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Despite the significant scientific advancement in deciphering the "deaths of despair" narrative, most relevant studies have focused on drug-, alcohol-, and suicide-related (DAS) deaths. This study directly investigated despair as a determinant of death and the temporal variation and racial heterogeneity among individuals. We used psychological distress (PD) as a proxy for despair and drew data from the US National Health Interview Survey-Linked Mortality Files 1997 to 2014, CDC (Centers for Disease Control and Prevention) Multiple Cause of Death database 1997 to 2014, CDC bridged-race population files 1997 to 2014, Current Population Survey 1997 to 1999, and the American Community Survey 2000 to 2014. We used Cox proportional hazards models to estimate mortality hazard ratios of PD and compared age-standardized PD- and DAS-related mortality rates by race/ethnicity and over time. We found that while Whites had a lower prevalence of PD than Blacks and Hispanics throughout the whole period, they underwent distinctive increases in PD-related death and have had a higher PD-related mortality rate than Blacks and Hispanics since the early 2000s. This was predominantly due to Whites' relatively high and increasing vulnerability to PD less the prevalence of PD. Furthermore, PD induced a more pervasive mortality consequence than DAS combined for Whites and Blacks. In addition, PD- and DAS-related deaths displayed a concordant trend among Whites but divergent patterns for Blacks and Hispanics. These findings suggest that 1) DAS-related deaths underestimated the mortality consequence of despair for Whites and Blacks but overestimated it for Hispanics; and 2) despair partially contributed to the DAS trend among Whites but probably not for Blacks and Hispanics.
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Morte , Etnicidade , Angústia Psicológica , Estresse Psicológico , Humanos , Etnicidade/psicologia , Etnicidade/estatística & dados numéricos , Hispânico ou Latino/psicologia , Hispânico ou Latino/estatística & dados numéricos , Estados Unidos/epidemiologia , Brancos/psicologia , Brancos/estatística & dados numéricos , Estresse Psicológico/epidemiologia , Estresse Psicológico/etnologia , Estresse Psicológico/mortalidade , Negro ou Afro-Americano/psicologia , Negro ou Afro-Americano/estatística & dados numéricosRESUMO
Behavioral testing constitutes the primary method to measure the emotional states of nonhuman animals in preclinical research. Emerging as the characteristic tool of the behaviorist school of psychology, behavioral testing of animals, particularly rodents, is employed to understand the complex cognitive and affective symptoms of neuropsychiatric disorders. Following the symptom-based diagnosis model of the DSM, rodent models and tests of depression and anxiety focus on behavioral patterns that resemble the superficial symptoms of these disorders. While these practices provided researchers with a platform to screen novel antidepressant and anxiolytic drug candidates, their construct validity-involving relevant underlying mechanisms-has been questioned. In this review, we present the laboratory procedures used to assess depressive- and anxiety-like behaviors in rats and mice. These include constructs that rely on stress-triggered responses, such as behavioral despair, and those that emerge with nonaversive training, such as cognitive bias. We describe the specific behavioral tests that are used to assess these constructs and discuss the criticisms on their theoretical background. We review specific concerns about the construct validity and translational relevance of individual behavioral tests, outline the limitations of the traditional, symptom-based interpretation, and introduce novel, ethologically relevant frameworks that emphasize simple behavioral patterns. Finally, we explore behavioral monitoring and morphological analysis methods that can be integrated into behavioral testing and discuss how they can enhance the construct validity of these tests.
