Car Crashes and Central Disorders of Hypersomnolence: A French Study

Background

Drowsiness compromises driving ability by reducing alertness and attentiveness, and delayed reaction times. Sleep-related car crashes account for a considerable proportion of accident at the wheel. Narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) are rare central disorders of hypersomnolence, the most severe causes of sleepiness thus being potential dangerous conditions for both personal and public safety with increasing scientific, social, and political attention. Our main objective was to assess the frequency of recent car crashes in a large cohort of patients affected with well-defined central disorders of hypersomnolence versus subjects from the general population.

Methods

We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 527 patients and 781 healthy subjects. All participants included needed to have a driving license, information available on potential accident events during the last 5 years, and on potential confounders; thus analyses were performed on 282 cases (71 IH, 82 NT2, 129 NT1) and 470 healthy subjects.

Results

Patients reported more frequently than healthy subjects the occurrence of recent car crashes (in the previous five years), a risk that was confirmed in both treated and untreated subjects at study inclusion (Untreated, OR = 2.21 95%CI = [1.30–3.76], Treated OR = 2.04 95%CI = [1.26–3.30]), as well as in all disease categories, and was modulated by subjective sleepiness level (Epworth scale and naps). Conversely, the risk of car accidents of patients treated for at least 5 years was not different to healthy subjects (OR = 1.23 95%CI = [0.56–2.69]). Main risk factors were analogous in patients and healthy subjects.

Conclusion

Patients affected with central disorders of hypersomnolence had increased risk of recent car crashes compared to subjects from the general population, a finding potentially reversed by long-term treatment.     

Drug discovery from natural products

Natural product compounds are the source of numerous therapeutic agents. Recent progress to discover drugs from natural product sources has resulted in compounds that are being developed to treat cancer, resistant bacteria and viruses and immunosuppressive disorders. Many of these compounds were discovered by applying recent advances in understanding the genetics of secondary metabolism in actinomycetes, exploring the marine environment and applying new screening technologies. In many instances, the discovery of a novel natural product serves as a tool to better understand targets and pathways in the disease process. This review describes recent progress in drug discovery from natural sources including several examples of compounds that inhibit novel drug targets.     

Genetics of anorexia nervosa: An overview of genome-wide association studies and emerging biological links

Anorexia nervosa (AN) is a complex disorder with a strong genetic component. Comorbidities are frequent and there is substantial overlap with other disorders. The lack of understanding of the molecular and neuroanatomical causes has made it difficult to develop effective treatments and it is often difficult to treat in clinical practice. Recent advances in genetics have changed our understanding of polygenic diseases, increasing the possibility of understanding better how molecular pathways are intertwined. This review synthetizes the current state of genetic research providing an overview of genome-wide association studies (GWAS) findings in AN as well as overlap with other disorders, traits, pathways, and imaging results. This paper also discusses the different putative global pathways that are contributing to the disease including the evidence for metabolic and psychiatric origin of the disease.     

A novel inhibitor of the insulin/IGF signaling pathway protects from age‐onset,neurodegeneration‐linked proteotoxicity

Aging manipulation is an emerging strategy aimed to postpone the manifestation of late‐onset neurodegenerative disorders such as Alzheimer's (AD) and Huntington's diseases (HD) and to slow their progression once emerged. Reducing the activity of the insulin/IGF signaling cascade (IIS), a prominent aging‐regulating pathway, protects worms from proteotoxicity of various aggregative proteins, including the AD‐associated peptide, Aβ‐ and the HD‐linked peptide, polyQ40. Similarly, IGF1 signaling reduction protects mice from AD‐like disease. These discoveries suggest that IIS inhibitors can serve as new drugs for the treatment of neurodegenerative maladies including AD and HD. Here, we report that NT219, a novel IIS inhibitor, mediates a long‐lasting, highly efficient inhibition of this signaling cascade by a dual mechanism; it reduces the autophosphorylation of the IGF1 receptor and directs the insulin receptor substrates 1 and 2 (IRS 1/2) for degradation. NT219 treatment promotes stress resistance and protects nematodes from AD‐ and HD‐associated proteotoxicity without affecting lifespan. Our discoveries strengthen the theme that IIS inhibition has a therapeutic potential as a cure for neurodegenerative maladies and point at NT219 as a promising compound for the treatment of these disorders through a selective manipulation of aging.     

