JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis.
Circulation
PUBLISHED: 01-30-2014
Show Abstract
Hide Abstract
Intimal smooth muscle cells (SMCs) contribute to the foam cell population in arterial plaque, and express lower levels of the cholesterol exporter ATP-binding cassette transporter A1 (ABCA1) in comparison with medial arterial SMCs. The relative contribution of SMCs to the total foam cell population and their expression of ABCA1 in comparison with intimal monocyte-derived macrophages, however, are unknown. Although the expression of macrophage markers by SMCs following lipid loading has been described, the relevance of this phenotypic switch by SMCs in human coronary atherosclerosis has not been determined.
Related JoVE Video
Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis.
Neurology
PUBLISHED: 01-24-2014
Show Abstract
Hide Abstract
To report outcomes of pregnancies that occurred during the fingolimod clinical development program.
Related JoVE Video
Early atherosclerosis detection in asymptomatic patients: a comparison of carotid ultrasound, coronary artery calcium score, and coronary computed tomography angiography.
Can J Cardiol
PUBLISHED: 07-08-2013
Show Abstract
Hide Abstract
Detailed multimodality assessment of subclinical atherosclerosis in asymptomatic subjects referred for risk stratification has not been performed. We analyzed the detection of early atherosclerosis using 3 imaging modalities: coronary artery calcium (CAC) scoring, carotid ultrasound (US), and coronary computed tomography angiography (CCTA).
Related JoVE Video
Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS.
J. Neurol.
PUBLISHED: 04-03-2013
Show Abstract
Hide Abstract
In the 12-month phase 3 TRANSFORMS study, fingolimod showed greater efficacy than intramuscular interferon beta (IFN?)-1a in patients with relapsing-remitting multiple sclerosis (RRMS). This study analyzed fingolimod efficacy compared with IFN?-1a in patient subgroups from TRANSFORMS. Patients were randomized to receive fingolimod or weekly IM IFN?-1a for 12 months. Analyses of efficacy included annualized relapse rate (ARR), and magnetic resonance imaging (MRI) measures [gadolinium (Gd)-enhancing T1 lesions, new/newly enlarged (active) T2 lesions, brain volume change]. Subgroups were defined based on demographics, disease characteristics (baseline EDSS score, relapse rate, and MRI parameters), and response to previous therapy. Fingolimod 0.5 mg reduced ARR over 12 months by 32-59 % relative to IFN?-1a in all subgroups defined by demographic factors or baseline disease characteristics. Fingolimod also reduced the number of new Gd-enhancing lesions, active T2 lesions, and the rate of brain volume loss, versus IFN?-1a in most (95 %) subgroups. In patients with high disease activity despite IFN? treatment in the year before study, fingolimod 0.5 mg reduced ARR by 61 % relative to IFN?-1a. Reductions in lesion counts and brain volume loss also favored fingolimod in these patients. In conclusion, consistently better efficacy was observed for fingolimod compared with IFN?-1a across different subgroups of patients with RRMS.
Related JoVE Video
Statins attenuate the development of atherosclerosis and endothelial dysfunction induced by exposure to urban particulate matter (PM10).
Toxicol. Appl. Pharmacol.
PUBLISHED: 03-30-2013
Show Abstract
Hide Abstract
Exposure to ambient air particulate matter (particles less than 10?m or PM10) has been shown to be an independent risk factor for the development and progression of atherosclerosis. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have well-established anti-inflammatory properties. The aim of this study was to determine the impact of statins on the adverse functional and morphological changes in blood vessels induced by PM10. New Zealand White rabbits fed with a high fat diet were subjected to balloon injury to their abdominal aorta followed by PM10/saline exposure for 4weeks±lovastatin (5mg/kg/day) treatment. PM10 exposure accelerated balloon catheter induced plaque formation and increased intimal macrophages and lipid accumulation while lovastatin attenuated these changes and promoted smooth muscle cell recruitment into plaques. PM10 impaired vascular acetylcholine (Ach) responses and increased vasoconstriction induced by phenylephrine as assessed by wire myograph. Supplementation of nitric oxide improved the impaired Ach responses. PM10 increased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in blood vessels and increased the plasma levels of endothelin-1 (ET-1). Incubation with specific inhibitors for iNOS, COX-2 or ET-1 in the myograph chambers significantly improved the impaired vascular function. Lovastatin decreased the expression of these mediators in atherosclerotic lesions and improved endothelial dysfunction. However, lovastatin was unable to reduce blood lipid levels to the baseline level in rabbits exposed to PM10. Taken together, statins protect against PM10-induced cardiovascular disease by reducing atherosclerosis and improving endothelial function via their anti-inflammatory properties.
