Hospital for Sick Children

About: Hospital for Sick Children is a healthcare organization based out in Toronto, Ontario, Canada. It is known for research contribution in the topics: Population & Medicine. The organization has 4097 authors who have published 3746 publications receiving 129066 citations. The organization is also known as: Sick Kids Hospital & SickKids.

Neurophysiological mechanisms of emotion regulation for subtypes of externalizing children.

Abstract: Children referred for externalizing behavior problems may not represent a homogeneous population. Our objective was to assess neural mechanisms of emotion regulation that might distinguish subtypes of externalizing children from each other and from their normal age mates. Children with pure externalizing (EXT) problems were compared with children comorbid for externalizing and internalizing (MIXED) problems and with age-matched controls. Only boys were included in the analysis because so few girls were referred for treatment. We used a go/no-go task with a negative emotion induction, and we examined dense-array EEG data together with behavioral measures of performance. We investigated two event-related potential (ERP) components tapping inhibitory control or self-monitoring—the inhibitory N2 and error-related negativity (ERN)—and we constructed source models estimating their cortical generators. The MIXED children's N2s increased in response to the emotion induction, resulting in greater amplitudes than EXT children in the following trial block. ERN amplitudes were greatest for control children and smallest for EXT children with MIXED children in between, but only prior to the emotion induction. These results were paralleled by behavioral differences in response time and performance monitoring. ERP activity was localized to cortical sources suggestive of the dorsal anterior cingulate for control children, posterior cingulate areas for the EXT children, and both posterior cingulate and ventral cingulate/prefrontal regions for the MIXED children. These findings highlight different mechanisms of self-regulation underlying externalizing subtypes and point toward distinct developmental pathways and treatment strategies.We gratefully acknowledge the financial support provided by Grant 1 R21 MH67357-01 from the Developmental Psychopathology and Prevention Research branch of the National Institute of Mental Health (NIMH), as well as support from the Canadian Institutes for Health Research (CIHR). We are also grateful for support provided (to P.D.Z.) by the Canadian Foundation for Innovation.

Patterns of Parental Bereavement following the Loss of a Child and Related Factors

Abstract: This study investigated the patterns of parental bereavement in 20 parents who have lost a child to cancer, congenital heart disease, meningitis, or drowning in the last 19 months, using semi-structured interviews and standardized questionnaires of depression and grief. Qualitative content analysis of interviews identified three bereavement patterns: The majority of parents (65%) presented uncomplicated, Integrated Grief five mothers were Consumed by Grief and one mother and one father expressed Minimal Grief. Quotes from parents exemplified these patterns. Parental gender, symptoms of depression, and pre-death relationship between parents and their deceased child differentially related to these patterns. Having surviving children, social support, and being active appeared to help to integrate grief into daily life. These findings illustrate differential patterns of parental bereavement and related factors, information that has important implications for identifying at-risk parents for complicated bereavement.

Unraveling the complex genetic model for cystic fibrosis: pleiotropic effects of modifier genes on early cystic fibrosis-related morbidities

Abstract: The existence of pleiotropy in disorders with multi-organ involvement can suggest therapeutic targets that could ameliorate overall disease severity. Here we assessed pleiotropy of modifier genes in cystic fibrosis (CF). CF, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects the lungs, liver, pancreas and intestines. However, modifier genes contribute to variable disease severity across affected organs, even in individuals with the same CFTR genotype. We sought to determine whether SLC26A9, SLC9A3 and SLC6A14, that contribute to meconium ileus in CF, are pleiotropic for other early-affecting CF co-morbidities. In the Canadian CF population, we assessed evidence for pleiotropic effects on (1) pediatric lung disease severity (n = 815), (2) age at first acquisition of Pseudomonas aeruginosa (P. aeruginosa) (n = 730), and (3) prenatal pancreatic damage measured by immunoreactive trypsinogen (n = 126). A multiple-phenotype analytic strategy assessed evidence for pleiotropy in the presence of phenotypic correlation. We required the same alleles to be associated with detrimental effects. SLC26A9 was pleiotropic for meconium ileus and pancreatic damage (p = 0.002 at rs7512462), SLC9A3 for meconium ileus and lung disease (p = 1.5 × 10(-6) at rs17563161), and SLC6A14 for meconium ileus and both lung disease and age at first P. aeruginosa infection (p = 0.0002 and p = 0.006 at rs3788766, respectively). The meconium ileus risk alleles in SLC26A9, SLC9A3 and SLC6A14 are pleiotropic, increasing risk for other early CF co-morbidities. Furthermore, co-morbidities affecting the same organ tended to associate with the same genes. The existence of pleiotropy within this single disorder suggests that complementary therapeutic strategies to augment solute transport will benefit multiple CF-associated tissues.

Influenza infects lung microvascular endothelium leading to microvascular leak: role of apoptosis and claudin-5.

Abstract: Severe influenza infections are complicated by acute lung injury, a syndrome of pulmonary microvascular leak. The pathogenesis of this complication is unclear. We hypothesized that human influenza could directly infect the lung microvascular endothelium, leading to loss of endothelial barrier function. We infected human lung microvascular endothelium with both clinical and laboratory strains of human influenza. Permeability of endothelial monolayers was assessed by spectrofluorimetry and by measurement of the transendothelial electrical resistance. We determined the molecular mechanisms of flu-induced endothelial permeability and developed a mouse model of severe influenza. We found that both clinical and laboratory strains of human influenza can infect and replicate in human pulmonary microvascular endothelium, leading to a marked increase in permeability. This was caused by apoptosis of the lung endothelium, since inhibition of caspases greatly attenuated influenza-induced endothelial leak. Remarkably, replication-deficient virus also caused a significant degree of endothelial permeability, despite displaying no cytotoxic effects to the endothelium. Instead, replication-deficient virus induced degradation of the tight junction protein claudin-5; the adherens junction protein VE-cadherin and the actin cytoskeleton were unaffected. Over-expression of claudin-5 was sufficient to prevent replication-deficient virus-induced permeability. The barrier-protective agent formoterol was able to markedly attenuate flu-induced leak in association with dose-dependent induction of claudin-5. Finally, mice infected with human influenza developed pulmonary edema that was abrogated by parenteral treatment with formoterol. Thus, we describe two distinct mechanisms by which human influenza can induce pulmonary microvascular leak. Our findings have implications for the pathogenesis and treatment of acute lung injury from severe influenza.

Spontaneous clearance of childhood hepatitis C virus infection.

Abstract: To describe the spontaneous clearance rate of childhood hepatitis C virus (HCV) infection, to determine whether route of transmission affects the clearance rate and to identify other predictors of clearance. Children with chronic hepatitis C were identified between 1990 and 2001. The rate of spontaneous clearance (defined as >or=2 positive anti-HCV antibody test but negative HCV RNA) was calculated using survival analysis. Univariate and multivariate predictor variables [route of transmission, age at infection, age at last follow-up, alanine aminotransferase (ALT) and gender] for clearance were evaluated. Of 157 patients, 28% of children cleared infection (34 transfusional and 10 nontransfusional cases). The 123 transfusional cases were older at time of infection and at follow-up, compared with the 34 nontransfusional cases. Younger age at follow-up (p < 0.0001) and normal ALT levels (p < 0.0001) favoured clearance. Among cases of neonatal infection, 25% demonstrated spontaneous clearance by 7.3 years. The rate of spontaneous clearance of childhood HCV infection was comparable between transfusional and nontransfusional cases. If clearance occurs, it tends to occur early in infection, at a younger age.