The effects of modafinil and atomoxetine on dopamine signaling in the striatal subregions of the rat

In an effort to combat diseases and disorders that impede our health, comfort and well-being, an abundance of prescription drugs have emerged in the past 60 years. Many prescription drugs have remarkable efficacy for treating the primary symptoms of these diseases and disorders; however, some drugs carry negative side effects that impose their own adverse symptoms, albeit, often to a lesser degree than the primary symptoms. Thus, one of the main objectives of the pharmaceutical industry is to innovate and develop novel therapeutics, which remediate the primary symptoms of disease and lack undesirable negative side effects. However, in order to develop effective novel therapeutics, a comprehensive understanding of the underlying mechanisms of current drugs is critical. The work within this thesis investigates the mechanisms of two neuroactive drugs, which are commonly prescribed by physicians. Chapter I investigates modafinil (Provigil®), which is therapeutic for sleep and psychiatric disorders, and drug addiction therapy. Chapter II investigates atomoxetine (Strattera®), which is prescribed for attention deficit hyperactivity disorder (ADHD) and possesses limited abuse potential, in contrast to current ADHD medications, Adderall® and Ritalin®, which are addictive. The effects of modafinil and atomoxetine on phasic dopamine signaling were investigated. Phasic dopamine signaling has been identified critical for reward learning and seeking, and is hypothesized to contribute to deficits in ADHD and drug addiction. The results herein suggest that alterations in phasic dopamine signaling are involved in the underlying mechanism of modafinil and atomoxetine action and may ultimately contribute to their therapeutic efficacy

Four-year trajectories of episodic memory decline in mid-late life by living arrangements : A cross-national comparison between China and England

Publisher Copyright: © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.There is mixed evidence on the association between living arrangements and mid-late life cognition, which may be due to distinct familial arrangements and preferences between populations. To address such heterogeneity, we assessed these associations in China and England. Four-year trajectories of episodic memory scores (0–20, word recall test) by living arrangements (living with partner only, living with partner and children/grandchildren, living with no partner but with children/grandchildren, and living alone) were estimated using latent growth curve modelling for men and women aged 50+ from China (n=12 801) and England (n=10 964). After adjusting for baseline socioeconomic, health behaviours and health covariates, worse baseline memory was found in Chinese adults living with no partner but with children/grandchildren and in Chinese women living with partner and children/grandchildren, compared with those living with partner only. Better baseline memory was associated with living alone in English women. A faster memory decline was found in Chinese men living with no partner but with children/grandchildren (−0.122 word/year, 95% CI −0.213 to –0.031), as well as in English women living with children/grandchildren with (−0.114, 95% CI −0.180 to –0.049) or without (−0.118, 95% CI −0.209 to –0.026) a partner, and those living alone (−0.075, 95% CI −0.127 to –0.024). No differences at baseline nor over follow-up were found between English men in different living arrangements. Overall, our findings did not confirm the protective effects of co-residence with children/grandchildren, nor the detrimental effects of living alone on mid-late life cognition in China and England.Peer reviewe

Alcohol use disorder increases the risk of nonfatal and fatal cardiovascular disease : an 11-year follow-up of a Polish population-based cohort. The HAPIEE study

INTRODUCTION Self‑reported alcohol intake is an inaccurate measure, especially in heavy drinkers. The simple 4‑item CAGE questionnaire assessing alcohol use disorder was found to be positively associated with alcohol consumption and mortality. OBJECTIVES This study aimed to investigate the relationship between alcohol use disorder assessed with the CAGE questionnaire and the incidence of cardiovascular disease (CVD) in a population‑based Polish sample. PATIENTS AND METHODS A cohort study with an 11‑year follow‑up was conducted. A random sample of 10 728 residents of Kraków aged 45 to 69 years completed baseline examination, including the CAGE questionnaire. Information on new cases of CVD was obtained from further questionnaires and confirmed by clinical diagnosis. Data on mortality and causes of death were obtained from the local registry, the Central Statistical Office, and the participants’ families. The effect of the CAGE score on the risk of CVD was assessed using Cox proportional hazard models. RESULTS The analysis included 7112 individuals who completed the CAGE questionnaire and were free of CVD at baseline. No alcohol use disorder was reported in 94% of the participants. There was a positive association between the CAGE score and the risk of CVD. In the fully adjusted model, compared with participants scoring 0, the hazard ratios among those scoring 3 and 4 points were 2.19 (95% CI, 1.43–3.37) and 2.79 (95% CI, 1.65–4.73), respectively. The association was somewhat stronger for fatal CVD. CONCLUSIONS We found a strong, graded association between the CAGE score and the risk of CVD incidence, which was independent of other risk factors for CVD. The CAGE questionnaire might be considered as an additional tool to identify individuals at high risk of CVD