Unraveling the complexity of histone-arginine methyltransferase CARM1 in cancer: From underlying mechanisms to targeted therapeutics

Coactivator-associated arginine methyltransferase 1 (CARM1), a type I protein arginine methyltransferase (PRMT), has been widely reported to catalyze arginine methylation of histone and non-histone substrates, which is closely associated with the occurrence and progression of cancer. Recently, accumulating studies have demonstrated the oncogenic role of CARM1 in many types of human cancers. More importantly, CARM1 has been emerging as an attractive therapeutic target for discovery of new candidate anti-tumor drugs. Therefore, in this review, we summarize the molecular structure of CARM1 and its key regulatory pathways, as well as further discuss the rapid progress in better understanding of the oncogenic functions of CARM1. Moreover, we further demonstrate several representative targeted CARM1 inhibitors, especially focusing on demonstrating their designing strategies and potential therapeutic applications. Together, these inspiring findings would shed new light on elucidating the underlying mechanisms of CARM1 and provide a clue on discovery of more potent and selective CARM1 inhibitors for the future targeted cancer therapy.     

Modelling neurodegenerative diseases in Drosophila: a fruitful approach?

Human neurodegenerative diseases are characterized by the progressive loss of specific neuronal populations, resulting in substantial disability and early death. The identification of causative single-gene mutations in families with inherited neurodegenerative disorders has facilitated the modelling of these diseases in experimental organisms, including the fruitfly Drosophila melanogaster. Many neurodegenerative diseases have now been successfully modelled in Drosophila, and genetic analysis is under way in each of these models. Using fruitfly genetics to define the molecular pathways that underlie the neurodegenerative process is likely to improve substantially our understanding of the pathogenesis of the human diseases, and to provide new therapeutic targets.     

Identification of significant pathways in gastric cancer based on protein-protein interaction networks and cluster analysis

Gastric cancer is one of the most common and lethal cancers worldwide. However, despite its clinical importance, the regulatory mechanisms involved in the aggressiveness of this cancer are still poorly understood. A better understanding of the biology, genetics and molecular mechanisms of gastric cancer would be useful in developing novel targeted approaches for treating this disease. In this study we used protein-protein interaction networks and cluster analysis to comprehensively investigate the cellular pathways involved in gastric cancer. A primary immunodeficiency pathway, focal adhesion, ECM-receptor interactions and the metabolism of xenobiotics by cytochrome P450 were identified as four important pathways associated with the progression of gastric cancer. The genes in these pathways, e.g., ZAP70, IGLL1, CD79A, COL6A3, COL3A1, COL1A1, CYP2C18 and CYP2C9, may be considered as potential therapeutic targets for gastric cancer.     

Developments in the clinical understanding of lupus

Advances in genetics and new understanding of the molecular pathways that mediate innate and adaptive immune system activation, along with renewed focus on the role of the complement system as a mediator of inflammation, have stimulated elaboration of a scheme that might explain key mechanisms in the pathogenesis of systemic lupus erythematosus. Clinical observations identifying important comorbidities in patients with lupus have been a recent focus of research linking immune mechanisms with clinical manifestations of disease. While these advances have identified rational and promising targets for therapy, so far the therapeutic trials of new biologic agents have not met their potential. Nonetheless, progress in understanding the underlying immunopathogenesis of lupus and its impact on clinical disease has accelerated the pace of clinical research to improve the outcomes of patients with systemic lupus erythematosus.     

