[Emotional Abuse in Childhood and Adolescence: Biological Embedding and Clinical Implications]. / Emotionaler Missbrauch in Kindheit und Jugend ­ Biologische Einbettung und klinische Implikationen.

Emotional abuse, defined as degrading, manipulative, or neglectful behaviors by caregivers, represents a common adverse experience for children and adolescents, often co-occurring with other maltreatment types. Exposure to emotional abuse significantly affects mental health across the lifespan and is particularly associated with elevated depression risk.This review examinesmechanisms, by which emotional abuse influences brain development and the neuroendocrine stress response system and discusses the roles of genetic vulnerability and epigenetic processes in contributing to an elevated mental health risk. Emotional abuse has similar effects on brain networks responsible for emotion processing and regulation as other maltreatment types.Moreover, it uniquely affects networks related to self-relevant information and socio-cognitive processes. Furthermore, emotional abuse is associated with an impaired recovery of the neuroendocrine response to acute stress. Similar to other maltreatment types, emotional abuse is associated with epigenetic changes in genes regulating the neuroendocrine stress response system that are implicated in increased mental health risk.These findings suggest that emotional abuse has equally detrimental effects on children'smental health as physical or sexual abuse, warranting broader societal awareness and enhanced early detection efforts. Early interventions should prioritize emotion regulation, social cognition, self-esteemenhancement, and relationship- oriented approaches for victims of emotional abuse.

Brain-Derived Neurotrophic Factor Dysregulation as an Essential Pathological Feature in Huntington's Disease: Mechanisms and Potential Therapeutics.

Brain-derived neurotrophic factor (BDNF) is a major neurotrophin whose loss or interruption is well established to have numerous intersections with the pathogenesis of progressive neurological disorders. There is perhaps no greater example of disease pathogenesis resulting from the dysregulation of BDNF signaling than Huntington's disease (HD)-an inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive impairments associated with basal ganglia dysfunction and the ultimate death of striatal projection neurons. Investigation of the collection of mechanisms leading to BDNF loss in HD highlights this neurotrophin's importance to neuronal viability and calls attention to opportunities for therapeutic interventions. Using electronic database searches of existing and forthcoming research, we constructed a literature review with the overarching goal of exploring the diverse set of molecular events that trigger BDNF dysregulation within HD. We highlighted research that investigated these major mechanisms in preclinical models of HD and connected these studies to those evaluating similar endpoints in human HD subjects. We also included a special focus on the growing body of literature detailing key transcriptomic and epigenetic alterations that affect BDNF abundance in HD. Finally, we offer critical evaluation of proposed neurotrophin-directed therapies and assessed clinical trials seeking to correct BDNF expression in HD individuals.

Appropriate Vestibular Stimulation in Children and Adolescents-A Prerequisite for Normal Cognitive, Motor Development and Bodily Homeostasis-A Review.

The structural development of the vestibular part of the inner ear is completed by birth but its central connections continue to develop until adolescence. Their development is dependent on vestibular stimulation-vestibular experience. Studies have shown that vestibular function, modulated by experience and epigenetic factors, is not solely an instrument for body position regulation, navigation, and stabilization of the head and images but also influences cognition, emotion, the autonomous nervous system and hormones. To emphasize the importance of appropriate vestibular stimulation, we present a literature review of its effect on bodily homeostasis, cognition and emotion.

Paneth cell maturation is related to epigenetic modification during neonatal-weaning transition.

Paneth cells are antimicrobial peptide-secreting epithelial cells located at the bottom of the intestinal crypts of Lieberkühn. The crypts begin to form around postnatal day 7 (P7) mice, and Paneth cells usually appear within the first 2 weeks. Paneth cell dysfunction has been reported to correlate with Crohn's disease-like inflammation, showing narrow crypts or loss of crypt architecture in mice. The morphology of dysfunctional Paneth cells is similar to that of Paneth/goblet intermediate cells. However, it remains unclear whether the formation of the crypt is related to the maturation of Paneth cells. In this study, we investigated the histological changes including epigenetic modification in the mouse ileum postnatally and assessed the effect of the methyltransferase inhibitor on epithelium development using an organoid culture. The morphological and functional maturation of Paneth cells occurred in the first 2 weeks and was accompanied by histone H3 lysine 27 (H3K27) trimethylation, although significant differences in DNA methylation or other histone H3 trimethylation were not observed. Inhibition of H3K27 trimethylation in mouse ileal organoids suppressed crypt formation and Paneth cell maturation, until around P10. Overall, our findings show that post-transcriptional modification of histones, particularly H3K27 trimethylation, leads to the structural and functional maturation of Paneth cells during postnatal development.

