The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

The prevalence of autism has increased in an exponential way in the past few years. Many monogenetic mutations as well as copy number variants and single nucleotide polymorphisms have been associated with autism spectrum disorders (ASD), a large proportion of which occur in genes associated with synaptogenesis and synaptic function. However, the increase in appearance of genetic alterations does not explain the etiology of an elevated number of ASD cases. Recent research is now focusing on the role of environmental/epigenetic factors, which by themselves and/or in combination with classical genetic factors, may be the root cause of a large number of ASDs. In this chapter we review the current literature regarding the epigenetic changes involved in ASD, including their possible mechanisms of action such as oxidative stress, altered fatty acid metabolism, mitochondrial dysfunction, DNA methylation and histone methylation (via the one‐carbon metabolism cycle), histone variants, and ATP‐dependent chromatin remodeling. We discuss possible new biochemical markers related to autism as well as new lines of research for therapeutic targets

GABAergic Interneurons in Severe Early Epileptic Encephalopathy with a Suppression-Burst Pattern: A Continuum of Pathology

Early infantile epileptic encephalopathy (EIEE) and early myoclonic encephalopathy (EME) are catastrophic epilepsies starting in the neonatal period. The International League Against Epilepsy classifies both of them as generalized symptomatic epilepsies of nonspecific etiology, characterized by early onset, presence of burst-suppression EEG pattern and serious prognosis. The critical difference lies in their presumed etiologies and the prevailing clinical seizure type at onset: EIEE (known as Ohtahara syndrome) usually manifests with tonic seizures, while EME is mainly associated with myoclonic seizures. However, the distinction between those two pathologies is not always easy due to clinical and etiological overlap. Both mutations in the ARX gene for EIEE (OMIM 308350) and disruption in the neuregulin receptor ErbB4 for EME (OMIM 609304) impair interneuron migration and alter the number of GABAergic interneurons in the postnatal cortex. These findings could explain the occurrence of severe epileptic encephalopathy with a burst-suppression pattern and represent a continuum of progressive pathology. In the present chapter we review the genes involved in EIEE and EME including their possible mechanisms of action, particularly via GABAegic interneurons. Their clinical manifestations are myoclonic or tonic seizures, which represent the expression of the underlying pathology and correlate with degree of brain damage

The Comorbidity of ADHD and Autism Spectrum Disorders (ASDs) in Community Preschoolers

Symptoms of inattention and hyperactivity, features of attention-deficit/hyperactivity disorder (ADHD), have been frequently documented in children with autism spectrum disorders (ASDs) and often co-occur. Evidence indicates that 20-50% of children with ADHD meet criteria for ASD, and 30-80% of ASD children meet criteria for ADHD

Therapeutic goals and treatment response evaluation in moderate to severe psoriasis: an experts opinion document

Objective: To critically analyse and define therapeutic objectives, response to treatment evaluation and related decisions in psoriasis. Methods: Expert consensus meetings, a systematic and narrative reviews and a collaborative Delphi procedure were carried out. A steering committee from the Spanish Group of Psoriasis was established who based on the reviews generated a set of related statements. Subsequently, a group of 40 experts tested their agreement with the statements, through 3 Delphi rounds. Results: We found a great variability in clinical guidelines regarding to the definition of treatment goal and the response. In general, treatment failure was considered if a PASI50 is not achieved. The panel of experts agreed on (1) clearly differentiate between ideal and a realistic goals when establishing the therapeutic goal in moderate to severe psoriasis; (2) treatment goals should be in general established regardless of the type of drug for psoriasis; (3) treatment failure if PASI75 response is not reached; (4) an absolute PASI is in general preferred to the rate of PASI improvement from baseline; (5) disease characteristics, patients and physicians opinions/needs and treatment adherence influence treatment goals. Conclusions: A clear treatment decision making framework is vital to improve management of psoriasis.KEY MESSAGES Psoriasis characteristics, patients and physicians opinions/needs and treatment adherence influence treatment goals. Different disease indexes could be used to assess treatment response but absolute PASI is preferred In general psoriasis treatment failure should be considered if PASI75 response is not reachedThis project was promoted and funded by the Spanish Academy of Dermatology and Venereology (AEDV) with unrestricted grant from Leo Pharma

Improvement of Remote Sensing-Based Assessment of Defoliation of Pinus spp. Caused by Thaumetopoea pityocampa Denis and Schiffermüller and Related Environmental Drivers in Southeastern Spain

