Construal Level Theory states that psychologically proximal outcomes are construed concretely while psychologically distal outcomes are construed abstractly. Previous research suggests that the ...principles of Construal Level Theory can be applied to enhance self-control, as measured by delay discounting. The present studies replicate and expand on this work by examining whether theory-informed priming manipulations lead to delay discounting reductions in a repeated-measures design. Study 1 conceptually replicated previous work, with reduced delay discounting observed as a function of thinking abstractly. Studies 2 and 3 expanded on this work by reinterpreting (a) preference for immediate outcomes as preference for outcomes that are construed concretely, and (b) dispreference for delayed outcomes as dispreference for outcomes that are construed abstractly. Study 2 provided support for the first interpretation, as reduced delay discounting was observed as a function of thinking concretely about the future. Study 3 provided support for the second interpretation, as reduced delay discounting was observed as a function of thinking abstractly about the present. In studies 1 and 3, significant condition × order interactions were observed. In all three studies, the same impact of order of exposure to priming manipulation was observed, indicating specific carryover effects.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Excessive discounting of future rewards has been observed in a variety of disorders and has been linked both to valuation of the past and to memory of past events. Methods To explore the ...functionality of discounting and memory, we examined whether training of working memory would result in less discounting of future rewards. In this study, 27 adults in treatment for stimulant use were randomly assigned to receive either working memory training or control training according to a yoked experimental design. Measures of delay discounting and several other cognitive behaviors were assessed pre- and posttraining. Results Rates of discounting of delayed rewards were significantly reduced among those who received memory training but were unchanged among those who received control training; other cognitive assessments were not affected by memory training. Discount rates were positively correlated with memory training performance measures. Conclusions To our knowledge, this is the first study demonstrating that neurocognitive training on working memory decreases delay discounting. These results offer further evidence of a functional relationship between delay discounting and working memory.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Freezing in the levodopa-medicated-state (ON-state) is a debilitating feature of Parkinson's disease without treatment options. Studies detailing the distinguishing features between people with ...freezing of gait that improves with levodopa and those whose freezing continues even on levodopa are lacking.
To characterize the gross motor, gait, and non-motor features of this phenotype.
Instrumented continuous gait was collected in the levodopa-medicated-state in 105 patients: 43 non-freezers (no-FOG), 36 with freezing only OFF-levodopa (OFF-FOG) and 26 with freezing both ON- and OFF-levodopa (ONOFF-FOG). Evaluation of motor and non-motor disease features was undertaken using validated scales. A linear mixed model with age, sex, disease duration, and motor UPDRS scores as covariates was used to determine differences in spatiotemporal gait and non-motor disease features among the groups.
Compared to OFF-FOG, the ONOFF-FOG group had greater disease severity (on the Unified Parkinson's disease Rating Scale) and worse cognition (on the Montreal Cognitive Assessment, Frontal Assessment Battery and Scales for Outcome in Parkinson's disease-Cognition scales) and quality of life (on the PDQ-39), but similar mood (on the Hamilton depression and anxiety scales) and sleep quality (on Epworth sleepiness scale and RBD questionnaire). For several gait features, differences between the ONOFF-OFF groups were at least as large and in the opposite direction as differences between OFF-no groups, controlling for disease severity. Variability in ONOFF-FOG was greater than in other groups. Using results from our study and others, a power analysis for a potential future study reveals sample sizes of at least 80 ONOFF and 80 OFF-FOG patients would be needed to detect clinically meaningful differences.