Ionenkanalerkrankungen der Niere und Nebenniere

Genetic kidney diseases represent a significant proportion of kidney diseases manifesting in childhood and adolescence, but are also gaining importance in slowly progressive or late-onset adult diseases. A significant portion of kidney diseases particularly in childhood are associated with end stage renal disease and/or other relevant morbidity. An early (molecular) diagnosis can be a prerequisite for a better prognostic assessment and provides opportunities in terms of optimized symptomatic therapy. Mechanistically speaking, mutations in ion channel-associated nephropathy represent—in addition to structural defects of the glomerular filter (e.g., COL4A3, LAMB2, nephrin) and disorders of signaling pathways that are relevant for the development of the urogenital tract (e.g., HNF1B, WT1)—a significant proportion of the group with respect to number and prototypes. Determination of the molecular genetics of (hypokalemic) salt-losing tubulopathies has contributed significantly to our understanding of the central role of the kidney in salt balance. The spectrum of renal ion channelopathies is shown using the example of classical salt-losing tubulopathies (Bartter syndrome and Gitelman syndrome), the transient receptor potential (TRP) channel group and the role of channel changes in aldosteronism and congenital hypertension.     

A feature of maternal sleep apnea during gestation causes autism-relevant neuronal and behavioral phenotypes in offspring

Mounting epidemiologic and scientific evidence indicates that many psychiatric disorders originate from a complex interplay between genetics and early life experiences, particularly in the womb. Despite decades of research, our understanding of the precise prenatal and perinatal experiences that increase susceptibility to neurodevelopmental disorders remains incomplete. Sleep apnea (SA) is increasingly common during pregnancy and is characterized by recurrent partial or complete cessations in breathing during sleep. SA causes pathological drops in blood oxygen levels (intermittent hypoxia, IH), often hundreds of times each night. Although SA is known to cause adverse pregnancy and neonatal outcomes, the long-term consequences of maternal SA during pregnancy on brain-based behavioral outcomes and associated neuronal functioning in the offspring remain unknown. We developed a rat model of maternal SA during pregnancy by exposing dams to IH, a hallmark feature of SA, during gestational days 10 to 21 and investigated the consequences on the offspring’s forebrain synaptic structure, synaptic function, and behavioral phenotypes across multiples stages of development. Our findings represent a rare example of prenatal factors causing sexually dimorphic behavioral phenotypes associated with excessive (rather than reduced) synapse numbers and implicate hyperactivity of the mammalian target of rapamycin (mTOR) pathway in contributing to the behavioral aberrations. These findings have implications for neuropsychiatric disorders typified by superfluous synapse maintenance that are believed to result, at least in part, from largely unknown insults to the maternal environment.

Correlative data in humans has hinted at an association between maternal sleep apnea during pregnancy and altered neuronal function in offspring. This study shows that in a rat model of sleep apnea, maternal gestational intermittent hypoxia leads to sex-specific changes in neuronal structure and function in offspring, accompanied by impaired behavioral phenotypes.     

The value of HDL genetics

PURPOSE OF REVIEW: To review studies on hereditary disorders of high-density lipoprotein (HDL) metabolism and studies on HDL genetics in mice, which have both provided valuable insight into the pathways of this intriguing lipoprotein and moreover revealed targets to raise HDLc to reduce atherosclerosis. RECENT FINDINGS: To date, as many as 11 genes are considered key players in the synthesis, maturation, conversion and/or catabolism of HDL. Five of these genes have been identified in humans, APOA1, LCAT, ABCA1, LIPC, and CETP, whereas the other six genes have been identified in mice, SCARB1, ABCG1, ATPB5, PLTP, LIPG and APOM. Genetic association studies are as yet the best line of evidence of the roles of the 'murine genes' in human HDL pathways. In addition to recent genetic association studies, a third section describes exciting news on six newly proposed HDL genes VNN1, GALNT2, MMAB/MVK, CTalpha, BMP-1 and SIRT1. SUMMARY: This review provides a summary of the current literature on the genetics of HDL. New information from this research area may assist us in obtaining a better understanding of HDL biology and identifying novel pharmacological targets.     

