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Understanding how an intervention impacts appetite in real-life settings and over several days remains a challenging and under-explored research question. To this end, we developed Momentary Appetite Capture (MAC), a form of ecological momentary assessment that combines automated text messaging with an online platform. Participants report their appetite using visual analogue scales (hunger, desire to eat, and fullness) and a virtual portion-size selection task. In two separate studies, we assessed the feasibility and test-retest reliability of MAC. Participants were prompted every 2 hours over a 14-hour window, and they repeated this assessment over two consecutive weekdays. For each participant, we calculated a daily time-averaged area under the curve (AUC) for each appetite measure. In Study One (N = 25) time-averaged AUC was significantly positively correlated across test days for hunger (r = 0.563, p = .003), desire to eat (r = 0.515, p = .008) and prospective portion size (r = 0.914, p < .001), but not for fullness (r = 0.342, p = .094). Participants completed 95% of MACs (380 of 400), and we used participant feedback to improve the MAC tool and study protocol for Study Two. In Study Two (N = 31), 94% of MACs were completed (468 of 496). Across days, time-averaged AUC was significantly positively correlated for hunger (r = 0.595, p = < .001), fullness (r = 0.501, p = .004), desire to eat (r = 0.585, p < .001), and prospective portion size (r = 0.757, p < .001). Together, these studies suggest that MAC could be an acceptable and reliable tool to track appetite throughout the day. In the future, MAC could be used to explore the impact of weight-loss interventions on natural fluctuations in appetite.
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Apetito , Ingestión de Energía , Humanos , Estudios Prospectivos , Reproducibilidad de los Resultados , HambreRESUMEN
Acute exercise suppresses appetite and alters food-cue reactivity, but the extent exercise-induced changes in cerebral blood flow (CBF) influences the blood-oxygen-level-dependent (BOLD) signal during appetite-related paradigms is not known. This study examined the impact of acute running on visual food-cue reactivity and explored whether such responses are influenced by CBF variability. In a randomised crossover design, 23 men (mean ± SD: 24 ± 4 years, 22.9 ± 2.1 kg/m2 ) completed fMRI scans before and after 60 min of running (68% ± 3% peak oxygen uptake) or rest (control). Five-minute pseudo-continuous arterial spin labelling fMRI scans were conducted for CBF assessment before and at four consecutive repeat acquisitions after exercise/rest. BOLD-fMRI was acquired during a food-cue reactivity task before and 28 min after exercise/rest. Food-cue reactivity analysis was performed with and without CBF adjustment. Subjective appetite ratings were assessed before, during and after exercise/rest. Exercise CBF was higher in grey matter, the posterior insula and in the region of the amygdala/hippocampus, and lower in the medial orbitofrontal cortex and dorsal striatum than control (main effect trial p ≤ .018). No time-by-trial interactions for CBF were identified (p ≥ .087). Exercise induced moderate-to-large reductions in subjective appetite ratings (Cohen's d = 0.53-0.84; p ≤ .024) and increased food-cue reactivity in the paracingulate gyrus, hippocampus, precuneous cortex, frontal pole and posterior cingulate gyrus. Accounting for CBF variability did not markedly alter detection of exercise-induced BOLD signal changes. Acute running evoked overall changes in CBF that were not time dependent and increased food-cue reactivity in regions implicated in attention, anticipation of reward, and episodic memory independent of CBF.
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Señales (Psicología) , Carrera , Humanos , Masculino , Encéfalo/fisiología , Circulación Cerebrovascular/fisiología , Imagen por Resonancia Magnética/métodos , Oxígeno , Estudios CruzadosRESUMEN
AIMS: Facilitated self-management support programmes have become central to the treatment of chronic diseases including diabetes. For many children and young people with diabetes (CYPD), the impact on glycated haemoglobin (HbA1c ) and a range of self-management behaviours promised by these programmes remain unrealised. This warrants an appraisal of current thinking and the existing evidence to guide the development of programmes better targeted at this age group. METHODS: Create a narrative review of systematic reviews produced in the last 3 years that have explored the impact on CYPD of the four key elements of self-management support programmes: education, instruction and advice including peer support; psychological counselling via a range of therapies; self-monitoring, including diaries and telemetric devices; and telecare, the technology-enabled follow-up and support by healthcare providers. RESULTS: Games and gamification appear to offer a promising means of engaging and educating CYPD. Psychological interventions when delivered by trained practitioners, appear to improve HbA1c and quality of life although effect sizes were small. Technology-enabled interactive diaries can increase the frequency of self-monitoring and reduce levels of HbA1c . Telecare provided synchronously via telephone produced significant improvements in HbA1c . CONCLUSIONS: The cost-effective flexibility of increasing the reliance on technology is an attractive proposition; however, there are resource implications for digital connectivity in underserved populations. The need remains to improve the understanding of which elements of each component are most effective in a particular context, and how to optimise the influence and input of families, caregivers and peers.
