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Find video protocols related to scientific articles indexed in Pubmed.
Genome-Wide Association Study of L-Arginine and Dimethylarginines Reveals Novel Metabolic Pathway for Symmetric Dimethylarginine.
Circ Cardiovasc Genet
PUBLISHED: 09-24-2014
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-Dimethylarginines (DMA) interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA) and L-arginine uptake into the cell (ADMA and symmetric dimethylarginine, SDMA). In prospective clinical studies ADMA has been characterized as a cardiovascular risk marker whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterise the environmental and genetic contributions to inter-individual variability of these biomarkers.
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The safe passage study: design, methods, recruitment, and follow-up approach.
Paediatr Perinat Epidemiol
PUBLISHED: 08-05-2014
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The Safe Passage Study is a large, prospective, multidisciplinary study designed to (1) investigate the association between prenatal alcohol exposure, sudden infant death syndrome (SIDS), and stillbirth, and (2) determine the biological basis of the spectrum of phenotypic outcomes from exposure, as modified by environmental and genetic factors that increase the risk of stillbirth, SIDS, and in surviving children, fetal alcohol spectrum disorders.
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A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas.
Acta Neuropathol.
PUBLISHED: 07-26-2014
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Pediatric glioblastomas (GBM) are highly aggressive and lethal tumors. Recent sequencing studies have shown that ~30 % of pediatric GBM and ~80 % of diffuse intrinsic pontine gliomas show K27M mutations in the H3F3A gene, a variant encoding histone H3.3. H3F3A K27M mutations lead to global reduction in H3K27me3. Our goal was to develop biomarkers for the histopathologic detection of these tumors. Therefore, we evaluated the utility of measuring H3K27me3 global reduction as a histopathologic and prognostic biomarker and tested an antibody directed specifically against the H3.3 K27M mutation in 290 samples. The study cohort included 203 pediatric (including 38 pediatric high-grade astrocytomas) and 38 adult brain tumors of various subtypes and grades and 49 non-neoplastic reactive brain tissues. Detection of H3.3 K27M by immunohistochemistry showed 100 % sensitivity and specificity and was superior to global reduction in H3K27me3 as a biomarker in diagnosing H3F3A K27M mutations. Moreover, cases that stained positive for H3.3 K27M showed a significantly poor prognosis compared to corresponding negative tumors. These results suggest that immunohistochemical detection of H3.3 K27M is a sensitive and specific surrogate for the H3F3A K27M mutation and defines a prognostically poor subset of pediatric GBM.
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Baseline levels, and changes over time in body mass index and fasting insulin, and their relationship to change in metabolic trait clustering.
Metab Syndr Relat Disord
PUBLISHED: 07-09-2014
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Multiple abnormal metabolic traits are found together or "cluster" within individuals more often than is predicted by chance. The individual and combined role of adiposity and insulin resistance (IR) on metabolic trait clustering is uncertain. We tested the hypothesis that change in trait clustering is a function of both baseline level and change in these measures.
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Significant immunohistochemical expression of human chorionic gonadotropin in high-grade osteosarcoma is rare, but may be associated with clinically elevated serum levels.
Pediatr. Dev. Pathol.
PUBLISHED: 05-23-2014
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Survival rates have plateaued at 70% for osteosarcoma. Proteins ectopically produced by malignant tumors may provide insight into new therapeutic targets. Osteosarcomas secreting human chorionic gonadotropin (hCG) have been suggested to have a worse prognosis. We examined the frequency of expression of ?-subunit of hCG (?-hCG) in pretreatment osteosarcoma biopsies, and asked if it was associated with various clinical prognostic parameters, and the development of metastases. We subjected 51 pretreatment biopsies of high-grade osteosarcoma, from 51 patients, to ?-hCG immunohistochemistry. In 19 of these patients, postchemotherapy metastatic biopsies also were examined for ?-hCG expression. Clinical information (patient age, sex, survival status, and serum hCG in females only), and tumor characteristics (site, size, and presence of metastases) were recorded. The ?-hCG positive and negative biopsies were separated and compared. Of 49 interpretable pretreatment biopsies, 28 (57%) showed positive cytoplasmic ?-hCG expression: 27 with sparse positivity (1% of tumor cells) and 1 with frequent positivity (10% of tumor cells). The patient with frequent ?-hCG positivity in her pretreatment biopsy had elevated serum hCG (88.2 mIU/mL) at diagnosis, decreasing to undetectable following chemotherapy and definitive resection. There was no difference in clinical parameters or rate of metastasis between ?-hCG positive versus negative groups. Expression of ?-hCG may be seen in high-grade osteosarcoma, but frequent ?-hCG immunohistochemical expression by tumor cells, associated with clinically elevated serum ?-hCG, is rare. Recognition that some nongerm cell tumors may produce ?-hCG can prevent confusion with malignancies containing neoplastic syncytiotrophoblast cells, including germ cell and trophoblastic tumors.
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Association of sex hormones, aging, and atrial fibrillation in men: the Framingham Heart Study.
Circ Arrhythm Electrophysiol
PUBLISHED: 03-08-2014
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Endogenous sex hormones have been related to cardiovascular outcomes and mortality. We hypothesized that sex hormones are related to atrial fibrillation (AF) in a community-based cohort of middle-aged to older men.
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Association of exhaled carbon monoxide with subclinical cardiovascular disease and their conjoint impact on the incidence of cardiovascular outcomes.
Eur. Heart J.
PUBLISHED: 02-25-2014
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Whereas endogenous carbon monoxide (CO) is cytoprotective at physiologic levels, excess CO concentrations are associated with cardiometabolic risk and may represent an important marker of progression from subclinical to clinical cardiovascular disease (CVD).
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Assessing the incremental predictive performance of novel biomarkers over standard predictors.
Stat Med
PUBLISHED: 02-13-2014
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It is unclear to what extent the incremental predictive performance of a novel biomarker is impacted by the method used to control for standard predictors. We investigated whether adding a biomarker to a model with a published risk score overestimates its incremental performance as compared to adding it to a multivariable model with individual predictors (or a composite risk score estimated from the sample of interest) and to a null model. We used 1000 simulated datasets (with a range of risk factor distributions and event rates) to compare these methods, using the continuous net reclassification index (NRI), the integrated discrimination index (IDI), and change in the C-statistic as discrimination metrics. The new biomarker was added to the following: null model, model including a published risk score, model including a composite risk score estimated from the sample of interest, and multivariable model with individual predictors. We observed a gradient in the incremental performance of the biomarker, with the null model resulting in the highest predictive performance of the biomarker and the model using individual predictors resulting in the lowest (mean increases in C-statistic between models without and with the biomarker: 0.261, 0.085, 0.030, and 0.031; NRI: 0.767, 0.621, 0.513, and 0.530; IDI: 0.153, 0.093, 0.053 and 0.057, respectively). These findings were supported by the Framingham Study data predicting atrial fibrillation using novel biomarkers. We recommend that authors report the effect of a new biomarker after controlling for standard predictors modeled as individual variables.
