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Find video protocols related to scientific articles indexed in Pubmed.
PCSK9 is a critical regulator of the innate immune response and septic shock outcome.
Sci Transl Med
PUBLISHED: 10-17-2014
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A decrease in the activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases the amount of low-density lipoprotein (LDL) receptors on liver cells and, therefore, LDL clearance. The clearance of lipids from pathogens is related to endogenous lipid clearance; thus, PCSK9 may also regulate removal of pathogen lipids such as lipopolysaccharide (LPS). Compared to controls, Pcsk9 knockout mice displayed decreases in inflammatory cytokine production and in other physiological responses to LPS. In human liver cells, PCSK9 inhibited LPS uptake, a necessary step in systemic clearance and detoxification. Pharmacological inhibition of PCSK9 improved survival and inflammation in murine polymicrobial peritonitis. Human PCSK9 loss-of-function genetic variants were associated with improved survival in septic shock patients and a decrease in inflammatory cytokine response both in septic shock patients and in healthy volunteers after LPS administration. The PCSK9 effect was abrogated in LDL receptor (LDLR) knockout mice and in humans who are homozygous for an LDLR variant that is resistant to PCSK9. Together, our results show that reduced PCSK9 function is associated with increased pathogen lipid clearance via the LDLR, a decreased inflammatory response, and improved septic shock outcome.
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Effective Nonvaccine Interventions to Be Considered Alongside Human Papilloma Virus Vaccine Delivery.
J Adolesc Health
PUBLISHED: 08-08-2014
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World Health Organization recommends that girls, ages 9-13 years, get the human papilloma virus (HPV) vaccine. Global Alliance for Vaccines Initiative, which provides low-cost vaccine to eligible countries, requires that an additional intervention to be offered alongside the vaccine. We systematically searched and assessed the published literature in lower- and middle-income countries to identify effective interventions. We conducted systematic searches of four databases: PubMed, EMBASE, Global Index Medicus Regional Databases, and Cochrane Reviews for effective adolescent health interventions that could be delivered with the HPV vaccine in the following areas: (1) iron and folic acid supplementation (iron alone or with folic acid); (2) voucher delivery and cash transfer programs; (3) hand washing and soap provision; (4) vision screening; (5) promotion of physical activity/exercise; (6) menstrual hygiene education; (7) sexual and reproductive health education; (8) human immunodeficiency virus prevention activities; and (9) condom promotion, condom use skill building, and demonstration. We found limited evidence of consistent positive impact. Iron supplementation reduced iron-deficiency anemia and raised serum ferritin levels. Promotion of physical activity lowered blood pressure and reduced weight gain. Sexual and reproductive health and human immunodeficiency virus interventions improved adolescent communication with adults but did not influence behavioral outcomes. Countries should consider locally relevant and proven interventions to be offered alongside the HPV vaccine.
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A functional synonymous coding variant in the IL1RN gene is associated with survival in septic shock.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 08-05-2014
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Death from infection is a highly heritable trait, yet there are few genetic variants with known mechanism influencing survival during septic shock.
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Very low density lipoprotein cholesterol associates with coronary artery calcification in type 2 diabetes beyond circulating levels of triglycerides.
Atherosclerosis
PUBLISHED: 07-22-2014
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While recent genomic studies have focused attention on triglyceride (TG) rich lipoproteins in cardiovascular disease (CVD), little is known of very low-density lipoprotein cholesterol (VLDL-C) relationship with atherosclerosis and CVD. We examined, in a high-risk type-2 diabetic population, the association of plasma VLDL-C with coronary artery calcification (CAC).
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Insulin sensitivity index in type 1 diabetes and following human islet transplantation: comparison of the minimal model to euglycemic clamp measures.
Am. J. Physiol. Endocrinol. Metab.
