Forced normalization: case series from a Spanish epilepsy unit.

INTRODUCTION: Forced normalization is a clinical situation of singular relationship betweenepilepsy and psychosis, in which a patient shows behavioural and psychiatric symptoms coinciding with a reduction or termination of seizures and a total or partial normalization ofelectroencephalogram. Behavioural symptoms (frequently psychosis) or mood disturbances may appear. More information about this phenomenon, risk factors and prognostic variables is needed. MATERIALS AND METHODS: We conducted a systematic review of allthe patients followed at the specific Epilepsy Office in Virgen de la Victoria hospital, in order todetect and analyse the cases of forced normalization and to describe the clinical variables relatedto it. RESULTS: We present a 10 patient case series, 6 women and 4 men with an average age of 51.5 years. Demographic data, neurological diagnosis, type of seizures, psychiatric comorbidity,related Antiepileptic Drugs (AEDs), pharmacoresistance, polytherapy, concomitant AEDs,therapeutic management and prognosis were analysed. CONCLUSION: This is a hospital-based studyabout the characteristics of forced normalization in patients with epilepsy. It is one of thelargest series reported in 30 years, to our knowledge. Psychiatric comorbidity and developmentaldelay seem to be strongly associated with forced normalization in our series, or this relationshipcould be biased by the special characteristics of an Epilepsy Office which proportionately assistsmore cases of refractory epilepsy, commonly associated with disabilities and comorbidity. Theprognosis is favourable. Our data could establish a starting point for the design of larger prospective and experimental studies.

Potential Involvement of Impaired BKCa Channel Function in Sensory Defensiveness and Some Behavioral Disturbances Induced by Unfamiliar Environment in a Mouse Model of Fragile X Syndrome.

In fragile X syndrome (FXS), sensory hypersensitivity and impaired habituation is thought to result in attention overload and various behavioral abnormalities in reaction to the excessive and remanent salience of environment features that would normally be ignored. This phenomenon, termed sensory defensiveness, has been proposed as the potential cause of hyperactivity, hyperarousal, and negative reactions to changes in routine that are often deleterious for FXS patients. However, the lack of tools for manipulating sensory hypersensitivity has not allowed the experimental testing required to evaluate the relevance of this hypothesis. Recent work has shown that BMS-204352, a BKCa channel agonist, was efficient to reverse cortical hyperexcitability and related sensory hypersensitivity in the Fmr1-KO mouse model of FXS. In the present study, we report that exposing Fmr1-KO mice to novel or unfamiliar environments resulted in multiple behavioral perturbations, such as hyperactivity, impaired nest building and excessive grooming of the back. Reversing sensory hypersensitivity with the BKCa channel agonist BMS-204352 prevented these behavioral abnormalities in Fmr1-KO mice. These results are in support of the sensory defensiveness hypothesis, and confirm BKCa as a potentially relevant molecular target for the development of drug medication against FXS/ASD.

Propuesta de un nuevo diseño de órtesis post-tratamiento de pie equino varo congénito / Proposal for a new design of post-treatment congenital club foot orthosis

La investigación tuvo como objetivo rediseñar la órtesis utilizada post-tratamiento Ponseti, en niños con pie equino varo congénito, de forma tal que permita la reducción de rechazo a su uso. Método: Se identificaron las necesidades de los niños con pie equino varo congénito, para verificar los inconvenientes con respecto a la funcionalidad, diseño y adaptabilidad a la órtesis dado que si la férula no se usa adecuadamente el riesgo de recidiva es de 80 %, por el contrario con el uso de la férula el riesgo es de 4 %. Se realizó un estudio biomecánico del movimiento de un paciente durante el gateo, con y sin la órtesis. Resultados: Se elaboró un modelo 3D de la propuesta, para simular el diseño sometido a las fuerzas generadas por los bebés durante el pataleo en posición supina. Se evaluó experimentalmente el desempeño del prototipo alfa, para determinar si cumplía con la meta prevista. Se obtuvo la fabricación y pruebas de la órtesis en plataforma virtual y físico. Acorde al alcance del proyecto, se determinó que es probable que se reduzca el rechazo al uso y por consiguiente la formación de recidiva, al reducir los factores determinantes propios de la férula del mercado, que propiciaban el mal uso de esta en el tratamiento. La velocidad promedio de gateo es de 0.48 m/s y con la férula se reduce a 0.37 m/s. Discusión: La férula del mercado pesa 304.07 g y la propuesta pesa 209.26 g. Se sugiere que se continúe la investigación en el estudio biomecánico.