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Ansiedade , Depressão , Modelos Animais de Doenças , Animais , Humanos , Camundongos , Ratos , Ansiedade/diagnóstico , Comportamento Animal/fisiologia , Depressão/diagnóstico , Reprodutibilidade dos Testes , Pesquisa Translacional BiomédicaRESUMO
BACKGROUND: Rising midlife mortality in the United States is largely attributable to 'deaths of despair' (deaths from suicide, drug poisonings, and alcohol-related diseases) and deaths from cardiometabolic conditions. Although despair- and cardiometabolic-related mortality are increasing concurrently, it is unclear whether they share common developmental origins. We tested adolescent psychopathology as a potential common origin of midlife diseases of despair and cardiometabolic risk. METHODS: Participants (N = 4578) were from the National Longitudinal Study of Adolescent to Adult Health, a nationally representative cohort followed from adolescence to early midlife. Adolescent psychopathology included depression, anxiety, eating disorders, PTSD, conduct disorder, and ADHD at ages 11-18. Diseases of despair (suicidality, substance misuse, pain, and sleep problems) and cardiometabolic risk (hypertension, hyperlipidemia, high-risk waist circumference, diabetes, and cardiovascular conditions) were multi-modally measured at ages 33-43. RESULTS: At midlife, adolescents who experienced psychopathology exhibited more indicators of despair-related diseases and cardiometabolic risk (IRRs = 1.67 [1.46-1.87] and 1.13 [1.04-1.21], respectively), even after accounting for demographics, adolescent SES, and adolescent cognitive ability. Associations were evident for internalizing and externalizing conditions, and in a dose-response fashion. In mediation analyses, low education explained little of these associations, but early-adult substance use explained 21.5% of psychopathology's association with despair-related diseases. Midlife despair-related diseases and cardiometabolic risk co-occurred within individuals (IRR = 1.12 [1.08-1.16]). Adolescent psychopathology accounted for 8.3% of this co-occurrence, and 16.7% together with adolescent SES and cognitive ability. CONCLUSIONS: Adolescent psychopathology precedes both diseases of despair and cardiometabolic risk. Prevention and treatment of psychopathology may mitigate multiple causes of poor midlife health, reducing premature mortality.
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BACKGROUND: Deaths from suicides, drug poisonings, and alcohol-related diseases ('deaths of despair') are well-documented among working-age Americans, and have been hypothesized to be largely specific to the U.S. However, support for this assertion-and associated policies to reduce premature mortality-requires tests concerning these deaths in other industrialized countries, with different institutional contexts. We tested whether the concentration and accumulation of health and social disadvantage forecasts deaths of despair, in New Zealand and Denmark. METHODS: We used nationwide administrative data. Our observation period was 10 years (NZ = July 2006-June 2016, Denmark = January 2007-December 2016). We identified all NZ-born and Danish-born individuals aged 25-64 in the last observation year (NZ = 1 555 902, Denmark = 2 541 758). We ascertained measures of disadvantage (public-hospital stays for physical- and mental-health difficulties, social-welfare benefit-use, and criminal convictions) across the first nine years. We ascertained deaths from suicide, drugs, alcohol, and all other causes in the last year. RESULTS: Deaths of despair clustered within a population segment that disproportionately experienced multiple disadvantages. In both countries, individuals in the top 5% of the population in multiple health- and social-service sectors were at elevated risk for deaths from suicide, drugs, and alcohol, and deaths from other causes. Associations were evident across sex and age. CONCLUSIONS: Deaths of despair are a marker of inequalities in countries beyond the U.S. with robust social-safety nets, nationwide healthcare, and strong pharmaceutical regulations. These deaths cluster within a highly disadvantaged population segment identifiable within health- and social-service systems.
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Suicídio , Humanos , Masculino , Adulto , Dinamarca/epidemiologia , Feminino , Pessoa de Meia-Idade , Suicídio/estatística & dados numéricos , Nova Zelândia/epidemiologia , Vulnerabilidade Social , Causas de Morte , Overdose de Drogas/mortalidade , Transtornos Relacionados ao Uso de Álcool/mortalidade , Transtornos Relacionados ao Uso de Álcool/epidemiologiaRESUMO
Nectin-like family members (Necls) are involved in synaptic organization. In contrast to that of Necl-2/CADM1/SynCAM1, which is critical in synaptic events, investigation of Necl-4/CADM4/SynCAM4 in synapses has largely lagged behind given the particularity of homophilic self-interactions compared to interactions with other Necls. We sought to further understand the role of Necl-4 in synapses and found that knockout of Necl-4 led to aberrant expression levels of proteins mediating synaptic function in cortex homogenates and augmented accumulation of ionotropic glutamate receptor in postsynaptic density fractions, although a compensatory effect of Necl-1 on the expression levels existed. Concurrently, we also found increased synaptic clefts in the cortex and simplified dendritic morphology of primary cultured cortical neurons. Experiments on individual behaviors suggested that compared to their wild-type littermates, Necl-4-KO mice exhibited impaired acquisition of spatial memory and working memory and enhanced behavioral despair and anxiety-like behavior. These findings suggest that Necl-4 mediates synaptic function and related behaviors through an indispensable role and offer a new perspective about collaboration and specialization among Necls.
