Michael Khoury

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here we examine human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, we found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, we show in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runt-related transcription factor-2 (RUNX2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (ADAMTS5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.

Role of the Waist/Height Ratio in the Cardiometabolic Risk Assessment of Children Classified by Body Mass Index

OBJECTIVES The aim of this study was to determine the utility of waist/height ratio (WHtR) in the specification of cardiometabolic risk in children already stratified by body mass index (BMI). BACKGROUND Reflective of its association with cardiometabolic risk, BMI is a commonly used indirect indicator of adiposity in children. The WHtR, a marker of central adiposity, has been advocated as a possibly superior indicator of cardiometabolic risk. METHODS Cross-sectional analysis of 5 National Health and Nutrition Examination Surveys from 1999 to 2008 (ages 5 to 18 years of age). The BMI percentile categories (normal, overweight, and obese) were further stratified on the basis of WHtR (<0.5, 0.5 to <0.6, ≥ 0.6). Outcome measures were lipid and glycemic profiles, C-reactive protein, liver transaminases, prevalence of hypertension, and metabolic syndrome. RESULTS Data were available for 14,493 subjects. Overweight and obese subjects with a WHtR <0.5 had a cardiometabolic risk approaching that of subjects with a normal BMI percentile category. Increasing WHtR was significantly associated with increased cardiometabolic risk in overweight and obese subjects, with the greatest associations observed in the obese population. Of obese subjects with WHtR ≥ 0.6, 26% had elevated non-high-density lipoprotein levels, 18% had elevated C-reactive protein levels, 69% had an elevated homeostatic model assessment-insulin resistance, and 32% had metabolic syndrome. CONCLUSIONS The WHtR further specifies cardiometabolic risk within classifications stratification on the basis of BMI percentile. A significant proportion of obese children with increased WHtRs have abnormal cardiometabolic risk factor levels. The WHtR should be included in the routine screening and assessment of overweight and obese children, and those with an elevated WHtR should undergo a further cardiometabolic risk assessment.

Prolonged β-catenin stabilization and tcf-dependent transcriptional activation in hyperplastic cutaneous wounds

Mesenchymal cells that accumulate during the proliferative phase of wound healing and that are present in hyperplastic wounds share cytologic similarities with the cells from fibroproliferative lesions in which there is activation of β-catenin-mediated transcription. Re-excision wounds from a previous biopsy and samples from hyperplastic cutaneous wounds were studied along with normal tissues. During normal wound healing, there was an increase in β-catenin protein level, peaking 4 weeks following the insult and returning towards baseline level by 12 weeks. Hyperplastic wounds exhibited a prolonged duration of elevated β-catenin, lasting more than 2 years following the initial injury. The level of expression of genes known to be upregulated in the proliferative phase of wound healing (α-smooth muscle actin and type three collagen), correlated with β-catenin protein level. The phosphorylation level of glycogen synthase kinase-3-β, a kinase important for β-catenin protein destabilization, correlated with β-catenin protein level. β-Catenin was transcriptionally active in these wounds as demonstrated by the expression of the β-catenin target genes (MMP-7 and FN) and by activation of a tcf-reporter in primary cell cultures. β-catenin stabilization increases cell proliferation and motility in fibroblasts in vitro, and likely has a similar function during its transient elevation in the proliferative phase of normal wound healing. In hyperplastic wounds, there is dysregulation of β-catenin, maintaining the mesenchymal cells in a prolonged proliferative state. As such, β-catenin likely plays a central role in mesenchymal cells during the healing process, and is an appealing therapeutic target for disorders of wound healing.

Reported electronic cigarette use among adolescents in the Niagara region of Ontario