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High-level transgene expression in induced pluripotent stem cell-derived megakaryocytes: correction of Glanzmann thrombasthenia.
Blood
PUBLISHED: 12-13-2013
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Megakaryocyte-specific transgene expression in patient-derived induced pluripotent stem (iPS) cells offers a new approach to study and potentially treat disorders affecting megakaryocytes and platelets. Using a Gp1ba promoter, we have developed a strategy to achieve a high level of protein expression in human megakaryocytes. The feasibility of this approach was demonstrated in iPS cells derived from two patients with Glanzmann thrombasthenia (GT), an inherited platelet disorder caused by mutations in integrin ?IIb?3. Hemizygous insertion of Gp1ba promoter-driven human ?IIb cDNA into the AAVS1 locus of iPS cells lead to high ?IIb mRNA and protein expression, and correction of surface ?IIb?3 in megakaryocytes. Agonist stimulation of these cells displayed recovery of integrin ?IIb?3 activation. Our findings demonstrate a novel approach to studying human megakaryocyte biology as well as functional correction of the GT defect, offering a potential therapeutic strategy for patients with diseases that affect platelet function.
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Baseline factors predicting placebo response to treatment in children and adolescents with autism spectrum disorders: a multisite randomized clinical trial.
JAMA Pediatr
PUBLISHED: 09-25-2013
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The finding of factors that differentially predict the likelihood of response to placebo over that of an active drug could have a significant impact on study design in this population.
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Association of sex steroids, gonadotrophins, and their trajectories with clinical cardiovascular disease and all-cause mortality in elderly men from the Framingham Heart Study.
Clin. Endocrinol. (Oxf)
PUBLISHED: 09-13-2013
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Emerging data from longitudinal studies suggest that low sex steroid concentrations in men are associated with increased cardiovascular risk and mortality. The impact of longitudinal trajectory patterns from serial sex steroid and gonadotrophin measurements on the observed associations is unknown to date.
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Atrial fibrillation patterns and risks of subsequent stroke, heart failure, or death in the community.
J Am Heart Assoc
PUBLISHED: 09-05-2013
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Atrial fibrillation (AF) patterns and their relations with long-term prognosis are uncertain, partly because pattern definitions are challenging to implement in longitudinal data sets. We developed a novel AF classification algorithm and examined AF patterns and outcomes in the community.
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Clonal genetic and hematopoietic heterogeneity among human-induced pluripotent stem cell lines.
Blood
PUBLISHED: 08-12-2013
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Induced pluripotent stem cells (iPSCs) hold great promise for modeling human hematopoietic diseases. However, intrinsic variability in the capacities of different iPSC lines for hematopoietic development complicates comparative studies and is currently unexplained. We created and analyzed 3 separate iPSC clones from fibroblasts of 3 different normal individuals using a standardized approach that included excision of integrated reprogramming genes by Cre-Lox mediated recombination. Gene expression profiling and hematopoietic differentiation assays showed that independent lines from the same individual were generally more similar to one another than those from different individuals. However, one iPSC line (WT2.1) exhibited a distinctly different gene expression, proliferation rate, and hematopoietic developmental potential relative to all other iPSC lines. This "outlier" clone also acquired extensive copy number variations (CNVs) during reprogramming, which may be responsible for its divergent properties. Our data indicate how inherent and acquired genetic differences can influence iPSC properties, including hematopoietic potential.
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Organizational readiness for change in community-based addiction treatment programs and adherence in implementing evidence-based practices: a national study.
J Subst Abuse Treat
PUBLISHED: 06-11-2013
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Prior studies by the authors identified that clinical staff who reported that their treatment unit had lower levels of organizational readiness to change experienced higher levels of barriers in implementing an evidence-based practice (EBP). The current study examined whether clinical staff perceptions of their treatment units organizational readiness to change were also associated with their adherence to EBP protocols during EBP implementation. Adherence was examined through a variable measuring the extent to which staff modified EBP standards and manuals when implementing a new EBP. Multivariate regression analyses identified that clinical staff who had five or more years of addiction counseling experience, who rated staff in their organization as having higher levels of influence, who less frequently implemented new counseling interventions and who reported higher levels of barriers when implementing a newly funded EBP also reported that their program made more modifications to the EBP in the implementation process. Finally, staff who implemented MI compared to any other EBP reported lower levels of EBP modifications. Implications: Continued federal funding is needed to enhance treatment unit organizational resources in order to reduce barriers and promote adherence to EBPs. Also, funders of treatment need to continue to provide ongoing technical assistance and training opportunities to promote implementation of EBPs with fidelity.
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Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients.
Blood
PUBLISHED: 06-06-2013
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Diamond Blackfan anemia (DBA) is a congenital disorder with erythroid (Ery) hypoplasia and tissue morphogenic abnormalities. Most DBA cases are caused by heterozygous null mutations in genes encoding ribosomal proteins. Understanding how haploinsufficiency of these ubiquitous proteins causes DBA is hampered by limited availability of tissues from affected patients. We generated induced pluripotent stem cells (iPSCs) from fibroblasts of DBA patients carrying mutations in RPS19 and RPL5. Compared with controls, DBA fibroblasts formed iPSCs inefficiently, although we obtained 1 stable clone from each fibroblast line. RPS19-mutated iPSCs exhibited defects in 40S (small) ribosomal subunit assembly and production of 18S ribosomal RNA (rRNA). Upon induced differentiation, the mutant clone exhibited globally impaired hematopoiesis, with the Ery lineage affected most profoundly. RPL5-mutated iPSCs exhibited defective 60S (large) ribosomal subunit assembly, accumulation of 12S pre-rRNA, and impaired erythropoiesis. In both mutant iPSC lines, genetic correction of ribosomal protein deficiency via complementary DNA transfer into the "safe harbor" AAVS1 locus alleviated abnormalities in ribosome biogenesis and hematopoiesis. Our studies show that pathological features of DBA are recapitulated by iPSCs, provide a renewable source of cells to model various tissue defects, and demonstrate proof of principle for genetic correction strategies in patient stem cells.
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Multilevel modeling versus cross-sectional analysis for assessing the longitudinal tracking of cardiovascular risk factors over time.