PUBLISHED: 04-01-2014
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Insulin sensitivity is impaired in type 1 diabetes (T1D) and may be enhanced by islet transplantation, an effect best explained by improved metabolic control. While the minimal model index of insulin sensitivity, SI, has been used in studies of T1D, it has not before been evaluated against gold-standard measures derived from the euglycemic clamp. We sought to determine how well minimal model SI derived from an insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test compared with total body and peripheral insulin sensitivity estimates derived from the hyperinsulinemic-euglycemic clamp in subjects with T1D and following islet transplantation. Twenty-one T1D subjects were evaluated, including a subgroup (n = 12) studied again after intrahepatic islet transplantation, with results compared with normal controls (n = 11 for the FSIGT). The transplant recipients received 9,648 ± 666 islet equivalents/kg with reduction in HbA1c from 7.1 ± 0.2 to 5.5 ± 0.1% (P < 0.01) and 10/12 were insulin independent. FSIGT-derived SI was reduced in T1D pre- compared with posttransplant and with normal [1.76 ± 0.45 vs. 4.21 ± 0.34 vs. 4.45 ± 0.81 × 10(-4)(?U/ml)(-1)·min(-1); P < 0.01 for both]. Similarly, clamp-derived total body, and by the isotopic dilution method with [6,6-(2)H2]glucose, peripheral insulin sensitivity increased in T1D from pre- to posttransplant (P < 0.05 for both). The predictive power (r(2)) between volume-corrected SIC and measures of total and peripheral insulin sensitivity was 0.66 and 0.70, respectively (P < 0.00001 for both). That the minimal model SIC is highly correlated to the clamp-derived measures indicates that the FSIGT is an appropriate methodology for the determination of insulin sensitivity in T1D and following islet transplantation.
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Tissue-specific RNA-Seq in human evoked inflammation identifies blood and adipose LincRNA signatures of cardiometabolic diseases.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 02-06-2014
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Inappropriate transcriptional activation of innate immunity is a pathological feature of several cardiometabolic disorders, but little is known about inflammatory modulation of long intergenic noncoding RNAs (lincRNAs) in disease-relevant human tissues.
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PennSeq: accurate isoform-specific gene expression quantification in RNA-Seq by modeling non-uniform read distribution.
Nucleic Acids Res.
PUBLISHED: 12-20-2013
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Correctly estimating isoform-specific gene expression is important for understanding complicated biological mechanisms and for mapping disease susceptibility genes. However, estimating isoform-specific gene expression is challenging because various biases present in RNA-Seq (RNA sequencing) data complicate the analysis, and if not appropriately corrected, can affect isoform expression estimation and downstream analysis. In this article, we present PennSeq, a statistical method that allows each isoform to have its own non-uniform read distribution. Instead of making parametric assumptions, we give adequate weight to the underlying data by the use of a non-parametric approach. Our rationale is that regardless what factors lead to non-uniformity, whether it is due to hexamer priming bias, local sequence bias, positional bias, RNA degradation, mapping bias or other unknown reasons, the probability that a fragment is sampled from a particular region will be reflected in the aligned data. This empirical approach thus maximally reflects the true underlying non-uniform read distribution. We evaluate the performance of PennSeq using both simulated data with known ground truth, and using two real Illumina RNA-Seq data sets including one with quantitative real time polymerase chain reaction measurements. Our results indicate superior performance of PennSeq over existing methods, particularly for isoforms demonstrating severe non-uniformity. PennSeq is freely available for download at http://sourceforge.net/projects/pennseq.
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Improvement in insulin sensitivity after human islet transplantation for type 1 diabetes.
J. Clin. Endocrinol. Metab.
PUBLISHED: 10-01-2013
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Islet transplantation can improve metabolic control for type 1 diabetes (T1D), an effect anticipated to improve insulin sensitivity. However, current immunosuppression regimens containing tacrolimus and sirolimus have been shown to induce insulin resistance in rodents.
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Impact of geographical region on urinary metabolomic and plasma fatty acid profiles in subjects with the metabolic syndrome across Europe: the LIPGENE study.
Br. J. Nutr.