Intra-patient variability in spatiotemporal gait features was much greater in ONOFF-FOG than in the other two groups. Our results suggest that multifactorial deficits may lead to ONOFF-FOG development.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
N-of-1 trials allow inference between two treatments given to a single individual. Most often, clinical investigators analyze an individual's N-of-1 trial data with usual t-tests or simple ...nonparametric methods. These simple methods do not account for serial correlation in repeated observations coming from the individual. Existing methods accounting for serial correlation require simulation, multiple N-of-1 trials, or both. Here, we develop t-tests that account for serial correlation in a single individual. The development includes effect size and precision calculations, both of which are useful for study planning. We then use Monte Carlo simulation to evaluate statistical properties of these serial t-tests, namely, Type I and II errors, and confidence interval widths, and compare these statistical properties to those of analogous usual t-test. The serial t-tests clearly outperform the usual t-tests commonly used in reporting N-of-1 results. Examples from N-of-1 clinical trials in fibromyalgia patients and from a behavioral health setting exhibit how accounting for serial correlation can change inferences. These t-tests are easily implemented and more appropriate than simple methods commonly used; however, caution is needed when analyzing only a few observations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Long Interspersed Nuclear Element 1 (LINE-1) retrotransposons are the major repetitive elements in mammalian genomes. LINE-1s are well-accepted as driving forces of evolution and critical regulators ...of the expression of genetic information. Alterations in LINE-1 DNA methylation may lead to its aberrant activity and are reported in virtually all human cancers and in experimental carcinogenesis. In this study, we investigated the endogenous DNA methylation status of the 5' untranslated region (UTR) of LINE-1 elements in the bone marrow hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs), and mononuclear cells (MNCs) in radioresistant C57BL/6J and radiosensitive CBA/J mice and in response to ionizing radiation (IR). We demonstrated that basal levels of DNA methylation within the 5'-UTRs of LINE-1 elements did not differ significantly between the two mouse strains and were negatively correlated with the evolutionary age of LINE-1 elements. Meanwhile, the expression of LINE-1 elements was higher in CBA/J mice. At two months after irradiation to 0.1 or 1 Gy of
Cs (dose rate 1.21 Gy/min), significant decreases in LINE-1 DNA methylation in HSCs were observed in prone to radiation-induced carcinogenesis CBA/J, but not C57BL/6J mice. At the same time, no residual DNA damage, increased ROS, or changes in the cell cycle were detected in HSCs of CBA/J mice. These results suggest that epigenetic alterations may potentially serve as driving forces of radiation-induced carcinogenesis; however, future studies are needed to demonstrate the direct link between the LINE-1 DNA hypomethylation and radiation carcinogenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Accidental exposure to ionizing radiation may lead to delayed effects of acute radiation exposure (DEARE) in many organ systems. Activated protein C (APC) is a known mitigator of the acute radiation ...syndrome. To examine the role of APC in DEARE, we used a transgenic mouse model with 2- to 3-fold increased plasma levels of APC (high in APC, APCHi). Male and female APCHi mice and wild-type littermates were exposed to 9.5 Gy γ-rays with their hind-legs (bone marrow) shielded from radiation to allow long-term survival. At 3 and 6 months after irradiation, cardiac function was measured with ultrasonography. At 3 months, radiation increased cardiac dimensions in APCHi males, while decreases were seen in wild-type females. At this early time point, APCHi mice of both sexes were more susceptible to radiation-induced changes in systolic function compared to wild-types. At 6 months, a decrease in systolic function was mainly seen in male mice of both genotypes. At 6 months, specimens of heart, small intestine and dorsal skin were collected for tissue analysis. Female APCHi mice showed the most severe radiation-induced deposition of cardiac collagens but were protected against a radiation-induced loss of microvascular density. Both male and female APCHi mice were protected against a radiation induced upregulation of toll-like receptor 4 in the heart, but this did not translate into a clear protection against immune cell infiltration. In the small intestine, the APCHi genotype had no effect on an increase in the number of myeloperoxidase positive cells (seen mostly in females) or an increase in the expression of T-cell marker CD2 (males). Lastly, both male and female APCHi mice were protected against radiation-induced epidermal thickening and increase in 3-nitrotyrosine positive keratinocytes. In conclusion, prolonged high levels of APC in a transgenic mouse model had little effects on indicators of DEARE in the heart, small intestine and skin, with some differential effects in male compared to female mice.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tandem gait performance reportedly predicts fall risk in people with Parkinson's disease (PwPD) and help distinguish PwPD from atypical parkinsonism. In a cross-sectional study, we previously showed ...that tandem gait step-width widens with increasing Hoehn and Yahr (H&Y) staging scores. In this longitudinal study, we aimed to determine if progression in tandem gait deficits is dependent on disease severity in PwPD.
Participants underwent an instrumented tandem gait measurement every 6 months for at least 2 years. The mean and variability of 4 tandem gait parameters were calculated at each visit: step-width, step-length, step-time, and step-velocity. The change in these parameters over time for 3 H&Y groups (stage 1, 2 and 2.5+) compared to aging controls was determined using a random coefficients regression model. The annual percent change in tandem gait parameters was correlated with initial disease features using Kendall's τB.