Stat Med
PUBLISHED: 05-22-2013
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Correlated data are obtained in longitudinal epidemiological studies, where repeated measurements are taken on individuals or groups over time. Such longitudinal data are ideally analyzed using multilevel modeling approaches, which appropriately account for the correlations in repeated responses in the same individual. Commonly used regression models are inappropriate as they assume that measurements are independent. In this tutorial, we use multilevel modeling to demonstrate its use for analysis of correlated data obtained from serial examinations on individuals. We focus on cardiovascular epidemiological research where investigators are often interested in quantifying the relations between clinical risk factors and outcome measures (X and Y, respectively), where X and Y are measured repeatedly over time, for example, using serial observations on participants attending multiple examinations in a longitudinal cohort study. For instance, it may be of interest to evaluate the relations between serial measures of left ventricular mass (outcome) and of its potential determinants (i.e., body mass index and blood pressure), both of which are measured over time. In this tutorial, we describe the application of multilevel modeling to cardiovascular risk factors and outcome data (using serial echocardiographic data as an example of an outcome). We suggest an analytical approach that can be implemented to evaluate relations between any potential outcome of interest and risk factors, including assessment of random effects and nonlinear relations. We illustrate these steps using echocardiographic data from the Framingham Heart Study with SAS PROC MIXED. Copyright © 2013 John Wiley & Sons, Ltd.
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Risk assessment for incident heart failure in individuals with atrial fibrillation.
Eur. J. Heart Fail.
PUBLISHED: 04-17-2013
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Atrial fibrillation (AF) is a strong risk factor for heart failure (HF); HF onset in patients with AF is associated with increased morbidity and mortality. Risk factors that predict HF in individuals with AF in the community are not well established.
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Immunohistochemical expression of glypican-3 in pediatric tumors: an analysis of 414 cases.
Pediatr. Dev. Pathol.
PUBLISHED: 03-26-2013
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Glypican-3 (GPC3) is a proteoglycan thought to play an important role during development. Germline GPC3 mutations are seen in the rare Simpson-Golabi-Behmel syndrome (SGBS), which predisposes patients to Wilms tumor, hepatoblastoma, and neuroblastoma. While numerous adult tumors have been evaluated by immunohistochemistry for GPC3, no comprehensive assessment has been done in pediatric tumors. We therefore investigated GPC3 expression in 143 pediatric central nervous system (CNS) tumors and 271 non-CNS tumors. Among non-CNS tumors, GPC3 expression was seen in 9/9 (100%) hepatoblastomas, 4/6 (67%) malignant rhabdoid tumors, 5/13 (38%) Wilms tumors, 11/37 (30%) alveolar rhabdomyosarcomas, and 8/45 (18%) embryonal rhabdomyosarcomas. All 136 neuroblastomas, 14 Ewing sarcoma/primitive neuroectodermal tumors, and 11 synovial sarcomas were immunonegative for GPC3. Among CNS tumors, GPC3 had restricted expression, with positivity in 6/6 (100%) atypical teratoid rhabdoid tumors and 1/4 (25%) craniopharyngiomas. The remaining 136 CNS tumors-23 medulloblastomas, 21 pilocytic astrocytomas, 13 gangliogliomas, 12 ependymomas, 12 glioblastomas, 11 choroid plexus neoplasms, 10 diffuse astrocytomas (grade II/III), 10 meningiomas, 8 dysembryoplastic neuroepithelial tumors, 8 oligodendrogliomas, 3 craniopharyngiomas, 3 germinomas, and 2 neurocytomas-were entirely negative for GPC3. These results showed GPC3 positivity in a number of non-CNS tumors, with no consistent discrimination between tumors that were or were not associated with SGBS. Within the CNS, GPC3 positivity was limited to a small subset of CNS neoplasms and may thus serve as a useful positive diagnostic biomarker (P < 0.0001) in addition to negative INI1/BAF47/SMARCB1 staining to differentiate atypical teratoid rhabdoid tumors from other high-grade pediatric brain tumors.
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Histone 3 lysine 9 trimethylation is differentially associated with isocitrate dehydrogenase mutations in oligodendrogliomas and high-grade astrocytomas.
J. Neuropathol. Exp. Neurol.
PUBLISHED: 03-14-2013
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Trimethylation of histone 3 lysine 9 (H3K9me3) is a marker of repressed transcription. Cells transfected with mutant isocitrate dehydrogenase (IDH) show increased methylation of histone lysine residues, including H3K9me3, because of inhibition of histone demethylases by 2-hydroxyglutarate. Here, we evaluated H3K9me3 and its association with IDH mutations in 284 gliomas. Trimethylation of H3K9 was significantly associated with IDH mutations in oligodendrogliomas. Moreover, 72% of World Health Organization grade II and 65% of grade III oligodendrogliomas showed combined H3K9me3 positivity and 1p19q codeletion. In astrocytic tumors, H3K9me3 positivity was found in all grades of tumors; it showed a significant relationship with IDH mutational status in grade II astrocytomas but not in grade III astrocytomas or glioblastomas. Finally, H3K9me3-positive grade II oligodendrogliomas, but not other tumor subtypes, showed improved overall survival compared with H3K9me3-negative cases. These results suggest that repressive trimethylation of H3K9 in gliomas may occur in a context-dependent manner and is associated with IDH mutations in oligodendrogliomas but may be differently regulated in high-grade astrocytic tumors. Furthermore, H3K9me3 may define a subset of grade II oligodendrogliomas with better overall survival. Our results suggest variable roles for IDH mutations in the pathogenesis of oligodendrogliomas versus astrocytic tumors.
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The alternative lengthening of telomere phenotype is significantly associated with loss of ATRX expression in high-grade pediatric and adult astrocytomas: a multi-institutional study of 214 astrocytomas.
Mod. Pathol.
PUBLISHED: 02-20-2013
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Loss-of-function of alpha thalassemia/mental retardation syndrome X-linked (ATRX) protein leads to a phenotype called alternative lengthening of telomeres (ALT) in some tumors. High-grade astrocytomas comprise a heterogeneous group of central nervous system tumors. We examined a large cohort of adult (91) and pediatric (n=88) high-grade astrocytomas as well as lower grade forms (n=35) for immunohistochemical loss of ATRX protein expression and the presence of ALT using telomere-specific fluorescence in situ hybridization, with further correlation to other known genetic alterations. We found that in pediatric high-grade astrocytomas, 29.6% of tumors were positive for ALT and 24.5% were immunonegative for the ATRX protein, these two alterations being highly associated with one another (P<0.0001). In adult high-grade astrocytomas, 26.4% of tumors were similarly positive for ALT, including 80% of ATRX protein immunonegative cases (P<0.0001). Similar frequencies were found in 11 adult low-grade astrocytomas, whereas all 24 pilocytic astrocytomas were negative for ALT. We did not find any significant correlations between isocitrate dehydrogenase status and either ALT positivity or ATRX protein expression in our adult high-grade astrocytomas. In both cohorts, however, the ALT positive high-grade astrocytomas showed more frequent amplification of the platelet-derived growth factor receptor alpha gene (PDGFRA; 45% and 50%, respectively) than the ALT negative counterparts (18% and 26%; P=0.03 for each). In summary, our data show that the ALT and ATRX protein alterations are common in both pediatric and adult high-grade astrocytomas, often with associated PDGFRA gene amplification.