Related JoVE Video
Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis.
Ophthalmology
PUBLISHED: 03-24-2013
Show Abstract
Hide Abstract
To report outcomes of ophthalmic evaluations in clinical studies of patients receiving fingolimod (Gilenya; Novartis Pharma AG, Basel, Switzerland) for multiple sclerosis (MS).
Related JoVE Video
Design and baseline data of a pediatric study with rosuvastatin in familial hypercholesterolemia.
J Clin Lipidol
PUBLISHED: 03-22-2013
Show Abstract
Hide Abstract
Statin therapy is recommended for children with familial hypercholesterolemia (FH), but most children do not reach treatment targets.
Related JoVE Video
2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.
Can J Cardiol
PUBLISHED: 01-29-2013
Show Abstract
Hide Abstract
Many developments have occurred since the publication of the widely-used 2009 Canadian Cardiovascular Society (CCS) Dyslipidemia guidelines. Here, we present an updated version of the guidelines, incorporating new recommendations based on recent findings and harmonizing CCS guidelines with those from other Societies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used, per present standards of the CCS. The total cardiovascular disease Framingham Risk Score (FRS), modified for a family history of premature coronary disease, is recommended for risk assessment. Low-density lipoprotein cholesterol remains the primary target of therapy. However, non-high density lipoprotein cholesterol has been added to apolipoprotein B as an alternate target. There is an increased emphasis on treatment of higher risk patients, including those with chronic kidney disease and high risk hypertension. The primary panel has recommended a judicious use of secondary testing for subjects in whom the need for statin therapy is unclear. Expanded information on health behaviours is presented and is the backbone of risk reduction in all subjects. Finally, a systematic approach to statin intolerance is advocated to maximize appropriate use of lipid-lowering therapy. This document presents the recommendations and principal conclusions of this process. Along with associated Supplementary Material that can be accessed online, this document will be part of a program of knowledge translation. The goal is to increase the appropriate use of evidence-based cardiovascular disease event risk assessment in the management of dyslipidemia as a fundamental means of reducing global risk in the Canadian population.
Related JoVE Video
ABCA1-dependent mobilization of lysosomal cholesterol requires functional Niemann-Pick C2 but not Niemann-Pick C1 protein.
