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BACKGROUND: Cardiomyopathy is a clinically and genetically heterogeneous heart condition that can lead to heart failure and sudden cardiac death in childhood. While it has a strong genetic basis, the genetic aetiology for over 50% of cardiomyopathy cases remains unknown. METHODS: In this study, we analyse the characteristics of tandem repeats from genome sequence data of unrelated individuals diagnosed with cardiomyopathy from Canada and the United Kingdom (n = 1216) and compare them to those found in the general population. We perform burden analysis to identify genomic and epigenomic features that are impacted by rare tandem repeat expansions (TREs), and enrichment analysis to identify functional pathways that are involved in the TRE-associated genes in cardiomyopathy. We use Oxford Nanopore targeted long-read sequencing to validate repeat size and methylation status of one of the most recurrent TREs. We also compare the TRE-associated genes to those that are dysregulated in the heart tissues of individuals with cardiomyopathy. FINDINGS: We demonstrate that tandem repeats that are rarely expanded in the general population are predominantly expanded in cardiomyopathy. We find that rare TREs are disproportionately present in constrained genes near transcriptional start sites, have high GC content, and frequently overlap active enhancer H3K27ac marks, where expansion-related DNA methylation may reduce gene expression. We demonstrate the gene silencing effect of expanded CGG tandem repeats in DIP2B through promoter hypermethylation. We show that the enhancer-associated loci are found in genes that are highly expressed in human cardiomyocytes and are differentially expressed in the left ventricle of the heart in individuals with cardiomyopathy. INTERPRETATION: Our findings highlight the underrecognized contribution of rare tandem repeat expansions to the risk of cardiomyopathy and suggest that rare TREs contribute to â¼4% of cardiomyopathy risk. FUNDING: Government of Ontario (RKCY), The Canadian Institutes of Health Research PJT 175329 (RKCY), The Azrieli Foundation (RKCY), SickKids Catalyst Scholar in Genetics (RKCY), The University of Toronto McLaughlin Centre (RKCY, SM), Ted Rogers Centre for Heart Research (SM), Data Sciences Institute at the University of Toronto (SM), The Canadian Institutes of Health Research PJT 175034 (SM), The Canadian Institutes of Health Research ENP 161429 under the frame of ERA PerMed (SM, RL), Heart and Stroke Foundation of Ontario & Robert M Freedom Chair in Cardiovascular Science (SM), Bitove Family Professorship of Adult Congenital Heart Disease (EO), Canada Foundation for Innovation (SWS, JR), Canada Research Chair (PS), Genome Canada (PS, JR), The Canadian Institutes of Health Research (PS).
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Cardiomiopatías , Cardiopatías Congénitas , Humanos , Adulto , Cardiopatías Congénitas/genética , Secuencias Repetidas en Tándem/genética , Metilación de ADN , Cardiomiopatías/genética , Ontario , Proteínas del Tejido Nervioso/genéticaRESUMEN
Cardiomyopathy has variable penetrance. We analyzed age and sex-related genetic differences in 1,397 cardiomyopathy patients (Ontario, UK) with whole genome sequencing. Pediatric cases (n = 471) harbored more deleterious protein-coding variants in Tier 1 cardiomyopathy genes compared to adults (n = 926) (34.6% vs 25.9% respectively, p = 0.0015), with variant enrichment in constrained coding regions. Pediatric patients had a higher burden of sarcomere and lower burden of channelopathy gene variants compared to adults. Specifically, pediatric patients had more MYH7 and MYL3 variants in hypertrophic cardiomyopathy, and fewer TTN truncating variants in dilated cardiomyopathy. MYH7 variants clustered in the myosin head and neck domains in children. OBSCN was a top mutated gene in adults, enriched for protein-truncating variants. In dilated cardiomyopathy, female patients had a higher burden of z-disc gene variants compared to males. Genetic differences may explain age and sex-related variability in cardiomyopathy penetrance. Genotype-guided predictions of age of onset can inform pre-test genetic counseling. Pediatric cardiomyopathy patients were more likely to be genotype-positive than adults with a higher burden of variants in MYH7, MYL3, TNNT2, VCL. Adults had a higher burden of OBSCN and TTN variants. Females with dilated cardiomyopathy (DCM) had a higher burden of z-disc gene variants compared to males.
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Cardiomiopatías , Cardiomiopatía Dilatada , Cardiomiopatía Hipertrófica , Adulto , Humanos , Masculino , Femenino , Niño , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/genética , Mutación , Caracteres Sexuales , Cardiomiopatías/genética , GenotipoRESUMEN
Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10-7 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7-58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP.