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PDGFRA amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognostic group in IDH1 mutant glioblastoma.
Brain Pathol.
PUBLISHED: 02-11-2013
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High-grade astrocytomas (HGAs), corresponding to World Health Organization grades III (anaplastic astrocytoma) and IV (glioblastoma; GBM), are biologically aggressive, and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non-amplified (normal and polysomy) or amplified (low-level and high-level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and isocitrate dehydrogenase 1 (IDH1)(R132H) mutation was a significant independent prognostic factor (P?=?0.01). In HGAs, PDGFRA amplification is common and can manifest as high-level and focal or low-level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs.
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Evaluation of histone 3 lysine 27 trimethylation (H3K27me3) and enhancer of Zest 2 (EZH2) in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas.
Brain Pathol.
PUBLISHED: 01-03-2013
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H3F3A mutations are seen in ?30% of pediatric glioblastoma (GBMs) and involve either the lysine residue at position 27 (K27M) or glycine at position 34 (G34R/V). Sixteen genes encode histone H3, each variant differing in only a few amino acids. Therefore, how mutations in a single H3 gene contribute to carcinogenesis is unknown. H3F3A K27M mutations are predicted to alter methylation of H3K27. H3K27me3 is a repressive mark critical to stem cell maintenance and is mediated by EZH2, a member of the polycomb-group (PcG) family. We evaluated H3K27me3 and EZH2 expression using immunohistochemistry in 76 pediatric brain tumors. H3K27me3 was lowered/absent in tumor cells but preserved in endothelial cells and infiltrating lymphocytes in six out of 20 GBMs. H3K27me3 showed strong immunoreactivity in all other tumor subtypes. Sequencing of GBMs showed H3F3A K27M mutations in all six cases with lowered/absent H3K27me3. EZH2 expression was high in GBMs, but absent/focal in other tumors. However, no significant differences in EZH2 expression were observed between H3F3A K27M mutant and wild type GBMs, suggesting that EZH2 mediated trimethylation of H3K27 is inhibited in GBM harboring K27M mutations. Our results indicate that H3F3A K27M mutant GBMs show decreased H3K27me3 that may be of both diagnostic and biological relevance.
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The effect of dietary supplementation with spent cider yeast on the Swine distal gut microbiome.
PLoS ONE
PUBLISHED: 01-01-2013
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There is an increasing need for alternatives to antibiotics for promoting animal health, given the increasing problems associated with antibiotic resistance. In this regard, we evaluated spent cider yeast as a potential probiotic for modifying the gut microbiota in weanling pigs using pyrosequencing of 16S rRNA gene libraries.
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AAV-mediated gene therapy for choroideremia: preclinical studies in personalized models.
PLoS ONE
PUBLISHED: 01-01-2013
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Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1(st) or 2(nd) decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM.
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The time and place of nostalgia: re-situating a French disease.
J Hist Med Allied Sci
PUBLISHED: 12-08-2011
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The history of nostalgia as a clinical category has many highly specific national stories. This paper traces an aspect of this history, examining aspects of nostalgias changing meanings in nineteenth-century France. Nostalgia was a disease triggered by displacement, which became medically and politically important after the French Revolution, when military surgeons encountered epidemics of nostalgia in the armed forces. Understood as a form of pathological homesickness, the category straddled environmental medicine and emerging ideas about insanity. The diagnosis became particularly important to Idéologue writers as a case study in regulating and redirecting the emotions, demonstrating the efficacy of their new "moral" treatments and an ability to generate patriotic attachment to the new nation state. Over the course of the century, nostalgia disintegrated as a medical condition reflecting a decline in environmental explanations for disease within medicine, and increasingly plastic meanings attached to nostalgic desire.
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Reference intervals for plasma L-arginine and the L-arginine:asymmetric dimethylarginine ratio in the Framingham Offspring Cohort.
J. Nutr.
PUBLISHED: 10-26-2011
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L-arginine, as a precursor of NO synthesis, has attracted much scientific attention in recent years. Experimental mouse models suggest that L-arginine supplementation can retard, halt, or even reverse atherogenesis. In human studies, supplementation with L-arginine improved endothelium-dependent vasodilation. However, L-arginine levels are best interpreted in the context of levels of asymmetric dimethylarginine (ADMA), a competitive inhibitor of NO synthase. Thus, reference limits for circulating L-arginine and the L-arginine:ADMA ratio may help to determine the nutritional state of individuals at high cardiovascular risk in light of increased ADMA levels. We defined reference limits for plasma L-arginine in 1141 people and for the L-arginine:ADMA ratio in 1138 relatively healthy individuals from the Framingham Offspring Cohort. Plasma L-arginine and ADMA concentrations were determined by using a stable isotope-based LC-MS/MS method. The reference limits (2.5th and 97.5th percentiles) for plasma L-arginine were 41.0 ?mol/L (95% CI = 39.5-42.5 ?mol/L) and 114 ?mol/L (95% CI = 112-115 ?mol/L), whereas corresponding reference limits (2.5th and 97.5th percentiles) for the L-arginine:ADMA ratio were 74.3 ?mol/L (95% CI = 71.1-77.3 ?mol/L) and 225 ?mol/L (95% CI = 222-228 ?mol/L). Plasma L-arginine was positively associated with the estimated glomerular filtration rate (eGFR) and blood glucose levels, whereas the L-arginine:ADMA ratio was positively associated with eGFR and diastolic blood pressure but inversely associated with homocysteine and (log)C-reactive protein. We report reference levels for plasma L-arginine and for the L-arginine:ADMA ratio that may be helpful for evaluation of the effects of L-arginine supplementation in participants with an impaired L-arginine/NO pathway.
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Improving self-care for heart failure for seniors: the impact of video and written education and decision aids.
