-
The Lancet. Psychiatry Aug 2016Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward... (Review)
Review
Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction.
Topics: Brain; Humans; Neural Pathways; Neurobiology; Substance-Related Disorders
PubMed: 27475769
DOI: 10.1016/S2215-0366(16)00104-8 -
Handbook of Clinical Neurology 2018More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome.... (Review)
Review
More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome. Expanded trinucleotide repeat diseases were discovered first and remain the most frequent. More recently tetra-, penta-, hexa-, and even dodeca-nucleotide repeat expansions have been identified as the cause of human disease, including some of the most common genetic disorders seen by neurologists. Repeat expansion diseases include both causes of myotonic dystrophy (DM1 and DM2), the most common genetic cause of amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72), Huntington disease, and eight other polyglutamine disorders, including the most common forms of dominantly inherited ataxia, the most common recessive ataxia (Friedreich ataxia), and the most common heritable mental retardation (fragile X syndrome). Here I review distinctive features of this group of diseases that stem from the unusual, dynamic nature of the underlying mutations. These features include marked clinical heterogeneity and the phenomenon of clinical anticipation. I then discuss the diverse molecular mechanisms driving disease pathogenesis, which vary depending on the repeat sequence, size, and location within the disease gene, and whether the repeat is translated into protein. I conclude with a brief clinical and genetic description of individual repeat expansion diseases that are most relevant to neurologists.
Topics: Humans; Nervous System Diseases; Repetitive Sequences, Nucleic Acid
PubMed: 29325606
DOI: 10.1016/B978-0-444-63233-3.00009-9 -
International Journal of Environmental... Jul 2021Increasing numbers of women are undergoing oocyte or tissue cryopreservation for medical or social reasons to increase their chances of having genetic children. Social... (Review)
Review
Increasing numbers of women are undergoing oocyte or tissue cryopreservation for medical or social reasons to increase their chances of having genetic children. Social egg freezing (SEF) allows women to preserve their fertility in anticipation of age-related fertility decline and ineffective fertility treatments at older ages. The purpose of this study was to summarize recent findings focusing on the challenges of elective egg freezing. We performed a systematic literature review on social egg freezing published during the last ten years. From the systematically screened literature, we identified and analyzed five main topics of interest during the last decade: (a) different fertility preservation techniques, (b) safety of freezing, (c) usage rate of frozen oocytes, (d) ethical considerations, and (e) cost-effectiveness of SEF. Fertility can be preserved for non-medical reasons through oocyte, embryos, or ovarian tissue cryopreservation, with oocyte vitrification being a new and optimal approach. Elective oocyte cryopreservation is better accepted, supports social gender equality, and enhances women's reproductive autonomy. Despite controversies, planned oocyte cryopreservation appears as a chosen strategy against age-related infertility and may allow women to feel that they are more socially, psychologically, and financially stable before motherhood.
Topics: Aged; Child; Cryopreservation; Female; Fertility; Fertility Preservation; Humans; Middle Aged; Oocytes; Reproductive Techniques, Assisted
PubMed: 34360381
DOI: 10.3390/ijerph18158088 -
Texas Heart Institute Journal 2013Mitochondrial disease is a heterogeneous group of multisystemic diseases that develop consequent to mutations in nuclear or mitochondrial DNA. The prevalence of... (Review)
Review
Mitochondrial disease is a heterogeneous group of multisystemic diseases that develop consequent to mutations in nuclear or mitochondrial DNA. The prevalence of inherited mitochondrial disease has been estimated to be greater than 1 in 5,000 births; however, the diagnosis and treatment of this disease are not taught in most adult-cardiology curricula. Because mitochondrial diseases often occur as a syndrome with resultant multiorgan dysfunction, they might not immediately appear to be specific to the cardiovascular system. Mitochondrial cardiomyopathy can be described as a myocardial condition characterized by abnormal heart-muscle structure, function, or both, secondary to genetic defects involving the mitochondrial respiratory chain, in the absence of concomitant coronary artery disease, hypertension, valvular disease, or congenital heart disease. The typical cardiac manifestations of mitochondrial disease--hypertrophic and dilated cardiomyopathy, arrhythmias, left ventricular myocardial noncompaction, and heart failure--can worsen acutely during a metabolic crisis. The optimal management of mitochondrial disease necessitates the involvement of a multidisciplinary team, careful evaluations of patients, and the anticipation of iatrogenic and noniatrogenic complications. In this review, we describe the complex pathophysiology of mitochondrial disease and its clinical features. We focus on current practice in the diagnosis and treatment of patients with mitochondrial cardiomyopathy, including optimal therapeutic management and long-term monitoring. We hope that this information will serve as a guide for practicing cardiologists who treat patients thus affected.
