Clodagh S. O'Gorman

Thyroid Cancer in Childhood: A Retrospective Review of Childhood Course

BACKGROUND Thyroid cancer (TC) is an uncommon childhood malignancy, but the incidence may be increasing. Recent American Thyroid Association guidelines focus primarily on adult data. Natural history studies of TC in childhood are important to determine outcomes. The objectives of this study were to describe the demographics and outcomes in children with TC treated at The Hospital for Sick Children, Toronto, from 1983 to 2006. We hypothesized that childhood TC was increasing at our institution. METHODS Cases of papillary TC (PTC) (including follicular variant PTC) and follicular TC (FTC) were identified from pathology databases. Chart review was performed, and data were extracted on clinical, treatment, and outcome variables. RESULTS Sixty-one cases were identified, and complete data were available in 54, including 36 girls and 18 boys. There was no statistical change in numbers of cases diagnosed yearly during the study period. Younger children were more likely to have metastases at presentation or during follow-up. Pathological TC diagnosis included 40 PTC, 1 diffuse-sclerosing papillary, 7 follicular variant PTC, and 6 FTC. There was no difference in pathology findings between children less than or greater than 10 years old. Five patients had a history of previous malignancy, and five had a history of previous thyroid conditions. Three patients were born in areas of high TC endemnicity. Twenty-three patients had thyroiditis on pathology examination. All patients underwent total thyroidectomy, and 53/54 patients received therapeutic radioactive iodine ablation. Twenty-seven patients had metastases at presentation (19 lymph nodes only, 2 lung only, and 6 lymph node and distant) and 6 developed distant metastases during follow-up (3 lung, 2 thymus, and 1 paraspinal). Male sex was associated with development of metastases during follow-up. On multiple regression, tumor size was predicted positively by PTC but not by age, sex, or metastases at presentation or during follow-up. CONCLUSION We did not find evidence of increasing numbers of cases of TC diagnosed yearly during the study period, or difference in tumor aggressiveness, or between outcomes in children aged less than or greater than 10 years. Children with metastases at presentation or during follow-up were likely to be younger than children without metastases. There is a need for prospective, collaborative multicenter studies of TC.

Identification of an Autoantigen Demonstrates a Link Between Interstitial Lung Disease and a Defect in Central Tolerance

A defect in immune tolerance to self-antigens may underlie the lung damage that accompanies many autoimmune diseases. Autoimmune diseases are intractable and varied, appearing in many guises. Patients with lupus, for example, experience destructive immune reactions that affect the heart, other organs, and the joints. This generalized attack is in stark contrast to the very selective autoimmune destruction of insulin-producing β islet cells in type I diabetes or the antibodies to the acetylcholine receptor that characterize myasthenia gravis. Why are there generalized immune responses in some diseases and very specific reactions in others? Shum et al. have exploited a mutant mouse defective in AIRE, a transcription factor that controls expression of many self-antigens in the thymus. As immune T cells pass through, these self-antigens in the thymus trigger the deletion of cells that react with them, preventing these autoreactive T cells from entering the circulation. Thus, when AIRE is absent or mutated, T cells directed at self-antigens are not deleted and escape into the circulation where they can trigger autoimmunity. This is not only true in mice: Patients with a genetic disease called autoimmune polyglandular syndrome type 1 (APS1) have defective AIRE and suffer from autoimmune disease. One organ that often deteriorates in autoimmune diseases is the lung, which can develop severe fibrosis, preventing effective breathing and oxygen exchange. To investigate the basis of this interstitial lung disease and other similar problems that arise sporadically, Shum et al. explored how lung damage occurs in AIRE-deficient mice and in a patient with APS1. The diseased lungs from both mice and human were infiltrated with T helper 1 CD4+ cells, with smaller numbers of other immune cells. Further work showed that one of the main targets of these cells in mice was, unexpectedly, a protein called vomeromodulin, which the authors determined is expressed in the thymus under AIRE control. Indeed, activated T cells to vomeromodulin cause lung-specific disease when given to immunodeficient mice. In the patient with the same genetic defect as the mice, the lung antigen was not vomeromodulin but was a similar protein called LPLUNC1 (long palate, lung, and nasal epithelium carcinoma–associated protein), located adjacent to the human version of vomeromodulin, which is a pseudogene. This multifaceted study offers several benefits. The lung-specific autoimmune disease seen in the AIRE-deficient mouse closely resembles human interstitial lung disease and can provide a tractable way to understand its progression and develop treatments. This clear example showing how a failure in establishing tolerance to self-antigens can produce an organ-specific disease points to similar mechanisms as possible causes of other autoimmune problems. Finally, the new results elevate vomeromodulin—and its human cousin LPLUNC1—from an interesting secretion product of the nasal epithelium to an autoimmune target in a serious disease, increasing our understanding of how to combat these illnesses. Interstitial lung disease (ILD) is a common manifestation of systemic autoimmunity characterized by progressive inflammation or scarring of the lungs. Patients who develop these complications can exhibit significantly impaired gas exchange that may result in hypoxemia, pulmonary hypertension, and even death. Unfortunately, little is understood about how these diseases arise, including the role of specific defects in immune tolerance. Another key question is whether autoimmune responses targeting the lung parenchyma are critical to ILD pathogenesis, including that of isolated idiopathic forms. We show that a specific defect in central tolerance brought about by mutations in the autoimmune regulator gene (Aire) leads to an autoreactive T cell response to a lung antigen named vomeromodulin and the development of ILD. We found that a human patient and mice with defects in Aire develop similar lung pathology, demonstrating that the AIRE-deficient model of autoimmunity is a suitable translational system in which to unravel fundamental mechanisms of ILD pathogenesis.

