Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015

Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61.7 years (95% uncertainty interval 61.4-61.9) in 1980 to 71.8 years (71.5-72.2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11.3 years (3.7-17.4), to 62.6 years (56.5-70.2). Total deaths increased by 4.1% (2.6-5.6) from 2005 to 2015, rising to 55.8 million (54.9 million to 56.6 million) in 2015, but age-standardised death rates fell by 17.0% (15.8-18.1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14.1% (12.6-16.0) to 39.8 million (39.2 million to 40.5 million) in 2015, whereas age-standardised rates decreased by 13.1% (11.9-14.3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42.1%, 39.1-44.6), malaria (43.1%, 34.7-51.8), neonatal preterm birth complications (29.8%, 24.8-34.9), and maternal disorders (29.1%, 19.3-37.1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Copyright (C) The Author(s). Published by Elsevier Ltd.Peer reviewe

Limbilise süsteemiga seotud membraanvalgu (LSAMP) geeni puudulikkusega hiire käitumuslik, farmakoloogiline ja neurokeemiline iseloomustus

Väitekirja elektrooniline versioon ei sisalda publikatsioone.LSAMP valk, mida kodeerib Lsamp geen, on raku adhesioonimolekul, mis on seotud aksonite suunamise ja neuriitide väljakasvuga. LSAMP valgul on oluline seos ärevuse taseme ja psühhiaatriliste häirete esinemissagedusega. LSAMPi tähtsust rõhutab ka asjaolu, et Lsamp on osutunud tuumorsupressorgeeniks. Üks levinud viis uurida geeni funktsiooni on luua mudelorganism, milles uuritav geen ja valk puuduvad (knockout mudel). Käesolevas uuringus kasutatigi Lsamp geeni funktsiooni edasiseks uurimiseks Lsamp geeni puudulikkusega hiireliini, s.o hiiri, kelle organismis funktsionaalne LSAMP valk puudub. Lsamp geeni puudulikkusega hiired on elujõulised ja normaalse sigivusega ning neil ei esine märgatavaid kõrvalekaldeid ajuanatoomias. Küll aga kutsub Lsamp geeni väljalülitamine esile ulatuslikke muutusi käitumises: Lsamp knockout hiired on hüperaktiivsed, vähenenud ärevusega, ujuvad aeglasemalt ning ei püga üksteisel vurrusid ega ilmuta muid hierarhia kehtestamise ja/või agressiivsuse märke. Lisaks on Lsamp geeni puudulikkusega hiired ülitundlikud bensodiasepiinide suhtes, kuid märkimisväärselt tundetud amfetamiini stimuleeriva toime suhtes. Neid farmakoloogilisi efekte, nagu ka Lsamp geeni puudulikkusega hiirte vähenenud ärevust ja agressiivsuse puudumist saab seletada GABA A retseptori alaühikute α1 ja α2 ekspressiooni suhte muutusega, dopamiini transporteri vähenenud tasemega keskajus ja serotoniinisüsteemi suurenenud aktiivsusega. Kokkuvõtteks, Lsamp geeni väljalülitamine kutsub esile ulatuslikke muutusi ärevuses, liikumisaktiivsuses ja sotsiaalses käitumises, halvendab kohanemisvõimet ning põhjustab olulisi muutusi põhiliste monoaminergiliste süsteemide tasakaalus ajus. Lsamp knockout hiired on paljutõotav mudel psühhiaatriliste häiretega kaasnevate sotsiaalse käitumise muutuste uurimiseks. Samuti võib LSAMP valgu ning tema lähisugulaste ja interaktsioonipartnerite – teiste IgLON valguperekonna liikmete – uurimine aidata avastada uusi psühhiaatriliste häirete kujunemisega seotud molekulaarseid radu ning töötada välja uusi paremaid psühhiaatrilisi ravimeid

Limbic system associated membrane protein as a potential target for neuropsychiatric disorders