[Immune system and allergies-An unholy alliance]. / Immunsystem und Allergien ­ eine unheilige Allianz.

Various factors affect the maturation of the infantile immune system both prenatally and postnatally, including risk and protective factors from the environment, nutrition, genetics and epigenetics. The microbiome seems to play a substantial role. The complex interaction and regulation of all these factors is ultimately decisive for whether a child develops an allergy during the course of development of the immune system. The genetic components play a decisive role in the development of allergic diseases. The epigenetic regulation could represent a mechanism where environmental influences act upon the immune regulation in the emergence of allergic diseases. The main factors in the pathophysiology of allergic reactions are a dysregulation of various cells of the innate and acquired immune systems as well as their interaction. This review describes the role of various T helper cell types in allergic diseases. The incidence and duration of airway infections are clearly increased in allergic patients compared to nonallergic controls. In addition to functional aspects, the reason for the more frequent infections is an impairment of the immune defence by the allergy-related persisting inflammation of the mucous membranes. These mechanisms must be differentiated from a true immunodeficiency. Allergic rhinitis (AR) and bronchial asthma are nowadays no longer defined as separate diseases but as two forms of expression of an atopic entity with a similar pathology. Both diseases can be mediated by immunoglobulin E and be elicited by identical triggers. A bronchial hyperreactivity is detectable in the majority of patients with AR but without clinical asthma.

Contribution of ghrelin to functional gastrointestinal disorders' pathogenesis.

Functional gastrointestinal disorders (FGID) are heterogeneous disorders with a variety of clinical manifestations, primarily defined by signs and symptoms rather than a definite underlying cause. Their pathophysiology remains obscure and, although it is expected to differ according to the specific FGID, disruptions in the brain-gut axis are now thought to be a common denominator in their pathogenesis. The hormone ghrelin is an important component of this axis, exerting a wide repertoire of physiological actions, including regulation of gastrointestinal motility and protection of mucosal tissue. Ghrelin's gene shows genetic polymorphism, while its protein product undergoes complex regulation and metabolism in the human body. Numerous studies have studied ghrelin's relation to the emergence of FGIDs, its potential value as an index of disease severity and as a predictive marker for symptom relief during attempted treatment. Despite the mixed results currently available in scientific literature, the plethora of statistically significant findings shows that disruptions in ghrelin genetics and expression are plausibly related to FGID pathogenesis. The aim of this paper is to review current literature studying these associations, in an effort to uncover certain patterns of alterations in both genetics and expression, which could delineate its true contribution to FGID emergence, either as a causative agent or as a pathogenetic intermediate.

Epigenetic processes in sporadic parathyroid neoplasms.

Parathyroid tumors (PTs) are highly variable in their genetic background. Increasing evidence demonstrates that endocrine diseases can be caused by epigenetic alterations. The present review is focused on epigenetic aberrations related to PTs. DNA methylation, posttranslational histone modification, and noncoding RNAs are epigenetic mechanisms involved in parathyroid tumorigenesis. The information in this review has the potential to define epigenetic signatures associated with PTs for future use as diagnostic markers and lead to the development of new epigenetic drugs with therapeutic applications for these tumors. However, several epigenetic aspects regarding the biomarkers involved and their interactions in tumorigenesis on PTs are still unknown. Key to future epigenetic research would be a focus on global epigenetic identification of biomarkers in the different types of PTs, especially in parathyroid carcinoma. Better understanding may be useful for diagnostic and therapeutic uncertainty.

Modulation of blood pressure in response to low ambient temperature: The role of DNA methylation of zinc finger genes.