Insulin sensitivity and secretion in children and adolescents with hypothalamic obesity following treatment for craniopharyngioma

Background  Craniopharyngioma (CP), a tumour occurring in the hypothalamic–pituitary area, results in morbid obesity in 25–60% of affected children. It has been suggested that abnormalities of insulin secretion and/or insulin action due to hypothalamic injury may be associated with weight gain and the metabolic syndrome in this population.

An evaluation of early cardiometabolic risk factors in children and adolescents with Turner syndrome

Turner syndrome (TS) confers increased lifetime risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors and measures of subcutaneous, visceral adipose tissue and intra‐myocellular lipid between young TS girls and an age‐ and BMI‐standard deviation scores (SDS)‐matched healthy female cohort.

Sleep-Disordered Breathing Is Increased in Obese Adolescents with Craniopharyngioma Compared with Obese Controls

CONTEXT Retrospective studies suggest that adolescents with craniopharyngioma and hypothalamic obesity have increased sleep-disordered breathing (SDB). OBJECTIVES The objectives of this study were to compare the prevalence of SDB in adolescents with craniopharyngioma-related obesity compared with body mass index (BMI)-matched controls and to explore possible relationships between SDB, insulin resistance, and adipocytokines. DESIGN This was a cross-sectional study of obese craniopharyngioma and obese control adolescents. SETTING Subjects were evaluated in the clinical investigation unit at the Hospital for Sick Children, Toronto. PATIENTS Fifteen patients with craniopharyngioma-related obesity and 15 BMI-matched controls were recruited and tested. INTERVENTIONS Each subject underwent fasting blood work, frequent sampled iv glucose tolerance test, polysomnography, and abdominal magnetic resonance imaging with calculation of visceral and sc adipose tissue. MAIN OUTCOME MEASURES Main measures included insulin sensitivity, sleep efficiency, and fragmentation. RESULTS Insulin sensitivity was lower in craniopharyngioma subjects compared with control subjects (0.96 +/- 0.34 vs. 1.67 +/- 0.7, P = 0.01). Sleep-onset latency (19.3 +/- 27.8 vs. 31.9 +/- 23.4, P = 0.03) and oxygen saturations (rapid eye movement sleep: 89.0 +/- 5.1 vs. 94.2 +/- 2.3, P < 0.001; non-rapid eye movement sleep: 88.4 +/- 5.6 vs. 94.3 +/- 1.5, P < 0.001) were lower in craniopharyngioma. Obstructive apnea-hypopnea index (OAHI) (7.5 +/- 9.0 vs. 1.5 +/- 1.5, P = 0.03) was higher in craniopharyngioma. Respiratory distress index and OAHI correlated negatively with adiponectin concentrations (r = -0.61, P = 0.03, r = -0.71, P = 0.006, respectively) in craniopharyngioma. On multiple regression, TNF-alpha and craniopharyngioma were independent positive predictors of sleep-onset latency and adiponectin and craniopharyngioma were significant predictors (negative and positive, respectively) of OAHI. CONCLUSIONS SDB is increased in adolescents with craniopharyngioma-related obesity compared with BMI-matched controls. Routine polysomnography should be considered in obese patients with craniopharyngioma and appropriate treatment initiated.