66 participants were analyzed (46 PD, 20 controls). Mean step-width increased over time in an H&Y stage-dependent manner, with H&Y 2 and H&Y 2.5+ experiencing increases of 6% and 10% per year (p = 0.001 and 0.024 respectively). Annual percent-change in step-width was correlated with initial motor Unified Parkinson's Disease Rating Scale (UPDRS) scores (Kendall's τB = 0.229), total UPDRS scores (τB = 0.249), H&Y scores (τB = 0.266) and inversely correlated with Montreal Cognitive Assessment (MoCA) scores (τB = −0.209; ps ≤ 0.019).
Tandem gait step-width widens over time more rapidly in more severely affected PD patients. These results suggest that tandem gait should be routinely clinically evaluated and considered in the management of imbalance in PwPD.
•Tandem gait step-width increases over time in Parkinson's disease.•Tandem gait step-width increases at a faster rate in more severe Parkinson's disease.•Widening of tandem gait step-width is associated with more severe cognitive deficits.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Given the lack of consensus regarding changes in temporal and probability discounting as a function of smoking abstinence in cigarette smokers, the present study comprehensively examined possible ...changes in these processes following a period of acute smoking abstinence consistent with elevated withdrawal symptoms and craving.
Computerized temporal and probability discounting assessments were collected from cigarette smokers following normal smoking and 24-hr smoking abstinence, with the order of normal smoking and abstinence sessions counterbalanced across participants. Other conditions included commodity (money and cigarettes), sign (gains and losses), and magnitude ($50 and $1,000).
Twenty four-hour smoking abstinence resulted in a reduction in expired carbon monoxide to near-zero levels and increases in withdrawal and craving. Examination of discounting parameters as a function of smoking abstinence revealed a general pattern of increase in the temporal discounting of monetary gains and losses following abstinence but not in the temporal discounting of cigarettes nor probability discounting of money or cigarettes. Pearson correlations also revealed an expected pattern of significant relationships.
The present study is a comprehensive examination of temporal and probability discounting following smoking abstinence and reveals a generalized change in intertemporal decision making for monetary rewards.
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BFBNIB, NMLJ, NUK, PNG, UL, UM, UPUK
Over the years, animal models of local heart irradiation have provided insight into mechanisms of and treatments for radiation-induced heart disease in human populations. However, it is not ...completely clear which manifestations of radiation injury are most commonly seen after whole heart irradiation, and whether certain biological factors impact experimental results. Combining 9 homogeneous studies in rat models of whole heart irradiation from one laboratory, we sought to identify experimental and/or biological factors that impact heart outcomes. We evaluated the usefulness of including (1) heart rate and (2) bodyweight as covariates when analyzing biological parameters, and (3) we determined which echocardiography, histological, and immunohistochemistry parameters are most susceptible to radiation effects. Finally, (4) as an educational example, we illustrate a hypothetical sample size calculation for a study design commonly used in evaluating radiation modifiers, using the pooled estimates from the 9 rat studies only for context. The results may assist investigators in the design and analyses of pre-clinical studies of whole heart irradiation.
We made use of data from 9 rat studies from our labs, 8 published elsewhere in 2008-2017, and one unpublished study. Echocardiography, histological, and immunohistochemical parameters were collected from these studies. Using mixed effects analysis of covariance models, we estimated slopes for heart rate and bodyweight and estimated the radiation effect on each of the parameters.
Bodyweight was related to most echocardiography parameters, and heart rate had an effect on echocardiography parameters related to the diameter of the left ventricle. For some parameters, there was evidence that heart rate and bodyweight relationships with the parameter depended on whether the rats were irradiated. Radiation effects were found in systolic measures of echocardiography parameters related to the diameter of the left ventricle, with ejection fraction and fractional shortening, with atrial wall thickness, and with histological measures of capillary density, collagen deposition, and mast cells infiltration in the heart.
Accounting for bodyweight, as well as heart rate, in analyses of echocardiography parameters should reduce variability in estimated radiation effects. Several echocardiography and histological parameters were particularly susceptible to whole heart irradiation, showing robust effects compared to sham-irradiation. Lastly, we provide an example approach for a sample size calculation that will contribute to a rigorous study design and reproducibility in experiments studying radiation modifiers.
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