PUBLISHED: 09-19-2013
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The application of metabolomics in multi-centre studies is increasing. The aim of the present study was to assess the effects of geographical location on the metabolic profiles of individuals with the metabolic syndrome. Blood and urine samples were collected from 219 adults from seven European centres participating in the LIPGENE project (Diet, genomics and the metabolic syndrome: an integrated nutrition, agro-food, social and economic analysis). Nutrient intakes, BMI, waist:hip ratio, blood pressure, and plasma glucose, insulin and blood lipid levels were assessed. Plasma fatty acid levels and urine were assessed using a metabolomic technique. The separation of three European geographical groups (NW, northwest; NE, northeast; SW, southwest) was identified using partial least-squares discriminant analysis models for urine (R 2 X: 0·33, Q 2: 0·39) and plasma fatty acid (R 2 X: 0·32, Q 2: 0·60) data. The NW group was characterised by higher levels of urinary hippurate and N-methylnicotinate. The NE group was characterised by higher levels of urinary creatine and citrate and plasma EPA (20 : 5 n-3). The SW group was characterised by higher levels of urinary trimethylamine oxide and lower levels of plasma EPA. The indicators of metabolic health appeared to be consistent across the groups. The SW group had higher intakes of total fat and MUFA compared with both the NW and NE groups (P? 0·001). The NE group had higher intakes of fibre and n-3 and n-6 fatty acids compared with both the NW and SW groups (all P< 0·001). It is likely that differences in dietary intakes contributed to the separation of the three groups. Evaluation of geographical factors including diet should be considered in the interpretation of metabolomic data from multi-centre studies.
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Differential Associations of Oral Glucose Tolerance Test-Derived Measures of Insulin Sensitivity and Pancreatic ?-Cell Function With Coronary Artery Calcification and Microalbuminuria in Type 2 Diabetes.
Diabetes Care
PUBLISHED: 08-15-2013
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OBJECTIVE We evaluated relationships of oral glucose tolerance testing (OGTT)-derived measures of insulin sensitivity and pancreatic ?-cell function with indices of diabetes complications in a cross-sectional study of patients with type 2 diabetes who are free of overt cardiovascular or renal disease. RESEARCH DESIGN AND METHODS A subset of participants from the Penn Diabetes Heart Study (n = 672; mean age 59 ± 8 years; 67% male; 60% Caucasian) underwent a standard 2-h, 75-g OGTT. Insulin sensitivity was estimated using the Matsuda Insulin Sensitivity Index (ISI), and ?-cell function was estimated using the Insulinogenic Index. Multivariable modeling was used to analyze associations between quartiles of each index with coronary artery calcification (CAC) and microalbuminuria. RESULTS The Insulinogenic Index and Matsuda ISI had distinct associations with cardiometabolic risk factors. The top quartile of the Matsuda ISI had a negative association with CAC that remained significant after adjusting for traditional cardiovascular risk factors (Tobit ratio -0.78 [95% CI -1.51 to -0.05]; P = 0.035), but the Insulinogenic Index was not associated with CAC. Conversely, the highest quartile of the Insulinogenic Index, but not the Matsuda ISI, was associated with lower odds of microalbuminuria (OR 0.52 [95% CI 0.30-0.91]; P = 0.022); however, this association was attenuated in models that included duration of diabetes. CONCLUSIONS Lower ?-cell function is associated with microalbuminuria, a microvascular complication, while impaired insulin sensitivity is associated with higher CAC, a predictor of macrovascular complications. Despite these pathophysiological insights, the Matsuda ISI and Insulinogenic Index are unlikely to be translated into clinical use in type 2 diabetes beyond established clinical variables, such as obesity or duration of diabetes.
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Genetics of coronary artery calcification among African Americans, a meta-analysis.
BMC Med. Genet.
PUBLISHED: 07-18-2013
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Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants.
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Omega-3 PUFA supplementation and the response to evoked endotoxemia in healthy volunteers.
Mol Nutr Food Res
PUBLISHED: 05-21-2013
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Fish oil-derived n-3 PUFA may improve cardiometabolic health through modulation of innate immunity. However, findings in clinical studies are conflicting. We hypothesized that n-3 PUFA supplementation would dose-dependently reduce the systemic inflammatory response to experimental endotoxemia in healthy humans.