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Moléculas de Adesão Celular , Neurônios , Camundongos , Animais , Nectinas/genética , Moléculas de Adesão Celular/metabolismo , Neurônios/metabolismo , Sinapses/metabolismoRESUMO
Depression is a prevalent psychological condition with limited treatment options. While its etiology is multifactorial, both chronic stress and changes in microbiome composition are associated with disease pathology. Stress is known to induce microbiome dysbiosis, defined here as a change in microbial composition associated with a pathological condition. This state of dysbiosis is known to feedback on depressive symptoms. While studies have demonstrated that targeted restoration of the microbiome can alleviate depressive-like symptoms in mice, translating these findings to human patients has proven challenging due to the complexity of the human microbiome. As such, there is an urgent need to identify factors upstream of microbial dysbiosis. Here we investigate the role of mucin 13 as an upstream mediator of microbiome composition changes in the context of stress. Using a model of chronic stress, we show that the glycocalyx protein, mucin 13, is selectively reduced after psychological stress exposure. We further demonstrate that the reduction of Muc13 is mediated by the Hnf4 transcription factor family. Finally, we determine that deleting Muc13 is sufficient to drive microbiome shifts and despair behaviors. These findings shed light on the mechanisms behind stress-induced microbial changes and reveal a novel regulator of mucin 13 expression.
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Depressão , Disbiose , Microbioma Gastrointestinal , Estresse Psicológico , Animais , Masculino , Camundongos , Comportamento Animal/fisiologia , Depressão/metabolismo , Depressão/microbiologia , Disbiose/metabolismo , Disbiose/microbiologia , Microbioma Gastrointestinal/fisiologia , Fator 4 Nuclear de Hepatócito/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucinas/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/microbiologiaRESUMO
PURPOSE: Although prior literature documented socioeconomic inequalities in deaths of despair among working age population, it is unclear whether and how (a) the link between socioeconomic status and deaths of despair differs by age (b) each measure of socioeconomic status has independent effects on deaths of despair. This study aims to reduce these knowledge gaps. METHODS: Using data from a large scale nationally representative linked dataset (2011 Canadian Census Health and Environment Cohorts), this study employed Fine-Gray subdistribution hazard models to estimate the link between socioeconomic status and deaths of despair due to suicide, drug overdose, and alcoholic liver disease among working age population (N = 4,076,530). Age stratified analysis was conducted to examine age heterogeneity. RESULTS: Socioeconomic status, such as housing tenure, employment status, household income, and education level, was associated with deaths of despair among working age population. Age differences in the association between socioeconomic status and deaths of despair were found. While education level was pronounced for deaths of despair for younger adults, a combination of socioeconomic status was significantly associated with deaths of despair for those in late adulthood. CONCLUSIONS: Socioeconomic inequalities in deaths of despair are manifest among Canadian working age population. This study lends support the social and health policies aimed at reducing gaps in mortalities.
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Classe Social , Suicídio , Adulto , Humanos , Canadá/epidemiologia , Emprego , Escolaridade , Fatores SocioeconômicosRESUMO
Brain neurons support arousal and cognitive activity in the form of spectral transient bursts and cooperate with the peripheral nervous system to adapt to the surrounding environment. However, the temporal dynamics of brain-heart interactions have not been confirmed, and the mechanism of brain-heart interactions in major depressive disorder (MDD) remains unclear. This study aimed to provide direct evidence for brain-heart synchronization in temporal dynamics and clarify the mechanism of brain-heart interaction disruption in MDD. Eight-minute resting-state (closed eyes) electroencephalograph and electrocardiogram signals were acquired simultaneously. The Jaccard index (JI) was used to measure the temporal synchronization between cortical theta transient bursts and cardiac cycle activity (diastole and systole) in 90 MDD patients and 44 healthy controls (HCs) at rest. The deviation JI was used to reflect the equilibrium of brain activity between diastole and systole. The results showed that the diastole JI was higher than the systole JI in both the HC and MDD groups; compared to HCs, the deviation JI attenuated at F4, F6, FC2, and FC4 in the MDD patients. The eccentric deviation JI was negatively correlated with the despair factor scores of the HAMD, and after 4 weeks of antidepressant treatment, the eccentric deviation JI was positively correlated with the despair factor scores of the HAMD. It was concluded that brain-heart synchronization existed in the theta band in healthy individuals and that disturbed rhythm modulation of the cardiac cycle on brain transient theta bursts at right frontoparietal sites led to brain-heart interaction disruption in MDD.
