The role of positive emotion in anorexia nervosa (AN) has been underappreciated in both theory and treatment. Yet, people with AN demonstrate high motivation for and sustained effort toward weight ...loss, achieving success to an extreme beyond the capability of most people. Positive emotion dysregulation may facilitate and reinforce such efforts. The positive emotion amplification (PE-AMP) model of AN describes a dynamic interplay between biologically based enhanced reward responding and cognitive-behavioral factors that amplify positive emotion, resulting in positive feedback cycles that motivate and reinforce weight loss behavior during the AN onset phase. These experiences subvert the pursuit of happiness by providing artificial senses of autonomy, competency, and relatedness to others (self-determination theory; Ryan & Deci, 2000) that provide a stark contrast to an otherwise negative emotional environment, resulting in the emergence and persistence of AN psychopathology as a self-sustaining sense of purpose. Ultimately, negative emotion, PE dysregulation, and artificial self-determination threats continue to drive AN behavior during the AN maintenance phase, pushing patients toward a genuine self-determination breakdown that can lead to hospitalization, health crises, relational strife and diminished quality of life, or even manifest in suicidal behavior. Future research directions and novel methodological approaches inspired by the PE-AMP model are discussed, as are important treatment implications for addressing this highly treatment-resistant disorder.
Pathological exercise in anorexia nervosa (AN) is a harmful behavior associated with a chronic course and poor prognosis. To date, no comprehensive theoretical model exists to describe pathological ...exercise in the context of AN, and as such, few treatments are effective at promoting direct and sustained pathological exercise extinction. Using a framework put forth by Wise & Koob (2014), debating the relative importance of positive and negative reinforcement in substance use, we present three hypotheses of behavioral reinforcement of exercise, encompassing biological, psychological, and environmental influences. Specifically, we argue that exercise is positively reinforced through receipt of biological and behavioral rewards, negatively reinforced through avoidance of aversive emotions, and that these two systems work in tandem over time to engrain pathological exercise as a habit. We then present suggestions for testing each of these hypotheses as future directions for the field.
Pathological exercise is a dangerous behavior often observed in eating disorders. Data investigating associated characteristics of pathological exercise in men are lacking, despite college men and ...women being at equally elevated risk for developing eating disorders.
Two hundred and twenty-four college men who exercise regularly completed a series of self-report questionnaires.
Latent profile analysis was used to identify empirically-derived homogenous subgroups of regular exercisers based on severity of other eating disorder attitudes and behaviors. Profiles were also compared on differences in exercise motivation and general psychopathology (i.e., depression, anxiety).
Fit indices indicated a three-profile solution. Profiles described an eating psychopathology group, a low psychopathology group, and a high exercise frequency group without eating disorder features.
Pathological exercise cannot be identified using exercise frequency alone. Other features like body dissatisfaction and exercise motivation style are relevant in identifying pathological exercise behavior in college men.
Anorexia nervosa (AN) is a complex and life‐threatening eating disorder. Current models of AN onset and maintenance have largely focused on the role of negative affect, while fewer models have ...described the role of positive affect (PA). Given that these theoretical models have informed current treatment approaches, and that treatment remains minimally effective for adults with AN, we advocate that targeting PA is one avenue for advancing maintenance models and by extension, treatment. We specifically propose that AN may arise and be chronically and pervasively maintained as a function of dysregulated PA in response to weight loss and weight loss behaviors (e.g., restriction, excessive exercise), to a degree that is not accounted for in existing models of AN. We present evidence from multiple domains, including biological, behavioral, and self‐report, supporting the hypothesis that PA dysregulation in AN contributes to the maintenance of the disorder. We conclude with several specific avenues for treatment development research as well as a call for future work elucidating the biological correlates of PA.
LPIN1 deficiency is an autosomal recessive form of early childhood recurrent severe rhabdomyolysis. Although not completely lucid yet, LPIN1 has been shown to modulate endosomal-related ...pro-inflammatory responses via peroxisome proliferator-activated receptor α (PPARα) and PPARγ coactivator 1α (PGC-1α). Treatment with anti-inflammatory agents such as dexamethasone has been proposed to improve the outcome.
We report a male toddler with recurrent episodes of complicated rhabdomyolysis, requiring prolonged intensive care unit admissions. Whole exome sequencing revealed a common homozygous 1.7 kb intragenic deletion in LPIN1. Despite optimal metabolic cares, the patient presented with an extremely high CK level where he benefited from intravenous dexamethasone (0.6 mg/Kg/day) for a period of 6 days.
Dexamethasone administration shortened the course of active rhabdomyolysis, intensive care admission and rehabilitation. It also prevented rhabdomyolysis-related complications such as kidney injury and compartment syndrome.
Our patient showed a favorable response to parenteral dexamethasone, in addition to hyperhydration with IV fluids, sufficient calorie intake, and restricted dietary fat. The improvement with corticosteroids suggests an uncontrolled inflammatory response as the pathophysiology of LPIN1 deficiency.
NGLY1-CDDG is a congenital disorder of deglycosylation caused by a defective peptide:N-glycanase (PNG). To date, all but one of the reported patients have been diagnosed through whole-exome or ...whole-genome sequencing, as no biochemical marker was available to identify this disease in patients. Recently, a potential urinary biomarker was reported, but the data presented suggest that this marker may be excreted intermittently.