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Analytic performance studies and clinical reproducibility of a real-time PCR assay for the detection of epidermal growth factor receptor gene mutations in formalin-fixed paraffin-embedded tissue specimens of non-small cell lung cancer.
BMC Cancer
PUBLISHED: 04-18-2013
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Epidermal growth factor receptor (EGFR) gene mutations identify patients with non-small cell lung cancer (NSCLC) who have a high likelihood of benefiting from treatment with anti-EGFR tyrosine kinase inhibitors. Sanger sequencing is widely used for mutation detection but can be technically challenging, resulting in longer turn-around-time, with limited sensitivity for low levels of mutations. This manuscript details the technical performance verification studies and external clinical reproducibility studies of the cobas EGFR Mutation Test, a rapid multiplex real-time PCR assay designed to detect 41 mutations in exons 18, 19, 20 and 21.
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Effective health interventions for adolescents that could be integrated with human papillomavirus vaccination programs.
J Adolesc Health
PUBLISHED: 02-26-2013
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We reviewed published data to identify health interventions for 9-15-year-old girls and boys that could to be usefully integrated with programs of human papillomavirus (HPV) vaccination in low- and middle-income countries (LMICs).
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Mixed modeling of meta-analysis P-values (MixMAP) suggests multiple novel gene loci for low density lipoprotein cholesterol.
PLoS ONE
PUBLISHED: 02-06-2013
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Informing missing heritability for complex disease will likely require leveraging information across multiple SNPs within a gene region simultaneously to characterize gene and locus-level contributions to disease phenotypes. To this aim, we introduce a novel strategy, termed Mixed modeling of Meta-Analysis P-values (MixMAP), that draws on a principled statistical modeling framework and the vast array of summary data now available from genetic association studies, to test formally for locus level association. The primary inputs to this approach are: (a) single SNP level p-values for tests of association; and (b) the mapping of SNPs to genomic regions. The output of MixMAP is comprised of locus level estimates and tests of association. In application of MixMAP to summary data from the Global Lipids Gene Consortium, we suggest twelve new loci (PKN, FN1, UGT1A1, PPARG, DMDGH, PPARD, CDK6, VPS13B, GAD2, GAB2, APOH and NPC1) for low-density lipoprotein cholesterol (LDL-C), a causal risk factor for cardiovascular disease and we also demonstrate the potential utility of MixMAP in small data settings. Overall, MixMAP offers novel and complementary information as compared to SNP-based analysis approaches and is straightforward to implement with existing open-source statistical software tools.
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Race and gender variation in response to evoked inflammation.
J Transl Med
PUBLISHED: 01-13-2013
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Race- and gender-variation in innate immunity may contribute to demographic differences in inflammatory and cardiometabolic disease; yet their influence on dynamic responses during inflammatory stress is poorly understood. Our objective was to examine race and gender influence on the response to experimental endotoxemia.
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Evaluating the impact of sequencing depth on transcriptome profiling in human adipose.
PLoS ONE
PUBLISHED: 01-01-2013
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Recent advances in RNA sequencing (RNA-Seq) have enabled the discovery of novel transcriptomic variations that are not possible with traditional microarray-based methods. Tissue and cell specific transcriptome changes during pathophysiological stress in disease cases versus controls and in response to therapies are of particular interest to investigators studying cardiometabolic diseases. Thus, knowledge on the relationships between sequencing depth and detection of transcriptomic variation is needed for designing RNA-Seq experiments and for interpreting results of analyses. Using deeply sequenced Illumina HiSeq 2000 101 bp paired-end RNA-Seq data derived from adipose of a healthy individual before and after systemic administration of endotoxin (LPS), we investigated the sequencing depths needed for studies of gene expression and alternative splicing (AS). In order to detect expressed genes and AS events, we found that ?100 to 150 million (M) filtered reads were needed. However, the requirement on sequencing depth for the detection of LPS modulated differential expression (DE) and differential alternative splicing (DAS) was much higher. To detect 80% of events, ?300 M filtered reads were needed for DE analysis whereas at least 400 M filtered reads were necessary for detecting DAS. Although the majority of expressed genes and AS events can be detected with modest sequencing depths (?100 M filtered reads), the estimated gene expression levels and exon/intron inclusion levels were less accurate. We report the first study that evaluates the relationship between RNA-Seq depth and the ability to detect DE and DAS in human adipose. Our results suggest that a much higher sequencing depth is needed to reliably identify DAS events than for DE genes.