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Organic thin films formed by molecular layer deposition (MLD) are important for next-generation electronics, energy storage, photoresists, protective barriers and other applications. This study uses in situ ellipsometry and quartz crystal microbalance to explore growth initiation and growth rate evolution during MLD of polyurea using aromatic p-phenylene diisocyanate (PDIC) or aliphatic 1,6-hexamethylene diisocyanate (HDIC) combined with ethylenediamine (ED) or 1,6-hexanediamine (HD) co-reactants. During the first 10-20 cycles of growth, we show the growth rate can increase and/or decrease substantially depending on the substrate as well as the flexibility, length, and structure of the isocyanate and amine reactants used. The transition from initial to steady growth is attributed to a change in active surface site density as the growth proceeds, where the number of sites is determined by a balance between steric effects that block active sites, double reactions that consume multiple active sites, and precursor physisorption and sub-surface diffusion that create new active sites, where the extent of each mechanism depends on the precursors and deposition conditions. Results shown here provide useful insight into mechanisms needed to control growth of ultra-thin organic films for advanced applications.
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BACKGROUND: Assess process, uptake, validity and resource needs for return of actionable research findings to biobank participants. METHODS: Participants were prospectively enrolled in a multicenter biorepository of childhood onset heart disease. Clinically actionable research findings were reviewed by a Return of Research Results Committee (RRR) and returned to the physician or disclosed directly to the participant through a research genetic counselor. Action taken following receipt of this information was reviewed. RESULTS: Genetic data was generated in 1963 of 7408 participants. Fifty-nine new findings were presented to the RRR committee; 20 (34%) were deemed reportable. Twelve were returned to the physician, of which 7 were disclosed to participants (median time to disclosure, 192 days). Seven findings were returned to the research genetic counselor; all have been disclosed (median time to disclosure, 19 days). Twelve families (86%) opted for referral to clinical genetics after disclosure of findings; 7 results have been validated, 5 results are pending. Average cost of return and disclosure per reportable finding incurred by the research program was $750 when utilizing a research genetic counselor; clinical costs associated with return were not included. CONCLUSIONS: Return of actionable research findings was faster if disclosed directly to the participant by a research genetic counselor. There was a high acceptability amongst participants for receiving the findings, for referral to clinical genetics, and for clinical validation of research findings, with all referred cases being clinically confirmed.
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Bases de Datos Factuales , Genómica/métodos , Pediatría , Costos y Análisis de Costo , HumanosRESUMEN
It has long been held that product developers should not rely solely on instrumental measures of texture. This study examined the widely accepted effects of salivary α amylase on mouth thinning during oral processing. To understand this phenomenon, 13 descriptive panelists were trained to manipulate starch thickened semisolid foods and note when changes in the perceived thickness occurred. The panelists were subsequently grouped based on their reports of how quickly these foods broke down in their oral cavity. The accepted effect of salivary α amylase was then analyzed and found to be consistent across the starch thickened foods examined but different among the panelists. Thus it became clear that starch containing foods with long residence times in the mouth can be perceived differently among people based on their amylase activity, making descriptive profiling difficult to calibrate. This study suggests that classic sensory techniques could also have limitations when considering the oral processing of starchy foods, especially those with long residence times in the oral cavity. Panelists' individual salivary amylase activity was not measured in this study. PRACTICAL APPLICATIONS: Food texture is an important sensory attribute that affects consumers' acceptance of products. Semisolid foods such as puddings and yogurts are expected to thin as the food is manipulated in the mouth. By the same token, starch systems in chewy candies can also be impacted over long periods of mastication. Understanding the impact of salivary amylase on how quickly these foods breakdown is important to developing foods that will be acceptable to consumers. Developers with an understanding of the effects salivary amylase has on various starches can lead them to design products that perform more consistently across individuals with different activity levels of salivary α amylase.
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Digestión/fisiología , Calidad de los Alimentos , Masticación/fisiología , Saliva/enzimología , alfa-Amilasas Salivales/fisiología , Almidón/metabolismo , Análisis por Conglomerados , Humanos , Saliva/metabolismoAsunto(s)
Trastorno Depresivo/tratamiento farmacológico , Terapia de Reemplazo de Hormonas , Perimenopausia , Antidepresivos/uso terapéutico , Quimioterapia Combinada , Moduladores de los Receptores de Estrógeno/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Norpregnenos/uso terapéutico , Perimenopausia/efectos de los fármacosRESUMEN
PURPOSE: The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of nonsyndromic individuals with AVSD. METHODS: Whole-exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. RESULTS: A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR): 1.52; 95% confidence interval (CI): 1.35-1.71; P = 4.8 × 10(-11)). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR: 2.25; 95% CI: 1.84-2.76; P = 2.2 × 10(-16)). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2, and MDM4) were enriched for rare variants in AVSD compared with controls, including three syndrome-associated genes (NIPBL, CHD7, and CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands. CONCLUSION: Mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort.
