Rôle de la péroxydation lipidique dans le développement de l'athérosclérose

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Mechanisms of lipid malabsorption in Cystic Fibrosis: the impact of essential fatty acids deficiency

Affiliation: CHU-Sainte-Justine, Université de MontréalTransport mechanisms, whereby alimentary lipids are digested and packaged into small emulsion particles that enter intestinal cells to be translocated to the plasma in the form of chylomicrons, are impaired in cystic fibrosis. The purpose of this paper is to focus on defects that are related to intraluminal and intracellular events in this life-limiting genetic disorder. Specific evidence is presented to highlight the relationship between fat malabsorption and essential fatty acid deficiency commonly found in patients with cystic fibrosis that are often related to the genotype. Given the interdependency of pulmonary disease, pancreatic insufficiency and nutritional status, greater attention should be paid to the optimal correction of fat malabsorption and essential fatty acid deficiency in order to improve the quality of life and extend the life span of patients with cystic fibrosis

Contributing factors of unmet needs among young adult survivors of childhood acute lymphoblastic leukemia with comorbidities

Purpose: This study aimed to: (1) describe the domains and levels of unmet needs of young adult survivors of childhood acute lymphoblastic leukemia (cALL) with comorbidities, and (2) to explore the factors associated with higher levels of unmet needs. Unmet need was considered as supportive care needs not met. Methods: The most vulnerable cALL survivors from the PETALE study cohort completed the Short-Form Survivor Unmet Needs Survey, the Brief Pain Inventory and the 15D instrument of health-related quality of life. Demographic and clinical information, including comorbidities, were obtained from medical records or self-reporting. The participants' needs and contributing factors to their needs were evaluated using nonparametric tests. Results: Of the 72 participants, 9 (13%) reported moderate/high levels of overall unmet needs. “Worry about earning money” (56%) and “Dealing with feeling tired” (51%) were the most frequent unmet needs (all levels combined). The factors associated significantly with any domain of unmet needs were: having a comorbidity, reporting altered functional health status, high ALL risk status, pain, age (<26 years), and having previously received psychological support. Conclusion: A minority of young adult survivors of cALL with comorbidities interviewed reported moderate/high levels of unmet needs. However, financial concerns and emotional health and relationship are the two domains of greatest need. Survivors with altered health condition are most at risk of experiencing moderate/high levels of unmet needs. If confirmed in larger samples, interventions should target modifiable contributors of unmet needs such as physical health and comfort, fatigue, and emotional health