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Ridge regression for longitudinal biomarker data.
Int J Biostat
PUBLISHED: 09-27-2011
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Technological advances facilitating the acquisition of large arrays of biomarker data have led to new opportunities to understand and characterize disease progression over time. This creates an analytical challenge, however, due to the large numbers of potentially informative markers, the high degrees of correlation among them, and the time-dependent trajectories of association. We propose a mixed ridge estimator, which integrates ridge regression into the mixed effects modeling framework in order to account for both the correlation induced by repeatedly measuring an outcome on each individual over time, as well as the potentially high degree of correlation among possible predictor variables. An expectation-maximization algorithm is described to account for unknown variance and covariance parameters. Model performance is demonstrated through a simulation study and an application of the mixed ridge approach to data arising from a study of cardiometabolic biomarker responses to evoked inflammation induced by experimental low-dose endotoxemia.
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Global burden of disease in young people aged 10-24 years: a systematic analysis.
Lancet
PUBLISHED: 06-07-2011
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Young people aged 10-24 years represent 27% of the worlds population. Although important health problems and risk factors for disease in later life emerge in these years, the contribution to the global burden of disease is unknown. We describe the global burden of disease arising in young people and the contribution of risk factors to that burden.
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Fractalkine is a novel human adipochemokine associated with type 2 diabetes.
Diabetes
PUBLISHED: 04-29-2011
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Leukocyte infiltration of adipose is a critical determinant of obesity-related metabolic diseases. Fractalkine (CX3CL1) and its receptor (CX3CR1) comprise a chemokine system involved in leukocyte recruitment and adhesion in atherosclerosis, but its role in adipose inflammation and type 2 diabetes is unknown.
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Qualitative insights into job satisfaction and dissatisfaction with management among community and hospital pharmacists.
Res Social Adm Pharm
PUBLISHED: 03-31-2011
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Job satisfaction research in pharmacy has predominantly been investigated using quantitative measures that have generally overlooked satisfaction with management.
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The novel atherosclerosis locus at 10q11 regulates plasma CXCL12 levels.
Eur. Heart J.
PUBLISHED: 03-17-2011
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Two single-nucleotide polymorphisms (SNPs), rs1746048 and rs501120, from genome wide association studies of coronary artery disease (CAD) map to chromosome 10q11 ?80 kb downstream of chemokine CXCL12. Therefore, we examined the relationship between these two SNPs and plasma CXCL12 levels.
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Calpain-10 interacts with plasma saturated fatty acid concentrations to influence insulin resistance in individuals with the metabolic syndrome.
Am. J. Clin. Nutr.
PUBLISHED: 03-09-2011
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Calpain-10 protein (intracellular Ca(2+)-dependent cysteine protease) may play a role in glucose metabolism, pancreatic ? cell function, and regulation of thermogenesis. Several CAPN10 polymorphic sites have been studied for their potential use as risk markers for type 2 diabetes and the metabolic syndrome (MetS). Fatty acids are key metabolic regulators that may interact with genetic factors and influence glucose metabolism.
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Docosahexaenoic acid attenuates macrophage-induced inflammation and improves insulin sensitivity in adipocytes-specific differential effects between LC n-3 PUFA.
J. Nutr. Biochem.
PUBLISHED: 03-04-2011
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Adipose tissue inflammation with immune cell recruitment plays a key role in obesity-induced insulin resistance (IR). Long-chain (LC) n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-inflammatory potential; however, their individual effects on adipose IR are ill defined. We hypothesized that EPA and DHA may differentially affect macrophage-induced IR in adipocytes.
