Andrew P. Demidowich

Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne).

OBJECTIVE To describe the genotypes, phenotypes, immunophenotypes, and treatments of PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), a rare autoinflammatory disease, in 5 patients. METHODS Clinical information was gathered from medical records and through interviews with 5 patients from 4 kindreds. PSTPIP1 (CD2BP1) exon 10 and exon 11 sequencing was performed in each patient. Neutrophil granule content and cytokine levels were determined in plasma and stimulated peripheral blood mononuclear cells (PBMCs) from patients and controls. RESULTS We identified 2 previously described PAPA syndrome-associated PSTPIP1 mutations, A230T and E250Q, and a novel change, E250K. Disease penetrance was incomplete, with variable expressivity. The cutaneous manifestations included pathergy, cystic acne, and pyoderma gangrenosum. Interleukin-1β (IL-1β) and circulating neutrophil granule enzyme levels were markedly elevated in patients compared to those in controls. PBMC stimulation studies demonstrated impaired production of IL-10 and enhanced production of granulocyte-macrophage colony-stimulating factor. Good resolution of pyoderma gangrenosum was achieved in 3 patients with tumor necrosis factor α (TNFα) blockade treatment. CONCLUSION This analysis of 5 patients demonstrates that mutations in PSTPIP1 are incompletely penetrant and variably expressed in the PAPA syndrome. Neutrophil granule proteins are markedly elevated ex vivo and in the plasma, and elevated levels might be compatible with a diagnosis of PAPA syndrome. TNFα blockade appears to be effective in treating the cutaneous manifestations of PAPA syndrome.

Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.

Attentional Bias to Food Cues in Youth with Loss of Control Eating

Emerging data indicate that adults with binge eating may exhibit an attentional bias toward highly palatable foods, which may promote obesogenic eating patterns and excess weight gain. However, it is unknown to what extent youth with loss of control (LOC) eating display a similar bias. We therefore studied 76 youth (14.5 ± 2.3 years; 86.8% female; BMI-z 1.7 ± .73) with (n = 47) and without (n = 29) reported LOC eating. Following a breakfast to reduce hunger, youth participated in a computerized visual probe task of sustained attention that assessed reaction time to pairs of pictures consisting of high palatable foods, low palatable foods, and neutral household objects. Although sustained attentional bias did not differ by LOC eating presence and was unrelated to body weight, a two-way interaction between BMI-z and LOC eating was observed (p = .01), such that only among youth with LOC eating, attentional bias toward high palatable foods versus neutral objects was positively associated with BMI-z. These findings suggest that LOC eating and body weight interact in their association with attentional bias to highly palatable foods cues, and may partially explain the mixed literature linking attentional bias to food cues with excess body weight.

Puberty and the manifestations of loss of control eating in children and adolescents

OBJECTIVE We investigated the manifestations of pediatric loss of control (LOC) eating at different stages of pubertal development. METHOD Participants were a nonclinical sample of 468 youth (8-17 years). Physical examination determined pubertal stage. LOC eating and disordered eating attitudes were assessed with the Eating Disorder Examination. In a randomized crossover design, a subset (n = 244) ate ad libitum from two test meals designed to capture normal and LOC eating. RESULTS There were no differences in the prevalence rates or frequency of reported LOC eating episodes across pubertal stages (ps ≥ 0.50). There were, however, puberty by LOC eating interactions in disordered eating attitudes and palatable food consumption (ps ≤ .05), even after adjusting for age and body composition. LOC eating was associated with elevated global disordered eating attitudes, weight concern, and shape concern in post-pubertal youth (ps ≤ .001), but not pre-pubertal youth (ps ≥ .49). In late-puberty, youth with LOC eating consumed less energy from protein (p < .001) and more from carbohydrate (p = .003) and snack-type foods (p = .02) than those without LOC eating, whereas endorsement of LOC eating in pre- or early-to-mid-puberty was not associated with differences in eating behavior (ps ≥ 0.20). CONCLUSIONS Findings suggest that puberty may be a critical risk period, when LOC eating behaviors in boys and girls may become accompanied by greater weight and shape concerns and more obesogenic food consumption patterns. Interventions for LOC eating during pre-puberty should be evaluated to determine if they are particularly beneficial for the prevention of exacerbated eating disorder psychopathology and adverse weight outcomes.

Excess Weight Gain Prevention in Adolescents: Three-Year Outcome Following a Randomized Controlled Trial.