BACKGROUND: Blood pressure rises with a drop in external temperature, but the role of DNA methylation in such blood pressure modulation has not been studied in detail. We evaluated blood pressure and DNA methylation of vascular disease-related genes in association with low temperature. METHODS: To examine changes in blood pressure and DNA methylation associated with low temperature, we conducted repeated measures analysis among 50 participants over 3 repeated visits, and validated the association among another 52 participants. In addition, the mean of methylation changes in the identified CpG sites was evaluated with changes in blood pressure. Mediation analyses were also conducted to model the indirect association between low ambient temperature and blood pressure through changes in DNA methylation. RESULTS: With a 1°C decrease in temperature, increases of 0.6mmHg (standard error (SE), 0.2) in SBP and 0.3mmHg (SE, 0.1) in DBP occurred (P<0.05). Of 24,490 CpG sites in vascular genes, 2 CpG sites of zinc finger (ZNF) genes were significantly associated with temperature after Bonferroni's correction in discovery and replication data. A 10% increase in methylation expression in 2 CpG sites in ZNF genes was associated with a 4-mmHg elevation in DBP (SE, 1.8; P=0.0236). The hypermethylation was attributable to the association of ambient temperature with DBP (proportion of mediation=11.8-20.4%). CONCLUSIONS: Methylation changes in ZNF genes might be involved in the elevation of blood pressure when the body is exposed to cold temperature.

ALS and FTD: an epigenetic perspective.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two fatal neurodegenerative diseases seen in comorbidity in up to 50 % of cases. Despite tremendous efforts over the last two decades, no biomarkers or effective therapeutics have been identified to prevent, decelerate, or stop neuronal death in patients. While the identification of multiple mutations in more than two dozen genes elucidated the involvement of several mechanisms in the pathogenesis of both diseases, identifying the hexanucleotide repeat expansion in C9orf72, the most common genetic abnormality in ALS and FTD, opened the door to the discovery of several novel pathogenic biological routes, including chromatin remodeling and transcriptome alteration. Epigenetic processes regulate DNA replication and repair, RNA transcription, and chromatin conformation, which in turn further dictate transcriptional regulation and protein translation. Transcriptional and post-transcriptional epigenetic regulation is mediated by enzymes and chromatin-modifying complexes that control DNA methylation, histone modifications, and RNA editing. While the alteration of DNA methylation and histone modification has recently been reported in ALS and FTD, the assessment of epigenetic involvement in both diseases is still at an early stage, and the involvement of multiple epigenetic players still needs to be evaluated. As the epigenome serves as a way to alter genetic information not only during aging, but also following environmental signals, epigenetic mechanisms might play a central role in initiating ALS and FTD, especially for sporadic cases. Here, we provide a review of what is currently known about altered epigenetic processes in both ALS and FTD and discuss potential therapeutic strategies targeting epigenetic mechanisms. As approximately 85 % of ALS and FTD cases are still genetically unexplained, epigenetic therapeutics explored for other diseases might represent a profitable direction for the field.

[RETRACTED ARTICLE] Culture as a variable in neuroscience and clinical neuropsychology / [ARTIGO RETRATADO] Cultura como variável na neurociência e clínica neuropsicológica: ensaio abrangente para revisão

Culture is a dynamic system of bidirectional influences among individuals and their environment, including psychological and biological processes, which facilitate adaptation and social interaction. One of the main challenges in clinical neuropsychology involves cognitive, behavioral and functional assessment of people with different sociocultural backgrounds. In this review essay, examining culture from a historical perspective to ethical issues in cross-cultural research, including the latest significant and publications, the authors sought to explore the main features related to cultural variables in neuropsychological practice and to debate the challenges found regarding the operational methods currently in use. Literature findings suggest a more comprehensive approach in cognitive and behavioral neuroscience, including an interface between elementary disciplines and applied neuropsychology. Thus, as a basis for discussion on this issue, the authors analyzed key-topics related to the study of new trends in sociocultural neuroscience and the application of their concepts from a clinical perspective.