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Exoma , Variación Genética , Defectos de los Tabiques Cardíacos/genética , Adolescente , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Masculino , Mutación , Fenotipo , Análisis de Secuencia de ADNRESUMEN
A right aortic arch with a retroesophageal brachiocephalic artery is a very rare type of vascular ring. We present a case report along with a review of published cases to date. Twelve publications from 1968-2014 describe a retroesophageal brachiocephalic artery in a total of 13 patients. The mean age at diagnosis was 8.7 ± 16 years. Four of the 13 patients were boys. Nearly half of the patients were symptomatic, with dysphagia or respiratory difficulties. Ten patients (77%) had associated congenital heart defects. Of the 13 patients with retroesophageal brachiocephalic artery, 12 had a right aortic arch, and only 1 had a left aortic arch associated with complex congenital heart disease. Investigations used in the diagnosis of the vascular ring include angiography, esophagography, echocardiography, and computed tomography. Only 2 patients had the diagnosis confirmed with magnetic resonance imaging (MRI), but this was in the setting of complex congenital heart disease. In conclusion, a right aortic arch with a retroesophageal left brachiocephalic artery is an extremely rare form of vascular ring and is often seen in association with other forms of congenital heart disease. Cardiac MRI can be used as a primary diagnostic modality for both the assessment of the vascular ring anatomy and the hemodynamics of associated cardiac malformations in the preoperative setting.
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Tronco Braquiocefálico/anomalías , Imagen por Resonancia Magnética/métodos , Malformaciones Vasculares/diagnóstico , Diagnóstico Diferencial , Esófago , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: The healthcare burden related to congenital heart disease (CHD) is increasing with improving survival. We assessed changing trends in prenatal risk factors for CHD in the current era in a Canadian cohort. METHODS AND RESULTS: CHD patients <18 years old (n=2339) and controls without structural heart disease (n=199) were prospectively enrolled in an Ontario province-wide biobank registry from 2008-2011. Family history, frequency of extra-cardiac anomalies (ECAs), and antenatal risk factors were assessed. Temporal trends were analyzed and associations with CHD were measured using linear and logistic regression. Family history of CHD and frequency of major ECAs was higher in cases versus controls (P<0.001). Despite an increase in genetic testing in the recent era, only 9.5% of cases with CHD had a confirmed genetic diagnosis. Yield of genetic testing (ie, frequency of abnormal results) was higher in familial and syndromic cases. There was an increase in parental age at conception, maternal prepregnancy body mass index, maternal urinary tract infections, type 1 diabetes, and exposure to nonfertility medications during pregnancy from 1990-2011. Later year of birth, family history of CHD, presence of major ECAs, maternal smoking during pregnancy, and maternal medication exposure were associated with increased odds of CHD (P<0.05 for all). Advanced parental age was associated with increased odds of CHD caused by genetic abnormalities. CONCLUSIONS: The increase in prenatal risk factors for CHD highlights the need for more rigorous ascertainment of genetic and environmental factors including gene-environment interactions that contribute to CHD.
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Cardiopatías Congénitas/epidemiología , Diagnóstico Prenatal , Femenino , Pruebas Genéticas , Cardiopatías Congénitas/genética , Humanos , Recién Nacido , Masculino , Embarazo , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Consenting minors for genetics research and biobanking involves ethical and social challenges. We examined factors influencing participation rates in a population-based biorepository for childhood heart disease. METHODS: Individuals were prospectively enrolled across 7 centers in Ontario by using a standardized consent form. Individuals were approached for consent for the donation of blood/saliva (DNA), tissue, and skin from the affected individual for future genomics and stem cell research. Consent rates were compared between pediatric and adult patients and factors affecting consent were analyzed by using multiple logistic regression analysis. RESULTS: From 2008 to 2011, 3637 patients were approached. A total of 2717 pediatric patients consented (90% consent rate); mean age was 8.5 ± 5.8 years (57% male; 76% white). A total of 561 adult patients consented (92% consent rate, P = .071 versus pediatric). Factors associated with lower pediatric consent rates included younger age, race, absence of complex defects, and location of consent; these were not associated with adult consent rates. Leading causes for refusal of consent were lack of interest in research (43%), overwhelmed clinically (14%), and discomfort with genetics (11%). Concerns related to privacy, insurability, indefinite storage, and ongoing access to medical records were not the leading causes for refusal. CONCLUSIONS: The high pediatric consent rate (90%) was comparable with that of adults. Ethical, social, or legal issues were not the leading reasons for refusal of consent.