letter to tHe eDitor

Bhat M, Lu Y, Marcil V, et al. Tumour necrosis factor-alpha polymorphism increases the risk for nonvariceal upper gastrointestinal bleeding in patients taking proton pump inhibitors. Can J Gastroenterol Hepatol 2014;28(9):488. To the Editor: Nonvariceal upper gastrointestinal bleeding (NVUGIB) is associated with significant morbidity, affecting 50 to 150 per 100,000 adults annually (1). Patients with NVUGIB may present with melena, hematochezia or coffee-ground emesis, often accompanied by a decrease in hemoglobin levels and even hemodynamic instability. Nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori infection are the principal risk factors for NVUGIB, accounting for &gt;95% of cases. Taking proton pump inhibitors (PPIs) is a known protective factor against NVUGIB. There has recently been growing interest in a possible genetic predisposition to NVUGIB, with investigation of single nucleotide polymorphisms (SNPs) associated with bleeding events. Of particular interest have been mutations in proinflammatory genes or genes that regulate NSAID/PPI metabolism, which may contribute to excessive inflammation and ulceration in the context of H pylori infection and NSAID use. A recent pharmacogenomic study The above literature describing a genetic predisposition for bleeding events applies principally to East Asian patient populations. Therefore, we decided to study whether such genetic associations could be elicited in the Canadian context. We performed a pilot study to assess the association of SNPs involved in NSAID metabolism (CYP2C9) and inflammatory response (TNF-α) with NVUGIB events. Patients who were part of the REASON-II NVUGIB study population at the McGill University Health Centre (Montreal, Quebec) were recruited (5). Study controls were asymptomatic patients undergoing screening colonoscopy, and excluded if there was any history of NVUGIB. DNA extracted from serum was genotyped for SNPs in the proinflammatory TNF-α (rs1799724, rs1800630, rs1799964) and NSAID-metabolizing CYP2C9 genes (rs1799853, rs1057910). Using STATA version 10, we assessed for any association between SNPs and NVUGIB events using logistic regression analysis and stratifying according to H pylori status, NSAID and PPI use. Our study included 23 patients and 46 controls of comparable age and sex, with NSAID (26.1% versus 6.7%) and PPI use (21.7% versus 13.0%) being more prevalent among patients. The TNFα1031C SNP, a proinflammatory cytokine polymorphism, was more common among patients with NVUGIB (OR 2.2 [95% CI 0.9 to 5.1]; P=0.084), particularly among those using PPIs (OR 20.0 [95% CI 0.9 to 429.9]; P=0.056) or not taking NSAIDs (OR 3.2 [95% CI 1.1 to 9.0]; P=0.027) at the time of the bleeding event. There was a trend in association of the TNF-α863A SNP with NVUGIB in patients not taking NSAIDs (OR 2.7 [95% CI 0.9 to 8.6]; P=0.071). We did not detect an association between CYP2C9 polymorphisms and NVUGIB, a result similar to that obtained in the study by Musumba et al (2). In conclusion, our pilot study demonstrates that TNF-α1031C SNP confers a risk for NVUGIB events among patients taking PPIs, a finding compatible with previous studies showing increased risk for peptic ulceration with this particular SNP (3

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30–79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30–79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306–359) million women and 317 (292–344) million men in 1990 to 626 (584–668) million women and 652 (604–698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55–62) of women and 49% (46–52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43–51) of women and 38% (35–41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20–27) for women and 18% (16–21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings

Ostéocalcine et métabolisme du glucose

L’ostéocalcine, sécrétée par les ostéoblastes, entre dans la composition de l’os et est un biomarqueur de la minéralisation osseuse. Des études expérimentales animales ont cependant montré que cette protéine peut aussi influencer le métabolisme du glucose. Au cours de la dernière décennie, plusieurs études réalisées chez l’homme ont montré, dans la grande majorité, l’existence d’une corrélation positive entre les niveaux d’ostéocalcine et la sécrétion/sensibilité à l’insuline ainsi qu’une association inverse avec les paramètres glycémiques. Ces travaux qui révèlent une relation entre ostéocalcine et métabolisme du glucose devraient contribuer à l’élaboration de nouvelles stratégies pharmacologiques pour le traitement des maladies endocriniennes

Circulatory Adipokines and Incretins in Adolescent Idiopathic Scoliosis: A Pilot Study

Adolescent idiopathic scoliosis (AIS) is a three-dimensional malformation of the spine of unknown cause that develops between 10 and 18 years old and affects 2&ndash;3% of adolescents, mostly girls. It has been reported that girls with AIS have a taller stature, lower body mass index (BMI), and bone mineral density (BMD) than their peers, but the causes remain unexplained. Energy metabolism discrepancies, including alterations in adipokine and incretin circulatory levels, could influence these parameters and contribute to disease pathophysiology. This pilot study aims to compare the anthropometry, BMD, and metabolic profile of 19 AIS girls to 19 age-matched healthy controls. Collected data include participants&rsquo; fasting metabolic profile, anthropometry (measurements and DXA scan), nutritional intake, and physical activity level. AIS girls (14.8 &plusmn; 1.7 years, Cobb angle 27 &plusmn; 10&deg;), compared to controls (14.8 &plusmn; 2.1 years), were leaner (BMI-for-age z-score &plusmn; SD: &minus;0.59 &plusmn; 0.81 vs. 0.09 &plusmn; 1.11, p = 0.016; fat percentage: 24.4 &plusmn; 5.9 vs. 29.2 &plusmn; 7.2%, p = 0.036), had lower BMD (total body without head z-score &plusmn; SD: &minus;0.6 &plusmn; 0.83 vs. 0.23 &plusmn; 0.98, p = 0.038; femoral neck z-score: &minus;0.54 &plusmn; 1.20 vs. 0.59 &plusmn; 1.59, p = 0.043), but their height was similar. AIS girls had higher adiponectin levels [56 (9&ndash;287) vs. 32 (7&ndash;74) &mu;g/mL, p = 0.005] and lower leptin/adiponectin ratio [0.042 (0.005&ndash;0.320) vs. 0.258 (0.024&ndash;1.053), p = 0.005]. AIS participants with a Cobb angle superior to 25&deg; had higher resistin levels compared to controls [98.2 (12.8&ndash;287.2) vs. 32.1 (6.6&ndash;73.8), p = 0.0013]. This pilot study suggests that adipokines are implicated in AIS development and/or progression, but more work is needed to confirm their role in the disease