Popul Health Manag
PUBLISHED: 10-17-2011
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Heart failure poses a substantial burden on health care expenditures and quality of life; therefore, strategies to improve health behaviors for heart failure are essential. Highly effective medical decision aids can enable health improvements for people with heart failure. In this randomized controlled study, individuals with heart failure in a private Medicare plan were randomized into either an intervention or control group. Participants in the intervention group received basic program information and a simple fact sheet about heart failure, plus a medical decision aid, Living with Heart Failure DVD and booklet; patients randomized to the control group received the basic written materials only. The study was powered to detect a 5% difference in the primary outcome measure (daily weight monitoring). Participants were surveyed 4 weeks after outreach materials were mailed. There were 480 survey respondents: 246 in the intervention group; 234 in the control group. Intervention group respondents were significantly more likely to weigh themselves daily (P=0.05) than control group respondents (44% versus 38%). The intervention group was more likely than the control group to monitor fluid intake (47% versus 44%) and follow a low-sodium diet (83% versus 77%). Other health behavior differences were not statistically significant. The DVD decision aid increased levels of daily weight monitoring and other important health behaviors. Broad application of inexpensive behavior change interventions, such as a DVD/booklet program, should help to facilitate important, routine self-care behaviors for individuals with heart failure.
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Malignant rhabdoid tumors express stem cell factors, which relate to the expression of EZH2 and Id proteins.
Am. J. Surg. Pathol.
PUBLISHED: 09-17-2011
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Malignant rhabdoid tumors (MRTs) are highly aggressive pediatric tumors associated with loss of expression of SMARCB1, commonly occurring in the central nervous system [referred to as atypical teratoid/rhabdoid tumors (AT/RTs)] and in the kidney and soft tissues. Histologically, MRTs are characterized by immunohistochemical evidence of primitive neuroectodermal, mesenchymal, and epithelial differentiation. The ability of MRTs to differentiate along multiple lines, as evidenced by both histologic features and polyphenotypic immunohistochemical staining, and the proliferative nature of MRT cells are characteristics shared with the self-renewal and plasticity of embryonic stem cells (ES). To test the hypothesis that MRTs share similarities with ES, we used immunohistochemistry to evaluate the expression of various stem cell markers in a tissue microarray containing 26 AT/RTs and 16 non-central nervous system MRTs (NCMRTs). Staining intensity was scored as negative (0), low (1+), moderate (2+), and strong (3+) and was multiplied by the percentage of positive tumor cells to establish a semiquantitative measure for each marker. In AT/RT, strong-to-low expression was noted with glypican-3 (20 of 26, 77%), Sall4 (23 of 26, 88%), T-cell leukemia/lymphoma 1 (25 of 26, 96%), and undifferentiated embryonic cell transcription factor 1 (19 of 26, 73%). Markers that showed low expression in AT/RT were Sox2 (8 of 26, 31%), Nanog (7 of 26, 27%), Klf4 (10 of 26, 38%), Zfp206 (5 of 26, 19%), and musashi-1 (21 of 26, 81%). Similarly, in NCMRT, expression was noted with glypican-3 (12 of 16, 75%), Sall4 (13 of 16, 81%), T-cell leukemia/lymphoma 1 (16 of 16, 100%), undifferentiated embryonic cell transcription factor 1 (12 of 16, 75%), Sox2 (5 of 16, 31%), Nanog (8 of 16, 50%), Klf4 (8 of 16, 50%), Zfp206 (13 of 16, 81%), and musashi-1 (11 of 16, 75%). Placental alkaline phosphatase, Oct4, c-KIT, CD30, ?-fetoprotein, and ?- -human chorionic gonadotrophin were not expressed in all cases. Markers that regulate the expression of stem cell transcription factors were also expressed in MRT. AT/RT cases showed expression of Id proteins: Id1 (17 of 26, 65%), Id2 (24 of 26, 92%), Id3 (22 of 26, 85%), and Id4 (22 of 26, 85%). Low expression was observed with EZH2 (15 of 26, 58%). Similarly, NCMRT cases showed expression of Id1 (15 of 16, 94%), Id2 (16 of 16, 100%), Id3 (16 of 16, 100%), Id4 (13 of 16, 81%), and EZH2 (13 of 16, 81%). Finally, regression analysis revealed a significant relationship between the expression of stem cell markers and EZH2 (P<0.0001), Id1 (P=0.0087), Id2 (P=0.0002), Id3 (P=0.0033), and Id4 (P<0.0001). These data suggest that MRTs express many stem cell-associated transcription factors, which may be regulated by the expression of EZH2 and the Id family of proteins. This study underscores similarities between MRTs and stem cells and may help elucidate common biologic pathways that could serve in advancing more effective therapeutic strategies to treat MRTs.
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Plasma symmetric dimethylarginine reference limits from the Framingham offspring cohort.
Clin. Chem. Lab. Med.
PUBLISHED: 08-25-2011
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Symmetric dimethylarginine (SDMA) is a by-product of protein methylation. Once released from proteins, SDMA is eliminated by the kidneys; consequently, plasma concentration has been suggested as a sensitive marker of renal function. Furthermore, recent work implicates SDMA in the pathogenesis of cardiovascular disease. To date, reference limits for SDMA plasma concentrations in healthy individuals are lacking.
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White blood cell count and risk of incident atrial fibrillation (from the Framingham Heart Study).
Am. J. Cardiol.
PUBLISHED: 06-22-2011
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Several studies have reported that inflammatory markers are associated with atrial fibrillation (AF). The white blood cell (WBC) count is a widely available and broadly used marker of systemic inflammation. We sought to investigate the association between an increased WBC count and incident AF and whether this association is mediated by smoking, myocardial infarction, and heart failure. We examined the participants in the Framingham Heart Study original cohort. Cox proportional hazard regression analysis was used to examine the relation between the WBC count and incident AF during a 5-year follow-up period. We adjusted for standard AF risk factors, smoking, previous myocardial infarction, and interim myocardial infarction and heart failure before the incident AF. Our sample consisted of 936 participants (mean age 76 ± 6 years and 61% women). The median WBC count was 6.4 × 10(9)/L (25th to 75th percentile 5.6 × 10(9)/L to 7.8 × 10(9)/L). During a median 5-year follow-up period, 82 participants (9%) developed new-onset AF. After adjusting for standard risk factors for AF, an increased WBC count was significantly associated with incident AF, with a hazard ratio per SD (0.26 × 10(9)/L) increase of 2.22 (95% confidence interval 1.10 to 4.48; p = 0.03). We found no substantive differences adjusting for smoking, previous myocardial infarction, interim myocardial infarction, or heart failure. In conclusion, in our community-based sample, an increased WBC count was associated with incident AF during 5 years of follow-up. Our findings provide additional evidence for the relation between systemic inflammation and AF.