Cultura é um sistema dinâmico de influencias bidirecionais entre indivíduos e seus ambientes, incluindo processos biológicos e psicológicos que facilitam na adaptação e interação social. Um dos maiores desafíos da clínica neuropsicológica se refere à avaliação cognitiva, comportamental e funcional de pessoas com diferentes contextos socioculturais. Neste ensaio para revisão, traçando uma trajetória partindo de perspectivas históricas até temas éticos em pesquisa transcultural, os autores procuraram explorar os principais achados relacionados a variáveis culturais na prática neuropsicológica, além de debater os desafíos encontrados que estão relacionados com métodos operacionais atualmente utilizados até as mais importantes e atuais publicações sobre o assunto. Achados da literatura sugerem uma abordagem mais apropriada da neurociência cognitiva e comportamental, incluindo a relação entre disciplinas elementares para seu entendimento com a clínica neuropsicológica. Assim, a fim de propor uma discussão sobre este tema, os autores analisaram neste artigo tópicos-chave relacionados ao estudo de novas tendências em neurociência sociocultural e a aplicação de seus conceitos através de uma perspectiva clínica.

Hepatitis D and hepatocellular carcinoma.

Hepatitis D virus (HDV) is a defective circular shape single stranded HDV RNA virus with two types of viral proteins, small and large hepatitis D antigens, surrounded by hepatitis B surface antigen. Superinfection with HDV in chronic hepatitis B is associated with a more threatening form of liver disease leading to rapid progression to cirrhosis. In spite of some controversy in the epidemiological studies, HDV infection does increase the risk of hepatocellular carcinoma (HCC) compared to hepatitis B virus (HBV) monoinfection. Hepatic decompensation, rather than development of HCC, is the first usual clinical endpoint during the course of HDV infection. Oxidative stress as a result of severe necroinflammation may progress to HCC. The large hepatitis D antigen is a regulator of various cellular functions and an activator of signal transducer and activator of transcription (STAT)3 and the nuclear factor kappa B pathway. Another proposed epigenetic mechanism by which HCC may form is the aberrant silencing of tumor suppressor genes by DNA Methyltransferases. HDV antigens have also been associated with increased histone H3 acetylation of the clusterin promoter. This enhances the expression of clusterin in infected cells, increasing cell survival potential. Any contribution of HBV DNA integration with chromosomes of infected hepatocytes is not clear at this stage. The targeted inhibition of STAT3 and cyclophilin, and augmentation of peroxisome proliferator-activated receptor γ have a potential therapeutic role in HCC.

Culture as a variable in neuroscience and clinical neuropsychology: A comprehensive review.

Culture is a dynamic system of bidirectional influences among individuals and their environment, including psychological and biological processes, which facilitate adaptation and social interaction. One of the main challenges in clinical neuropsychology involves cognitive, behavioral and functional assessment of people with different sociocultural backgrounds. In this review essay, examining culture from a historical perspective to ethical issues in cross-cultural research, including the latest significant and publications, the authors sought to explore the main features related to cultural variables in neuropsychological practice and to debate the challenges found regarding the operational methods currently in use. Literature findings suggest a more comprehensive approach in cognitive and behavioral neuroscience, including an interface between elementary disciplines and applied neuropsychology. Thus, as a basis for discussion on this issue, the authors analyzed key-topics related to the study of new trends in sociocultural neuroscience and the application of their concepts from a clinical perspective.

Cultura é um sistema dinâmico de influencias bidirecionais entre indivíduos e seus ambientes, incluindo processos biológicos e psicológicos que facilitam na adaptação e interação social. Um dos maiores desafíos da clínica neuropsicológica se refere à avaliação cognitiva, comportamental e funcional de pessoas com diferentes contextos socioculturais. Neste ensaio para revisão, traçando uma trajetória partindo de perspectivas históricas até temas éticos em pesquisa transcultural, os autores procuraram explorar os principais achados relacionados a variáveis culturais na prática neuropsicológica, além de debater os desafíos encontrados que estão relacionados com métodos operacionais atualmente utilizados até as mais importantes e atuais publicações sobre o assunto. Achados da literatura sugerem uma abordagem mais apropriada da neurociência cognitiva e comportamental, incluindo a relação entre disciplinas elementares para seu entendimento com a clínica neuropsicológica. Assim, a fim de propor uma discussão sobre este tema, os autores analisaram neste artigo tópicos-chave relacionados ao estudo de novas tendências em neurociência sociocultural e a aplicação de seus conceitos através de uma perspectiva clínica.