Biochim. Biophys. Acta
PUBLISHED: 10-04-2011
Show Abstract
Hide Abstract
Niemann-Pick disease type C (NPC) is caused by mutations leading to loss of function of NPC1 or NPC2 proteins, resulting in accumulation of unesterified cholesterol in late endosomes and lysosomes. We previously reported that expression of the ATP-binding cassette transporter A1 (ABCA1) is impaired in human NPC1(-/-) fibroblasts, resulting in reduced HDL particle formation and providing a mechanism for the reduced plasma HDL cholesterol seen in the majority of NPC1 patients. We also found that treatment of NPC1(-/-) fibroblasts with an agonist of liver X-receptor corrects ABCA1 expression and HDL formation and reduces lysosomal cholesterol accumulation. We have confirmed that ABCA1 expression is also reduced in NPC2(-/-) cells, and found that ?-HDL particle formation is impaired in these cells. To determine whether selective up-regulation of ABCA1 can correct lysosomal cholesterol accumulation in NPC disease cells and HDL particle formation, we produced and infected NPC1(-/-) and NPC2(-/-) fibroblasts with an adenovirus expressing full-length ABCA1 and enhanced green fluorescent protein (AdABCA1-EGFP). ABCA1-EGFP expression in NPC1(-/-) fibroblasts resulted in normalization of cholesterol efflux to apolipoprotein A-I (apoA-I) and ?-HDL particle formation, plus a marked reduction in filipin staining of unesterified cholesterol in late endosomes/lysosomes. In contrast, AdABCA1-EGFP treatment of NPC2(-/-) fibroblasts to normalize ABCA1 expression had no effect on cholesterol efflux to apoA-I or accumulation of excess cholesterol in lysosomes, and only partially corrected ?-HDL formation by these cells. These results suggest that correction of ABCA1 expression can bypass the mutation of NPC1 but not NPC2 to mobilize excess cholesterol from late endosomes and lysosomes in NPC disease cells. Expression of ABCA1-EGFP in NPC1(-/-) cells increased cholesterol available for esterification and reduced levels of HMG-CoA reductase protein, effects that were abrogated by co-incubation with apoA-I. A model can be generated in which ABCA1 is able to mobilize cholesterol, to join the intracellular regulatory pool or to be effluxed for HDL particle formation, either directly or indirectly from the lysosomal membrane, but not from the lysosomal lumen. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
Related JoVE Video
Incidence of pancreatitis, secondary causes, and treatment of patients referred to a specialty lipid clinic with severe hypertriglyceridemia: a retrospective cohort study.
Lipids Health Dis
PUBLISHED: 07-18-2011
Show Abstract
Hide Abstract
Severe hypertriglyceridemia (HTG) is one cause of acute pancreatitis, yet the level of plasma triglycerides likely to be responsible for inducing pancreatitis has not been clearly defined.
Related JoVE Video
Lysosomal acid lipase deficiency impairs regulation of ABCA1 gene and formation of high density lipoproteins in cholesteryl ester storage disease.
J. Biol. Chem.
PUBLISHED: 07-10-2011
Show Abstract
Hide Abstract
ATP-binding cassette transporter A1 (ABCA1) mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, and its expression is regulated primarily by oxysterol-dependent activation of liver X receptors. We previously reported that ABCA1 expression and HDL formation are impaired in the lysosomal cholesterol storage disorder Niemann-Pick disease type C1 and that plasma HDL-C is low in the majority of Niemann-Pick disease type C patients. Here, we show that ABCA1 regulation and activity are also impaired in cholesteryl ester storage disease (CESD), caused by mutations in the LIPA gene that result in less than 5% of normal lysosomal acid lipase (LAL) activity. Fibroblasts from patients with CESD showed impaired up-regulation of ABCA1 in response to low density lipoprotein (LDL) loading, reduced phospholipid and cholesterol efflux to apolipoprotein A-I, and reduced ?-HDL particle formation. Treatment of normal fibroblasts with chloroquine to inhibit LAL activity reduced ABCA1 expression and activity, similar to that of CESD cells. Liver X receptor agonist treatment of CESD cells corrected ABCA1 expression but failed to correct LDL cholesteryl ester hydrolysis and cholesterol efflux to apoA-I. LDL-induced production of 27-hydroxycholesterol was reduced in CESD compared with normal fibroblasts. Treatment with conditioned medium containing LAL from normal fibroblasts or with recombinant human LAL rescued ABCA1 expression, apoA-I-mediated cholesterol efflux, HDL particle formation, and production of 27-hydroxycholesterol by CESD cells. These results provide further evidence that the rate of release of cholesterol from late endosomes/lysosomes is a critical regulator of ABCA1 expression and activity, and an explanation for the hypoalphalipoproteinemia seen in CESD patients.
Related JoVE Video
Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study.
Lancet Neurol
PUBLISHED: 05-13-2011
Show Abstract
Hide Abstract
In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with fingolimod.
Related JoVE Video
Deactivation of the lipopolysaccharide antagonist eritoran (E5564) by high-density lipoprotein-associated apolipoproteins.