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Diabetes Mellitus , Automanejo , Humanos , Niño , Adolescente , Calidad de Vida , Revisiones Sistemáticas como Asunto , TeléfonoRESUMEN
INTRODUCTION: There is a growing understanding of the benefits of patient and public involvement (PPI), and its evaluation, in research. An online version of the CUBE PPI evaluation framework has been developed. We sought to use the CUBE to evaluate the value of early PPI with two small healthcare companies during product development. METHODS: Contributors were recruited online and had lived experience of either type 1 diabetes or obesity. Two 1-h sessions were run with a company developing a smartphone application to manage diabetes (DEE-EM): one with young people (YP; n = 5) and one with parents (n = 7). Two 1-h sessions were run with a company developing a weight-loss product, both with adults (n = 7 in each session). Sessions were facilitated by an independent University researcher and attended by company representatives, who presented their product. One facilitator led the evaluation of the session by giving a demonstration of the CUBE and asking simple questions in the YP session. RESULTS: A high proportion of contributors completed the CUBE (80.5% DEE-EM; 93% Oxford Medical Products). Responses were positive to all four CUBE dimensions (in italics). Contributors felt there were diverse ways to contribute to the sessions, and that they had a strong voice to add to the discussion. Balance was achieved regarding whose concerns (public or company) led the agenda, and contributors felt that both companies would make changes based on the discussion. The supportive attitude of both companies resulted in most contributors feeling comfortable participating in PPI sessions with the industry, while recognising the profit-making aspect of their work. CONCLUSIONS: PPI with small healthcare companies is both feasible and worthwhile. The CUBE framework facilitated the evaluation of the interaction between experts in different knowledge spaces. We provide recommendations for future projects, including considerations of who should participate and the level of implicit endorsement of the product that participation implies. PATIENT OR PUBLIC CONTRIBUTION: People with lived experience of type 1 diabetes or obesity were invited to contribute to one of four PPI sessions, which they then evaluated. One contributor agreed to contribute to the analysis of the evaluation data and interpretation and preparation of the manuscript.
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Diabetes Mellitus Tipo 1 , Adulto , Humanos , Adolescente , Diabetes Mellitus Tipo 1/terapia , Participación del Paciente , InvestigadoresRESUMEN
BACKGROUND: This paper details the development of the Adolescent Intrinsic Motivation 'AIM2Change' intervention to support weight-management in young people previously unable to make changes whilst attending a tier 3 weight management service for children and young people. AIM2Change is an acceptance and commitment therapy based intervention that will be delivered one-to-one online over a seven-week period. METHODS: To develop this intervention, we have triangulated results from a qualitative research study, patient and public involvement groups (PPI) and a COM-B (capability, opportunity, motivation, behaviour) analysis, in a method informed by the person-based approach. RESULTS: The integrated development approach yielded a broad range of perspectives and facilitated the creation of a tailored intervention to meet the needs of the patient group whist remaining pragmatic and deliverable. CONCLUSIONS: The next steps for this intervention will be in-depth co-development of the therapy sessions with service users, before implementing a proof of concept trial.
