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.

Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (γ‐hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1−/− mice and characterization of γ‐hydroxybutyric acid pharmacology

Abstract: We overview the pathophysiological bases, clinical approaches and potential therapeutic options for succinate semialdehyde dehydrogenase (SSADH; EC1.2.1.24) deficiency (γ-hydroxybutyric aciduria, OMIM 271980, 610045) in relation to studies on SSADH gene-deleted mice, outcome data developed from 25 years of patient evaluation, and characterization of γ-hydroxybutyric acid (GHB) pharmacology in different species. The clinical picture of this disorder encompasses a wide spectrum of neurological and psychiatric dysfunction, such as psychomotor retardation, delayed speech development, epileptic seizures and behavioural disturbances, emphasizing the multifactorial pathophysiology of SSADH deficiency. The murine SSADH−/− (e.g. Aldh5a1−/−) mouse model suffers from epileptic seizures and succumbs to early lethality. Aldh5a1−/− mice accumulate GHB and γ-aminobutyric acid (GABA) in the central nervous system, exhibit alterations of amino acids such as glutamine (Gln), alanine (Ala) and arginine (Arg), and manifest disturbances in other systems including dopamine, neurosteroids and antioxidant status. Therapeutic concepts in patients with SSADH deficiency and preclinical therapeutic experiments are discussed in light of data collected from research in Aldh5a1−/− mice and animal studies of GHB pharmacology; these studies are the foundation for novel working approaches, including pharmacological and dietary trials, which are presented for future evaluation in this disease.

Recent developments in clinimetric instruments.

Abstract: Assessment of impairment and function is essential in order to monitor joint status and evaluate therapeutic interventions in patients with haemophilia. The improvements in the treatment of haemophilia have required the development of more sensitive tools to detect the more minor dysfunctions that may now be apparent. This paper outlines some of the recent developments in this field. The Haemophilia Joint Health Score (HJHS) provides a systematic and robust measure of joint impairment. The MRI Scoring System has been designed to provide a comprehensive scoring system combining both progressive and additive scales. The Functional Independence Score for Haemophilia (FISH) has been developed to assess performance of functional activities and can be used in conjunction with the Haemophilia Activities List (HAL) which provides a self report measure of function. It is recommended that both measures are evaluated as these tools measure different constructs. Further refinement and testing of the psychometric properties of all of these tools is in progress. More widespread use of these tools will enable the sharing of data across the world so promoting best practice and ultimately enhancing patient care.

MPGN II – genetically determined by defective complement regulation?

Abstract: MPGN II is a rare disease which is characterized by complement containing deposits within the GBM. The disease is characterized by functional impairment of the GBM causing progressive loss of renal function eventually resulting in end stage renal disease.

Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations.

Abstract: Familial hemophagocytic lymphohistiocytosis 5 (FHL5) is an autosomal recessive disease caused by mutations in STXBP2, coding for Munc18-2, which is required for SNARE-mediated membrane fusion. FHL5 causes hematologic and gastrointestinal symptoms characterized by chronic enteropathy that is reminiscent of microvillus inclusion disease (MVID). However, the molecular pathophysiology of FHL5-associated diarrhea is poorly understood. Five FHL5 patients, including four previously unreported patients, were studied. Morphology of duodenal sections was analyzed by electron and fluorescence microscopy. Small intestinal enterocytes and organoid-derived monolayers displayed the subcellular characteristics of MVID. For the analyses of Munc18-2-dependent SNARE-protein interactions, a Munc18-2 CaCo2-KO model cell line was generated by applying CRISPR/Cas9 technology. Munc18-2 is required for Slp4a/Stx3 interaction in fusion of cargo vesicles with the apical plasma membrane. Cargo trafficking was investigated in patient biopsies, patient-derived organoids, and the genome-edited model cell line. Loss of Munc18-2 selectively disrupts trafficking of certain apical brush-border proteins (NHE3 and GLUT5), while transport of DPPIV remained unaffected. Here, we describe the molecular mechanism how the loss of function of Munc18-2 leads to cargo-selective mislocalization of brush-border components and a subapical accumulation of cargo vesicles, as it is known from the loss of polarity phenotype in MVID.

Readiness for Transition to Adult Health Care for Young Adolescents with Congenital Heart Disease.

Abstract: This study evaluates transition readiness, medical condition knowledge, self-efficacy, and illness uncertainty in young adolescents (ages 12 to 15 years) with congenital heart disease (CHD), and medical, patient, and parental factors associated with transition readiness. We enrolled 82 patients with moderate or complex CHD (n = 36, 44% male; mean age 13.6 ± 1.3 years), and their parents. Patients completed standardized self-report measures: Transition Readiness Assessment Questionnaire (TRAQ), MyHeart scale, General Self-Efficacy scale, and Children's Uncertainty in Illness Scale. Parents completed the MyHeart scale and demographic information. Many young adolescents had not discussed transfer with a health care provider (n = 20, 24%) or parent (n = 34, 41%). Transition readiness was higher among patients who were older, more knowledgeable about their condition, had a history of primary cardiac repair and greater self-efficacy, and was lower for boys and patients on cardiac medications. Transition readiness was unrelated to CHD diagnosis and patients' illness uncertainty. Patients' self-advocacy skills were superior to their chronic disease self-management skills. Increased parental medical condition knowledge was positively correlated with patient knowledge, and patient-parent discussion of transfer was associated with increased patient's self-management skills. Transition is not uniformly discussed with young adolescent CHD patients. Parental involvement is correlated with increased transition readiness and patient disease self-management skills. Young adolescent transition programs should focus on education around improving patient medical condition knowledge, promote chronic disease self-management skills development, and include parental involvement.