Innate Immun
PUBLISHED: 03-07-2011
Show Abstract
Hide Abstract
Lipid A, the active moiety of LPS, exerts its effects through interaction with TLR4, triggering a signalling cascade that results in the release of pro-inflammatory cytokines. Eritoran is a lipid A analogue that competes with LPS for binding to TLR4; however, after intravenous administration, it undergoes a time-dependent deactivation as a consequence of binding to high-density lipoproteins (HDLs). The site of eritoran association with HDL remains unknown. Therefore the aim of this study was to determine if HDL-associated apolipoproteins A1, A2, serum amyloid A (SAA) and C1, inhibit the ability of eritoran to block LPS-induced TNF-? release from whole blood. Eritoran activity after LPS stimulation in human whole blood was assessed in the presence of reconstituted HDL (rHDL) containing different apos. In rHDL, the major apolipoproteins in both the healthy and septic state, A1 and SAA, caused a significant reduction in eritoran antagonistic activity and had a greater effect than minor apolipoproteins A2 and C1. Apolipoproteins associated with HDL are likely to facilitate eritoran deactivation. Apolipoproteins A1 and SAA should be of particular focus as they are the major apos found on HDL in both the healthy and septic state. Further evaluation of the physical association between apolipoproteins and eritoran should be explored.
Related JoVE Video
Prevalence of dyslipidemia in statin-treated patients in Canada: results of the DYSlipidemia International Study (DYSIS).
Can J Cardiol
PUBLISHED: 11-16-2010
Show Abstract
Hide Abstract
Despite clear guideline recommendations, there is a growing body of evidence that there is suboptimal use of lipid-lowering treatment in Canadians.
Related JoVE Video
Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis.
Nat Rev Drug Discov
PUBLISHED: 10-29-2010
Show Abstract
Hide Abstract
The discovery of fingolimod (FTY720/Gilenya; Novartis), an orally active immunomodulatory drug, has opened up new approaches to the treatment of multiple sclerosis, the most common inflammatory disorder of the central nervous system. Elucidation of the effects of fingolimod--mediated by the modulation of sphingosine 1-phosphate (S1P) receptors--has indicated that its therapeutic activity could be due to regulation of the migration of selected lymphocyte subsets into the central nervous system and direct effects on neural cells, particularly astrocytes. An improved understanding of the biology of S1P receptors has also been gained. This article describes the discovery and development of fingolimod, which was approved by the US Food and Drug Administration in September 2010 as a first-line treatment for relapsing forms of multiple sclerosis, thereby becoming the first oral disease-modifying therapy to be approved for multiple sclerosis in the United States.
Related JoVE Video
Cholesterol homeostasis and high-density lipoprotein formation in arterial smooth muscle cells.
Trends Cardiovasc. Med.
PUBLISHED: 08-31-2010
Show Abstract
Hide Abstract
The balance between lipid accumulation and removal from cells in the artery wall is a key factor in atherogenesis. Smooth muscle cells (SMCs) are the main cell type in human intimal thickenings and some stages of atherosclerosis; however, cholesterol homeostasis in these cells has received little attention when compared with intimal macrophages. In addition, it has been demonstrated that SMCs may change phenotype to express macrophage markers upon cholesterol loading, indicating that a large portion of what are considered monocyte-derived human macrophages in human lesions may actually have originated as SMCs. We have recently reported low expression of the key regulator of cholesterol removal to apolipoprotein A-I to form high-density lipoprotein particles, the adenosine-triphosphate-binding cassette transporter A1, in cultured intima-phenotype epithelioid rat SMCs, as well as reduced expression of adenosine-triphosphate-binding cassette transporter A1 in intimal as compared with medial SMCs in human coronary atheromas. These combined observations suggest that SMCs and SMC-derived macrophage-like cells may contribute a much larger amount of the excess cholesterol accumulated in the atherosclerotic intima than previously known. The aim of this review is to present the current state of knowledge of cholesterol homeostasis in arterial SMC and to frame questions requiring further study to understand the relative importance to SMCs in overall atheroma lipid metabolism.