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Bancos de Muestras Biológicas , Cardiopatías , Participación del Paciente/estadística & datos numéricos , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: Hypoxia-inducible factor (HIF1A) regulates the myocardial response to hypoxia and hemodynamic load. We investigated the association of HIF1A variants with right-ventricular (RV) remodeling after tetralogy of Fallot (TOF) repair. METHODS: Children with TOF were genotyped for three single-nucleotide polymorphisms in HIF1A. Genotypes were analyzed for association with RV myocardial protein expression and fibrosis at complete repair (n = 42) and RV dilation, fractional area change, and freedom from pulmonary valve/conduit replacement on follow-up. RESULTS: In 180 TOF patients, mean age at repair was 1.0 ± 0.8 y with follow-up at 9.0 ± 3.5 y; 82% had moderate to severe pulmonary insufficiency. Freedom from RV reinterventions at 5, 10, and 15 y was 92, 84, and 67%, respectively. Patients with more functioning HIF1A alleles had higher transforming growth factor ß1 expression and more fibrosis at initial repair as compared with controls (P < 0.05). During follow-up, patients with more functioning HIF1A alleles showed less RV dilation, better preservation of RV function, and greater freedom from RV reinterventions (P < 0.05). This was confirmed in a replication cohort of 69 patients. CONCLUSION: In children who have had TOF repair, a lower number of functioning HIF1A alleles was associated with RV dilation and dysfunction, suggesting that hypoxia adaptation in unrepaired TOF may influence RV phenotype after repair.
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Procedimientos Quirúrgicos Cardíacos , Ventrículos Cardíacos/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Polimorfismo de Nucleótido Simple , Tetralogía de Fallot/cirugía , Remodelación Ventricular/genética , Adaptación Fisiológica , Proteínas Angiogénicas/genética , Proteínas Angiogénicas/metabolismo , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Preescolar , Fibrosis , Estudios de Seguimiento , Frecuencia de los Genes , Genotipo , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Humanos , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/cirugía , Hipoxia/genética , Hipoxia/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Lactante , Estimación de Kaplan-Meier , Modelos Lineales , Modelos Logísticos , Fenotipo , Estudios Prospectivos , Sistema de Registros , Reoperación , Tetralogía de Fallot/genética , Tetralogía de Fallot/metabolismo , Tetralogía de Fallot/patología , Tetralogía de Fallot/fisiopatología , Factores de Tiempo , Factor de Crecimiento Transformador beta1/metabolismo , Resultado del Tratamiento , Disfunción Ventricular Derecha/genética , Disfunción Ventricular Derecha/patología , Disfunción Ventricular Derecha/cirugíaRESUMEN
Brugada syndrome is a channelopathy characterised electrocardiographically by distinctive coved ST-segment elevation in the right precordial leads and is associated with a predisposition for sudden death secondary to ventricular arrhythmias in otherwise healthy patients. Previously known as Brugada-like patterns, Brugada phenocopies include agents and conditions that mimic true Brugada syndrome, presenting with an acquired Brugada Type-1 ECG pattern. We describe the first reported case of a 17-month-old female with an asymptomatic rhabdomyoma of the interventricular septum that presented as a Brugada phenocopy.
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Síndrome de Brugada/etiología , Neoplasias Cardíacas/complicaciones , Rabdomioma/complicaciones , Tabique Interventricular , Femenino , Humanos , Recién NacidoRESUMEN
We present the case of a 20-year old male that underwent a surgical ventricular septal myectomy at 8 months of age for symptomatic and drug-refractory obstructive hypertrophic cardiomyopathy (HCM). Though he has remained asymptomatic since the operation, he now demonstrates findings of cardiac arrhythmia and left ventricular dysfunction. His case is of particular interest as it represents a detailed and lengthy follow-up from early childhood to adulthood. Recognizing the post-myectomy state as a potentially separate entity from non-operated HCM can promote an individualized approach to long-term medical management.