Objective: Interpersonal psychotherapy (IPT) prevents weight gain in adults with obesity and binge-eating-disorder, and is especially effective among those with increased psychosocial problems. However, IPT was not superior to health education (HE) to prevent excess weight gain at 1-year follow-up in 113 adolescent girls at high-risk for excess weight gain because of loss-of-control eating and high body mass index (BMI; kg/m2; Tanofsky-Kraff et al., 2014). Method: Participants from the original trial were recontacted 3 years later for assessment. At baseline, adolescent- and parent-reported social-adjustment problems and trait anxiety were evaluated. At baseline and follow-ups, BMIz and adiposity by dual-energy x-ray absorptiometry were obtained. Results: Nearly 60% were reassessed at 3 years, with no group differences in participation (ps ≥ .70). Consistent with 1 year, there was no main effect of group on change in BMIz/adiposity (ps ≥ .18). In exploratory analyses, baseline social-adjustment problems and trait-anxiety moderated outcome (ps < .01). Among girls with high self-reported baseline social-adjustment problems or anxiety, IPT, compared to HE, was associated with the steepest declines in BMIz (p < .001). For adiposity, girls with high or low anxiety in HE and girls with low anxiety in IPT experienced gains (ps ⩽ .03), while girls in IPT with high anxiety stabilized. Parent-reports yielded complementary findings. Conclusion: In obesity-prone adolescent girls, IPT was not superior to HE in preventing excess weight gain at 3 years. Consistent with theory, exploratory analyses suggested that IPT was associated with improvements in BMIz over 3 years among youth with high social-adjustment problems or trait anxiety. Future studies should test the efficacy of IPT for obesity prevention among at-risk girls with social-adjustment problems and/or anxiety.

Metabolic characteristics of youth with loss of control eating.

PURPOSE Preliminary data in adults suggest that binge eating is associated with greater prevalence of metabolic syndrome (MetS) components. However, there are limited data in youth, and little is known of the role of binge episode size in these relationships. METHODS We examined the relationship between loss of control eating and metabolic characteristics in a convenience sample of 329 treatment-seeking and non-treatment-seeking adolescent boys and girls. The sample was enriched by design with adolescents who were overweight or obese and with individuals who reported episodes of loss of control over their eating (either objectively large binge episodes, OBEs or subjectively large binge episodes, SBEs, in the past month), as assessed by clinical interview. MetS components (blood pressure, lipids, glucose, and waist circumference) were the primary variables of interest. RESULTS 46% of the cohort reported loss of control eating; among those, 53% reported SBEs only and 47% reported OBEs. Youth with loss of control eating had higher systolic blood pressure (p=.001) and higher low-density lipoprotein cholesterol (LDL-c) (p=.002) compared to those without loss of control eating, in analyses adjusted for intervention-seeking status, fat mass and sociodemographic characteristics. Youth reporting OBEs had higher LDL-c (p=.013) compared to those reporting only SBEs. CONCLUSIONS Adolescents reporting loss of control episodes had greater dysfunction in some components of the MetS compared to youth without loss of control; episode size may contribute to metabolic dysfunction.

A preliminary examination of Loss of Control Eating Disorder (LOC-ED) in middle childhood ☆

Loss of Control Eating Disorder (LOC-ED) has been proposed as a diagnostic category for children 6-12years with binge-type eating. However, characteristics of youth with LOC-ED have not been examined. We tested the hypothesis that the proposed criteria for LOC-ED would identify children with greater adiposity, more disordered eating attitudes, and greater mood disturbance than those without LOC-ED. Participants were 251 youth (10.29years±1.54, 53.8% female, 57.8% White, 35.5% Black, 2.0% Asian, 4.8% Hispanic, 53.0% overweight). Youth were interviewed regarding eating attitudes and behaviors, completed questionnaires to assess general psychopathology, and underwent measurements of body fat mass. Using previously proposed criteria for LOC-ED, children were classified as LOC-ED (n=19), LOC in the absence of the full disorder (subLOC, n=33), and youth not reporting LOC (noLOC, n=199). LOC-ED youth had higher BMIz (p=0.001) and adiposity (p=0.003) and reported greater disordered eating concerns (p<0.001) compared to noLOC youth. Compared to subLOC youth, LOC-ED youth had non-significantly higher BMIz (p=0.11), and significantly higher adiposity (p=0.04) and disordered eating attitudes (p=0.02). SubLOC youth had greater disordered eating concerns (p<0.001) and BMIz (p=0.03) but did not differ in adiposity (p=0.33) compared to noLOC youth. These preliminary data suggest that LOC-ED youth are elevated on disordered eating cognitions and anthropometric measures compared to youth without LOC-ED. Longitudinal studies are needed to determine if those with LOC-ED are at particularly increased risk for progression of disordered eating and excess weight gain.