This research was developed with the objective of redesigning the orthosis used in the post- Ponseti treatment in children with clubfoot, with the intention of reducing the rejection to its use. Method: A research on the needs of children with congenital clubfoot was conducted to identify the disadvantages on functionality, design and adaptability of the orthosis if the splint is not used appropriately, the risk of relapse is 80 %, whereas using the splint, the risk is 4 %. A biomechanical study of a patient's movement during the crawl was performed with and without the orthosis. Results: A 3D model of the design was developed to simulate computationally its performance under the forces generated by the babies during the kick in supine position. Finally, an experimental evaluation of the alpha prototype performance was made to determine whether it met the intended goal. Thus, the manufacturing and testing of the orthosis on virtual and in physical platform took place. Taking in account the goal of this project, it 3 was determined that it is possible to reduce the reject to the use and therefore the formation of relapse by reducing the determinant factors of the common market splint, which promotes its incorrect use of this in the treatment. The average crawl speed is 0.48 m/s and with the splint, it decreases to 0.37 m/s. Discussion: The weight of the common market splint is 304.07 g and the weight of the one designed in the study is 209.26 g. Further biomechanical research is suggested to get conclusive results

Epidemiological study of mortality in epilepsy in a Spanish population.

PURPOSE: Studies concerning mortality in epilepsy have been performed primarily in Northern-Central Europe and US. The aim of this study was to provide information about mortality in people with epilepsy in Southern European countries. METHOD: We studied a Spanish prevalence and incidence cohort of 2309 patients aged ≥14 years with epilepsy who were treated in an outpatient epilepsy clinic between 2000 and 2013. The deceased were identified through Civil Registries. Causes of death were determined using death certificates, forensic autopsies, hospital reports, family practitioners, and care-givers' records. Standardised mortality ratios (SMRs) were calculated. RESULTS: In a total of 15,865 person-years of follow-up, 152 patients died, resulting in an SMR of 2.11 (95% CI 1.79-2.47), which was higher for those aged 14-24. There was also a high rate of death for symptomatic epilepsies, progressive causes (SMR=6.12, CI 3.50-9.94), and remote causes (SMR=2.62, CI 2.12-3.21). High SMRs were found for all kinds of epilepsy and for respiratory and tumoural causes. Patients who died of epilepsy itself were 12.5%. Sudden unexpected death in epilepsy incidence was 0.44:1000. Death from status epilepticus incidence was 20:100,000. SMRs for external causes were of no statistical significance. CONCLUSIONS: This is the first epidemiological study to examine rate of mortality in epilepsy in a Southern European country. The identified mortality pattern is similar to the one provided by researchers from developed countries. The similarities between our results concerning epilepsy-related deaths and those provided by population-based studies are the result of the scarcely selected character of our study cohort.

[Control of epilepsy in adult patients with tuberous sclerosis]. / Control de la epilepsia en pacientes adultos con esclerosis tuberosa.

