Effect of maternal panic disorder on mother-child interaction and relation to child anxiety and child self-efficacy

To determine whether mothers with panic disorder with or without agoraphobia interacted differently with their children than normal control mothers, 86 mothers and their adolescents (aged between 13 and 23 years) were observed during a structured play situation. Maternal as well as adolescent anxiety status was assessed according to a structured diagnostic interview. Results showed that mothers with panic disorder/agoraphobia showed more verbal control, were more criticizing and less sensitive during mother-child interaction than mothers without current mental disorders. Moreover, more conflicts were observed between mother and child dyadic interactions when the mother suffered from panic disorder. The comparison of parenting behaviors among anxious and non-anxious children did not reveal any significant differences. These findings support an association between parental over-control and rejection and maternal but not child anxiety and suggest that particularly mother anxiety status is an important determinant of parenting behavior. Finally, an association was found between children’s perceived self-efficacy, parental control and child anxiety symptoms

iPSCs-Based Neural 3D Systems: A Multidimensional Approach for Disease Modeling and Drug Discovery

Induced pluripotent stem cells (iPSCs)-based two-dimensional (2D) protocols have offered invaluable insights into the pathophysiology of neurological diseases. However, these systems are unable to reproduce complex cytoarchitectural features, cell-cell and tissue-tissue interactions like their in vivo counterpart. Three-dimensional (3D)-based culture protocols, though in their infancy, have offered new insights into modeling human diseases. Human neural organoids try to recapitulate the cellular diversity of complex tissues and can be generated from iPSCs to model the pathophysiology of a wide spectrum of pathologies. The engraftment of iPSCs into mice models and the improvement of differentiation protocols towards 3D cultures has enabled the generation of more complex multicellular systems. Consequently, models of neuropsychiatric disorders, infectious diseases, brain cancer and cerebral hypoxic injury can now be investigated from new perspectives. In this review, we consider the advancements made in modeling neuropsychiatric and neurological diseases with iPSC-derived organoids and their potential use to develop new drugs

Don't tax me? : Determinants of individual attitudes toward progressive taxation

This contribution empirically analyses the individual determinants of tax rate preferences. For that purpose we make use of the representative German General Social Survey (ALLBUS) that offers data on the individual attitudes toward progressive, proportional, and regressive taxation. Our theoretical considerations suggest that beyond self-interest, information, fairness considerations, economic beliefs and several other individual factors drive individual preferences for tax rate structures. Our empirical results indicate that the self-interest view does not offer the sole explanation for the heterogeneity in attitudes toward progressive taxation. Rather, we show that the choice of the favoured tax rate is also driven by fairness considerations

Long-Term Effects of the Periconception Period on Embryo Epigenetic Profile and Phenotype: The Role of Stress and How This Effect Is Mediated

Stress represents an unavoidable aspect of human life, and pathologies associated with dysregulation of stress mechanisms - particularly psychiatric disorders - represent a significant global health problem. While it has long been observed that levels of stress experienced in the periconception period may greatly affect the offspring's risk of psychiatric disorders, the mechanisms underlying these associations are not yet comprehensively understood. In order to address this question, this chapter will take a 'top-down' approach, by first defining stress and associated concepts, before exploring the mechanistic basis of the stress response in the form of the hypothalamic-pituitary-adrenal (HPA) axis, and how dysregulation of the HPA axis can impede our mental and physical health, primarily via imbalances in glucocorticoids (GCs) and their corresponding receptors (GRs) in the brain. The current extent of knowledge pertaining to the impact of stress on developmental programming and epigenetic inheritance is then extensively discussed, including the role of chromatin remodelling associated with specific HPA axis-related genes and the possible role of regulatory RNAs as messengers of environmental stress both in the intrauterine environment and across the germ line. Furthering our understanding of the role of stress on embryonic development is crucial if we are to increase our predictive power of disease risk and devise-effective treatments and intervention strategies

iPSC-Based Models to Unravel Key Pathogenetic Processes Underlying Motor Neuron Disease Development

Motor neuron diseases (MNDs) are neuromuscular disorders affecting rather exclusively upper motor neurons (UMNs) and/or lower motor neurons (LMNs). The clinical phenotype is characterized by muscular weakness and atrophy leading to paralysis and almost invariably death due to respiratory failure. Adult MNDs include sporadic and familial amyotrophic lateral sclerosis (sALS-fALS), while the most common infantile MND is represented by spinal muscular atrophy (SMA). No effective treatment is ccurrently available for MNDs, as for the vast majority of neurodegenerative disorders, and cures are limited to supportive care and symptom relief. The lack of a deep understanding of MND pathogenesis accounts for the difficulties in finding a cure, together with the scarcity of reliable in vitro models. Recent progresses in stem cell field, in particular in the generation of induced Pluripotent Stem Cells (iPSCs) has made possible for the first time obtaining substantial amounts of human cells to recapitulate in vitro some of the key pathogenetic processes underlying MNDs. In the present review, recently published studies involving the use of iPSCs to unravel aspects of ALS and SMA pathogenesis are discussed with an overview of their implications in the process of finding a cure for these still orphan disorders

Ophthalmoplegia due to Miller Fisher syndrome in a patient with myasthenia gravis