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Transtorno Depressivo Maior , Humanos , Encéfalo , Eletroencefalografia , Mapeamento Encefálico , Nível de Alerta , Imageamento por Ressonância Magnética/métodosRESUMO
In the accompanying article, Spark et al. (Am J Epidemiol. 2023;192(5):720-731) estimate the undercounting of deaths due to suicide, drug use, and alcohol use in a Colorado veteran population and argue for a standardized case definition for the 3 causes of mortality. Use of a case definition for these 3 causes of death combined implies that they should be analyzed together. This is problematic, given the disparate trends in and historical contexts behind these 3 different causes of death.
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Consumo de Bebidas Alcoólicas , Transtornos Relacionados ao Uso de Substâncias , Suicídio , Humanos , Consumo de Bebidas Alcoólicas/mortalidade , Causas de Morte , Colorado , Transtornos Relacionados ao Uso de Substâncias/mortalidadeRESUMO
BACKGROUND: Midlife adults are experiencing a crisis of deaths of despair (i.e. deaths from suicide, drug overdose, and alcohol-related liver disease). We tested the hypothesis that a syndrome of despair-related maladies at midlife is preceded by psychopathology during adolescence. METHODS: Participants are members of a representative cohort of 1037 individuals born in Dunedin, New Zealand in 1972-73 and followed to age 45 years, with 94% retention. Adolescent mental disorders were assessed in three diagnostic assessments at ages 11, 13, and 15 years. Indicators of despair-related maladies across four domains - suicidality, substance misuse, sleep problems, and pain - were assessed at age 45 using multi-modal measures including self-report, informant-report, and national register data. RESULTS: We identified and validated a syndrome of despair-related maladies at midlife involving suicidality, substance misuse, sleep problems, and pain. Adults who exhibited a more severe syndrome of despair-related maladies at midlife tended to have had early-onset emotional and behavioral disorders [ß = 0.23, 95% CI (0.16-0.30), p < 0.001], even after adjusting for sex, childhood SES, and childhood IQ. A more pronounced midlife despair syndrome was observed among adults who, as adolescents, were diagnosed with a greater number of mental disorders [ß = 0.26, 95% CI (0.19-0.33), p < 0.001]. Tests of diagnostic specificity revealed that associations generalized across different adolescent mental disorders. CONCLUSIONS: Midlife adults who exhibited a more severe syndrome of despair-related maladies tended to have had psychopathology as adolescents. Prevention and treatment of adolescent psychopathology may mitigate despair-related maladies at midlife and ultimately reduce deaths of despair.
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Transtornos Mentais , Transtornos do Sono-Vigília , Transtornos Relacionados ao Uso de Substâncias , Adulto , Humanos , Adolescente , Criança , Pessoa de Meia-Idade , Transtornos Mentais/epidemiologia , Psicopatologia , Dor , Transtornos do Sono-Vigília/epidemiologiaRESUMO
BACKGROUND: Research from various countries has shown increases in alcohol- and drug-related deaths and suicide, known as 'deaths of despair' over recent decades, particularly among low-educated middle-aged individuals. However, little is known about trends in death-of-despair causes in Spain. Therefore, we aim to descriptively examine this among 25-64-year-olds from 1980 to 2019 and by educational attainment for the years 2017-19. METHODS: We obtained mortality and population data from the National Institute of Statistics to estimate age-standardized mortality rates and assess educational inequalities using the relative index of inequality (RII). RESULTS: Deaths of despair as a share of total mortality slightly increased from 2000 onwards, particularly among 25-64-year-old men (from 9 to 10%). Only alcohol-related mortality declined relatively more since 1980 compared with all-cause mortality. Regarding educational differences, low-educated men presented higher mortality rates in all death-of-despair causes (alcohol-related: RII 3.54 (95% CI: 2.21-5.66); drug-related: RII 3.49 (95% CI: 1.80-6.77); suicide: RII 1.97 (95% CI: 1.49-2.61)). Women noteworthy differences were only observed for alcohol-related (RII 3.50 (95% CI: 2.13-5.75)). CONCLUSIONS: Findings suggest an increasing proportion of deaths of despair among 25-64-year-olds since 2000, particularly among men. Public health policies are needed to reduce and prevent these premature and preventable causes of mortality.