INTRODUCTION: Tuberous sclerosis is a genetic disease, the main manifestations of which are the formation of neuroectodermal tumours, which are very often associated to secondary epilepsy. AIM: To describe the epileptic profile, control, frequency of seizures and effectiveness of treatment in adult patients with tuberous sclerosis. PATIENTS AND METHODS: The study was descriptive and included adult patients (over 14 years of age) with a confirmed diagnosis of tuberous sclerosis. Both the frequency and type of seizures were analysed. A study was conducted to analyse and record the number of different antiepileptic drugs in each patient and the frequency of use of each active ingredient, and the control of seizures and the type of therapy were also included in another comparative study. RESULTS: Of a total of 19 adults who were studied, 16 of them (84%) had epileptic seizures. Results showed that 44%, 25% and 31% of them presented full control of seizures, sporadic seizures and frequent seizures, respectively. A certain frequency of focal, general and both types of seizures existed in 38%, 6% and 25%, respectively. Likewise, 38%, 44% and 19% of them were under treatment with antiepileptic drugs in monotherapy, bitherapy and tritherapy, respectively. Overall, the most commonly consumed drug was levetiracetam, followed by carbamazepine and valproic acid. In monotherapy the most common was carbamazepine, with a higher proportion of full control. CONCLUSIONS: Epilepsy in tuberous sclerosis is relatively benign and an acceptable degree of control is achieved in most cases with a number of the antiepileptic drugs recommended in the treatment guidelines. In our series, we observed stability of involvement and there was no progression to a malignant status. The small number of individuals in the sample limits the study, but the proportions of treatment effectiveness are seen to be similar to those observed in another series published in the literature.

TITLE: Control de la epilepsia en pacientes adultos con esclerosis tuberosa.Introduccion. La esclerosis tuberosa es una enfermedad genetica cuyas manifestaciones principales son la formacion de tumores neuroectodermicos, que asocia epilepsia secundaria muy frecuentemente. Objetivo. Describir el perfil epileptico, el control, la frecuencia de crisis y la efectividad del tratamiento en pacientes adultos con esclerosis tuberosa. Pacientes y metodos. Estudio descriptivo en el que se han incluido pacientes adultos (mayores de 14 anos) con diagnostico confirmado de esclerosis tuberosa. Se ha analizado la frecuencia y tipos de crisis. Se ha realizado un estudio y contabilizacion de los diferentes farmacos antiepilepticos en cada paciente, la frecuencia de uso de cada principio activo y un estudio comparativo entre control de crisis y tipo de terapia. Resultados. De 19 adultos estudiados, tuvieron crisis epilepticas 16 (84%). Presentaron control de crisis completo, crisis esporadicas y crisis frecuentes el 44%, 25% y 31%, respectivamente. Hubo frecuencia de crisis focales, generalizadas y ambas en el 38%, 6% y 25%, respectivamente. Estaban en tratamiento con farmacos antiepilepticos en monoterapia, biterapia y triterapia el 38%, 44% y 19%, respectivamente. El mas consumido globalmente fue el levetiracetam, seguido de la carbamacepina y el acido valproico. En monoterapia, el mas frecuente fue la carbamacepina, con mayor proporcion de control completo. Conclusiones. La epilepsia en la esclerosis tuberosa es relativamente benigna, y se consigue un aceptable control en la mayoria de casos con un numero de antiepilepticos acorde con lo aconsejado en las guias de tratamiento. Se observa estabilidad de lesiones, y no hay malignizacion en nuestra serie. El bajo numero de la muestra limita el estudio, pero se observan proporciones similares de efectividad del tratamiento respecto a otra serie publicada.

Designing the safety of healthcare. Participation of ergonomics to the design of cooperative systems in radiotherapy.

This communication deals with the involvement of ergonomists in a research-action design process of a software platform in radiotherapy. The goal of the design project is to enhance patient safety by designing a workflow software that supports cooperation between professionals producing treatment in radiotherapy. The general framework of our approach is the ergonomics management of a design process, which is based in activity analysis and grounded in participatory design. Two fields are concerned by the present action: a design environment which is a participatory design process that involves software designers, caregivers as future users and ergonomists; and a reference real work setting in radiotherapy. Observations, semi-structured interviews and participatory workshops allow the characterization of activity in radiotherapy dealing with uses of cooperative tools, sources of variability and non-ruled strategies to manage the variability of the situations. This production of knowledge about work searches to enhance the articulation between technocentric and anthropocentric approaches, and helps in clarifying design requirements. An issue of this research-action is to develop a framework to define the parameters of the workflow tool, and the conditions of its deployment.