Labour-Market Characteristics and Self-Rated Health: Evidence from the China Health and Retirement Longitudinal Study

In the face of labour-force ageing, understanding labour-market characteristics and the health status of middle-aged and older workers is important for sustainable social and economic development. Self-rated health (SRH) is a widely-used instrument to detect health problems and predict mortality. This study investigated labour-market characteristics that may have an impact on the SRH among Chinese middle-aged and older workers, using data from the national baseline wave of the China Health and Retirement Longitudinal Study. The analytical sample included 3864 individuals who at the time held at least one non-agricultural job. Fourteen labour-market characteristics were clearly defined and investigated. Multiple logistic regression models of the associations of each labour-market characteristic with SRH were estimated. Seven labour-market characteristics were associated with higher odds of poor SRH when controlled for age and sex. Employment status and earned income remained significantly associated with poor SRH, when controlling for all the sociodemographic factors and health behaviours. Doing unpaid work in family businesses is associated with 2.07 (95% CI, 1.51–2.84) times probability of poor SRH, compared with employed individuals. Compared with more affluent individuals (highest quintile of earned income), people in the fourth and fifth quintiles had 1.92 (95% CI, 1.29–2.86) times and 2.72 (95% CI, 1.83–4.02) times higher chance, respectively, of poor SRH. In addition, residence type and region were important confounders. Measures improving adverse working conditions should be taken to prevent future risk of impaired health among the Chinese middle-aged and older workforce

Reliability and predictive validity of two scales of self-rated health in China: results from China Health and Retirement Longitudinal Study (CHARLS)

Background Despite the widespread use of the single item self-rated health (SRH) question, its reliability has never been evaluated in Chinese population. Methods We used data from the China Health and Retirement Longitudinal Study, waves 1–4 (2011–2019). In wave 1, the same SRH question was asked twice, separated by other questions, on a subset of 4533 subjects, allowing us to examine the test–retest reliability of SRH. In addition, two versions of SRH questions (the WHO and US versions) were asked (n = 11,429). Kappa (κ), weighted kappa ($${\kappa}_{w}$$ κ w ), and polychoric correlation coefficient (ρ) were used for reliability assessment. Cox proportional-hazards models were estimated to assess the predictive validity of SRH measurement for mortality over 7 years of follow up. To do so, relative index of inequality (RII) and slope index of inequality (SII) were estimated for each SRH scale. Results There was moderate to substantial test–retest reliability (κ = 0.54, $${\kappa}_{w}$$ κ w =0.63) of SRH; 31% of respondents who used the same scale twice changed their ratings after answering other questions. There was strong positive association between the two SRH measured by the two scales (ρ > 0.8). Compared with excellent/very good SRH, adjusted hazard ratios (HR) of death are 2.30 (95% CI, 1.70–3.13) for the US version and 1.86 (95% CI, 1.33–2.60) for the WHO version. Using slope indices of inequality, the WHO version estimated slightly larger mortality differences (RII = 3.50, SII = 15.53) than the US version (RII = 3.25, SII = 14.80). Conclusions In Chinese middle-aged and older population, the reliability of SRH is generally good, although the two commonly used versions of SRH scales could not be compared directly. Both indices predict mortality, with similar predictive validity

Life Course Socioeconomic Position and Cognitive Aging Trajectories: A Cross-National Cohort Study in China and England