Effect of Oxidative Stress on the Status of Adhesion Molecules, Nuclear Receptors and Cholesterol Flux in Endothelial Cells: Priming of Monocytes

Circumstantial evidence suggests that oxidative stress plays a crucial role in the initiation and progression of atherosclerosis, but little is known about the relationship between oxidative stress per se , cholesterol transport and endothelial cell integrity. The aim of the present work is to tackle this issue by treating human umbilical vein endothelial cells (HUVEC) with iron/ascorbate for 4 and 8 hours and by subsequently evaluating the cholesterol flux, the gene expression status of cholesterol transporters, nuclear receptors and adhesion molecules, as well as the cellular adhesion of THP-1 monocytes to HUVEC. The incubation of HUVEC with iron/ascorbate resulted in marked lipid peroxidation as reflected by high malondialdehyde levels, which were reduced by pre-treatment with the antioxidant Trolox. Our experiments could not reveal any modifications in the protein and gene expression of the transporters (ABCA1, SR-BI, LOX-1), the adhesion molecules (VCAM-1, ICAM-1 and E-selectin) and the nuclear receptors (PPARs and LXRs) under the influence of iron/ascorbate. However, oxidative stress enhanced monocyte adhesion to HUVEC, induced the gene expression of ICAM-1, E-selectin and MCP-1, whereas it downregulated eNOS mRNA in the presence of monocytes. Overall, our data suggest that oxidative stress is more harmful in the presence of heterocellular communication between endothelial cells and monocytes

Tissue Distribution and Regulation of the Small Sar1b GTPase in Mice

Background/Aims: Sar1b GTPase (Sar1b) represents an obligatory component of COPII vesicles that bud from the endoplasmic reticulum to transport proteins to the Golgi apparatus. Its genetic mutations lead to a severe disorder known as chylomicron retention disease. Despite growing knowledge on Sar1b, little is known about it tissue distribution and regulation, which constitute the aims of the present study. We aimed to determine the Sar1b tissue distribution and modulation by a high-fat diet and gene forcing using transgenic mice in comparison to wild-type mice. Methods: The expression pattern of Sar1b was studied in different organs of wild-type and Sar1b transgenic mice by qRT-PCR and Western blot. The effect of transgenesis and insulin resistance induced by a 12-week high-fat diet on Sar1b gene expression was also assessed by qRT-PCR. Results: Evaluation of Sar1b mRNA revealed the skeletal muscle as the tissue with the highest Sar1b expression, followed by the heart and liver, the organs composing the digestive tract, the brain and finally the lung and the adipose tissue. Sar1b protein expression levels follow a similar pattern among the organs, except for its lower expression in the heart. While the high-fat diet did not exert any significant alterations, Sar1b transgenic mice displayed higher gene expression in the liver, ileum, jejunum, proximal and distal colon compared to wild-type mice. Conclusion: Our study supports the importance of Sar1b in organs involved in lipid transport and/or calcium trafficking such as the liver, intestine, skeletal muscle and heart