Associations of adolescent emotional and loss of control eating with 1‐year changes in disordered eating, weight, and adiposity

OBJECTIVE Adolescent emotional-eating, referring to eating in response to negative affective states, is frequently reported by those with loss of control (LOC) eating. Although LOC eating has been shown to predict exacerbated disordered eating and excess weight/adiposity gain, the extent to which emotional-eating, either alone or in combination with LOC, predicts adverse outcomes has not been determined. Thus, we examined associations of baseline emotional-eating with changes in disordered eating, BMI, and adiposity over 1-year, and to what degree the presence or absence of baseline LOC moderated these associations. METHODS 189 non-treatment-seeking youth (15.4 ± 1.4y; 66% female; 67% non-Hispanic White, 38% overweight [BMI ≥ 85th %ile]) completed the emotional-eating Scale for Children/Adolescents and the Eating Disorder Examination interview at baseline and again at 1-year. Air displacement plethysmography assessed adiposity at both time points. RESULTS Baseline emotional-eating alone was not significantly associated with the development of objective binge eating or changes in disordered eating attitudes, BMI or adiposity 1-year later. However, baseline emotional-eating interacted with the presence of baseline LOC in the prediction of 1-year outcomes. Among adolescents with LOC eating, greater baseline emotional-eating was related to increased disordered eating attitudes (p = .03), BMI (p = .04), and adiposity (p = .04) at 1-year, after correcting for false discovery rate. DISCUSSION Emotional-eating among youth also reporting LOC was associated with adverse outcomes over 1-year. Adolescents who report both behaviors may represent a subset of individuals at especially high risk for exacerbated disordered eating and excess weight gain.

Hair cortisol in the evaluation of Cushing syndrome

PurposeHair cortisol evaluation has been used to help detect patients with suspected Cushing syndrome. Our goal was to correlate segmental hair cortisol with biochemical testing in patients with Cushing syndrome and controls. This study was a prospective analysis of hair cortisol in confirmed Cushing syndrome cases over 16 months.MethodsThirty-six subjects (26.5 ± 18.9 years, 75% female, and 75% Caucasian) were analyzed by diurnal serum cortisol, 24 h urinary free cortisol corrected for body surface area (UFC/BSA), and 24 h urinary 17-hydroxysteroids corrected for creatinine (17OHS/Cr). Thirty patients were diagnosed with Cushing syndrome, and six were defined as controls. 3-cm hair samples nearest to the scalp, cut into 1-cm segments (proximal, medial, and distal), were analyzed for cortisol by enzyme immunoassay and measured as pmol cortisol/g dry hair. Hair cortisol levels were compared with laboratory testing done within previous 2 months of the evaluation.ResultsProximal hair cortisol was higher in Cushing syndrome patients (266.6 ± 738.4 pmol/g) than control patients (38.9 ± 25.3 pmol/g) (p = 0.003). Proximal hair cortisol was highest of all segments in 25/36 (69%) patients. Among all subjects, proximal hair cortisol was strongly correlated with UFC/BSA (r = 0.5, p = 0.005), midnight serum cortisol (r = 0.4, p = 0.03), and 17OHS/Cr, which trended towards significance (r = 0.3, p = 0.06).ConclusionsAmong the three examined hair segments, proximal hair contained the highest cortisol levels and correlated the most with the initial biochemical tests for Cushing syndrome in our study. Further studies are needed to validate proximal hair cortisol in the diagnostic workup for Cushing syndrome.

Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation.

Obesity is a major risk-factor for the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Circulating molecules associated with obesity, such as saturated fatty acids and cholesterol crystals, stimulate the innate immune system to incite a chronic inflammatory state. Studies in mouse models suggest that suppressing the obesity-induced chronic inflammatory state may prevent or reverse obesity-associated metabolic dysregulation. Human studies, however, have been far less positive, possibly because targeted interventions were too far downstream of the inciting inflammatory events. Recently, it has been shown that, within adipose tissue macrophages, assembly of a multi-protein member of the innate immune system, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, is essential for the induction of this inflammatory state. Microtubules enable the necessary spatial arrangement of the components of the NLRP3 inflammasome in the cell, leading to its activation and propagation of the inflammatory cascade. Colchicine, a medication classically used for gout, mediates its anti-inflammatory effect by inhibiting tubulin polymerization, and has been shown to attenuate macrophage NLRP3 inflammasome arrangement and activation in vitro and in vivo. Given these findings, we hypothesize that, in at-risk individuals (those with obesity-induced inflammation and metabolic dysregulation), long-term colchicine use will lead to suppression of inflammation and thus cause improvements in insulin sensitivity and other obesity-related metabolic impairments.