Topics: Animals; Cardiomyopathies; DNA, Mitochondrial; Energy Metabolism; Genetic Predisposition to Disease; Humans; Mitochondria, Heart; Mitochondrial Diseases; Phenotype; Predictive Value of Tests; Risk Factors; Treatment Outcome
PubMed: 24082366
DOI: No ID Found -
Neuropsychopharmacologia Hungarica : a... Sep 2020The incidence of borderline personality disorder (BPD) in psychiatric care has shown growing tendencies. Despite its frequency, it is an underdiagnosed disease. Profound... (Review)
Review
The incidence of borderline personality disorder (BPD) in psychiatric care has shown growing tendencies. Despite its frequency, it is an underdiagnosed disease. Profound knowledge of etiological factors of BPD is essential for the proper diagnosis and treatment. The present study aims to provide a developmental psychopathological analysis of borderline personality disorder, which includes a thorough review of genetic and environmental etiological factors, an introduction to the functionalist approach of evolutionary perspective, and an overview of age specific characteristics of borderline symptoms. Recent research suggests that in addition to neurobiological and psychosocial factors, genetic vulnerability may be responsible for the development of BPD. Psychosocial background includes childhood trauma, maternal mental illness, maladaptive parenting styles and dysfunctional parent-child relationship, all of which are recognized as contributing factors to the development of insecure or disorganized attachment styles in the infant. Regarding the neurobiological background, changes in the hypothalamic-pituitary-adrenal axis, neurotransmission, endogenous opioid system, and neuroplasticity play a prominent role, the development of which is also affected by childhood traumatic events. Brain imaging studies reveal differences in the limbic system (hippocampus, amygdala) and frontal cortex, which are also involved in stress response, cognition, memory function, and emotion regulation. Early developmental processes may also play an important role in the development of the disorder, as depression during pregnancy or increased stress affects the quality of maternal care and may also affect gene expression through epigenetic mechanisms. With respect to the gene-environment interaction, the interaction of the child's impulsive traits and the invalidating family environment can be highlighted, which can lead to disruption of emotion regulation. The persistence of BPD symptoms is supported by the evolutionary approach concerning several aspects. Fear of abandonment can be explained by the anticipation of exclusion and maladaptive attempts to avoid it. Developmental psychopathological analysis contributes to the development of effective prevention and intervention tools through a better understanding of the background of borderline personality disorder. In terms of prognosis, as a result of effective treatments, symptoms can be reduced, so improvement can be achieved in a large proportion of patients.