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Hepatic pathology may develop before the Fontan operation in children with functional single ventricle: an autopsy study.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 05-12-2011
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Liver fibrosis has emerged as an important long-term complication of the Fontan operation. We aimed to describe liver histology at autopsy in patients who had undergone the Fontan operation and to determine whether patient variables are associated with the degree of fibrosis.
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Plasma resistin, adiponectin, and risk of incident atrial fibrillation: the Framingham Offspring Study.
Am. Heart J.
PUBLISHED: 05-03-2011
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We sought to investigate whether higher concentrations of resistin and lower concentrations of adiponectin relate to incident atrial fibrillation (AF) and whether this association is mediated by AF risk factors and inflammation. Resistin and adiponectin are adipokines that have been associated with multiple known risk factors for AF including diabetes, obesity, inflammation, and heart failure.
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Leclercia adecarboxylata cellulitis in a child with acute lymphoblastic leukemia.
Pediatr Dermatol
PUBLISHED: 03-08-2011
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Leclercia adecarboxylata is a rare, gram-negative rod that has been infrequently reported in the literature. The organism has been documented to cause solitary infections in immunocompromised hosts and polymicrobial wound infections in the immunocompetent. We present a case of an 8-year-old boy with significant past medical history of acute lymphoblastic leukemia who developed cellulitis due to local infection by L. adecarboxylata. This case is presented to raise awareness of this rare organisms ability to cause common cutaneous disease, especially in the immunocompromised.
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Barriers to implementation of evidence-based addiction treatment: a national study.
J Subst Abuse Treat
PUBLISHED: 02-11-2011
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Prior studies have identified that working in an addiction treatment unit with higher levels of organizational capacity is a factor associated with positive staff attitudes about evidence-based addiction treatment practices (EBPs). The study presented here explored whether staff perceptions about the organizational capacity of their treatment unit are also associated with staff experience of barriers to implementing EBPs. Multivariate regression methods examined the relationship between the clinical staff (n = 510) and director (n = 296) perceptions of organizational capacity (Texas Christian University Organizational Readiness for Change [TCU ORC]-staff and TCU ORC-director) and level of barriers experienced when implementing a new EBP controlling for a range of treatment unit characteristics, staff characteristics, and type of EBP implemented. For both samples, reporting higher levels of stress in their organizations was significantly associated with reporting higher levels of barriers when implementing a new EBP. For clinical staff only, experiencing lower levels of program needs in their organization, working in a program that had been in existence for a shorter period, and implementing motivational interviewing techniques compared with other EBPs were all factors significantly associated with experiencing lower levels of barriers with EBP implementation.
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Relation of brachial and digital measures of vascular function in the community: the Framingham heart study.
Hypertension
PUBLISHED: 01-24-2011
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Impaired vascular function contributes to the development of clinical cardiovascular disease. The relation between vasodilator function assessed noninvasively in the brachial and digital arteries remains incompletely defined. In the Framingham Offspring, Third Generation and Omni Cohorts, we measured flow-mediated dilation (FMD; n = 7031; age 48 ± 13 years; age range, 19 to 88 years; 54% women) and peripheral arterial tonometry (PAT) ratio (n = 4352; 55 ± 16 years; age range, 19 to 90 years; 51% women). Abnormal vascular function for each measure was defined by the sex-specific fifth percentile in a reference group free of conventional cardiovascular risk factors. The prevalence of abnormal FMD but not abnormal PAT ratio was higher with advancing age. In multivariable models, higher body mass index was associated with a higher prevalence of both abnormal FMD and PAT ratio. Additional correlates of abnormal FMD included increasing age and higher systolic blood pressure. In contrast, correlates of abnormal PAT ratio included lower systolic blood pressure, increasing total/high-density lipoprotein cholesterol ratio, diabetes, smoking, and lipid-lowering medication. Whereas women had higher FMD and PAT ratios compared with men, using sex-specific reference values, women had a higher prevalence of abnormal brachial and digital vascular function. In participants who had concurrent testing (n = 1843), PAT ratio was not significantly associated with FMD in multivariable models. In this large, community-based cohort, brachial and digital measures of vascular function had differing relations with cardiovascular risk factors and were nearly uncorrelated with each other. These results suggest that FMD and PAT provide distinct information regarding vascular function in conduit versus smaller digital vessels.
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P wave duration and risk of longitudinal atrial fibrillation in persons ? 60 years old (from the Framingham Heart Study).
Am. J. Cardiol.
PUBLISHED: 01-20-2011
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Long-term risk prediction is a priority for the prevention of atrial fibrillation (AF). P wave indices are electrocardiographic measurements describing atrial conduction. The role of P wave indices in the prospective determination of AF and mortality risk has had limited assessment. We quantified by digital caliper the P wave indices of maximum duration and dispersion in 1,550 Framingham Heart Study participants ? 60 years old (58% women) from single-channel electrocardiograms recorded from 1968 through 1971. We examined the association of selected P wave indices and long-term outcomes using Cox proportional hazards regression incorporating age, gender, body mass index, systolic blood pressure, treatment for hypertension, significant murmur, heart failure, and PR interval. Over a median follow-up of 15.8 years (range 0 to 38.7), 359 participants developed AF and 1,525 died. Multivariable-adjusted hazard ratios (HRs) per SD increase in maximum P wave duration were 1.15 (95% confidence interval [CI] 0.90 to 1.47, p = 0.27) for AF and 1.02 (95% CI 0.96 to 1.08, p = 0.18) for mortality. The upper 5% of P wave maximum duration had a multivariable-adjusted HR of 2.51 (95% CI 1.13 to 5.57, p = 0.024) for AF and an HR of 1.11 (95% CI 0.87 to 1.40, p = 0.20) for mortality. We found no significant associations between P wave dispersion with incidence of AF or mortality. In conclusion, maximum P wave duration at the upper fifth percentile was associated with long-term AF risk in an elderly community-based cohort. P wave duration is an electrocardiographic endophenotype for AF.
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Type 2 diabetes risk in persons with dysglycemia: the Framingham Offspring Study.
Diabetes Res. Clin. Pract.
PUBLISHED: 01-15-2011
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Detection of risk of type 2 diabetes mellitus (T2DM) among adults with dysglycemia.
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A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.
Hum. Mol. Genet.
PUBLISHED: 01-07-2011
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Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.
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Dietary factors and incident atrial fibrillation: the Framingham Heart Study.
Am. J. Clin. Nutr.