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Terapia de Aceptación y Compromiso , Obesidad Infantil , Adolescente , Humanos , Motivación , Obesidad Infantil/terapia , Investigación Cualitativa , Autocuidado/métodosRESUMEN
Eating at a faster speed is positively correlated with having a higher BMI. Modifying eating speed may offer a treatment opportunity for those with overweight and obesity. This review sought to understand the feasibility, acceptability, and benefit to using eating speed interventions in paediatric clinical weight-management settings. The PICO Framework was used. Clinical studies of eating speed interventions as a treatment for paediatric patients with overweight or obesity were included. No limits to search date were implemented. A systematic search of MEDLINE, PsychINFO and EMBASE via OVID, Web of Science and JBI, Database of systematic reviews and Implementation reports, along with trial registers NICE, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials was conducted. Two authors were responsible for screening, extraction, and evaluation of the risk of bias. Fifteen papers reporting twelve interventions addressing eating-speed were identified, involving a total of 486 active participants (range 7-297). Study design was weak with only one full RCT and there were some concerns over quality and risk of bias (Cochrane RoB 2.0). Limited sample sizes and different measured outcomes did not allow powered evaluations of effect for all outcomes. There is some indication, overall, that addressing eating speed has the potential to be a beneficial adjunct to clinical obesity treatment, although the pooled effect estimate did not demonstrate a difference in BMISDS status following eating speed interventions compared to control [pooled mean difference (0.04, 95% CI -0.39 to 0.46, N = 3)]. Developments to improve the engagement to, and acceptability of, interventions are required, alongside rigorous high-quality trials to evaluate effectiveness.
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Sobrepeso , Obesidad Infantil , Adolescente , Niño , Ejercicio Físico , Estudios de Factibilidad , Humanos , Sobrepeso/terapia , Obesidad Infantil/terapiaRESUMEN
Modifying eating behaviours may be an effective strategy to limit excess food intake, such as eating slower and mindfully. We hypothesized that regularly rating fullness whilst eating a standard meal in one course would increase post-meal satiety and reduce intake in a subsequent course during the same sitting. A between-subjects design was employed (n = 65; 75% female; mean age = 26.7 (s.d. = 9.5); mean body mass index = 22.4 (s.d. = 3.3)), with three conditions of within-meal visual-analogue-scale ratings: 'Fullness' (rated fullness); 'Taste' (rated pleasantness of taste of food); 'Control' (rated comfort of room). Fasted participants ate a pasta meal (327 kcal) followed by cookies ad libitum. Appetite ratings were measured at baseline, following each course and for 3-h post-meal. Satiety responsiveness was measured using the Adult Eating Behaviour Questionnaire, Intuitive Eating Scale and by calculating the satiety quotient of the pasta course alone and the whole meal. The primary outcomes were fullness ratings post-pasta course [mean (s.d.): Fullness = 67.1 (21.9); Taste = 64.4 (13.7); Control = 60.2 (21.5)] and cookie intake [mean kcal (s.d.): Fullness = 249 (236); Taste = 279 (231); Control = 255 (208)]. Eating speed was included as a secondary, control outcome [mean (s.d.): Fullness = 59.3 (9.0); Taste = 59.2 (17.7); Control = 60.7 (19.6)]. No evidence for a difference in outcomes was identified between conditions (p > 0.05). Future work could involve testing the impact of rating fullness during multiple meals over a longer period. Secondly, this study explored whether levels of satiety responsiveness influenced the impact of the manipulation on outcomes; however only weak evidence for a relationship with eating speed was found. Finally, only a weak relationship was found between the satiety responsiveness measures, suggesting that different aspects of the underlying construct are being captured.
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Ingestión de Alimentos , Saciedad , Adulto , Apetito , Ingestión de Energía , Conducta Alimentaria , Femenino , Humanos , Masculino , ComidasRESUMEN
The reduction of portion sizes supports weight-loss. This study looks at whether children have a conceptual understanding of portion size, by studying their ability to manually serve a portion size that corresponds to what they eat. In a clinical setting, discussion around portion size is subjective thus a computerised portion size tool is also trialled, with the portion sizes chosen on the screen being compared to amounts served manually. Children (n = 76) age 5-6, 7-8 and 10-11 were asked to rate their hunger (VAS scale), liking (VAS scale) and 'ideal portion size for lunch' of eight interactive meal images using a computerised portion size tool. Children then manually self-served and consumed a portion of pasta. Plates were weighed to allow for the calculation of calories served and eaten. A positive correlation was found between manually served food portions and the amount eaten (r = 0.53, 95%CI [0.34, 0.82, P < .001), indicating that many children were able to anticipate their likely food intake prior to meal onset. A regression model demonstrates that age contributes to 9.4% of the variance in portion size accuracy (t(68) = -2.3, p = .02). There was no relationship between portion size and either hunger or liking. The portion sizes chosen on the computer at lunchtime correlated to the amount manually served overall (r = .34, 95%CI [0.07, 0.55], p < .01), but not in 5-6-year-old children. Manual portion-size selection can be observed in five-year olds and from age seven, children's 'virtual' responses correlate with their manual portion selections. The application of the computerised portion-size tool requires further development but offers considerable potential.