The studies performed in laboratory animals and psychiatric patients suggest a possible role of limbic system-associated membrane protein (LAMP) in the mechanisms of psychiatric disorders. Stressful manipulations and genetic invalidation have revealed a role of the Lsamp gene in the regulation of anxiety in rodents. Besides that, Lsamp-deficient mice display reduced aggressiveness and impaired adaptation in novel and stressful environments. The behavioral effects of amphetamine were blunted in genetically modified mice. Recent pharmacological and biochemical studies point toward altered function of GABA-, 5-hydroxytryptamine-, and dopaminergic systems in Lsamp-deficient mice. Moreover, we found an association between the gene polymorphisms of LSAMP and major depressive disorder (MDD). Patients suffering from MDD had significantly increased ratio between risk and protective haplotypes of the LSAMP gene compared to healthy volunteers. However, the impact of these haplotypes for the function of LAMP is not clear and remains to be elucidated in future studies

Taurine and Epidermal Growth Factor Belong to the Signature of First-Episode Psychosis

This study evaluated the levels of two amino acid derivatives taurine and spermine in first-episode psychosis (FEP) patients and their response to antipsychotic treatment. The levels of taurine and spermine were significantly up-regulated in antipsychotic-naïve FEP patients compared to control subjects (CS). Treatment of FEP patients with antipsychotic drugs significantly reduced the positive symptoms of schizophrenia. This positive effect was accompanied by a significant reduction of taurine and spermine to the levels measured in CS. General linear model was used to establish associations of taurine and spermine with the levels of cytokines and growth factors, measured in our previous experiments using the same study sample. There was a strong association between taurine and epidermal growth factor (EGF). Both biomarkers significantly correlated with the disease symptoms as well as with the effectiveness of antipsychotic treatment. Accordingly one can conclude that taurine and EGF belong to the signature of FEP. Most probably they reflect altered oxidative stress and corrupted function of N-methyl-D-aspartate (NMDA) receptors in FEP

Repeated Administration of D-Amphetamine Induces Distinct Alterations in Behavior and Metabolite Levels in 129Sv and Bl6 Mouse Strains

The main goal of the study was to characterize the behavioral and metabolomic profiles of repeated administration (for 11 days) of d-amphetamine (AMPH, 3 mg/kg i. p.), indirect agonist of dopamine (DA), in widely used 129S6/SvEvTac (129Sv) and C57BL/6NTac (Bl6) mouse strains. Acute administration of AMPH (acute AMPH) induced significantly stronger motor stimulation in Bl6. However, repeated administration of AMPH (repeated AMPH) caused stronger motor sensitization in 129Sv compared acute AMPH. Body weight of 129Sv was reduced after repeated saline and AMPH, whereas no change occurred in Bl6. In the metabolomic study, acute AMPH induced an elevation of isoleucine and leucine, branched chain amino acids (BCAA), whereas the level of hexoses was reduced in Bl6. Both BCAAs and hexoses remained on level of acute AMPH after repeated AMPH in Bl6. Three biogenic amines [asymmetric dimethylarginine (ADMA), alpha-aminoadipic acid (alpha-AAA), kynurenine] were significantly reduced after repeated AMPH. Acute AMPH caused in 129Sv a significant reduction of valine, lysophosphatidylcholines (lysoPC a C16:0, lysoPC a C18:2, lysoPC a C20:4), phosphatidylcholine (PC) diacyls (PC aa C34:2, PC aa C36:2, PC aa C36:3, PC aa C36:4) and alkyl-acyls (PC ae C38:4, PC ae C40:4). However, repeated AMPH increased the levels of valine and isoleucine, long-chain acylcarnitines (C14, C14:1-OH, C16, C18:1), PC diacyls (PC aa C38:4, PC aa C38:6, PC aa C42:6), PC acyl-alkyls (PC ae C38:4, PC ae C40:4, PC ae C40:5, PC ae C40:6, PC ae C42:1, PC ae C42:3) and sphingolipids [SM(OH)C22:1, SM C24:0] compared to acute AMPH in 129Sv. Hexoses and kynurenine were reduced after repeated AMPH compared to saline in 129Sv. The established changes probably reflect a shift in energy metabolism toward lipid molecules in 129Sv because of reduced level of hexoses. Pooled data from both strains showed that the elevation of isoleucine and leucine was a prominent biomarker of AMPH-induced behavioral sensitization. Simultaneously a significant decline of hexoses, citrulline, ADMA, and kynurenine occurred. The reduced levels of kynurenine, ADMA, and citrulline likely reflect altered function of N-methyl-D-aspartate (NMDA) and NO systems caused by repeated AMPH. Altogether, 129Sv strain displays stronger sensitization toward AMPH and larger variance in metabolite levels than Bl6