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Procedimientos Quirúrgicos Cardíacos/tendencias , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/cirugía , Complicaciones Posoperatorias/diagnóstico , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Humanos , Masculino , Complicaciones Posoperatorias/etiología , Resultado del Tratamiento , Ultrasonografía , Adulto JovenRESUMEN
BACKGROUND: Rising incidences of Kawasaki disease (KD) have been reported worldwide. Reported herein are the results of 4 triennial KD surveillances conducted in Ontario. METHODS: Between 1995 and 2006 all hospitals in Ontario were asked on 4 occasions to identify all patients with discharge diagnoses of KD and report incident cases. RESULTS: The latest surveillance identified 697 new KD patients (100% response rate) for a total of 2378 KD patients through all 4 surveillances. Yearly incidence was 26.2/100,000 for <5 years old, 6.7/100,000 for 5-9 years old and 0.9/100,000 for 10-14 years old. KD incidence significantly increased from 1995 to 2006, although the increase seemed to plateau between the 3rd and 4th surveillance. There was an increase in the proportion of patients diagnosed with incomplete KD and a significant reduction in the rate of coronary artery abnormalities, possibly due to better disease recognition and treatment. Hospitals reporting <20 cases per surveillance were found to be more likely to report cases with incomplete KD. These patients were also less likely to be treated with i.v. immunoglobulin and aspirin but were more likely to be treated with antibiotics, suggesting uncertainties regarding diagnosis and management of KD patients in those centers. CONCLUSIONS: The incidence of KD in Ontario is possibly one of the highest outside of Asia and has been rising since 1995. Although the most recent surveillance demonstrated improved cardiac outcomes, treatment delays or absence thereof continue to be a problem. Effective diagnosis and prompt treatment remain critical aspects of KD management.
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Brotes de Enfermedades , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/epidemiología , Adolescente , Distribución por Edad , Niño , Preescolar , Femenino , Encuestas Epidemiológicas , Hospitalización/estadística & datos numéricos , Humanos , Incidencia , Lactante , Recién Nacido , Clasificación Internacional de Enfermedades , Masculino , Ontario/epidemiología , Medición de Riesgo , Estaciones del Año , Índice de Severidad de la Enfermedad , Distribución por Sexo , Factores de Tiempo , Adulto JovenRESUMEN
OBJECTIVE: To determine whether exercise intolerance and recommended activity restrictions are associated with development of overweight and obesity in children with congenital heart disease. DESIGN: Retrospective review. SETTING: Pediatric cardiology practice at a teaching hospital. PARTICIPANTS: A total of 110 pediatric congenital heart disease patients followed up for a mean of 8.4 years. MAIN OUTCOME MEASURES: Body mass index (BMI), sex-appropriate BMI percentiles, overweight (BMI percentile > or =85), and obesity (BMI percentile > or =95) at follow-up. RESULTS: As a group, the increase in BMI percentiles was close to 10 points, but the increase was 21.6 points for exercise intolerant children and 27.3 points for activity restricted children. Activity restriction was significantly associated with both overweight (risk ratio [RR], 2.60; 95% confidence interval [CI], 1.34-3.54) and obesity at follow-up (RR, 4.08; 95% CI, 1.42-7.38) after adjusting for weight at baseline. For the subset of 92 children at a healthy weight at baseline, activity restriction was again significantly associated with overweight (RR, 2.51; 95% CI, 1.24-3.52) and obesity (RR, 6.14; 95% CI, 2.54-8.82) at follow-up. Exercise intolerance did not attain statistical significance. CONCLUSIONS: Exercise intolerant and activity restricted children experienced larger increases in absolute BMI and BMI percentile than children with neither exercise intolerance nor activity restriction. Activity restriction was the strongest predictor of risk of overweight and obesity at follow-up. Elevated weight and obesity may cause these children significant additional health burdens. Therefore, when patients must be counseled against physical exertion, they also need to be educated about the importance of appropriate physical activity and good dietary practices.
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Índice de Masa Corporal , Tolerancia al Ejercicio , Cardiopatías Congénitas/complicaciones , Obesidad/etiología , Adolescente , Canadá/epidemiología , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Registros Médicos , Estudios RetrospectivosRESUMEN
A series of experiments investigated the nature of metallic taste reports and whether they can be attributed to the development of a retronasal smell. Two studies showed that the metallic sensation reports following oral stimulation with solutions of FeSO4 were reduced to baseline when the nose was occluded. No such reduction was seen for CuSO4 or ZnSO4, which were more bitter and astringent, respectively, and less metallic. A discrimination test based on weak but equi-intense levels of FeSO4 and CuSO4 showed that FeSO4 could be discriminated from water with the nose open but not when occluded, but that discrimination of CuSO4 from water was not impaired by nasal occlusion. A discrimination test demonstrated that the headspace over solutions of FeSO4 was not different from water, although some subjects could discriminate FeSO4 solutions from water in the mouth when the nose was occluded, perhaps by tactile or astringent cues. These results confirm that metallic taste reports following oral stimulation with FeSO4 are likely due to development of a retronasal smell, possibly following a lipid oxidation reaction in the mouth. However, metallic taste reports may arise from different mechanisms with copper and zinc salts.