PUBLISHED: 11-24-2010
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There have been conflicting reported associations between dietary factors and incident atrial fibrillation (AF).
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P-wave indices: derivation of reference values from the Framingham Heart Study.
Ann Noninvasive Electrocardiol
PUBLISHED: 10-16-2010
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P-wave indices, an electrocardiographic phenotype reflecting atrial electrophysiology and morphology, may be altered in multiple disease states or by cardiovascular risk factors. Reference values for P-wave indices, providing cut points for their classification and interpretation, have not yet been established and are essential toward facilitating clinical application and comparison between studies.
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Aortic root remodeling over the adult life course: longitudinal data from the Framingham Heart Study.
Circulation
PUBLISHED: 08-16-2010
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Aortic root remodeling in adulthood is known to be associated with cardiovascular outcomes. However, there is a lack of longitudinal data defining the clinical correlates of aortic root remodeling over the adult life course.
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Correlates of echocardiographic indices of cardiac remodeling over the adult life course: longitudinal observations from the Framingham Heart Study.
Circulation
PUBLISHED: 07-26-2010
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The heart progressively remodels over the life course, yet longitudinal data characterizing such remodeling in the community are limited.
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P wave duration is associated with cardiovascular and all-cause mortality outcomes: the National Health and Nutrition Examination Survey.
Heart Rhythm
PUBLISHED: 07-13-2010
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P wave indices are an intermediate phenotype modulated by atrial conduction and electrophysiology. Their clinical correlates and association with all-cause mortality have received limited scrutiny.
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Parenteral antibiotics reduce bifidobacteria colonization and diversity in neonates.
Int J Microbiol
PUBLISHED: 04-28-2010
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We investigated the impact of parenteral antibiotic treatment in the early neonatal period on the evolution of bifidobacteria in the newborn. Nine babies treated with intravenous ampicillin/gentamicin in the first week of life and nine controls (no antibiotic treatment) were studied. Denaturing gradient gel electrophoresis was used to investigate the composition of Bifidobacterium in stool samples taken at four and eight weeks. Bifidobacteria were detected in all control infants at both four and eight weeks, while only six of nine antibiotic-treated infants had detectable bifidobacteria at four weeks and eight of nine at eight weeks. Moreover, stool samples of controls showed greater diversity of Bifidobacterium spp. compared with antibiotic-treated infants. In conclusion, short-term parenteral antibiotic treatment of neonates causes a disturbance in the expected colonization pattern of bifidobacteria in the first months of life. Further studies are required to probiotic determine if supplementation is necessary in this patient group.
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Lack of association between serum magnesium and the risks of hypertension and cardiovascular disease.
Am. Heart J.
PUBLISHED: 04-08-2010
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Experimental studies have linked hypomagnesemia with the development of vascular dysfunction, hypertension, and atherosclerosis. Prior clinical studies have yielded conflicting results but were limited by the use of self-reported magnesium intake or short follow-up periods.
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Circulating insulin-like growth factor-1 and its binding protein-3: metabolic and genetic correlates in the community.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 04-08-2010
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The metabolic and genetic correlates of circulating insulin-like growth factor-1 (IGF-1) and its main circulating carrier, IGF-1-binding-protein-3 (IGFBP-3), are unclear.
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Clinical and genetic correlates of circulating angiopoietin-2 and soluble Tie-2 in the community.
Circ Cardiovasc Genet
PUBLISHED: 03-26-2010
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Experimental studies suggest that endothelial growth factors play an important role in angiogenesis and vascular remodeling. The clinical and genetic correlates of circulating angiopoietin-2 (Ang-2) and its soluble receptor/regulator Tie-2 (sTie-2) have not been determined in a community-based sample.
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P-wave indices, distribution and quality control assessment (from the Framingham Heart Study).
Ann Noninvasive Electrocardiol
PUBLISHED: 02-12-2010
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P-wave indices of maximum P-wave duration and P-wave dispersion have been examined in a broad array of cardiovascular and noncardiovascular disease states. The P-wave indices literature has been highly heterogeneous in measurement methodologies, described quality control metrics, and distribution of values. We therefore sought to determine the reproducibility of P-wave indices in a community-based cohort.
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Longitudinal tracking of left atrial diameter over the adult life course: Clinical correlates in the community.
Circulation
PUBLISHED: 01-25-2010
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Increased left atrial diameter (LAD) is associated with elevated risk of atrial fibrillation (AF) and cardiovascular disease. Information is limited regarding the short- or long-term correlates of LAD.
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Urethral stricture following high dose rate brachytherapy for prostate cancer.
Radiother Oncol
PUBLISHED: 08-12-2009
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To evaluate the incidence, timing, nature and outcome of urethral strictures following high dose rate brachytherapy (HDRB) for prostate carcinoma.
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Plasma asymmetric dimethylarginine, L-arginine and left ventricular structure and function in a community-based sample.
Atherosclerosis
PUBLISHED: 08-06-2009
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Increasing evidence indicates that cardiac structure and function are modulated by the nitric oxide (NO) system. Elevated plasma concentrations of asymmetric dimethylarginine (ADMA; a competitive inhibitor of NO synthase) have been reported in patients with end-stage renal disease. It is unclear if circulating ADMA and L-arginine levels are related to cardiac structure and function in the general population.
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Plasma leptin levels and incidence of heart failure, cardiovascular disease, and total mortality in elderly individuals.
Diabetes Care
PUBLISHED: 07-30-2009
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Obesity predisposes individuals to congestive heart failure (CHF) and cardiovascular disease (CVD). Leptin regulates energy homeostasis, is elevated in obesity, and influences ventricular and vascular remodeling. We tested the hypothesis that leptin levels are associated with greater risk of CHF, CVD, and mortality in elderly individuals.
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Asymmetric dimethylarginine reference intervals determined with liquid chromatography-tandem mass spectrometry: results from the Framingham offspring cohort.
Clin. Chem.
PUBLISHED: 06-18-2009
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Accumulating evidence links higher circulating asymmetric dimethylarginine (ADMA) to greater risk of cardiovascular disease (CVD). Relatively small differences in ADMA concentrations between healthy individuals and those with disease underscore the need to formulate reference intervals that may aid risk stratification of individuals.
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Longitudinal tracking of left ventricular mass over the adult life course: clinical correlates of short- and long-term change in the framingham offspring study.
Circulation
PUBLISHED: 06-08-2009
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Information is limited on the longitudinal tracking of left ventricular (LV) mass over the adult life course and the determinants of such change.
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Association of the endogenous nitric oxide synthase inhibitor ADMA with carotid artery intimal media thickness in the Framingham Heart Study offspring cohort.