Here, we describe a 79-year-old man, admitted to our unit for worsening diplopia and fatigue, started a few weeks after an episode of bronchitis and flu vaccination. Past medical history includes myasthenia gravis (MG), well-controlled by Pyridostigmine, Azathioprine, and Prednisone. During the first days, the patient developed progressive ocular movement abnormalities up to complete external ophthalmoplegia, severe limb and gait ataxia, and mild dysarthria. Deep tendon reflexes were absent in lower limbs. Since not all the symptoms were explainable with the previous diagnosis of myasthenia gravis, other etiologies were investigated. Brain MRI and cerebrospinal fluid analysis were normal. Electromyography showed a pattern of predominantly sensory multiple radiculoneuritis. Suspecting Miller Fisher syndrome (MFS), the patient was treated with plasmapheresis with subsequent clinical improvement. Antibodies against GQ1b turned out to be positive. MFS is an immune-mediated neuropathy presenting with ophthalmoplegia, ataxia, and areflexia. Even if only a few cases of MFS overlapping with MG have been described so far, the coexistence of two different autoimmune disorders can occur. It is always important to evaluate possible differential diagnosis even in case of known compatible diseases, especially when some clinical features seem atypical

C. elegans expressing D76N β2-microglobulin: a model for in vivo screening of drug candidates targeting amyloidosis

The availability of a genetic model organism with which to study key molecular events underlying amyloidogenesis is crucial for elucidating the mechanism of the disease and the exploration of new therapeutic avenues. The natural human variant of β2-microglobulin (D76N β2-m) is associated with a fatal familial form of systemic amyloidosis. Hitherto, no animal model has been available for studying in vivo the pathogenicity of this protein. We have established a transgenic C. elegans line, expressing the human D76N β2-m variant. Using the INVertebrate Automated Phenotyping Platform (INVAPP) and the algorithm Paragon, we were able to detect growth and motility impairment in D76N β2-m expressing worms. We also demonstrated the specificity of the β2-m variant in determining the pathological phenotype by rescuing the wild type phenotype when β2-m expression was inhibited by RNA interference (RNAi). Using this model, we have confirmed the efficacy of doxycycline, an inhibitor of the aggregation of amyloidogenic proteins, in rescuing the phenotype. In future, this C. elegans model, in conjunction with the INVAPP/Paragon system, offers the prospect of high-throughput chemical screening in the search for new drug candidates

Sodium Levels Predict Disability at Discharge in Guillain-Barré Syndrome: A Retrospective Cohort Study

Guillain-Barré syndrome (GBS) is an inflammatory polyradiculopathy with potentially severe complications. Clinical tools for risk stratification have been developed, but no definitive prognostic biomarker has been reported. Hyponatremia is frequent in GBS patients, but the impact of serum sodium levels on clinical outcomes is still ill-defined. In this retrospective cohort study, we included all adult patients diagnosed with GBS spectrum disorders at our center from January 2010 to July 2020. Disability at discharge was assessed with the GBS Disability Score (GDS), and all clinical and laboratory data was retrieved from medical charts. Thirty (58.8%) of the 51 subjects included in the study were discharged with severe residual disability (GDS ≥ 3). After accounting for relevant confounders, the odds of experiencing severe disability decreased by 27% (p = 0.027) for each unitary increase in serum sodium concentration. Thirteen (25.5%) patients were diagnosed with mild to moderate hyponatremia; the use of intravenous immune globulin (IVIG) independently increased the odds of developing hyponatremia. In conclusion, we found a significant, independent association between baseline serum sodium levels and severe disability at discharge in GBS patients. In our cohort, hyponatremia was more frequently observed after treatment with IVIG, suggesting dilutional pseudohyponatremia as a probable cause

Motor neuron derivation from human embryonic and induced pluripotent stem cells: experimental approaches and clinical perspectives

Motor neurons are cells located in specific areas of the central nervous system, such as brain cortex (upper motor neurons), brain stem, and spinal cord (lower motor neurons), which maintain control over voluntary actions. Motor neurons are affected primarily by a wide spectrum of neurological disorders, generally indicated as motor neuron diseases (MNDs): these disorders share symptoms related to muscular atrophy and paralysis leading to death. No effective treatments are currently available. Stem cell-derived motor neurons represent a promising research tool in disease modeling, drug screening, and development of therapeutic approaches for MNDs and spinal cord injuries. Directed differentiation of human pluripotent stem cells - human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) - toward specific lineages is the first crucial step in order to extensively employ these cells in early human development investigation and potential clinical applications. Induced pluripotent stem cells (iPSCs) can be generated from patients' own somatic cells (for example, fibroblasts) by reprogramming them with specific factors. They can be considered embryonic stem cell-like cells, which express stem cell markers and have the ability to give rise to all three germ layers, bypassing the ethical concerns. Thus, hiPSCs constitute an appealing alternative source of motor neurons. These motor neurons might be a great research tool, creating a model for investigating the cellular and molecular interactions underlying early human brain development and pathologies during neurodegeneration. Patient-specific iPSCs may also provide the premises for autologous cell replacement therapies without related risks of immune rejection. Here, we review the most recent reported methods by which hESCs or iPSCs can be differentiated toward functional motor neurons with an overview on the potential clinical applications

Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.

To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID-associated genes using targeted next-generation sequencing. Likely pathogenic rare variants were found in ∼11% of the cases (113 variants in 107/986 individuals: ∼8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ∼3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%-15% yield from array CGH alone.Action Medical Research (SP4640); the Birth Defect Foundation (RG45448); the Cambridge National Institute for Health Research Biomedical Research Centre (RG64219); the NIHR Rare Diseases BioResource (RBAG163); Wellcome Trust award WT091310; The Cell lines and DNA bank of Rett Syndrome, X-linked mental retardation and other genetic diseases (member of the Telethon Network of Genetic Biobanks (project no. GTB12001); the Genetic Origins of Congenital Heart Disease Study (GO-CHD)- funded by British Heart Foundation (BHF)This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/humu.2290