Dopamine System, NMDA Receptor and EGF Family Expressions in Brain Structures of Bl6 and 129Sv Strains Displaying Different Behavioral Adaptation

C57BL/6NTac (Bl6) and 129S6/SvEvTac (129Sv) mice display different coping strategies in stressful conditions. Our aim was to evaluate biomarkers related to different adaptation strategies in the brain of male 129Sv and Bl6 mice. We focused on signaling pathways related to the dopamine (DA) system, N-methyl-D-aspartate (NMDA) receptor and epidermal growth factor (EGF) family, shown as the key players in behavioral adaptation. Mice from Bl6 and 129Sv lines were divided into either home cage controls (HCC group) or exposed to repeated motility testing and treated with saline for 11 days (RMT group). Distinct stress responses were reflected in severe body weight loss in 129Sv and the increased exploratory behavior in Bl6 mice. Besides that, amphetamine caused significantly stronger motor stimulation in Bl6. Together with the results from gene expression (particularly Maob), this study supports higher baseline activity of DA system in Bl6. Interestingly, the adaptation is reflected with opposite changes of DA markers in dorsal and ventral striatum. In forebrain, stress increased the gene expressions of Egf-Erbb1 and Nrg1/Nrg2-Erbb4 pathways more clearly in 129Sv, whereas the corresponding proteins were significantly elevated in Bl6. We suggest that not only inhibited activity of the DA system, but also reduced activity of EGF family and NMDA receptor signaling underlies higher susceptibility to stress in 129Sv. Altogether, this study underlines the better suitability of 129Sv for modelling neuropsychiatric disorders than Bl6

Altered Expression Profile of IgLON Family of Neural Cell Adhesion Molecules in the Dorsolateral Prefrontal Cortex of Schizophrenic Patients

Neural adhesion proteins are crucial in the development and maintenance of functional neural connectivity. Growing evidence suggests that the IgLON family of neural adhesion molecules LSAMP, NTM, NEGR1, and OPCML are important candidates in forming the susceptibility to schizophrenia (SCZ). IgLON proteins have been shown to be involved in neurite outgrowth, synaptic plasticity and neuronal connectivity, all of which have been shown to be altered in the brains of patients with the diagnosis of schizophrenia. Here we optimized custom 5′-isoform-specific TaqMan gene-expression analysis for the transcripts of human IgLON genes to study the expression of IgLONs in the dorsolateral prefrontal cortex (DLPFC) of schizophrenic patients (n = 36) and control subjects (n = 36). Uniform 5′-region and a single promoter was confirmed for the human NEGR1 gene by in silico analysis. IgLON5, a recently described family member, was also included in the study. We detected significantly elevated levels of the NEGR1 transcript (1.33-fold increase) and the NTM 1b isoform transcript (1.47-fold increase) in the DLPFC of schizophrenia patients compared to healthy controls. Consequent protein analysis performed in male subjects confirmed the increase in NEGR1 protein content both in patients with the paranoid subtype and in patients with other subtypes. In-group analysis of patients revealed that lower expression of certain IgLON transcripts, mostly LSAMP 1a and 1b, could be related with concurrent depressive endophenotype in schizophrenic patients. Additionally, our study cohort provides further evidence that cannabis use may be a relevant risk factor associated with suicidal behaviors in psychotic patients. In conclusion, we provide clinical evidence of increased expression levels of particular IgLON family members in the DLPFC of schizophrenic patients. We propose that alterations in the expression profile of IgLON neural adhesion molecules are associated with brain circuit disorganization in neuropsychiatric disorders, such as schizophrenia. In the light of previously published data, we suggest that increased level of NEGR1 in the frontal cortex may serve as molecular marker for a wider spectrum of psychiatric conditions