Epigenética: definición, bases moleculares e implicaciones en la salud y en la evolución humana / Epigenetics: definition, molecular bases and implications in human health and evolution / Epigenética: definição, bases moleculares e implicações na saúde e na evolução humana

La Epigenética se refiere a los cambios heredables en el ADN e histonas que no implican altera ciones en la secuencia de nucleótidos y modifican la estructura y condensación de la cromatina por lo que afectan la expresión génica y el fenotipo. Las modificaciones epigenéticas son metilación del ADN y modificaciones de histonas. Objetivo: hacer una revisión de la literatura sobre e concepto de epigenética y su impacto en la salud. Materiales y métodos: se realizó una revisión de la bibliografía sobre el concepto de epigenética, sus bases biológicas, el impacto sobre la salud y la enfermedad y su relación con la evolución. Resultados: los mecanismos epigenéticos ha cobrado cada vez más importancia debido a la creciente asociación con enfermedades compleja y comunes, así como por su impacto en la salud de generaciones futuras y en la evolución humana. Conclusiones: la Epigenética tiene un claro impacto en la salud del individuo, en la de su descendencia y en la evolución de la especie humana.

Epigenetics refers to inheritable changes in DNA and histones that do not involve changes in the sequence of nucleotides and that modifies structure and chromatin condensation, thus affecting gene expression and phenotype. Epigenetic modifications are DNA methylation and histone modifications. Objective: A review of the literature on the concept of Epigenetics and its impact on health. Materials and methods: A review of the literature was performed on the concept of epigenetics, its biological basis, the impact on health and disease and its relation to evolution. Results: Epigenetic mechanisms have become increasingly important because of the growing association with common complex diseases as well as its impact on health of future generations and in human evolution. Conclusions: Epigenetics has a clear impact on the health of individuals in their offspring and with the evolution of the human species.

A Epigenética refere-se às mudanças hereditárias no ADN e histonas que não implicam alterações nas sequencia de nucleotídeos e modificam a estrutura e condensação da cromatina, pelo que afetam a expressão gênica e o fenótipo. As modificações epigenéticas são metilação do ADN e modificações de histonas. Objetivo: fazer uma revisão da literatura sobre o conceito de epigenética e seu impacto na saúde. Materiais e métodos: realizou-se uma revisão da bibliografia sobre o conceito de epigenética, suas bases biológicas, o impacto sobre a saúde e a doença e sua relação com a evolução. Resultados: os mecanismos epigenéticos têm adquirido cada vez mais importância devido à crescente associação com doenças complexas e comunes, assim como por seu impacto na saúde de gerações futuras e na evolução humana. Conclusões: a Epigenética tem um impacto evidente na saúde do individuo, na sua descendência e na evolução da espécie humana.

Mallory-Denk body pathogenesis revisited.

This editorial reviews the recent evidence showing that Mallory-Denk bodies (MDBs) form in hepatocytes as the result of a drug-induced shift from the 26s proteasome formation to the immunoproteasome formation. The shift is the result of changes in gene expression induced in promoter activation, which is induced by the IFNγ and TNFα signaling pathway. This activates TLR 2 and 4 receptors. The TLR signaling pathway stimulates both the induction of a cytokine proinflammatory response and an up regulation of growth factors. The MDB- forming hepatocytes proliferate as a result of the increase in growth factor expression by the MDB- forming cells, which selectively proliferate in response to drug toxicity. All of these mechanisms are induced by drug toxicity, and are prevented by feeding the methyl donors SAMe and betaine, supporting the epigenetic response of MDB formation.

Animal models of autism: an epigenetic and environmental viewpoint.

Autism is a neurodevelopmental disorder of social behavior, which is more common in males than in females. The causes of autism are unknown; there is evidence for a substantial genetic component, but it is likely that a combination of genetic, environmental and epigenetic factors contribute to its complex pathogenesis. Rodent models that mimic the behavioral deficits of autism can be useful tools for dissecting both the etiology and molecular mechanisms. This review discusses animal models of autism generated by prenatal or neonatal environmental challenges, including virus infection and exposure to valproic acid (VPA) or stress. Studies of viral infection models suggest that interleukin-6 can influence fetal development and programming. Prenatal exposure to the histone deacetylase inhibitor VPA has been linked to autism in children, and male VPA-exposed rats exhibit a spectrum of autistic-like behaviors. The experience of prenatal stress produces male-specific behavioral abnormalities in rats. These effects may be mediated by epigenetic modifications such as DNA methylation and histone acetylation resulting in alterations to the transcriptome.