Genome-scale modeling of human metabolism – a systems biology approach

Altered metabolism is linked to the appearance of various human diseases and a better understanding of disease-associated metabolic changes may lead to the identification of novel prognostic biomarkers and the development of new therapies. Genome-scale metabolic models (GEMs) have been employed for studying human metabolism in a systematic manner, as well as for understanding complex human diseases. In the past decade, such metabolic models – one of the fundamental aspects of systems biology – have started contributing to the understanding of the mechanistic relationship between genotype and phenotype. In this review, we focus on the construction of the Human Metabolic Reaction database, the generation of healthy cell type- and cancer-specific GEMs using different procedures, and the potential applications of these developments in the study of human metabolism and in the identification of metabolic changes associated with various disorders. We further examine how in silico genome-scale reconstructions can be employed to simulate metabolic flux distributions and how high-throughput omics data can be analyzed in a context-dependent fashion. Insights yielded from this mechanistic modeling approach can be used for identifying new therapeutic agents and drug targets as well as for the discovery of novel biomarkers. Finally, recent advancements in genome-scale modeling and the future challenge of developing a model of whole-body metabolism are presented. The emergent contribution of GEMs to personalized and translational medicine is also discussed.     

Molecular aspects of hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower limbs spasticity and weakness. What was first thought to be a small group of rare Mendelian disorder has now become a large group that includes many complex syndromes. While large families with defined modes of inheritance were used for the initial HSP gene discovery, new sequencing technologies have recently allowed the study of small families, with the identification of many new disease causative genes. These discoveries are slowly leading to a better understanding of the molecular mechanisms underlying HSP with the identification of precise disease pathways. These insights may lead to new therapeutic strategies for what is a group of largely untreatable diseases. This review looks at the key players involved in HSP and where they act in their specific pathways.     

Mitochondria,endoplasmic reticulum and innate immune dysfunction in mood disorders: Do Mitochondria-Associated Membranes (MAMs) play a role?

Mood disorders like major depression and bipolar disorder (BD) are among the most prevalent forms of mental illness. Current knowledge of the neurobiology and pathophysiology of these disorders is still modest and clear biological markers are still missing. Thus, a better understanding of the underlying pathophysiological mechanisms to identify potential therapeutic targets is a prerequisite for the design of new drugs as well as to develop biomarkers that help in a more accurate and earlier diagnosis.Multiple pieces of evidence including genetic and neuro-imaging studies suggest that mood disorders are associated with abnormalities in endoplasmic-reticulum (ER)-related stress responses, mitochondrial function and calcium signalling. Furthermore, deregulation of the innate immune response has been described in patients diagnosed with mood disorders, including depression and BD. These disease-related events are associated with functions localized to a subdomain of the ER, known as Mitochondria-Associated Membranes (MAMs), which are lipid rafts-like domains that connect mitochondria and ER, both physically and biochemically.This review will outline the current understanding of the role of mitochondria and ER dysfunction under pathological brain conditions, particularly in major depressive disorder (MDD) and BD, that support the hypothesis that MAMs can act in these mood disorders as the link connecting ER-related stress response and mitochondrial impairment, as well as a mechanisms behind sterile inflammation arising from deregulation of innate immune responses. The role of MAMs in the pathophysiology of these pathologies and its potential relevance as a potential therapeutic target will be discussed.     

A Biochemical Approach to Understand the Pathogenesis of Advanced Pulmonary Arterial Hypertension: Metabolomic Profiles of Arginine,Sphingosine-1-Phosphate,and Heme of Human Lung

Pulmonary arterial hypertension (PAH) is a vascular disease characterized by persistent precapillary pulmonary hypertension (PH), leading to progressive right heart failure and premature death. The pathological mechanisms underlying this condition remain elusive. Analysis of global metabolomics from lung tissue of patients with PAH (n = 8) and control lung tissue (n = 8) leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted arginine pathways with increased Nitric oxide (NO) and decreased arginine. Our results also showed specific metabolic pathways and genetic profiles with increased Sphingosine-1-phosphate (S1P) metabolites as well as increased Heme metabolites with altered oxidative pathways in the advanced stage of the human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to the vascular remodeling in severe pulmonary hypertension. Profiling metabolomic alterations of the PAH lung has provided a new understanding of the pathogenic mechanisms of PAH, which benefits therapeutic targeting to specific metabolic pathways involved in the progression of PAH.     