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Sucesso Acadêmico , Suicídio , Pessoa de Meia-Idade , Masculino , Humanos , Feminino , Adulto , Causas de Morte , Espanha/epidemiologia , Escolaridade , Mortalidade , Fatores SocioeconômicosRESUMO
Chronic stress is a core risk factor for developing a myriad of neurological disorders, including major depression. The chronicity of such stress can lead to adaptive responses or, on the contrary, to psychological maladaptation. The hippocampus is one of the most affected brain regions displaying functional changes in chronic stress. Egr1, a transcription factor involved in synaptic plasticity, is a key molecule regulating hippocampal function, but its role in stress-induced sequels has been poorly addressed. Emotional and cognitive symptoms were induced in mice by using the chronic unpredictable mild stress (CUMS) protocol. We used inducible double-mutant Egr1-CreERT2 x R26RCE mice to map the formation of Egr1-dependent activated cells. Results show that short- (2 days) or long-term (28 days) stress protocols in mice induce activation or deactivation, respectively, of hippocampal CA1 neural ensembles in an Egr1-activity-dependent fashion, together with an associated dendritic spine pathology. In-depth characterization of these neural ensembles revealed a deep-to-superficial switch in terms of Egr1-dependent activation of CA1 pyramidal neurons. To specifically manipulate deep and superficial pyramidal neurons of the hippocampus, we then used Chrna7-Cre (to express Cre in deep neurons) and Calb1-Cre mice (to express Cre in superficial neurons). We found that specific manipulation of superficial but not deep pyramidal neurons of the CA1 resulted in the amelioration of depressive-like behaviors and the restoration of cognitive impairments induced by chronic stress. In summary, Egr1 might be a core molecule driving the activation/deactivation of hippocampal neuronal subpopulations underlying stress-induced alterations involving emotional and cognitive sequels.
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Região CA1 Hipocampal , Cognição , Proteína 1 de Resposta de Crescimento Precoce , Emoções , Células Piramidais , Estresse Psicológico , Animais , Camundongos , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Doença Crônica , Região CA1 Hipocampal/fisiopatologiaRESUMO
There is currently an emphasis on the biopsychosocial concept of pain in pain therapy programs. However, the complexity of chronic pain, in particular its importance for those affected by it, can only be insufficiently captured with this concept. This is due to the fact that, to date, one core aspect of the phenomenon chronic pain has only rarely been taken into account: its existential character. Chronic pain can threaten the self-image and the individual's understanding of the world, their wishes and goals in life, and ultimately the entire integrity of those affected. Statements by chronic pain sufferers show that such pain always represents an existential experience and affects the person as a whole. Two aspects make this very clear: the existential despair of the pain on the one hand, as well as questions of meaning and reorientation on the other. Current treatment concepts, however, do not adequately consider the existential character of such challenges. Chronic pain should therefore always be perceived and treated from a holistic perspective. In this context, the aspects of recognizing its uniqueness, helping to express the pain and giving space to the experience are to be given special consideration in order to support chronic pain patients in dealing with their pain.
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Dor Crônica , Humanos , Dor Crônica/terapia , Dor Crônica/psicologia , Existencialismo , Manejo da DorRESUMO
Women have a high susceptibility to the negative effects of stress. Hormonal changes experienced throughout their reproductive life partially contribute to a higher incidence of anxiety and depression symptoms, particularly, during natural or surgical menopause. In preclinical research, the flavonoid chrysin (5,7-dihydroxyflavone) exerts anxiolytic- and anti-despair-like effects; however, it is unknown whether chrysin exerts a protective effect against the behavioral changes produced by acute stress on locomotor activity and behavioral despair in rats at 12-weeks post-ovariectomy. Ovariectomized female Wistar rats were assigned to eight groups: vehicle group (10% DMSO), three groups with chrysin and three groups with the same dose of allopregnanolone (0.5, 1, and 2 mg/kg), and one group with diazepam (2 mg/kg). The treatments were administered for seven consecutive days and the effects were evaluated in the locomotor activity and swimming tests. Chrysin (2 mg/kg) increased the latency to first immobility and decreased the total immobility time in the swimming test as the reference drugs allopregnanolone and diazepam (2 mg/kg); while locomotor activity prevented the behavioral changes produced by swimming. In conclusion, chrysin exerts a protective effect against the behavioral changes induced by acute stress, similarly to the neurosteroid allopregnanolone and the benzodiazepine diazepam in rats subjected to a surgical menopause model.