This study used Landsat temporal series to describe defoliation levels due to the Pine Processionary Moth (PPM) in Pinus forests of southeastern Andalusia (Spain), utilizing Google Earth Engine. A combination of remotely sensed data and field survey data was used to detect the defoliation levels of different Pinus spp. and the main environmental drivers of the defoliation due to the PPM. Four vegetation indexes were also calculated for remote sensing defoliation assessment, both inside the stand and in a 60-m buffer area. In the area of study, all Pinus species are affected by defoliation due to the PPM, with a cyclic behavior that has been increasing in frequency in recent years. Defoliation levels were practically equal for all species, with a high increase in defoliation levels 2 and 3 since 2014. The Moisture Stress Index (MSI) and Normalized Difference Infrared Index (NDII) exhibited similar overall (p < 0.001) accuracy in the assessment of defoliation due to the PPM. The synchronization of NDII-defoliation data had a similar pattern for all together and individual Pinus species, showing the ability of this index to adjust the model parameters based on the characteristics of specific defoliation levels. Using Landsat-based NDII-defoliation maps and interpolated environmental data, we have shown that the PPM defoliation in southeastern Spain is driven by the minimum temperature in February and the precipitation in June, March, September, and October. Therefore, the NDII-defoliation assessment seems to be a general index that can be applied to forests in other areas. The trends of NDII-defoliation related to environmental variables showed the importance of summer drought stress in the expansion of the PPM on Mediterranean Pinus species. Our results confirm the potential of Landsat time-series data in the assessment of PPM defoliation and the spatiotemporal patterns of the PPM; hence, these data are a powerful tool that can be used to develop a fully operational system for the monitoring of insect damage

Estudio comparativo de RM perfusión en pacientes diagnosticados de hidrocefalia normotensiva con pacientes controles

Diversos estudis han demostrat que existeix una disminució en la irrigació de la substància blanca periventricular en pacients diagnosticats d'hidrocefàlia normotensiva quan es comparen amb subjectes normals. Amb l'objectiu de demostrar aquestes troballes, pacients afectes d'aquesta patología es van sotmetre a una RM cerebral morfológica, un estudi de dinàmica de fluxe de LCR i un estudi de perfusió. Amb aquestes exploracions es va demostrar un augment en l'índex d'Evans i una disminución dels valors de VSC (Volum Sanguini Cerebral) de la substància blanca periventricular als pacients casos enfront dels controls.Diversos estudios han demostrado que existe una disminución en la irrigación de la sustancia blanca periventricular en pacientes diagnosticados de hidrocefalia normotensiva cuando se comparan con sujetos normales. Con el objetivo de demostrar estos hallazgos, pacientes afectos de dicha patología se sometieron a una RM cerebral morfológica, un estudio de dinámica de flujo del LCR y un estudio de perfusión. Con estas exploraciones se demostró un aumento en el índice de Evans y una disminución de los valores de VSC (Volumen Sanguíneo Cerebral) de la sustancia blanca periventricular en los pacientes casos frente a los controles

Bivalent therapeutic vaccine against HPV16/18 genotypes consisting of a fusion protein between the extra domain A from human fibronectin and HPV16/18 E7 viral antigens.

In vivo targeting of human papillomavirus (HPV) derived antigens to dendritic cells might constitute an efficient immunotherapeutic strategy against cervical cancer. In previous works, we have shown that the extra domain A from murine fibronectin (mEDA) can be used to target antigens to toll-like receptor 4 (TLR4) expressing dendritic cells and induce strong antigen-specific immune responses. In the present study, we have produced a bivalent therapeutic vaccine candidate consisting of the human EDA (hEDA) fused to E7 proteins from HPV16 and HPV18 (hEDA-HPVE7-16/18) and evaluate its potential as a therapeutic vaccine against cervical cancer. Recombinant fusion proteins containing HPV E7 proteins from HPV16 and HPV18 virus subtypes fused to hEDA were produced and tested in vitro on their capacity to bind TLR4 and induce the production of tumor necrosis factor-α or interleukin (IL)-12 by human monocytes and dendritic cells. The immunogenicity and potential therapeutic activity of the vaccine in combination with cisplatin or with the TLR3 agonist molecules polyinosinic-polycytidylic acid (Poly IC) or Poly ICLC was evaluated in mice bearing subcutaneous or genital orthotopic HPV16 TC-1 tumors. hEDA-HPVE7-16/18 prototype vaccine binds human TLR4 and stimulate TLR4-dependent signaling pathways and IL-12 production by human monocyte-derived dendritic cell. Vaccination with hEDA-HPVE7-16/18 induced strong HPVE7-specific Cytotoxic T lymphocyte (CTL) responses and eliminated established tumors in the TC-1-based tumor model. The antitumor efficacy was significantly improved by combining the fusion protein with cisplatin or with the TLR-3 ligand Poly IC and especially with the stabilized analog Poly ICLC. Moreover, hEDA-HPVE7-16/18+Poly ICLC induced full tumor regression in 100% of mice bearing orthotopic genital HPV tumors. Our results suggest that this therapeutic vaccine formulation may be an effective treatment for cervical tumors that do not respond to current therapies