Stroke
PUBLISHED: 06-04-2009
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Higher plasma concentrations of the endogenous nitric oxides synthase inhibitor asymmetrical dimethylarginine (ADMA) are associated with increased risk of cardiovascular and cerebrovascular events and death, presumably by promoting endothelial dysfunction and subclinical atherosclerosis. We hypothesized that plasma ADMA concentrations are positively related to common carotid artery intimal-media thickness (CCA-IMT) and to internal carotid (ICA)/bulb IMT.
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The association of tumor necrosis factor alpha receptor 2 and tumor necrosis factor alpha with insulin resistance and the influence of adipose tissue biomarkers in humans.
Metab. Clin. Exp.
PUBLISHED: 05-06-2009
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Tumor necrosis factor alpha (TNFalpha) is a proinflammatory adipokine hypothesized to link obesity with insulin resistance. Functional studies suggest that TNFalpha acts through pathways involving adipokines and fatty acids to induce insulin resistance. We tested the hypothesis that the association of measures of TNFalpha activity with insulin resistance is independent of obesity and adipose tissue biomarkers. We analyzed data from 2131 participants (without diabetes) of the Framingham Offspring Study examination 7. The outcome of interest was insulin resistance, measured using the homeostasis model assessment (HOMA-IR). Tumor necrosis factor alpha activity was measured by plasma tumor necrosis factor alpha receptor 2 (TNFr2) or TNFalpha; possible confounders included adipose tissue biomarkers (plasma adiponectin, resistin, and triglycerides). We used multivariable age- and sex-adjusted linear regression analyses to adjust for waist circumference and for biomarkers individually and simultaneously, and in biomarker-stratified (above and below median) models. We found that TNFr2 was positively associated with HOMA-IR (r = 0.21, P < .0001). In age- and sex-adjusted model, for each increase of 1 standard deviation of TNFr2 (SD = 746 pg/mL), the log (HOMA-IR) value was increased by 0.11 units (P < .0001). Adjustment for waist circumference reduced the TNFr2 beta-coefficient (by about 45%), but the association between TNFr2 and HOMA-IR remained significant (P < .0001). Tumor necrosis factor alpha receptor 2 was still associated to HOMA-IR after adding adiponectin, resistin, and triglycerides (individually and simultaneously). We found similar associations with plasma levels of TNFalpha. We conclude that, in a representative community sample, measures of TNFalpha activity are associated with insulin resistance, even after accounting for central adiposity and other adipose tissue biomarkers.
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A parallel and distributed-processing model of joint attention, social cognition and autism.
Autism Res
PUBLISHED: 04-10-2009
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The impaired development of joint attention is a cardinal feature of autism. Therefore, understanding the nature of joint attention is central to research on this disorder. Joint attention may be best defined in terms of an information-processing system that begins to develop by 4-6 months of age. This system integrates the parallel processing of internal information about ones own visual attention with external information about the visual attention of other people. This type of joint encoding of information about self and other attention requires the activation of a distributed anterior and posterior cortical attention network. Genetic regulation, in conjunction with self-organizing behavioral activity, guides the development of functional connectivity in this network. With practice in infancy the joint processing of self-other attention becomes automatically engaged as an executive function. It can be argued that this executive joint attention is fundamental to human learning as well as the development of symbolic thought, social cognition and social competence throughout the life span. One advantage of this parallel and distributed-processing model of joint attention is that it directly connects theory on social pathology to a range of phenomena in autism associated with neural connectivity, constructivist and connectionist models of cognitive development, early intervention, activity-dependent gene expression and atypical ocular motor control.
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Cross channel infections: nostalgia, spleen and the construction of national character.
Endeavour
PUBLISHED: 03-31-2009
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In the nineteenth century, both spleen and nostalgia were considered clinical categories, and each associated with the character of a nation. English medical commentators boasted of their compatriots resistance to nostalgia, an often fatal form of homesickness, while the French in turn argued that the splenetic English were flocking to France to escape their own insalubrious climate. Behind such jingoistic claims were broader concerns, on both sides of the channel but particularly acute for the French, about the impact of modernity on subjectivity, the relation between home, homeland and empire, and the fitness of both nations to succeed in the modern age.
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Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community.
Circulation
PUBLISHED: 03-16-2009
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Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, induces endothelial dysfunction. Although elevated ADMA has been associated with an increased risk of cardiovascular disease events and death in referral samples, the prognostic significance of ADMA in the community has not been adequately evaluated.
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Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study.
Lancet
PUBLISHED: 03-03-2009
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Atrial fibrillation contributes to substantial increases in morbidity and mortality. We aimed to develop a risk score to predict individuals absolute risk of developing the condition, and to provide a framework for researchers to assess new risk markers.
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Vascular endothelial growth factor, its soluble receptor, and hepatocyte growth factor: clinical and genetic correlates and association with vascular function.
Eur. Heart J.
PUBLISHED: 02-17-2009
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Growth factors play an important role in regulating vascular function. Data are limited regarding clinical and genetic correlates of endothelial growth factors and their associations with vascular function.
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Relation of serum leptin with cardiac mass and left atrial dimension in individuals >70 years of age.
Am. J. Cardiol.
PUBLISHED: 01-19-2009
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Experimental evidence indicates that leptin-deficient animals develop left ventricular (LV) hypertrophy, but data relating circulating leptin levels to cardiac structure and function in subjects >70 years old are lacking. We related circulating leptin concentrations to echocardiographic measurements of cardiac structure and function in 432 participants of the community-based Framingham Heart Study (mean age 75 years, 67% women) who underwent echocardiography at a routine examination (approximately 4 years before leptin concentrations were assayed). In multivariable linear regression, logarithmically transformed gender-standardized leptin concentrations were related to the following echocardiographic measurements: LV mass, left atrial size, and fractional shortening (primary analysis); LV wall thickness and LV end-diastolic dimensions (the 2 components of LV mass); and transmitral early/late diastolic filling velocities (secondary analysis). Leptin concentrations were inversely associated with LV mass, LV wall thickness, and left atrial size (p <0.04 for all). The top gender-specific tertile of leptin was associated with an adjusted LV mass 16 g lower compared with the lowest tertile (p = 0.007 for trend across tertiles). Leptin levels were not associated with LV fractional shortening, transmitral early/late diastolic filling velocities, or LV end-diastolic diameter (p >0.16). In conclusion, our cross-sectional observations suggest a cardioprotective influence of leptin on LV remodeling consistent with experimental data and may provide insight into the potential role of leptin resistance as a mediator of obesity-associated cardiomyopathy.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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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.