Investigating psychological mechanisms of self-controlled decisions for food and leisure activity.

Maintaining a healthy body weight requires balancing energy intake and expenditure. While previous research investigated energy input or food decisions, little is known about energy output or leisure activity decisions. By combining experimental decision-making paradigms and computational approaches, we investigated the psychological mechanisms of self-controlled food and leisure activity decisions through the effects of reward-oriented and health-oriented preferences as well as body weight status, stress, and coping. Based on individual's responses, the self-controlled food and leisure activity choices were indexed as the proportions of "no" unhealthy but tasty (or enjoyable) (inhibitory self-control against short-term pleasure) and "yes" healthy but not tasty (or not enjoyable) responses (initiatory self-control for long-term health benefits). The successful self-control decisions for food and leisure activity were positively correlated with each other, r = 22, p < .01. In beta regression analyses, the successful self-controlled food decisions decreased as the taste-oriented process increased, ß = - 0.50, z = -2.99, p < .005, and increased as the health-oriented process increased, ß = 1.57, z = 4.68, p < .001. Similarly, the successful self-controlled leisure activity decisions decreased as the enjoyment-oriented process increased, ß = - 0.79, z = -5.31, p < .001, and increased as the health-oriented process increased, ß = 0.66, z = 2.19, p < .05. The effects of the other factors were not significant. Overall, our findings demonstrated the mutual interrelationship between food and leisure activity decision-making and suggest that encouraging health-oriented processes may benefit both energy input and expenditure domains and improve self-controlled choices.

Hazard function effects on promoting self-control in variable interval time-based interventions in rats.

The present experiments investigated properties of time-based interventions used to increase self-control. Rats received impulsive-choice assessments before and after interventions that consisted of different distributions of delays to reinforcement. In Experiment 1, rats received an intervention with an increasing hazard function where delays were more evenly distributed, a decreasing hazard function where delays were mostly short, or a constant hazard function where delays were exponentially distributed. Surprisingly, rats that received the decreasing hazard function made the most self-controlled choices. Response rates during intervention trials showed that rats anticipated reinforcement based on the shape of the distributions they received. In Experiment 2, rats received an intervention with a decreasing hazard function with a steep slope or a shallow slope. Both time-based interventions increased self-control and produced similar response-rate patterns, indicating that the slope of the decreasing hazard function may not play a strong role in intervention efficacy. While this research aligns with previous literature showing that time-based interventions improved self-control, exposure to short delays produced the biggest improvements. Ultimately, exposure to short delays may increase the subjective value of the larger-later choice while occasional long delays may promote the ability to wait, which may have important implications for translational applications.

A time-based intervention to treat impulsivity in male and female rats.

Time-based interventions have emerged as promising treatments for disorders associated with impulsivity. These interventions can be implemented to test their efficacy in preventing or treating impulsive choice in animal models of diseases related to impulsivity such as drug abuse. Impulsive choice is typically defined as choosing a smaller-sooner (SS) reward over a larger-later (LL) reward when the LL is relatively more optimal. Previous research has shown that these interventions promote LL choices in males and females, but sex differences have not been assessed. Because sex differences can complicate the application of therapies, it is critical to compare the effects of the intervention in males and females. The intervention group received exposure to 10-s and 30-s interval schedules, and the control rats received no delay to reward. Different impulsive choice tasks were used to assess the intervention efficacy across the two experiments. Following the intervention, reductions in impulsive choice were found in male and female rats, but the degree of improvement was inconsistent across sex and task. Bayesian analyses that combined the results revealed robust evidence of an overall intervention effect with the intervention group showing greater self-control, but there was no evidence for the intervention affecting males and females differently. Taken together, these results suggest that time-based interventions are effective tools to treat impulsivity in both males and females and offer promising translational capability to humans.

Cognitive and behavioral training interventions to promote self-control.