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Association of the vitamin D metabolism gene CYP24A1 with coronary artery calcification.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 09-16-2010
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The vitamin D endocrine system is essential for calcium homeostasis, and low levels of vitamin D metabolites have been associated with cardiovascular disease risk. We hypothesized that DNA sequence variation in genes regulating vitamin D metabolism and signaling pathways might influence variation in coronary artery calcification (CAC).
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Mapping a global agenda for adolescent health.
J Adolesc Health
PUBLISHED: 08-30-2010
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Major changes in health are underway in many low- and middle-income countries that are likely to bring greater focus on adolescents. This commentary, based on a 2009 London meeting, considers the need for strategic information for future global initiatives in adolescent health. Current coverage of adolescent health in global data collections is patchy. There is both the need and scope to extend existing collections into the adolescent years as well as achieve greater harmonization of measures between surveys. The development of a core set of global adolescent health indicators would aid this process. Other important tasks include adapting and testing interventions in low- and middle-income countries, growing research capacity in those settings, better communication of research from those countries, and building structures to implement future global initiatives. A global agenda needs more than good data, but sound information about adolescent health and its social and environmental determinants, will be important in both advocacy and practice.
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NOS3 gene polymorphisms are associated with risk markers of cardiovascular disease, and interact with omega-3 polyunsaturated fatty acids.
Atherosclerosis
PUBLISHED: 03-18-2010
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Omega-3 polyunsaturated fatty acids (n-3 PUFA) may protect against the development of cardiovascular disease (CVD). Genotype at key genes such as nitric oxide synthase (NOS3) may determine responsiveness to fatty acids. Gene-nutrient interactions may be important in modulating the development of CVD, particularly in high-risk individuals with the metabolic syndrome (MetS).
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Additive effect of polymorphisms in the IL-6, LTA, and TNF-{alpha} genes and plasma fatty acid level modulate risk for the metabolic syndrome and its components.
J. Clin. Endocrinol. Metab.
PUBLISHED: 01-15-2010
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Context: Cytokine polymorphisms and dietary fat composition may influence the risk of the metabolic syndrome (MetS). Objective: The objective of the study was to determine the relationship between lymphotoxin-alpha (LTA), TNF-alpha, and IL-6 gene polymorphisms with MetS risk and investigate whether plasma fatty acid composition, a biomarker of dietary fat intake, modulated these associations. Design: Polymorphisms (LTA rs915654, TNF-alpha rs1800629, IL-6 rs1800797), biochemical measurements, and plasma fatty acids were determined in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754). Results: LTA rs915654 minor A allele carriers and TNF-alpha rs1800629 major G allele homozygotes had increased MetS risk [odds ratio (OR) 1.37 (confidence interval [CI] 1.12-1.66), P = 0.002 and OR 1.35 (CI 1.08-1.70), P = 0.009] compared with their TT homozygotes and A allele carriers. Possession of the IL-6 rs1800797 GG genotype by the LTA and TNF-alpha risk genotype carriers further increased risk of the MetS [OR 2.10 (CI 1.19-3.71) P = 0.009], fasting hyperglycemia [OR 2.65 (CI 1.12-6.28), P = 0.027], high systolic blood pressure [OR 1.99 (CI 1.07-3.72), P = 0.03], and abdominal obesity [OR 1.52 (CI 1.01-2.28), P = 0.04]. Plasma polyunsaturated to saturated fat ratio exacerbated these effects; subjects in the lowest 50th percentile had even greater risk of the MetS [OR 4.40 (CI 1.55-12.45), P = 0.005], fasting hyperglycemia, high systolic blood pressure, and abdominal obesity (P < 0.05). Conclusions: LTA, TNF-alpha, and IL-6 genotype interactions increased MetS risk, which was further exacerbated by a low plasma polyunsaturated to saturated fat exposure, indicating important modulation of genetic risk by dietary fat exposure.
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Complement component 3 polymorphisms interact with polyunsaturated fatty acids to modulate risk of metabolic syndrome.
Am. J. Clin. Nutr.