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Ingestión de Energía , Tamaño de la Porción , Niño , Preescolar , Ingestión de Alimentos , Humanos , Aprendizaje , Almuerzo , ComidasRESUMEN
BACKGROUND: Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance. METHODS: Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found. RESULTS: We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss. CONCLUSION: The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.
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Proteínas Adaptadoras Transductoras de Señales/genética , Síndrome de Beckwith-Wiedemann/genética , Desiminasas de la Arginina Proteica/genética , Síndrome de Silver-Russell/genética , Proteínas Reguladoras de la Apoptosis , Síndrome de Beckwith-Wiedemann/patología , Cromosomas Humanos Par 11/genética , Metilación de ADN/genética , Femenino , Impresión Genómica/genética , Mutación de Línea Germinal/genética , Humanos , Recién Nacido , Enfermedades del Recién Nacido/genética , Enfermedades del Recién Nacido/fisiopatología , Herencia Materna , Linaje , Embarazo , Arginina Deiminasa Proteína-Tipo 6 , Síndrome de Silver-Russell/fisiopatologíaRESUMEN
The IGF system has an important role in growth and development. IGF-II is a recognized fetal growth promoter. However, its physiological postnatal role remains uncertain, although it is maintained in the circulation at a substantially high level throughout life. IGF-II has been strongly linked to obesity in genetic studies, and more recent evidence suggests a metabolic role. We examined fat depot differences in IGF-II's action on differentiation and metabolism. We speculate a specific effect on visceral adipocytes in relation to the differential distribution of insulin receptors between visceral and subcutaneous fat depots. We used a previously established adipocyte, cell culture system of matched pairs of visceral and subcutaneous fat biopsies from 20 normal weight children undergoing routine surgery for nonmalignant, nonseptic conditions. Preadipocytes were differentiated for 14 days in the presence or absence of IGF-II. Oil Red O staining, Western blotting, and reverse transcription polymerase chain reaction techniques were employed to assess levels of adipogenesis markers and levels of the insulin receptor and insulin receptor isoforms. Our data indicate that IGF-II promotes preadipocyte differentiation in subcutaneous preadipocytes but showed a protective, opposing effect restricting visceral preadipocyte differentiation, confirmed by reductions in the differentiation markers peroxisome proliferator-activated receptor gamma and adiponectin and in triglyceride staining. Additionally, IGF-II reduced mRNA expression of the insulin receptor in adipocytes and downregulated insulin receptor isoform A and glucose transporter 4 abundance and corresponding glucose uptake in visceral adipocytes. In conclusion, IGF-II is a regulator of preadipocyte differentiation and metabolism by acting as a differential modulator of fat accumulation favoring less visceral fat deposition in children.