BACKGROUND AND OBJECTIVES: Cross-national research on cognitive aging inequality has largely concentrated on Western countries. It is unclear whether socioeconomic position (SEP) has similar effects on cognitive decline in emerging economies. We compared the association between life course SEP and cognitive function trajectories between China and England, the largest nation under state socialism and one of the oldest capitalist countries. RESEARCH DESIGN AND METHODS: This cross-cohort study examined participants aged 50 years and older from the China Health and Retirement Longitudinal Study (n = 12,832) and the English Longitudinal Study of aging (n = 8,875). Cognition z-scores were derived using comparable measures of memory and time orientation on 4 occasions. Life course SEP was self-reported by participants at baseline. Seven- to 8-year trajectories of cognition z-scores were estimated using latent growth curve modeling. Country- and gender-specific associations between childhood/adolescent deprivation, education, material wealth, and home ownership were evaluated in relation to model intercept (baseline level) and linear slope (annual rate of change) of cognition. RESULTS: After multivariable adjustment, education was positively associated with the greatest differences in baseline cognition across country and gender. Education was further linked to a slower rate of cognitive decline (z-score units per year); but compared with those with low education, Chinese men (b = 0.032) and women (b = 0.065) with high education had significantly slower declines than English men (b = -0.004) and women (b = 0.010) with high education. DISCUSSION AND IMPLICATIONS: Despite substantial between-cohort differences in downstream and upstream determinants of dementia, education provided the greatest benefits to cognitive aging in England but particularly in China

Mortality in Transition: Study Protocol of the PrivMort Project, a multilevel convenience cohort study

Background: Previous research using routine data identified rapid mass privatisation as an important driver of mortality crisis following the collapse of Communism in Central and Eastern Europe. However, existing studies on the mortality crisis relying on individual level or routine data cannot assess both distal (societal) and proximal (individual) causes of mortality simultaneously. The aim of the PrivMort Project is to overcome these limitations and to investigate the role of societal factors (particularly rapid mass privatisation) and individual-level factors (e.g. alcohol consumption) in the mortality changes in post-communist countries. Methods: The PrivMort conducts large-sample surveys in Russia, Belarus and Hungary. The approach is unique in comparing towns that have undergone rapid privatisation of their key industrial enterprises with those that experienced more gradual forms of privatisation, employing a multi-level retrospective cohort design that combines data on the industrial characteristics of the towns, socio-economic descriptions of the communities, settlement-level data, individual socio-economic characteristics, and individuals’ health behaviour. It then incorporates data on mortality of different types of relatives of survey respondents, employing a retrospective demographic approach, which enables linkage of historical patterns of mortality to exposures, based on experiences of family members. By May 2016, 63,073 respondents provided information on themselves and 205,607 relatives, of whom 102,971 had died. The settlement-level dataset contains information on 539 settlements and 12,082 enterprises in these settlements in Russia, 96 settlements and 271 enterprises in Belarus, and 52 settlement and 148 enterprises in Hungary. Discussion: In addition to reinforcing existing evidence linking smoking, hazardous drinking and unemployment to mortality, the PrivMort dataset will investigate the variation in transition experiences for individual respondents and their families across settlements characterized by differing contextual factors, including industrial characteristi

Prognostic Implications of Physical Activity on Mortality from Ischaemic Heart Disease: Longitudinal Cohort Study Data

Background: The prevalence of physical inactivity has been rising in many countries in recent years, adding to the burden of non-communicable diseases and affecting overall health worldwide. The aim of this study was to determine the comprehensive assessment of the prognostic value of physical activity in leisure time on mortality from ischemic heart disease (IHD) by gender separately for those respondents who were diagnosed with IHD and for those who were not diagnosed with IHD in their baseline health survey. Methods: In the baseline survey (2006–2008), 7100 men and women ages 45–72 were examined within the framework of the international study Health, Alcohol, and Psychosocial Factors in Eastern Europe (HAPIEE). A total of 6770 participants were available for statistical analysis (after excluding 330 respondents due to missing information on study variables). Physical activity was determined by leisure-time physical activities (hours/week). All participants in the baseline survey were followed up for IHD mortality events until 31 December 2018. Results: Using multivariate Cox regression analysis, it was found that moderate and higher levels of physical activity significantly reduced the risk of IHD mortality (HR = 0.54, p = 0.016 and HR = 0.60, p = 0.031, respectively) in men who were not diagnosed with IHD at baseline compared with physically inactive subjects. It was found that among men and women who were diagnosed with IHD at baseline, physical activity reduced the risk of mortality from IHD compared with those who were physically inactive (HR = 0.54, p = 0.021 and HR = 0.41, p = 0.025, respectively). Using mediation analysis, it was found that physical activity directly predicted statistically lower IHD mortality (p < 0.05) in men and women. Conclusion: High physical activity was a significant factor that directly predicted statistically lower IHD mortality in men, regardless of whether subjects had IHD at baseline or not. However, only moderate physical activity was a significant factor that directly predicted statistically lower IHD mortality in the women group with IHD at baseline