PUBLISHED: 10-14-2009
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Complement component 3 (C3) is a novel determinant of the metabolic syndrome (MetS). Gene-nutrient interactions with dietary fat may affect MetS risk.
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Global patterns of mortality in young people: a systematic analysis of population health data.
Lancet
PUBLISHED: 09-15-2009
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Pronounced changes in patterns of health take place in adolescence and young adulthood, but the effects on mortality patterns worldwide have not been reported. We analysed worldwide rates and patterns of mortality between early adolescence and young adulthood.
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Exploring the relationship between pharmacists job satisfaction, intention to quit the profession, and actual quitting.
Res Social Adm Pharm
PUBLISHED: 01-21-2009
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To date there has been no published research on the link between job satisfaction and intentions to quit the profession among pharmacists.
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Setting research priorities for adolescent sexual and reproductive health in low- and middle-income countries.
Bull. World Health Organ.
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To conduct an expert-led process for identifying research priorities in adolescent sexual and reproductive health in low- and middle-income countries.
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Resource needs for adolescent friendly health services: estimates for 74 low- and middle-income countries.
PLoS ONE
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In order to achieve Millennium Development Goals 4, 5 and 6, it is essential to address adolescents health.
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Peroxisome Proliferator-Activated Receptor-? Agonism With Fenofibrate Does Not Suppress Inflammatory Responses to Evoked Endotoxemia.
J Am Heart Assoc
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Data conflict with regard to whether peroxisome proliferator-activated receptor-? agonism suppresses inflammation in humans. We hypothesized that in healthy adults peroxisome proliferator-activated receptor-? agonism with fenofibrate would blunt the induced immune responses to endotoxin (lipopolysaccharide [LPS]), an in vivo model for the study of cardiometabolic inflammation.
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A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial.
J Transl Med
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Chronic inflammation may contribute to insulin resistance (IR), metabolic syndrome and atherosclerosis although evidence of causality is lacking in humans. We hypothesized that very low-dose experimental endotoxemia would induce adipose tissue inflammation and systemic IR during a low-grade but asymptomatic inflammatory response and thus provide an experimental model for future tests of pharmacologic and genomic modulation of cardio-metabolic traits in humans.
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Health of the worlds adolescents: a synthesis of internationally comparable data.
Lancet
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Adolescence and young adulthood offer opportunities for health gains both through prevention and early clinical intervention. Yet development of health information systems to support this work has been weak and so far lagged behind those for early childhood and adulthood. With falls in the number of deaths in earlier childhood in many countries and a shifting emphasis to non-communicable disease risks, injuries, and mental health, there are good reasons to assess the present sources of health information for young people. We derive indicators from the conceptual framework for the Series on adolescent health and assess the available data to describe them. We selected indicators for their public health importance and their coverage of major health outcomes in young people, health risk behaviours and states, risk and protective factors, social role transitions relevant to health, and health service inputs. We then specify definitions that maximise international comparability. Even with this optimisation of data usage, only seven of the 25 indicators, covered at least 50% of the worlds adolescents. The worst adolescent health profiles are in sub-Saharan Africa, with persisting high mortality from maternal and infectious causes. Risks for non-communicable diseases are spreading rapidly, with the highest rates of tobacco use and overweight, and lowest rates of physical activity, predominantly in adolescents living in low-income and middle-income countries. Even for present global health agendas, such as HIV infection and maternal mortality, data sources are incomplete for adolescents. We propose a series of steps that include better coordination and use of data collected across countries, greater harmonisation of school-based surveys, further development of strategies for socially marginalised youth, targeted research into the validity and use of these health indicators, advocating for adolescent-health information within new global health initiatives, and a recommendation that every country produce a regular report on the health of its adolescents.
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Genetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium.
Atherosclerosis
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Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ?50,000 SNPs across ?2100 candidate genes to identify genetic variants for ABI.
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Translational studies of lipoprotein-associated phospholipase A? in inflammation and atherosclerosis.
J. Am. Coll. Cardiol.
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This study sought to examine the role of lipoprotein-associated phospholipase A? (Lp-PLA?/PLA2G7) in human inflammation and coronary atherosclerosis.