Related JoVE Video
The complexity of HDL.
Biochim. Biophys. Acta
PUBLISHED: 06-25-2010
Show Abstract
Hide Abstract
Plasma high-density lipoprotein cholesterol (HDL-C) levels are inversely associated with coronary artery disease risk in large epidemiologic studies. This rule, however, has many exceptions in individual patients, and evidence suggests that other facets of high-density lipoprotein particle biology not captured by measuring HDL-C levels are responsible for HDLs effects in vivo. This article reviews the evidence for the protective nature of HDL, current evidence from animal and human studies regarding HDL-based therapies, the major steps in HDL particle formation and metabolism, alterations leading to dysfunctional HDL in diabetes and inflammatory states, and potential alternatives to HDL-C to measure HDL function and predict its protective value clinically.
Related JoVE Video
Physiological and coordinate downregulation of the NPC1 and NPC2 genes are associated with the sequestration of LDL-derived cholesterol within endocytic compartments.
J. Cell. Biochem.
PUBLISHED: 09-12-2009
Show Abstract
Hide Abstract
The Niemann-Pick C1 and C2 (NPC1 and NPC2) proteins have a central role in regulating the transport of lipoprotein-derived cholesterol from endocytic compartments to the endoplasmic reticulum for esterification by acyl-CoA:cholesterol acyltransferase (ACAT) and feedback inhibition of the sterol regulatory element-binding protein (SREBP) pathway. Since the NPC1 gene/protein has recently been shown to be downregulated by feedback inhibition of the SREBP pathway, the present study was performed to determine whether physiological downregulation of the NPC1 gene/protein alters the transport and metabolism of low-density lipoprotein (LDL)-derived cholesterol in human fibroblasts. To perform this study, three different culture conditions were used that included fibroblasts grown in lipoprotein-deficient serum (LPDS), LPDS supplemented with LDL, and LPDS supplemented with LDL, followed by equilibration in the absence of LDL to allow the transport of LDL-derived cholesterol from endocytic compartments and equilibration of cellular sterol pools. The results from this study indicated that in addition to the NPC1 gene/protein, the NPC2 gene/protein was also downregulated by LDL-derived cholesterol-dependent feedback inhibition and that downregulation of both the NPC1 and NPC2 genes/proteins was associated with the sequestration of LDL-derived cholesterol within endocytic compartments, including late endosomes/lysosomes after equilibration. Therefore, it is proposed that physiological and coordinate downregulation of the NPC1 and NPC2 genes/proteins promotes the sequestration of LDL-derived cholesterol within endocytic compartments and serves a role in maintaining intracellular cholesterol homeostasis.
Related JoVE Video
The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes.
J. Lipid Res.
PUBLISHED: 09-09-2009
Show Abstract
Hide Abstract
Niemann-Pick type C1 disease (NPC1) is an autosomal recessive lysosomal storage disorder characterized by neonatal jaundice, hepatosplenomegaly, and progressive neurodegeneration. The present study provides the lipid profiles, mutations, and corresponding associations with the biochemical phenotype obtained from NPC1 patients who participated in the National NPC1 Disease Database. Lipid profiles were obtained from 34 patients (39%) in the survey and demonstrated significantly reduced plasma LDL cholesterol (LDL-C) and increased plasma triglycerides in the majority of patients. Reduced plasma HDL cholesterol (HDL-C) was the most consistent lipoprotein abnormality found in male and female NPC1 patients across age groups and occurred independent of changes in plasma triglycerides. A subset of 19 patients for whom the biochemical severity of known NPC1 mutations could be correlated with their lipid profile showed a strong inverse correlation between plasma HDL-C and severity of the biochemical phenotype. Gene mutations were available for 52 patients (59%) in the survey, including 52 different mutations and five novel mutations (Y628C, P887L, I923V, A1151T, and 3741_3744delACTC). Together, these findings provide novel information regarding the plasma lipoprotein changes and mutations in NPC1 disease, and suggest plasma HDL-C represents a potential biomarker of NPC1 disease severity.