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Flavonoides , Pregnanolona , Ratos , Feminino , Animais , Ratos Wistar , Pregnanolona/farmacologia , Flavonoides/farmacologia , Diazepam/farmacologia , MenopausaRESUMO
Applying machine-based learning and synthetic cognition, commonly referred to as artificial intelligence (AI), to medicine intimates prescient knowledge. The ability of these algorithms to potentially unlock secrets held within vast data sets makes them invaluable to healthcare. Complex computer algorithms are routinely used to enhance diagnoses in fields like oncology, cardiology, and neurology. These algorithms have found utility in making healthcare decisions that are often complicated by seemingly endless relationships between exogenous and endogenous variables. They have also found utility in the allocation of limited healthcare resources and the management of end-of-life issues. With the increase in computing power and the ability to test a virtually unlimited number of relationships, scientists and engineers have the unprecedented ability to increase the prognostic confidence that comes from complex data analysis. While these systems present exciting opportunities for the democratization and precision of healthcare, their use raises important moral and ethical considerations around Christian concepts of autonomy and hope. The purpose of this essay is to explore some of the practical limitations associated with AI in medicine and discuss some of the potential theological implications that machine-generated diagnoses may present. Specifically, this article examines how these systems may disrupt the patient and healthcare provider relationship emblematic of Christ's healing mission. Finally, this article seeks to offer insights that might help in the development of a more robust ethical framework for the application of these systems in the future.
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Affective behaviours and mental health are profoundly affected by disturbances in circadian rhythms. Casein kinase 1 epsilon (CSNK1E) is a core component of the circadian clock. Mice with tau or null mutation of this gene have shortened and lengthened circadian period respectively. Here, we examined anxiety-like, fear, and despair behaviours in both male and female mice of these two different mutants. Compared with wild-type mice, we found reductions in fear and anxiety-like behaviours in both mutant lines and in both sexes, with the tau mutants exhibiting the greatest phenotypic changes. However, the behavioural despair had distinct phenotypic patterns, with markedly less behavioural despair in female null mutants, but not in tau mutants of either sex. To determine whether abnormal light entrainment of tau mutants to 24-h light-dark cycles contributes to these phenotypic differences, we also examined these behaviours in tau mutants on a 20-h light-dark cycle close to their endogenous circadian period. The normalized entrainment restored more wild-type-like behaviours for fear and anxiety, but it induced behavioural despair in tau mutant females. These data show that both mutations of Csnk1e broadly affect fear and anxiety-like behaviours, while the effects on behavioural despair vary with genetics, photoperiod, and sex, suggesting that the mechanisms by which Csnk1e affects fear and anxiety-like behaviours may be similar, but distinct from those affecting behavioural despair. Our study also provides experimental evidence in support of the hypothesis of beneficial outcomes from properly entrained circadian rhythms in terms of the anxiety-like and fear behaviours.
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Caseína Quinase 1 épsilon , Relógios Circadianos , Animais , Caseína Quinase 1 épsilon/genética , Ritmo Circadiano/genética , Feminino , Masculino , Camundongos , Atividade Motora , FotoperíodoRESUMO
Repetitive transcranial magnetic stimulation (rTMS) could effectively relieve the pain and depression in neuropathic pain (NP) patients. However, the specific treatment parameters and exact mechanism are still unclear. Our purpose is to observe the effects of rTMS on pain and despair-like behaviour in chronic constriction injury (CCI) rats and explore its possible mechanism. Thirty-two 8-week-old male Sprague-Dawley rats were randomly divided into four groups: sham operation group (S, n = 8), CCI group (n = 8), 1 Hz-rTMS group (n = 8) and 10 Hz-rTMS group (n = 8). The rTMS was applied to the left dorsal anterior agranular insular (AId) 1 week after the operation, once a day, 5 days/week for 4 consecutive weeks. Mechanical hyperalgesia, despair-like behaviours and sciatic nerve function were used to evaluate the effects of rTMS. Besides, glucose metabolism, the metabotropic glutamate receptors 5 (mGluR5), N-Methyl-D-Aspartic acid receptor type 2B (NMDAR2B), tumour necrosis factor-α (TNF-α), interleukin-6 (Ll-6) and interleukin-1ß (Ll-1ß) in AId were tested to explore the possible mechanism. Compared with 1 Hz-rTMS, the rats of 10 Hz-rTMS had higher the mechanical hyperalgesia, higher sugar preference and shorter swimming immobility time. Besides, the expressions of mGluR5, NMDAR2B, TNF-α, Ll-1ß and Ll-6 both in 1 Hz-rTMS and 10 Hz-rTMS groups were reduced compared with the CCI group; the 10 Hz-rTMS group had a more decrease than that of 1 Hz-rTMS. Furthermore, the [18]F-FDG uptake was lower than that in the 1 Hz-rTMS group. Compared with 1 Hz-rTMS, 10 Hz-rTMS could more effectively relieve mechanical hyperalgesia and reverse despair-like behaviour in rats. The mechanism could be related to regulating mGluR5/NMDAR2B-related inflammatory signalling pathways in the AId.