Topics: Borderline Personality Disorder; Female; Humans; Hypothalamo-Hypophyseal System; Impulsive Behavior; Pituitary-Adrenal System; Pregnancy; Psychopathology
PubMed: 33055291
DOI: No ID Found -
Pharmacological Reviews Jan 2021Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication,... (Review)
Review
Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) and three domains of dysfunction (incentive salience/pathologic habits, negative emotional states, and executive function, respectively) via changes in the basal ganglia, extended amygdala/habenula, and frontal cortex, respectively. This review focuses on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the addiction cycle. Hyperkatifeia provides an additional source of motivation for compulsive drug seeking via negative reinforcement. Negative reinforcement reflects an increase in the probability of a response to remove an aversive stimulus or drug seeking to remove hyperkatifeia that is augmented by genetic/epigenetic vulnerability, environmental trauma, and psychiatric comorbidity. Neurobiological targets for hyperkatifeia in addiction involve neurocircuitry of the extended amygdala and its connections via within-system neuroadaptations in dopamine, enkephalin/endorphin opioid peptide, and γ-aminobutyric acid/glutamate systems and between-system neuroadaptations in prostress corticotropin-releasing factor, norepinephrine, glucocorticoid, dynorphin, hypocretin, and neuroimmune systems and antistress neuropeptide Y, nociceptin, endocannabinoid, and oxytocin systems. Such neurochemical/neurocircuitry dysregulations are hypothesized to mediate a negative hedonic set point that gradually gains allostatic load and shifts from a homeostatic hedonic state to an allostatic hedonic state. Based on preclinical studies and translational studies to date, medications and behavioral therapies that reset brain stress, antistress, and emotional pain systems and return them to homeostasis would be promising new targets for medication development. SIGNIFICANCE STATEMENT: The focus of this review is on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the drug addiction cycle and a driving force for negative reinforcement in addiction. Medications and behavioral therapies that reverse hyperkatifeia by resetting brain stress, antistress, and emotional pain systems and returning them to homeostasis would be promising new targets for medication development.
Topics: Drug Development; Humans; Motivation; Reinforcement, Psychology; Reward; Substance-Related Disorders
PubMed: 33318153
DOI: 10.1124/pharmrev.120.000083 -
The New England Journal of Medicine Jun 2023Telomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is...
BACKGROUND
Telomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is advantageous is poorly understood.
METHODS
We examined the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related gene and noncarrier relatives.
RESULTS
A total of 17 mutation carriers and 21 noncarrier relatives were initially included in the study, and a validation cohort of 6 additional mutation carriers was subsequently recruited. A majority of the mutation carriers with telomere length evaluated (9 of 13) had long telomeres (>99th percentile). mutation carriers had a range of benign and malignant neoplasms involving epithelial, mesenchymal, and neuronal tissues in addition to B- and T-cell lymphoma and myeloid cancers. Five of 18 mutation carriers (28%) had T-cell clonality, and 8 of 12 (67%) had clonal hematopoiesis of indeterminate potential. A predisposition to clonal hematopoiesis had an autosomal dominant pattern of inheritance, as well as penetrance that increased with age; somatic and hotspot mutations were common. These and other somatic driver mutations probably arose in the first decades of life, and their lineages secondarily accumulated a higher mutation burden characterized by a clocklike signature. Successive generations showed genetic anticipation (i.e., an increasingly early onset of disease). In contrast to noncarrier relatives, who had the typical telomere shortening with age, mutation carriers maintained telomere length over the course of 2 years.
CONCLUSIONS
mutations associated with long telomere length conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms. The risk of these phenotypes was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. (Funded by the National Institutes of Health and others.).
Topics: Humans; Aging; Clonal Hematopoiesis; Heterozygote; Loss of Function Mutation; Mutation; Neoplasms; Shelterin Complex; Syndrome; Telomere; Telomere Homeostasis; Telomere-Binding Proteins
PubMed: 37140166
DOI: 10.1056/NEJMoa2300503 -
American Journal of Human Genetics May 2021Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent... (Review)
Review
Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent manner. The expansion of repeat length across generations is a well-established process that results in human disorders mainly affecting the central nervous system. At least 50 disorders associated with expansion loci have been described to date, with half recognized only in the last ten years, as prior methodological difficulties limited their identification. These limitations still apply to the current widely used molecular diagnostic methods (exome or gene panels) and thus result in missed diagnosis detrimental to affected individuals and their families, especially for disorders that are very rare and/or clinically not recognizable. Most of these disorders have been identified through family-driven approaches and many others likely remain to be identified. The recent development of long-read technologies provides a unique opportunity to systematically investigate the contribution of tandem repeats and repeat expansions to the genetic architecture of human disorders. In this review, we summarize the current and most recent knowledge about the genetics of repeat expansion disorders and the diversity of their pathophysiological mechanisms and outline the perspectives of developing personalized treatments in the future.