Considering statins for cholesterol-reduction in children if lifestyle and diet changes do not improve their health: A review of the risks and benefits

Children who appear healthy, even if they have one or more recognized cardiovascular risk factors, do not generally have outcomes of cardiovascular or other vascular disease during childhood. Historically, pediatric medicine has not aggressively screened for or treated cardiovascular risk factors in otherwise healthy children. However, studies such as the P-Day Study (Pathobiological Determinants of Atherosclerosis in Youth), and the Bogalusa Heart Study, indicate that healthy children at remarkably young ages can have evidence of significant atherosclerosis. With the increasing prevalence of pediatric obesity, can we expect more health problems related to the consequences of pediatric dyslipidemia, hypertriglyceridemia, and atherosclerosis in the future? For many years, medications have been available and used in adult populations to treat dyslipidemia. In recent years, reports of short-term safety of some of these medications in children have been published. However, none of these studies have detailed long-term follow-up, and therefore none have described potential late side-effects of early cholesterol-lowering therapy, or potential benefits in terms of reduction of or delay in cardiovascular or other vascular end-points. In 2007, the American Heart Association published a scientific statement on the use of cholesterol-lowering therapy in pediatric patients. In this review paper, we discuss some of the current literature on cholesterol-lowering therapy in children, including the statins that are currently available for use in children, and some of the cautions with using these and other cholesterol-lowering medications. A central tenet of this review is that medications are not a substitute for dietary and lifestyle interventions, and that even in children on cholesterol-lowering medications, physicians should take every opportunity to encourage children and their parents to make healthy diet and lifestyle choices.

The Impact of Telemedicine Interventions Involving Routine Transmission of Blood Glucose Data with Clinician Feedback on Metabolic Control in Youth with Type 1 Diabetes: A Systematic Review and Meta-Analysis

Our objective was to determine the impact of telemedicine (TM) interventions on the management of type 1 diabetes (T1DM) in youth. We performed a systematic review of randomized trials that evaluated TM interventions involving transmission of blood glucose data followed by unsolicited scheduled clinician feedback. We found no apparent effect of the TM interventions on hemoglobin A1c (HbA1c), severe hypoglycemia, or diabetic ketoacidosis. The limited data available on patient satisfaction, quality of life, and cost also suggested no differences between groups. It is unlikely that TM interventions, as performed in the assessed studies, had a substantial effect on glycemic control or acute complications. However, it remains possible that there are other benefits of TM not adequately reported, that newer TM strategies may be more effective and that interventions may benefit subgroups of youth, such as those with the poor glycemic control, adolescents, or those living in remote areas.

Psychosocial Interventions for Alcohol Use Among Problem Drug Users: Protocol for a Feasibility Study in Primary Care

Background Alcohol use is an important issue among problem drug users. Although screening and brief intervention (SBI) are effective in reducing problem alcohol use in primary care, no research has examined this issue among problem drug users. Objective The objective of this study is to determine if a complex intervention including SBI for problem alcohol use among problem drug users is feasible and acceptable in practice. This study also aims to evaluate the effectiveness of the intervention in reducing the proportion of patients with problem alcohol use. Methods Psychosocial intervention for alcohol use among problem drug users (PINTA) is a pilot feasibility study of a complex intervention comprising SBI for problem alcohol use among problem drug users with cluster randomization at the level of general practice, integrated qualitative process evaluation, and involving general practices in two socioeconomically deprived regions. Practices (N=16) will be eligible to participate if they are registered to prescribe methadone and/or at least 10 patients of the practice are currently receiving addiction treatment. Patient must meet the following inclusion criteria to participate in this study: 18 years of age or older, receiving addiction treatment/care (eg, methadone), or known to be a problem drug user. This study is based on a complex intervention supporting SBI for problem alcohol use among problem drug users (experimental group) compared to an “assessment-only” control group. Control practices will be provided with a delayed intervention after follow-up. Primary outcomes of the study are feasibility and acceptability of the intervention to patients and practitioners. Secondary outcome includes the effectiveness of the intervention on care process (documented rates of SBI) and outcome (proportion of patients with problem alcohol use at the follow-up). A stratified random sampling method will be used to select general practices based on the level of training for providing addiction-related care and geographical area. In this study, general practitioners and practice staff, researchers, and trainers will not be blinded to treatment, but patients and remote randomizers will be unaware of the treatment. Results This study is ongoing and a protocol system is being developed for the study. This study may inform future research among the high-risk population of problem drug users by providing initial indications as to whether psychosocial interventions for problem alcohol use are feasible, acceptable, and also effective among problem drug users attending primary care. Conclusions This is the first study to examine the feasibility and acceptability of complex intervention in primary care to enhance alcohol SBI among problem drug users. Results of this study will inform future research among this high-risk population and guide policy and service development locally and internationally.