Trajectories in physical functioning at older age in relation to childhood and adulthood SES and social mobility: a population-based cohort study

IntroductionOlder age is associated with the deterioration of physical functioning (PF), and low PF is strongly related to poor quality of life among older people. We conducted a study to examine the trajectories of PF between middle and old age, considering sex differences as well as the association between socioeconomic status (SES) at different life stages and changes in PF.MethodsWe analyzed data from the Polish arm of the HAPIEE (Health, Alcohol and Psychosocial factors In Eastern Europe) study, including 1,116 men and 1,178 women aged 45–64 years at baseline. Adult and childhood SES and social mobility were assessed using a retrospectively focused questionnaire. PF was assessed using the 10-question SF-36 scale at baseline examination, face-to-face re-examination, and three postal surveys, covering up to 20 years (on average, 18 years). We employed Generalized Estimating Equations models to assess changes in PF scores over time and compare PF trajectories across different SES categories.ResultsAfter adjusting for age and other covariates, we found that, in both sexes, participants with always middle or high SES, as well as those who reported upward mobility, had higher PF scores at baseline compared to those with always low SES. A decline in PF between middle and old age was observed in all SES groups; however, the decline was slower in participants with always middle or high SES compared to those with always low SES.ConclusionThis cohort study revealed that lower SES and downward social mobility were cross-sectionally associated with poorer PF, while upward social mobility seemed to largely reverse the effect of low childhood SES. In addition to the cross-sectional associations observed at baseline, advantaged SES was also significantly associated with a slower decline in PF over an 18-year follow-up period

Determinants of depressive symptoms increase in older persons during the COVID-19 pandemic: evidence from Czech cohort study using repeated assessments

Background Numerous studies reported higher levels of mental health issues during the COVID-19 pandemic but only a minority used repeated measurements. We investigated change in depressive symptoms in the Czech ageing cohort and the impact of pre-existing and COVID-19-related stressors. Methods We used data on 2853 participants (mean age 73.4 years) from the Czech part of the prospective Health, Alcohol and Psychosocial factors In Eastern Europe cohort that participated in postal questionnaire surveys before (September 2017-June 2018) and during the pandemic (October 2020-April 2021). Participants reported their depressive symptoms using the Centre for Epidemiological Studies-Depression Scale including 10 (CESD-10) tool. A principal component analysis (PCA) was used to create representative components of the pandemic-related stressors. The impact of the stressors on change in depressive symptoms was tested using multivariable linear regression, after adjustment for age and potential confounders. Results Three patterns of the pandemic-related stressors ( financial stressors', social and perception stressors' and death and hospitalisation stressors') were extracted from the PCA. The mean CESD-10 score increased from 4.90 to 5.37 (p<0.001). In fully adjusted models, significantly larger increases in depression score were reported by older people (β=0.052; p=0.006), those with poor self-rated health (β=0.170; p<0.001), those who experienced death or hospitalisation of a close person (β=0.064; p<0.001), social deprivation (β=0.057; p<0.001), delays in healthcare (β=0.048; p=0.005) and those who suffered from COVID-19 (β=0.045; p=0.008). Conclusion This study confirms an increase in depressive symptoms in older persons during the pandemic and identified several pandemic-related risk factors suggesting that public health policies should address this vulnerable group by adopting the preventing strategies