Topics: Anticipation, Genetic; Biomedical Research; Founder Effect; Genes, Dominant; Genes, Recessive; Genome, Human; Humans; Time Factors; Trinucleotide Repeat Expansion
PubMed: 33811808
DOI: 10.1016/j.ajhg.2021.03.011 -
Stress (Amsterdam, Netherlands) 2015This manuscript summarizes the proceedings of the symposium entitled, "Stress, Palatable Food and Reward", that was chaired by Drs. Linda Rinaman and Yvonne Ulrich-Lai... (Review)
Review
This manuscript summarizes the proceedings of the symposium entitled, "Stress, Palatable Food and Reward", that was chaired by Drs. Linda Rinaman and Yvonne Ulrich-Lai at the 2014 Neurobiology of Stress Workshop held in Cincinnati, OH. This symposium comprised research presentations by four neuroscientists whose work focuses on the biological bases for complex interactions among stress, food intake and emotion. First, Dr Ulrich-Lai describes her rodent research exploring mechanisms by which the rewarding properties of sweet palatable foods confer stress relief. Second, Dr Stephanie Fulton discusses her work in which excessive, long-term intake of dietary lipids, as well as their subsequent withdrawal, promotes stress-related outcomes in mice. Third, Dr Mark Wilson describes his group's research examining the effects of social hierarchy-related stress on food intake and diet choice in group-housed female rhesus macaques, and compared the data from monkeys to results obtained in analogous work using rodents. Finally, Dr Gorica Petrovich discusses her research program that is aimed at defining cortical-amygdalar-hypothalamic circuitry responsible for curbing food intake during emotional threat (i.e. fear anticipation) in rats. Their collective results reveal the complexity of physiological and behavioral interactions that link stress, food intake and emotional state, and suggest new avenues of research to probe the impact of genetic, metabolic, social, experiential and environmental factors on these interactions.
Topics: Animals; Choice Behavior; Diet; Dietary Fats; Dietary Sucrose; Eating; Emotions; Feeding Behavior; Female; Hypothalamo-Hypophyseal System; Macaca mulatta; Mice; Pituitary-Adrenal System; Rats; Reward; Stress, Psychological
PubMed: 26303312
DOI: 10.3109/10253890.2015.1062981 -
Blood Mar 2023Inherited or de novo germ line heterozygous mutations in the gene encoding the transcription factor GATA2 lead to its deficiency. This results in a constellation of...
Inherited or de novo germ line heterozygous mutations in the gene encoding the transcription factor GATA2 lead to its deficiency. This results in a constellation of clinical features including nontuberculous mycobacterial, bacterial, fungal, and human papillomavirus infections, lymphedema, pulmonary alveolar proteinosis, and myelodysplasia. The onset, or even the presence, of disease is highly variable, even in kindreds with the identical mutation in GATA2. The clinical manifestations result from the loss of a multilineage progenitor that gives rise to B lymphocytes, monocytes, natural killer cells, and dendritic cells, leading to cytopenias of these lineages and subsequent infections. The bone marrow failure is typically characterized by hypocellularity. Dysplasia may either be absent or subtle but typically evolves into multilineage dysplasia with prominent dysmegakaryopoiesis, followed in some instances by progression to myeloid malignancies, specifically myelodysplastic syndrome, acute myelogenous leukemia, and chronic myelomonocytic leukemia. The latter 3 malignancies often occur in the setting of monosomy 7, trisomy 8, and acquired mutations in ASXL1 or in STAG2. Importantly, myeloid malignancy may represent the primary presentation of disease without recognition of other syndromic features. Allogeneic hematopoietic stem cell transplantation (HSCT) results in reversal of the phenotype. There remain important unanswered questions in GATA2 deficiency, including the following: (1) Why do some family members remain asymptomatic despite harboring deleterious mutations in GATA2? (2) What are the genetic changes that lead to myeloid progression? (3) What causes the apparent genetic anticipation? (4) What is the role of preemptive HSCT?
Topics: Humans; GATA2 Deficiency; Myelodysplastic Syndromes; Myeloproliferative Disorders; Mutation; Germ-Line Mutation; GATA2 Transcription Factor
PubMed: 36455197
DOI: 10.1182/blood.2022017764