Background: Use of electronic cigarettes (e-cigarettes) among adolescents has not been fully described, in particular their motivations for using them and factors associated with use. We sought to evaluate the frequency, motivations and associated factors for e-cigarette use among adolescents in Ontario. Methods: We conducted a cross-sectional study in the Niagara region of Ontario, Canada, involving universal screening of students enrolled in grade 9 in co-operation with the Heart Niagara Inc. Healthy Heart Schools’ Program (for the 2013–2014 school year). We used a questionnaire to assess cigarette, e-cigarette and other tobacco use, and self-rated health and stress. We assessed household income using 2011 Canadian census data by matching postal codes to census code. Results: Of 3312 respondents, 2367 answered at least 1 question in the smoking section of the questionnaire (1274 of the 2367 respondents [53.8%] were male, with a mean [SD] age of 14.6 [0.5] yr) and 2292 answered the question about use of e-cigarettes. Most respondents to the questions about use of e-cigarettes (n = 1599, 69.8%) had heard of e-cigarettes, and 380 (23.8%) of these respondents had learned about them from a store sign or display. Use of e-cigarettes was reported by 238 (10.4%) students. Most of the respondents who reported using e-cigarettes (171, 71.9%) tried them because it was “cool/fun/new,” whereas 14 (5.8%) reported using them for smoking reduction or cessation. Male sex, recent cigarette or other tobacco use, family members who smoke and friends who smoke were strongly associated with reported e-cigarette use. Reported use of e-cigarettes was associated with self-identified fair/poor health rating (odds ratio [OR] 1.9 (95% confidence interval [CI] 1.2–3.0), p < 0.001), high stress level (OR 1.7 (95% CI 1.1–2.7), p < 0.001) and lower mean (33.4 [8.4] ×

Catheter-Based Palliation in an Infant With Obstructed Cor Triatriatum

1000 v. 36.1 [10.7] ×

Associations Between Beverage Consumption, Cardiometabolic Risk and Adiposity in Adolescents Undergoing Universal Screening

1000, p = 0.001) and median [interquartile range] (26.2 [5.6] ×

Role of Waist Measures in Characterizing the Lipid and Blood Pressure Assessment of Adolescents Classified by Body Mass Index

1000 v. 28.1 [5.7] ×

Universal screening for cardiovascular disease risk factors in adolescents to identify high-risk families: a population-based cross-sectional study

1000) household incomes. Interpretation: Use of e-cigarettes is common among adolescents in the Niagara region and is associated with sociodemographic features. Engaging in seemingly exciting new behaviours appears to be a key motivating factor rather than smoking cessation.

EVALUATING THE ASSOCIATIONS BETWEEN BUYING LUNCH AT SCHOOL, EATING AT RESTAURANTS, AND EATING TOGETHER AS A FAMILY AND CARDIOMETABOLIC RISK IN ADOLESCENTS

A 33-day-old infant with obstructed cor triatriatum sinister and partial anomalous pulmonary venous drainage presented with respiratory distress and fever. Her suprasystemic pulmonary hypertension was relieved by opening the connection to the right atrium using balloon atrial septoplasty and septostomy, and to the inferior chamber using balloon dilation of a fenestration in the dividing membrane. This enabled extubation and discharge, with elective surgical repair at 2 months. To our knowledge, this is the youngest patient to receive a catheter intervention for obstructed cor triatriatum sinister, providing relief of pulmonary hypertension and postponement of surgical repair.

Abstract 19593: Cardiac Rehabilitation in Premature Coronary Artery Disease

Background and Objective: The association between milk intake, diet soda and caffeinated drinks and cardiometabolic risk in adolescents is not well understood. We sought to evaluate this in adolescents having universal screening. Methods: Cross-sectional study of grade 9 adolescents over 4 school years who underwent universal risk factor screening through the Heart Niagara Inc. Healthy Heart Schools’ Program. Questionnaires assessing dietary intake and habits (24 hour recall and general intake habits) were completed. Height, weight, waist circumference (WC), blood pressure, and non-fasting lipids were measured. Results: Of the 10 659 (50%male, average age 14.5 years) students who participated, 17% (1769) were overweight (body mass index [BMI] 85- 95th percentile). Each additional daily intake of diet soda was associated with a 2.5-point (standard error (SE) 0.5, p< 0.001) increase in BMI percentile. Identifying skim/non-fat milk as the milk typically ingested was associated with a 7-point (SE 1.5, p<0.001) increase in BMI percentile, while no significant associations were observed with whole milk. Increased intake of caffeinated coffee/ tea-based beverages and caffeinated soda beverages was associated with a 2.1-point (SE 0.5, p<0.001) and 2.3-point (SE 0.6, p<0.001) increase in BMI percentile, respectively. Similar associations were seen with waist-to-height ratio (WC/height). No clinically significant associations with lipid or blood pressure measures were seen. Conclusions: Associationswere noted between increased intake of low/non-fat milk intake, diet sodas, and caffeinated beverages and increasing adiposity. Further studies are required to assess causality and evaluate potential mechanisms.