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Adipocitos/metabolismo , Adipogénesis/fisiología , Factor II del Crecimiento Similar a la Insulina/metabolismo , Grasa Intraabdominal/metabolismo , Células Cultivadas , Niño , Preescolar , Femenino , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Humanos , Lactante , Recién Nacido , Masculino , Receptor de Insulina/metabolismoRESUMEN
BACKGROUND: Slowing eating rate using the Mandolean® previously helped obese adolescents to self-select smaller portion sizes, with no reduction in satiety, and enhanced ghrelin suppression. The objective of this pilot, randomised trial was to investigate the neural response to food cues following Mandolean® training using functional Magnetic Resonance Imaging (fMRI), and measures of ghrelin, PYY, glucose and self-reported appetite. METHOD: Twenty-four obese adolescents (11-18 years; BMI ≥ 95th centile) were randomised (but stratified by age and gender) to receive six-months of standard care in an obesity clinic, or standard care plus short-term Mandolean® training. Two fMRI sessions were conducted: at baseline and post-intervention. These sessions were structured as an oral glucose tolerance test, with food cue-reactivity fMRI, cannulation for blood samples, and appetite ratings taken at baseline, 30 (no fMRI), 60 and 90 min post-glucose. As this was a pilot trial, a conservative approach to the statistical analysis of the behavioural data used Cliff's delta as a non-parametric measure of effect size between groups. fMRI data was analysed using non-parametric permutation analysis (RANDOMISE, FSL). RESULTS: Following Mandolean® training: (i) relatively less activation was seen in brain regions associated with food cue reactivity after glucose consumption compared to standard care group; (ii) 22% reduction in self-selected portion size was found with no reduction in post-meal satiety. However, usage of the Mandolean® by the young people involved was variable and considerably less than planned at the outset (on average, 28 meals with the Mandolean® over six-months). CONCLUSION: This pilot trial provides preliminary evidence that Mandolean® training may be associated with changes in how food cues in the environment are processed, supporting previous studies showing a reduction in portion size with no reduction in satiety. In this regard, the study supports targeting eating behaviour in weight-management interventions in young people. However, given the variable usage of the Mandolean® during the trial, further work is required to design more engaging interventions reducing eating speed. TRIAL REGISTRATION: ISRCTN, ISRCTN84202126 , retrospectively registered 22/02/2018.
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Encéfalo/diagnóstico por imagen , Conducta Alimentaria , Imagen por Resonancia Magnética , Neurorretroalimentación/métodos , Neuroimagen , Obesidad Infantil/diagnóstico por imagen , Obesidad Infantil/terapia , Adolescente , Regulación del Apetito , Glucemia/metabolismo , Niño , Señales (Psicología) , Azúcares de la Dieta/administración & dosificación , Estudios de Factibilidad , Femenino , Ghrelina/sangre , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Cooperación del Paciente , Obesidad Infantil/sangre , Obesidad Infantil/psicología , Proyectos Piloto , Tamaño de la Porción , Respuesta de SaciedadRESUMEN
Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic ß cells altered insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.
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Hiperinsulinismo Congénito/complicaciones , Hiperinsulinismo Congénito/genética , Mutación , Fosfotransferasas (Fosfomutasas)/genética , Enfermedades Renales Poliquísticas/complicaciones , Enfermedades Renales Poliquísticas/genética , Regiones Promotoras Genéticas/genética , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
BACKGROUND: Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined. METHODS AND RESULTS: We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known. CONCLUSIONS: The HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype.
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Síndrome de Fanconi/genética , Factor Nuclear 4 del Hepatocito/genética , Mutación/genética , Síndrome de Fanconi/diagnóstico por imagen , Síndrome de Fanconi/metabolismo , Femenino , Heterocigoto , Humanos , Masculino , Nefrocalcinosis/diagnóstico por imagen , Fenotipo , UltrasonografíaRESUMEN
INTRODUCTION: Craniopharyngiomas are rare brain tumours (incidence 1.1-1.7 cases/million/year). Although non-malignant, craniopharyngioma causes major endocrine and visual morbidities including hypothalamic obesity, yet mechanisms leading to obesity are poorly understood. This study investigated the feasibility and acceptability of eating behaviour measures in patients with craniopharyngioma to inform the design of future trials. METHODS: Patients with childhood-onset craniopharyngioma and controls matched for sex, pubertal stage, and age were recruited. After an overnight fast, participants received the following measures: body composition, resting metabolic rate, oral glucose tolerance test including magnetic resonance imaging (patients only), appetite ratings, eating behaviour, and quality of life questionnaires, ad libitum lunch, and an acceptability questionnaire. Data are reported as median ± IQR, with effect size measure (Cliff's delta) and Kendall's tau for correlations, due to the small sample size. RESULTS: Eleven patients (median age = 14 years; 5 F/6 M) and matched controls (median age = 12 years; 5 F/6 M) were recruited. All patients had received surgery, and 9/11 also received radiotherapy. Hypothalamic damage post-surgery was graded (Paris grading): grade 2 n = 6; grade 1 n = 1; grade 0 n = 2. The included measures were deemed highly tolerable by participants and their parent/carers. Preliminary data suggest a difference in hyperphagia between patients and controls (d = 0.5), and a relationship between hyperphagia with body mass index standard deviation score (BMISDS) in patients (τ = 0.46). DISCUSSION: These findings demonstrate that eating behaviour research is feasible and acceptable to craniopharyngioma patients and there is an association between BMISDS and hyperphagia in patients. Thus, food approach and avoidance behaviours may be useful targets for interventions to manage obesity in this patient group.