This review article discusses various cognitive and behavioral interventions that have been developed with the goal of promoting self-controlled responding. Self-control can exert a significant impact on human health and impulsive behaviors are associated with a wide range of diseases and disorders, leading to the suggestion that impulsivity is a trans-disease process. The self-control interventions include effort exposure, reward discrimination, reward bundling, interval schedules of reinforcement, impulse control training, and mindfulness training. Most of the interventions have been consistently shown to increase self-control, except for mindfulness training. Some of the successful interventions are long-lasting, whereas others may be transient. Most interventions are domain-specific, targeting specific cognitive and behavioral processes that relate to self-control rather than targeting overall self-control. For example, effort exposure appears to primarily increase effort tolerance, which in turn can improve self-control. Similarly, interval schedules primarily target interval timing, which promotes self-controlled responses. A diagram outlining a proposed set of intervention effects on self-control is introduced to motivate further research in this area. The diagram suggests that the individual target processes of the interventions may potentially summate to produce general self-control, or perhaps even produce synergistic effects. In addition, it is suggested that developing a self-control profile may be advantageous for aligning specific interventions to mitigate specific deficits. Overall, the results indicate that interventions are a promising avenue for promoting self-control and may help to contribute to changing health outcomes associated with a wide variety of diseases and disorders. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Durability and generalizability of time-based intervention effects on impulsive choice in rats.

Impulsive choice involves choosing a smaller-sooner (SS) reward over a larger-later (LL) reward. Due to the importance of timing processes in impulsive choice, time-based interventions have been developed to decrease impulsive choice. The present set of experiments assessed the durability and generalizability of time-based interventions. Experiment 1 assessed fixed interval (FI) or variable interval (VI) intervention efficacy over 9 months. The FI intervention decreased impulsive choice, and this effect persisted over time, but the VI intervention effects were only apparent when tested immediately after the intervention. Experiment 2 examined the generalizability of the FI and VI interventions on choice tasks manipulating the SS delay, LL delay, or LL magnitude. The FI intervention decreased sensitivity to delay, promoting LL choices in both delay tasks, but the VI intervention only altered choices when manipulating the SS delay. Experiment 3 further examined the FI intervention effects on tasks that manipulated the LL delay or magnitude immediately following the intervention. The intervention decreased sensitivity to both delay and magnitude. The experiments indicate that the FI intervention is effective at decreasing impulsive choice behavior for an extended period across changing delays and magnitudes, suggesting a relatively broad effect on choice behavior.

Three cases of multi-generational Pompe disease: Are current practices missing diagnostic and treatment opportunities?

Pompe disease (Glycogen storage disease type II, GSDII, or acid maltase deficiency) is an autosomal recessive metabolic myopathy with a broad clinical spectrum, ranging from infantile to late-onset presentations. In 2015, Pompe disease was added as a core condition to the Recommended Uniform Screening Panel for state newborn screening (NBS). The clinical importance of Pompe disease is evolving with the use of NBS, increasing awareness of the disease, and higher than previously reported disease prevalence; however, current practices miss additional diagnostic and potential treatment opportunities in close relatives of the family proband. In this report, we describe three families with multiple individuals in multiple generations affected by both infantile and late-onset clinical presentations of Pompe disease. The presence of multi-generational disease within these families highlights the importance of subsequent risk assessment through medical history and physical examination, with a low threshold for the screening of a proband's family members. We recommend enzymology (GAA activity assay) as the first screening method, as opposed to targeted mutation analysis, for at-risk family members. Given that the initial symptoms of the slowly progressive late-onset presentation of Pompe disease may be mild or non-specific, enzymatic testing of all parents of affected infants should be considered.

Anaplerotic therapy in propionic acidemia.

BACKGROUND: Propionic acidemia is a rare metabolic disorder caused by a deficiency of propionyl- CoA carboxylase, the enzyme converting propionyl-CoA to methylmalonyl-CoA that subsequently enters the citric acid cycle as succinyl-CoA. Patients with propionic acidemia cannot metabolize propionic acid, which combines with oxaloacetate to form methylcitric acid. This, with the defective supply of succinyl-CoA, may lead to a deficiency in citric acid cycle intermediates. PURPOSE: The objective of this study was to determine whether supplements with glutamine (400mg/kg per day), citrate (7.5mEq/kg per day), or ornithine α-ketoglutarate (400mg/kg per day) (anaplerotic agents that could fill up the citric acid cycle) would affect plasma levels of glutamine and ammonia, the urinary excretion of Krebs cycle intermediates, and the clinical outcome in 3 patients with propionic acidemia. METHODS: Each supplement was administered daily for four weeks with a two week washout period between supplements. The supplement that produced the most favorable changes was supplemented for 30 weeks following the initial study period and then for a 2 year extension. RESULTS: The urinary excretion of the Krebs cycle intermediates, α-ketoglutarate, succinate, and fumarate increased significantly compared to baseline during citrate supplementation, but not with the other two supplements. For this reason, citrate supplements were continued in the second part of the study. The urinary excretion of methylcitric acid and 3-hydroxypropionic acid did not change with any intervention. No significant changes in ammonia or glutamine levels were observed with any supplement. However, supplementation with any anaplerotic agents normalized the physiological buffering of ammonia by glutamate, with plasma glutamate and alanine levels significantly increasing, rather than decreasing with increasing ammonia levels. No significant side effects were observed with any therapy and safety labs (blood counts, chemistry and thyroid profile) remained unchanged. Motor and cognitive development was severely delayed before the trial and did not change significantly with therapy. Hospitalizations per year did not change during the trial period, but decreased significantly (p<0.05) in the 2years following the study (when citrate was continued) compared to the 2years before and during the study. CONCLUSIONS: These results indicate that citrate entered the Krebs cycle providing successful anaplerotic therapy by increasing levels of the downstream intermediates of the Krebs cycle: α-ketoglutarate, succinate and fumarate. Citrate supplements were safe and might have contributed to reduce hospitalizations in patients with propionic acidemia.

Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses.

BACKGROUND: Enzyme replacement therapy (ERT) has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD), a rapidly progressive neuromuscular disorder. Yet marked interindividual variability in response to ERT, primarily attributable to the development of antibodies to ERT, remains an ongoing challenge. Immune tolerance to ongoing ERT has yet to be described in the setting of an entrenched immune response. METHODS: Three infantile Pompe patients who developed high and sustained rhGAA IgG antibody titers (HSAT) and received a bortezomib-based immune tolerance induction (ITI) regimen were included in the study and were followed longitudinally to monitor the long-term safety and efficacy. A trial to taper the ITI protocol was attempted to monitor if true immune tolerance was achieved. RESULTS: Bortezomib-based ITI protocol was safely tolerated and led to a significant decline in rhGAA antibody titers with concomitant sustained clinical improvement. Two of the 3 IPD patients were successfully weaned off all ITI protocol medications and continue to maintain low/no antibody titers. ITI protocol was significantly tapered in the third IPD patient. B cell recovery was observed in all 3 IPD patients. CONCLUSION: This is the first report to our knowledge on successful induction of long-term immune tolerance in patients with IPD and HSAT refractory to agents such as cyclophosphamide, rituximab, and methotrexate, based on an approach using the proteasome inhibitor bortezomib. As immune responses limit the efficacy and cost-effectiveness of therapy for many conditions, proteasome inhibitors may have new therapeutic applications. FUNDING: This research was supported by a grant from the Genzyme Corporation, a Sanofi Company (Cambridge, Massachusetts, USA), and in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network (RDCRN).

Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: lessons learned from Pompe disease.

PURPOSE: High sustained antibody titers complicate many disorders treated with a therapeutic protein, including those treated with enzyme replacement therapy, such as Pompe disease. Although enzyme replacement therapy with alglucosidase alfa (Myozyme) in Pompe disease has improved the prognosis of this otherwise lethal disorder, patients who develop high sustained antibody titers to alglucosidase alfa enter a prolonged phase of clinical decline resulting in death despite continued enzyme replacement therapy. Clinically effective immune-tolerance induction strategies have yet to be described in the setting of an entrenched immune response characterized by high sustained antibody titers, wherein antibody-producing plasma cells play an especially prominent role. METHODS: We treated three patients with infantile Pompe disease experiencing marked clinical decline due to high sustained antibody titers. To target the plasma cell source of high sustained antibody titers, a regimen based on bortezomib (Velcade) was used in combination with rituximab, methotrexate, and intravenous immunoglobulin. RESULTS: The treatment regimen was well tolerated, with no obvious side effects. Patient 1 had a 2,048-fold, and patients 2 and 3 each had a 64-fold, reduction in anti-alglucosidase alfa antibody titer, with concomitant sustained clinical improvement. CONCLUSION: The addition of bortezomib to immunomodulatory regimens is an effective and safe treatment strategy in infantile Pompe disease, with potentially broader clinical implications.

Negotiating participation: how women living with disabilities address barriers to exercise.

Exercise participation among women living with disabilities can be limited as a result of pain, decreased muscle strength, and limited mobility. More "disabling" than these symptoms, however, is a lack of accessible exercise facilities in women's communities. Our study explores how material and social structures and functions existing and operating within women's communities and at community-based exercise facilities affect their participation. Interviews with 15 women living with disabilities were conducted and qualitatively analyzed. Participants discuss the benefits of their exercise participation, in addition to how they experience and negotiate structural and attitudinal barriers within community-based facilities.