Related JoVE Video
ATP-binding cassette transporter A1 expression and apolipoprotein A-I binding are impaired in intima-type arterial smooth muscle cells.
Circulation
PUBLISHED: 06-15-2009
Show Abstract
Hide Abstract
Accumulation of excess cholesterol by intimal arterial smooth muscle cells (SMCs) contributes to the formation of foam cells in atherosclerotic lesions. The purpose of this study was to examine the expression and activity of ATP-binding cassette transporter A1 (ABCA1) in model intimal and medial arterial SMCs, in human atherosclerotic coronary artery intimal and medial layers, and in human intimal and medial SMCs.
Related JoVE Video
Lack of phosphatidylethanolamine N-methyltransferase alters plasma VLDL phospholipids and attenuates atherosclerosis in mice.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 06-11-2009
Show Abstract
Hide Abstract
Impaired hepatic phosphatidylcholine (PC) synthesis lowers plasma lipids. We, therefore, tested the hypothesis that lack of phosphatidylethanolamine N-methyltransferase (PEMT), a hepatic enzyme catalyzing PC biosynthesis, attenuates the development of atherosclerosis.
Related JoVE Video
Multiple sclerosis patients benefit-risk preferences: serious adverse event risks versus treatment efficacy.
J. Neurol.
PUBLISHED: 04-27-2009
Show Abstract
Hide Abstract
The aim of this study is to estimate the willingness of multiple sclerosis (MS) patients to accept life-threatening adverse event risks in exchange for improvements in their MS related health outcomes.
Related JoVE Video
Dealing with excess of zeros in the statistical analysis of magnetic resonance imaging lesion count in multiple sclerosis.
Pharm Stat
Show Abstract
Hide Abstract
Lesion count observed on brain magnetic resonance imaging scan is a common end point in phase?2 clinical trials evaluating therapeutic treatment in relapsing remitting multiple sclerosis (MS). This paper compares the performances of Poisson, zero-inflated poisson (ZIP), negative binomial (NB), and zero-inflated NB (ZINB) mixed-effects regression models in fitting lesion count data in a clinical trial evaluating the efficacy and safety of fingolimod in comparison with placebo, in MS. The NB and ZINB models prove to be superior to the Poisson and ZIP models. We discuss the advantages and limitations of zero-inflated models in the context of MS treatment.
Related JoVE Video
Oxysterol generation and liver X receptor-dependent reverse cholesterol transport: not all roads lead to Rome.
Mol. Cell. Endocrinol.
Show Abstract
Hide Abstract
Cell cholesterol metabolism is a tightly regulated process, dependent in part on activation of nuclear liver X receptors (LXRs) to increase expression of genes mediating removal of excess cholesterol from cells in the reverse cholesterol transport pathway. LXRs are thought to be activated predominantly by oxysterols generated enzymatically from cholesterol in different cell organelles. Defects resulting in slowed release of cholesterol from late endosomes and lysosomes or reduction in sterol-27-hydroxylase activity lead to specific blocks in oxysterol production and impaired LXR-dependent gene activation. This block does not appear to be compensated by oxysterol production in other cell compartments. The purpose of this review is to summarize current knowledge about oxysterol-dependent activation by LXR of genes involved in reverse cholesterol transport, and what these defects of cell cholesterol homeostasis can teach us about the critical pathways of oxysterol generation for expression of LXR-dependent genes.
Related JoVE Video
Familial hypobetalipoproteinemia-induced nonalcoholic steatohepatitis.