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Craneofaringioma , Obesidad Infantil , Neoplasias Hipofisarias , Humanos , Adolescente , Niño , Craneofaringioma/complicaciones , Estudios de Factibilidad , Obesidad Infantil/epidemiología , Obesidad Infantil/complicaciones , Calidad de Vida , Neoplasias Hipofisarias/epidemiología , Neoplasias Hipofisarias/complicaciones , Hiperfagia/complicaciones , Conducta Alimentaria , HomeostasisRESUMEN
There have been over 100 cases of Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome reported, but there is currently no curative treatment for children with this condition. We aimed to better characterise adipose cells from a child with ROHHAD syndrome. We isolated pre-adipocytes from a 4 year-old female patient with ROHHAD syndrome and assessed proliferation rate of these cells. We evaluated levels of DLP-Pref-1(pre-adipocyte marker) using western blotting, and concentrations of interleukin-6(IL-6) using ELISA. We performed next-generation sequencing (NGS) and bioinformatic analyses on these cells compared to tissue from an age/sex-matched control. The two most up-/down-regulated genes were validated using QPCR. We successfully isolated pre-adipocytes from a fat biopsy, by confirming the presence of Pref-1 and differentiated them to mature adipocytes. Interleukin 6, (Il-6) levels were 5.6-fold higher in ROHHAD cells compared to a control age/sex-matched biopsy. NGS revealed 25,703 differentially expressed genes (DEGs) from ROHHAD cells vs. control of which 2,237 genes were significantly altered. The 20 most significantly up/down-regulated genes were selected for discussion. This paper describes the first transcriptomic analysis of adipose cells from a child with ROHHAD vs. normal control adipose tissue as a first step in identifying targetable pathways/mechanisms underlying this condition with novel therapeutic interventions.
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OBJECTIVES: Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation (ROHHAD) is a rare syndrome associated with high morbidity and mortality. Diagnosis is often challenging. We describe three cases of ROHHAD with heterogeneous presentations but some consistent clinical features, including hyperprolactinaemia at diagnosis. We highlight when the diagnosis of ROHHAD should be considered at an early stage. CASE PRESENTATION: All three patients presented between 4 and 6 years old with rapid-onset obesity. They all have central hypoventilation requiring nocturnal BiPAP, varying degrees of hypothalamic dysfunction with hyperprolactinaemia being a consistent feature, and autonomic dysfunction. One patient has a neuro-endocrine tumour (NET) and two have glucose dysregulation. CONCLUSIONS: High prolactin was a consistent early feature. Central hypoventilation and NET may present later and therefore regular sleep studies and screening for NETs are required. A high suspicion of ROHHAD is warranted in patients with rapid, early-onset obesity and hyperprolactinaemia without structural pituitary abnormality.
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Enfermedades del Sistema Nervioso Autónomo , Hiperprolactinemia , Enfermedades Hipotalámicas , Neoplasias , Humanos , Preescolar , Niño , Hipoventilación/diagnóstico , Hipoventilación/etiología , Obesidad/complicaciones , Obesidad/diagnóstico , Enfermedades Hipotalámicas/complicaciones , Enfermedades Hipotalámicas/diagnóstico , Síndrome , Enfermedades del Sistema Nervioso Autónomo/complicaciones , Enfermedades del Sistema Nervioso Autónomo/diagnósticoRESUMEN
Previously, narrative reviews have considered the effects of intermittent fasting on appetite. One suggestion is that intermittent fasting attenuates an increase in appetite that typically accompanies weight loss. Here, we conducted the first systematic review and meta-analysis to quantify the effects of intermittent fasting on appetite, when compared to a continuous energy restriction intervention. Five electronic databases and trial registers were searched in February 2021 and February 2022. Abstracts (N = 2800) were screened and 17 randomized controlled trials (RCTs), consisting of a variety of intermittent fasting regimes, met our inclusion criteria. The total number of participants allocated to interventions was 1111 and all RCTs were judged as having either some concerns or a high risk of bias (Cochrane RoB 2.0 tool). Random effects meta-analyses were conducted on change-from-baseline appetite ratings. There was no clear evidence that intermittent fasting affected hunger (WMD = -3.03; 95% CI [-8.13, 2.08]; p = 0.25; N = 13), fullness (WMD = 3.11; 95% CI [-1.46, 7.69]; p = 0.18; N = 10), desire to eat (WMD = -3.89; 95% CI [-12.62, 4.83]; p = 0.38; N = 6), or prospective food consumption (WMD = -2.82; 95% CI [-3.87, 9.03]; p = 0.43; N = 5), differently to continuous energy restriction interventions. Our results suggest that intermittent fasting does not mitigate an increase in our drive to eat that is often associated with continuous energy restriction.
