10,502 research outputs found
Unraveling molecular pathways shared by Kabuki and Kabuki‐like syndromes
No full textKabuki syndrome (KS) is a rare genetic syndrome characterized by a typical facial gestalt, variable degrees of intellectual disability, organ malformations, postnatal growth retardation and skeletal abnormalities. So far, KMT2D or KDM6A mutation has been identified as the main cause of KS, accounting for 56%-75% and 3%-8% of cases, respectively. Patients without mutations in 1 of the 2 causative KS genes are often referred to as affected by Kabuki-like syndrome. Overall, they represent approximately 30% of KS cases, pointing toward substantial genetic heterogeneity for this condition. Here, we review all currently available literature describing KS-like phenotypes (or phenocopies) associated with genetic variants located in loci different from KMT2D and KDM6A . We also report on a new KS phenocopy harboring a 5 Mb de novo deletion in chr10p11.22-11.21. An enrichment analysis aimed at identifying functional Gene Ontology classes shared by the 2 known KS causative genes and by new candidate genes currently associated with KS-like phenotypes primarily converges upon abnormal chromatin remodeling and transcriptional dysregulation as pivotal to the pathophysiology of KS phenotypic hallmarks. The identification of mutations in genes belonging to the same functional pathways of KMT2D and KDM6A can help design molecular screenings targeted to KS-like phenotypes
Autistic phenotypes and genetic testing: State-of-the-art for the clinical geneticist
No full textAutism spectrum disorders represent a group of developmental disorders with strong genetic underpinnings. Several cytogenetic abnormalities or de novo mutations able to cause autism have recently been uncovered. In this study, the literature was reviewed to highlight genotype–phenotype correlations between causal gene mutations or cytogenetic abnormalities and behavioural or morphological phenotypes. Based on this information, a set of practical guidelines is proposed to help clinical geneticists pursue targeted genetic testing for patients with autism whose clinical phenotype is suggestive of a specific genetic or genomic aetiology
Altered mesolimbic dopamine system in THC dependence
No full textTo explore the functional consequences of cannabinoid withdrawal in the rat mesolimbic dopamine system, we investigated the anatomical morphology of the mesencephalic, presumed dopaminergic, neurons and their main post-synaptic target in the Nucleus Accumbens. We found that TH-positive neurons shrink and Golgi-stained medium spiny neurons loose dendritic spines in withdrawal rats after chronic cannabinoids administration. Similar results were observed after administration of the cannabinoid antagonist rimonabant to drug-naïve rats supporting a role for endocannabinoids in neurogenesis, axonal growth and synaptogenesis. This evidence supports the tenet that withdrawal from addictive compounds alters functioning of the mesolimbic system. The data add to a growing body of work which indicates a hypodopaminergic state as a distinctive feature of the "addicted brain"
Addiction and cognitive functions
No full textDrug addiction is a compulsive behavioral abnormality. In spite of pharmacologic and psychosocial treatments to reduce or eliminate drug taking, addiction tends to persist over time. Preclinical and human observations have converged on the hypothesis that addiction represents the pathologic deterioration of neural processes that normally serve affective and cognitive functioning. The major elements of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie enduring changes in a number of forebrain circuits (involving the ventral striatum and prefrontal cortex) that receive input from midbrain dopamine neurons and are involved in affective and cognitive mechanisms, respectively. Here we review progress in identifying crucial elements useful in understanding the pathophysiology of the disease and its pharmacologic treatment. Pharmacologic targeting of K-opiate receptors, with their discrete distribution within the dopaminergic system(s), and thus different actions on dopaminoceptive areas, may provide beneficial effects at the affective and cognitive level
Measurement of arylesterase enzymatic activity and assessment of genetic polymorphisms located in the PON1 gene as a diagnostic tool in autism-spectrum disorders
No full textThe present invention concerns a method for detecting the presence of or predisposition to autism, an autism spectrum disorder, or an autism-associated disorder in a subject, the method comprising measuring an arylesterase enzymatic activity in a sample from the subject, optionally combined with the determination of alleles of PON1 polymorphisms
Nicotine-induced increase of dopaminergic mesoaccumbal neuron activity is prevented by acute restraint stress. In vivo electrophysiology in rats
No full textDecision models in the evaluation of psychotropic drugs. Useful tool or useless toy?
No full textA current contribution in the European Journal of Health Economics employs a decision model to compare health care costs of olanzapine and risperidone treatment for schizophrenia. The model suggests that a treatment strategy of first-line olanzapine is cost-saving over a 1-year period, with additional clinical benefits in the form of avoided relapses in the long-term. From a clinical perspective this finding is indubitably relevant, but can physicians and policy makers believe it? The study is presented in a balanced way, assumptions are based on data extracted from clinical trials published in major psychiatric journals, and the theoretical underpinnings of the model are reasonable. Despite these positive aspects, we believe that the methodology used in this study-the decision model approach-is an unsuitable and potentially misleading tool for evaluating psychotropic drugs. In this commentary, taking the olanzapine vs. risperidone model as an example, arguments are provided to support this statement. © 2006 Springer Medizin Verlag
2. TIME-DEPENDENT MORPHOLOGICAL AND ELECTROPHYSIOLOGICAL CHANGES DURING OPIATE WITHDRAWAL IN ACCUMBAL MEDIUM SPINY NEURONS.
No full textAltered architecture and functional consequences of the mesolimbic dopamine system in cannabis dependence
No full textCannabinoid withdrawal produces a hypofunction of mesencephalic dopamine neurons that impinge upon medium spiny neurons (MSN) of the forebrain. After chronic treatment with two structurally different cannabinoid agonists, Delta(9)-tetrahydrocannabinol and CP55 940 (CP) rats were withdrawn spontaneously and pharmacologically with the CB1 antagonist SR141716A (SR). In these two conditions, evaluation of tyrosine hydroxylase (TH)-positive neurons revealed significant morphometrical reductions in the ventrotegmental area but not substantia nigra pars compacta of withdrawn rats. Similarly, confocal analysis of Golgi-Cox-stained sections of the nucleus accumbens revealed a decrease in the shell, but not the core, of the spines' density of withdrawn rats. Administration of the CB1 antagonist SR to control rats, provoked structural abnormalities reminiscent of those observed in withdrawal conditions and support the regulatory role of cannabinoids in neurogenesis, axonal growth and synaptogenesis by acting as eu-proliferative signals through the CB1 receptors. Further, these measures were incorporated into a realistic computational model that predicts a strong reduction in the excitability of morphologically altered MSN, yielding a significant reduction in action potential output. These pieces of evidence support the tenet that withdrawal from addictive compounds alters functioning of the mesolimbic system and provide direct morphological evidence for functional abnormalities associated with cannabinoid dependence at the level of dopaminergic neurons and their postsynaptic counterpart and are coherent with recent hypothesis underscoring a hypodopaminergic state as a distinctive feature of the 'addicted brain'
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