Case Rep Gastroenterol
Show Abstract
Hide Abstract
Familial hypobetalipoproteinemia (FHBL) is a rare genetic disorder of lipid metabolism that is associated with abnormally low serum levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. It is an autosomal co-dominant disorder, and depending on zygosity, the clinical manifestations may vary from none to neurological, endocrine, hematological or liver dysfunction. Nonalcoholic fatty liver disease is common in persons with FHBL, however progression to nonalcoholic steatohepatitis is unusual. We describe here a patient with a novel APOB mutation, V703I, which appears to contribute to the severity of the FHBL phenotype. He had liver enzyme abnormalities, increased echogenicity of the liver consistent with steatosis, very low LDL cholesterol at 0.24 mmol/l (normal 1.8-3.5 mmol/l) and an extremely low apolipoprotein B level of 0.16 g/l (normal 0.6-1.2 g/l). APOB gene sequencing revealed him to be a compound heterozygote with two mutations (R463W and V703I). APOB R463W has previously been reported to cause FHBL. Genetic sequencing of his first-degree relatives identified the APOB V703I mutation in his normolipidemic brother and father and the APOB R463W mutation in his mother and sister, both of whom have very low LDL cholesterol levels. These results suggest that the APOB V703I mutation alone does not cause the FHBL phenotype. However, it is possible that it has a contributory role to a more aggressive phenotype in the presence of APOB R463W.
Related JoVE Video
Impact of fingolimod therapy on magnetic resonance imaging outcomes in patients with multiple sclerosis.
Arch. Neurol.
Show Abstract
Hide Abstract
To assess the impact of fingolimod (FTY720) therapy on magnetic resonance imaging measures of inflammatory activity and tissue damage in patients participating in a 2-year, placebo-controlled, phase 3 study.
Related JoVE Video
Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study.
Lancet Neurol
Show Abstract
Hide Abstract
Fingolimod 0·5 mg once daily is approved for treatment of relapsing multiple sclerosis (MS). In the phase 3, 2-year FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in MS) study, fingolimod significantly reduced annualised relapse rates (ARRs) and the risk of confirmed disability progression compared with placebo. We aimed to investigate whether the beneficial treatment effect reported for the overall population is consistent in subgroups of patients with different baseline characteristics.
Related JoVE Video
Contribution of monocyte-derived macrophages and smooth muscle cells to arterial foam cell formation.
Cardiovasc. Res.
Show Abstract
Hide Abstract
Smooth muscle cells (SMCs) are the main cell type in intimal thickenings and some stages of human atherosclerosis. Like monocyte-derived macrophages, SMCs accumulate excess lipids and contribute to the total intimal foam cell population. In contrast, apolipoprotein (Apo)E-deficient and LDL receptor-deficient mice develop atherosclerotic lesions that are macrophage- as opposed to SMC-rich. The lesser contribution of SMCs to lesion development in these mouse models has distracted attention away from the importance of SMC cholesterol homeostasis in the artery wall. Intimal SMCs accumulate excess amounts of cholesteryl esters when compared with medial layer SMCs, possibly explained by reduced ATP-binding cassette transporter A1 expression and ApoA-I binding to intimal-type SMCs. The aim of this review is to compare the relative contribution of monocyte-derived macrophages and SMCs to human vs. mouse atherosclerosis, and describe what is known about lipid uptake and removal mechanisms contributing to arterial macrophage and SMC foam cell formation. An increased understanding of the contribution of these cell types to lesion development will help to delineate their relative importance in atherogenesis and as potential therapeutic targets.
Related JoVE Video
Lipid-bound apolipoproteins in tyrosyl radical-oxidized HDL stabilize ABCA1 like lipid-free apolipoprotein A-I.
BMC Biochem.
Show Abstract
Hide Abstract
ATP-binding cassette transporter A1 (ABCA1) mediates the lipidation of exchangeable apolipoproteins, the rate-limiting step in the formation of high density lipoproteins (HDL). We previously demonstrated that HDL oxidized ex vivo by peroxidase-generated tyrosyl radical (tyrosylated HDL, tyrHDL) increases the availability of cellular cholesterol for efflux and reduces the development of atherosclerosis when administered to apolipoprotein E-deficient mice as compared to treatment with control HDL.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.