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Apetito , Ayuno Intermitente , Humanos , Ingestión de Energía , Hambre , Pérdida de Peso , AyunoRESUMEN
INTRODUCTION: Hypoglycemia elicits coordinated counter-regulatory neuroendocrine responses. The extent to which this process involves an increased drive to eat, together with greater preference for foods high in carbohydrate content, is unclear. Our objective was to examine this effect in children and adolescents (age 5-19 years) without diabetes and no prior known experience of hypoglycemic episodes. RESEARCH DESIGN AND METHODS: We administered a computerised task designed to examine preference for high-carbohydrate foods (sweet and savory) to pediatric patients (n=26) undergoing an insulin tolerance test as part of the routine clinical assessment of pituitary hormone secretory capacity. The task was completed at baseline and three time points after intravenous infusion of insulin (approximately 7, 20 and 90 min). RESULTS: Although all patients reached insulin-induced hypoglycemia (mean venous glucose at nadir=1.9 mmol/L), there was moderate evidence of no effect on preference for high-carbohydrate foods (moderate evidence for the null hypothesis) compared with euglycemia. Patients also did not display an increase in selection of foods of high compared with low energy density. Sensitivity of the task was demonstrated by decreased preference for sweet, high-carbohydrate foods after consumption of sweet food and drink. CONCLUSIONS: Results support the view that acute hypoglycemia does not automatically prompt the choice of high-carbohydrate foods for rapid glucose restoration, and further stresses the importance that people and families with children vulnerable to hypoglycemic episodes ensure that 'rapidly absorbed glucose rescue therapy' is always available.
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Glucemia , Hipoglucemia , Humanos , Adolescente , Niño , Preescolar , Adulto Joven , Adulto , Hipoglucemia/inducido químicamente , Insulina/uso terapéutico , Glucosa , Hipoglucemiantes/uso terapéuticoRESUMEN
OBJECTIVES: Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation, and neural-crest tumour (ROHHAD(NET)) is a rare syndrome presenting in early childhood associated with high morbidity and mortality. There is no specific diagnostic biomarker and diagnosis is based on clinical features. An autoimmune origin has been postulated. CASE PRESENTATION: Management is largely supportive. We report a case of a five-year old female who presented in respiratory arrest after 6-months of rapid weight gain. She had central hypoventilation, central diabetes insipidus, growth hormone deficiency and hyperprolactinaemia. She displayed elevated interleukin-6 levels on cytokine serology which normalised after rituximab treatment. After rituximab treatment, her weight reduced significantly from greatly above the 99.6th to the 50th centile in 12 months. CONCLUSIONS: This response possibly reflects an underlying, immune-inflammatory pathology driving excess adiposity in this condition. Potentially, other aspects of ROHHAD(NET) may be mediated through autoimmune dysregulation in which case rituximab may provide benefits for prognosis and survival.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo , Enfermedades Hipotalámicas , Preescolar , Femenino , Humanos , Hipoventilación , Obesidad , Enfermedades Raras , Rituximab/uso terapéutico , Síndrome , Aumento de PesoRESUMEN
BACKGROUND: Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population. OBJECTIVE: The aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease. METHODS: The CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase. RESULTS: A total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021. CONCLUSIONS: This trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/22533.