In this study, we performed untargeted direct-infusion high-resolution mass spectrometry metabolomics in seven dried blood spots (DBS) from four recently diagnosed NGLY1-CDDG patients, to test for small-molecule biomarkers, in order to identify a potential diagnostic marker. Results were compared to 125 DBS of healthy controls and to 238 DBS of patients with other diseases.
We identified aspartylglycosamine as the only significantly increased compound with a median Z-score of 4.8 (range: 3.8–8.5) in DBS of NGLY1-CDDG patients, compared to a median Z-score of −0.1 (range: −2.1–4.0) in DBS of healthy controls and patients with other diseases.
The increase of aspartylglycosamine can be explained by lack of function of PNG. PNG catalyzes the cleavage of the proximal N-acetylglucosamine residue of an N-glycan from the asparagine residue of a protein, a step in the degradation of misfolded glycoproteins. PNG deficiency results in a single N-acetylglucosamine residue left attached to the asparagine residue which results in free aspartylglycosamine when the glycoprotein is degraded. Thus, we here identified aspartylglycosamine as the first potential small-molecule biomarker in DBS for NGLY1-CDDG, making a biochemical diagnosis for NGLY1-CDDG potentially feasible.
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Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). ...This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone).
A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2.
A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine TTSTAND velocity, week 24 least squares mean LSM SE 0.052 0.0130 rises/s vs week 48 LSM SE 0.0446 0.0138). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM SE 0.49 1.14; 95% CI -1.80 to 2.78,
= 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups.
Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone.
ClinicalTrials.gov Identifier: NCT03439670.
This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.
IntroductionLPIN1 deficiency is an autosomal recessive form of early childhood recurrent severe rhabdomyolysis. Although not completely lucid yet, LPIN1 has been shown to modulate endosomal-related ...pro-inflammatory responses via peroxisome proliferator-activated receptor α (PPARα) and PPARγ coactivator 1α (PGC-1α). Treatment with anti-inflammatory agents such as dexamethasone has been proposed to improve the outcome. CaseWe report a male toddler with recurrent episodes of complicated rhabdomyolysis, requiring prolonged intensive care unit admissions. Whole exome sequencing revealed a common homozygous 1.7 kb intragenic deletion in LPIN1. Despite optimal metabolic cares, the patient presented with an extremely high CK level where he benefited from intravenous dexamethasone (0.6 mg/Kg/day) for a period of 6 days. ResultsDexamethasone administration shortened the course of active rhabdomyolysis, intensive care admission and rehabilitation. It also prevented rhabdomyolysis-related complications such as kidney injury and compartment syndrome. ConclusionOur patient showed a favorable response to parenteral dexamethasone, in addition to hyperhydration with IV fluids, sufficient calorie intake, and restricted dietary fat. The improvement with corticosteroids suggests an uncontrolled inflammatory response as the pathophysiology of LPIN1 deficiency.
The Interpersonal Theory of Suicide proposes that suicidal behavior is so frightening that in order for an individual to engage in suicidal behavior, desire for suicide must be accompanied by the ...capability to do so. The capability for suicide is characterized by both a sense of fearlessness about death and elevated physiological pain tolerance. The primary aim of the current project was to reevaluate and revise the Acquired Capability for Suicide Scale (ACSS; Van Orden, Witte, Gordon, Bender, & Joiner, 2008) and offer a revision to the scale. Expert review of the scale items resulted in retaining 7 items assessing fearlessness about death. The recommendation is made to refer to the revised scale as the ACSS-Fearlessness About Death (ACSS-FAD) to reflect its content more specifically. A model with the 7 retained items provided good fit to the data across 3 independent samples of young adults. Multiple-group analyses examining measurement invariance across men and women found that the latent structure of the scale is comparable across gender. Data are also presented demonstrating convergent and discriminant validity for the scale in young adults and an inpatient psychiatric sample. Findings support the viability of the ACSS-FAD, indicating the scale has a replicable factor structure that generalizes across males and females and is substantively related to the construct of fearlessness about death. Taken together, the present work extends knowledge of the psychometrics of the ACSS-FAD in particular and the nature of fearlessness about death in general.
Research has identified functions of non-suicidal self-harm/self-injury (NSSH) but whether functions change over time, from adolescence to early adulthood, or predict the continuation of the behavior ...prospectively remains unclear. This study aimed to prospectively explore whether intrapersonal and interpersonal NSSH functions in adolescence predict repetition of self-harm (regardless of suicidal intent) and incident suicide attempts in early adulthood.
Participants were 528 individuals with NSSH at age 16 years from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort in the UK. Descriptive statistics were used to explore changes in functions over time from age 16 to 21, and logistic regression used to examine associations between NSSH functions and repeat self-harm and suicide attempts at age 21, 24, and 25 years.
The majority of 16-year-olds with NSSH endorsed intrapersonal (e.g., affect regulatory) functions only (73% at 16 years and 64% at 21 years). Just under half of adolescents (42%) and three quarters of 21 years olds reported more than one function simultaneously. A greater number of intrapersonal functions at 16 years independently predicted future repetition of self-harm at ages 21-25 years, over and above interpersonal functions (OR = 1.46, 95% CI 1.06-2.01). Interpersonal functions during adolescence did not predict repeat self-harm or suicide attempts in adulthood.
Our findings suggest that intrapersonal but not interpersonal NSSH functions are a prospective risk factor for future self-harm and might also predict incident suicide attempts. The results highlight the central role of underlying affective difficulties and motivations in self-harm maintenance.
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