Genome-wide association study of idiopathic hypersomnia in a Japanese population

Sleep and Biological Rhythms - Idiopathic hypersomnia (IH) is a rare sleep disorder characterized by excessive daytime sleepiness, great difficulty upon awakening, and prolonged sleep time. In...     

Human immunodeficiency virus type 1 Vpr induces apoptosis in human neuronal cells

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) causes AIDS dementia complex (ADC) in certain infected individuals. Recent studies have suggested that patients with ADC have an increased incidence of neuronal apoptosis leading to neuronal dropout. Of note, a higher level of the HIV-1 accessory protein Vpr has been detected in the cerebrospinal fluid of AIDS patients with neurological disorders. Moreover, extracellular Vpr has been shown to form ion channels, leading to cell death of cultured rat hippocampal neurons. Based on these previous findings, we first investigated the apoptotic effects of the HIV-1 Vpr protein on the human neuronal precursor NT2 cell line at a range of concentrations. These studies demonstrated that apoptosis induced by both Vpr and the envelope glycoprotein, gp120, occurred in a dose-dependent manner compared to protein treatment with HIV-1 integrase, maltose binding protein (MBP), and MBP-Vpr in the undifferentiated NT2 cells. For mature, differentiated neurons, apoptosis was also induced in a dose-dependent manner by both Vpr and gp120 at concentrations ranging from 1 to 100 ng/ml, as demonstrated by both the terminal deoxynucleotidyltransferase (Tdt)-mediated dUTP-biotin nick end labeling and Annexin V assays for apoptotic cell death. In order to clarify the intracellular pathways and molecular mechanisms involved in Vpr- and gp120-induced apoptosis in the NT2 cell line and differentiated mature human neurons, we then examined the cellular lysates for caspase-8 activity in these studies. Vpr and gp120 treatments exhibited a potent increase in activation of caspase-8 in both mature neurons and undifferentiated NT2 cells. This suggests that Vpr may be exerting selective cytotoxicity in a neuronal precursor cell line and in mature human neurons through the activation of caspase-8. These data represent a characterization of Vpr-induced apoptosis in human neuronal cells, and suggest that extracellular Vpr, along with other lentiviral proteins, may increase neuronal apoptosis in the CNS. Also, identification of the intracellular activation of caspase-8 in Vpr-induced apoptosis of human neuronal cells may lead to therapeutic approaches which can be used to combat HIV-1-induced neuronal apoptosis in AIDS patients with ADC.     

Focus: Rare Disease: Neuromonitoring in Rare Disorders of Metabolism

Inborn errors of metabolism (IEM) are a unique class of genetic diseases due to mutations in genes involved in key metabolic pathways. The combined incidence of IEM has been estimated to be as high as 1:1000. Urea Cycle disorders (UCD), one class of IEM, can present with cerebral edema and represent a possible target to explore the utility of different neuromonitoring techniques during an hyperammonemic crisis. The last two decades have brought advances in the early identification and comprehensive management of UCD, including further understanding of neuroimaging patterns associated with neurocognitive function. Nonetheless, very important questions remain about the potential acute neurotoxic effects of hyperammonemia to better understand how to treat and prevent secondary brain injury. In this review, we describe existing neuromonitoring techniques that have been used in rare metabolic disorders to assess and allow amelioration of ongoing brain injury. Directions of future research should be focused on identifying new diagnostic approaches in the management of metabolic crises to optimize care and reduce long term morbidity and mortality in patients with IEM.