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Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci.
Richa Saxena, Clara C Elbers, Yiran Guo, Inga Peter, Tom R Gaunt, Jessica L Mega, Matthew B Lanktree, Archana Tare, Berta Almoguera Castillo, Yun R Li, Toby Johnson, Marcel Bruinenberg, Diane Gilbert-Diamond, Ramakrishnan Rajagopalan, Benjamin F Voight, Ashok Balasubramanyam, John Barnard, Florianne Bauer, Jens Baumert, Tushar Bhangale, Bernhard O Böhm, Peter S Braund, Paul R Burton, Hareesh R Chandrupatla, Robert Clarke, Rhonda M Cooper-DeHoff, Errol D Crook, George Davey-Smith, Ian N Day, Anthonius de Boer, Mark C H de Groot, Fotios Drenos, Jane Ferguson, Caroline S Fox, Clement E Furlong, Quince Gibson, Christian Gieger, Lisa A Gilhuijs-Pederson, Joseph T Glessner, Anuj Goel, Yan Gong, Struan F A Grant, Diederick E Grobbee, Claire Hastie, Steve E Humphries, Cecilia E Kim, Mika Kivimäki, Marcus Kleber, Christa Meisinger, Meena Kumari, Taimour Y Langaee, Debbie A Lawlor, Mingyao Li, Maximilian T Lobmeyer, Anke-Hilse Maitland-van der Zee, Matthijs F L Meijs, Cliona M Molony, David A Morrow, Gurunathan Murugesan, Solomon K Musani, Christopher P Nelson, Stephen J Newhouse, Jeffery R O'Connell, Sandosh Padmanabhan, Jutta Palmen, Sanjey R Patel, Carl J Pepine, Mary Pettinger, Thomas S Price, Suzanne Rafelt, Jane Ranchalis, Asif Rasheed, Elisabeth Rosenthal, Ingo Ruczinski, Sonia Shah, Haiqing Shen, Günther Silbernagel, Erin N Smith, Annemieke W M Spijkerman, Alice Stanton, Michael W Steffes, Barbara Thorand, Mieke Trip, Pim van der Harst, Daphne L van der A, Erik P A van Iperen, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Bruce H R Wolffenbuttel, Taylor Young, M Hadi Zafarmand, Joseph M Zmuda, , Michael Boehnke, David Altshuler, Mark McCarthy, W H Linda Kao, James S Pankow, Thomas P Cappola, Peter Sever, Neil Poulter, Mark Caulfield, Anna Dominiczak, Denis C Shields, Deepak L Bhatt, Deepak Bhatt, Li Zhang, Sean P Curtis, John Danesh, Juan P Casas, Yvonne T van der Schouw, N Charlotte Onland-Moret, Pieter A Doevendans, Gerald W Dorn, Martin Farrall, Garret A FitzGerald, Anders Hamsten, Robert Hegele, Aroon D Hingorani, Marten H Hofker, Gordon S Huggins, Thomas Illig, Gail P Jarvik, Julie A Johnson, Olaf H Klungel, William C Knowler, Wolfgang Koenig, Winfried März, James B Meigs, Olle Melander, Patricia B Munroe, Braxton D Mitchell, Susan J Bielinski, Daniel J Rader, Muredach P Reilly, Stephen S Rich, Jerome I Rotter, Danish Saleheen, Nilesh J Samani, Eric E Schadt, Alan R Shuldiner, Roy Silverstein, Kandice Kottke-Marchant, Philippa J Talmud, Hugh Watkins, Folkert W Asselbergs, Folkert Asselbergs, Paul I W de Bakker, Jeanne McCaffery, Cisca Wijmenga, Marc S Sabatine, James G Wilson, Alex Reiner, Donald W Bowden, Hakon Hakonarson, David S Siscovick, Brendan J Keating.
Am. J. Hum. Genet.
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To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ?50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ?2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.
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A genome-wide association study for coronary artery disease identifies a novel susceptibility locus in the major histocompatibility complex.
Circ Cardiovasc Genet
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Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.
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