Impaired endothelial function in pediatric patients with Turner Syndrome and healthy controls: a case-control study

BackgroundTurner Syndrome women are at high risk of vascular disease and the assessment of early risk factors in Turner Syndrome girls is an emerging focus of research. Our objective was to evaluate endothelial function (EF), a preclinical measure of atherosclerosis, in Turner Syndrome girls compared with controls.MethodsA cross-sectional case-control study of Turner Syndrome girls and healthy controls. Subjects underwent fasting insulin and glucose with calculation of HOMA-IR, fasting lipid profile, anthropometrics, and EF testing using peripheral arterial tonometry (PAT). Subjects, aged 10-18 years, had karyotype-confirmed Turner Syndrome; growth hormone (GH), thyroxine and estrogen use were not exclusion criteria. Controls were age- and BMI-matched healthy girls. Fifteen Turner Syndrome and 15 controls were recruited.ResultsTurner Syndrome girls had lower height, higher HDL and higher waist:height ratio than controls. PAT-hyperemia ratio (RH-PAT) scores were lower in Turner Syndrome (1.64 ± 0.34 vs. 2.08 ± 0.32, p = 0.002) indicating impaired EF. Among Turner Syndrome, RH-PAT did not vary with estrogen therapy or with karyotype 45,XO compared with other karyotypes. However, endothelial function was better in GH-treated compared with GH-untreated Turner Syndrome (1.80 ± 0.36 vs. 1.4 + 0.22, p = 0.02) although there were no differences in HOMA-IR, adiponectin or IGF-1.ConclusionGirls with Turner Syndrome exhibit impaired endothelial function compared with controls, which may explain higher risk for vascular disease. GH may protect endothelial function in Turner Syndrome.

Food and beverage cues in UK and Irish children—television programming

Objectives Increased time in which children spend watching television is a well-described contributor to paediatric obesity. This study investigated the frequency and type of food and beverage placement in children-specific television broadcasts and compared data from UK (UK) and Irish television stations. Design Content analysis, totalling 82.5 h, reflecting 5 weekdays of children-specific television broadcasting on UK and Irish television channels was performed. To allow comparison between UK and Irish food and beverage cues, only broadcasts between 06.00 and 11.30 were analysed. Data were coded separately by two analysts and transferred to SPSS for analyses. Food and beverage cues were coded based on type of product, product placement, product use, motivation, outcome and characters involved. Results A total of 1155 food and beverage cues were recorded. Sweet snacks were the most frequent food cue (13.3%), followed by sweets/candy (11.4%). Tea/coffee was the most frequent beverage cue (13.5%), followed by sugar-sweetened beverages (13.0%). The outcome of the cue was positive in 32.6%, negative in 19.8%, and neutral in 47.5% of cases. The most common motivating factor associated with each cue was celebratory/social (25.2%), followed by hunger/thirst (25.0%). Comparison of UK and Irish placements showed both to portray high levels of unhealthy food cues. However, placements for sugar-sweetened beverages were relatively low on both channels. Conclusions This study provides further evidence of the prominence of unhealthy foods in childrens programming. These data may provide guidance for healthcare professionals, regulators and programme makers in planning for a healthier portrayal of food and beverage in childrens television.