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Hiperalgesia , Neuralgia , Animais , Constrição , Hiperalgesia/metabolismo , Masculino , Neuralgia/metabolismo , Doenças Neuroinflamatórias , Ratos , Ratos Sprague-Dawley , Estimulação Magnética Transcraniana , Fator de Necrose Tumoral alfa/metabolismoRESUMO
This paper estimates the impact of Daylight Saving Time (DST) on deaths from suicide and substance abuse in the United States. Using Multiple Cause-of-Death Mortality Data from the National Vital Statistics System of the National Center for Health Statistics from 1979 to 1988, the effect is identified in two ways: a regression discontinuity design that exploits discrete time changes in the Spring and Fall; and a fixed effects model that uses a policy change and a switching mechanism that introduces random variation to DST's start and end dates. This is one of the first attempts to estimate the impact of DST on deaths due to suicide and substance abuse and the first to use either identification strategy. The results from both methods suggest that the sleep disruptions during the Spring transition cause the suicide rate to rise by 6.25 percent and the death rate from suicide and substance abuse combined to increase by 6.59 percent directly after the time change. There is no evidence for any change in these outcomes during the Fall transition. The contrasting results from Spring to Fall suggest the entire effect can be attributed to disruptions in sleep patterns rather than changes in ambient light exposure.
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Transtornos Relacionados ao Uso de Substâncias , Suicídio , Humanos , Estações do Ano , Estados Unidos/epidemiologiaRESUMO
There has been plenty of philosophical discussion about the morality and/or rationality of suicide and physician-assisted suicide. There has also been plenty of discussion about non-prosecution policies (such as the British DPP 2010 Guidance) as a legal response to cases of one friend assisting the suicide of another. There has been much less attention paid to the particular conversations that might follow the request for suicidal assistance, and to the particular kinds of moral complexity involved. I will consider a 'Subject', who wants to commit suicide, but lacks the means or the information to do so, and therefore asks his 'Friend' for assistance. (Importantly, the Friend is not a physician.) Without aiming for anything comprehensive or theoretical, I sketch three 'easier' cases and two 'harder' cases, in order to explore the sorts of things that might be said, and thought, by each party, based on the different sources of meaning and morality.
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Médicos , Suicídio Assistido , Amigos , Humanos , Princípios MoraisRESUMO
Serotoninergic psychedelics such as psilocybin have been reported to elicit a long-lasting reduction in depressive symptoms. Although the main target for serotoninergic psychedelics, serotonin type 2A receptor (5-HT2A), has been established, the possible mechanism of the antidepressant action of psychedelics remains unknown. Using the mouse forced swim test model, we examined whether the administration of the synthetic serotoninergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) would modulate 5-HT2A receptor levels in the medial prefrontal cortex (mPFC) and revert stress-induced changes in behavior. Mice subjected to swim stress developed a passive stress-coping strategy when tested in the forced swim test 6 days later. This change in behavior was not associated with the hypothesized increase in 5-HT2A receptor-dependent head twitch behaviors or consistent changes in 5-HT2A receptor levels in the mPFC. When DOI was administered 1 day before the forced swim test, a low dose (0.2 mg/kg i.p.) unexpectedly increased immobility while a high dose (2 mg/kg i.p.) had no significant effect on immobility. Nevertheless, DOI evoked a dose-dependent decrease in 5-HT2A levels in the mPFC of mice previously exposed to swim stress. Our findings do not support the hypothesis that the downregulation of 5-HT2A receptors in the mPFC contributes to the antidepressant-like properties of serotoninergic psychedelics.