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Find video protocols related to scientific articles indexed in Pubmed.
Design and synthesis of ultrasensitive off-on fluoride detecting fluorescence probe via autoinductive signal amplification.
Analyst
PUBLISHED: 11-20-2014
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We prepared an off-on fluorometric probe, DPF1, by incorporating the concept of autoinductive signal amplification into its molecular design. In the presence of fluoride, DPF1 undergoes a cascade of self-immolative reactions concomitant with unmasking fluorogenic coumarin, which results in the ejection of two fluoride ions. These fluoride ions are continuously activating the cascade reaction and accumulating coumarins, which leads to exponentially amplifying the signal with high sensitivity. The fluorescence signal generated by this cascade reaction is rapid, specific and insensitive to other anions. Its limit of detection was 0.5 pM, considerably lower than other current methods of fluoride detection. In addition, DCC, a long wavelength fluorometric probe, was prepared. Interestingly, an assay platform coupling DPF1 and DCC showed an outstanding sensing ability at higher wavelengths, suggesting that this can be a promising method for the sensitive and selective detection of fluoride in biological samples. The practical applicability of the proposed approach has been demonstrated in urine and water samples.
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Increased prevalence of JC polyomavirus viruria was associated with arthritis/arthralgia in patients with systemic lupus erythematosus.
Lupus
PUBLISHED: 11-20-2014
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The objective of this paper is to investigate the prevalence of reactivation of the human polyomavirus John Cunningham virus (JCV) in patients with systemic lupus erythematosus (SLE) and its associated clinical manifestations.
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Distinct aetiopathogenesis in subgroups of functional dyspepsia according to the Rome III criteria.
Gut
PUBLISHED: 11-20-2014
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Whether there is distinct pathogenesis in subgroups of functional dyspepsia (FD), the postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) remains controversial. We aimed to identify the risk factors of FD and its subgroups in the Chinese population.
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Tandem DEDs and CARDs suggest novel mechanisms of signaling complex assembly.
Apoptosis
PUBLISHED: 11-16-2014
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Apoptosis is an important process to maintain cellular homeostasis. Deregulated apoptosis has linked to a number of diseases, such as inflammatory diseases, neurodegenerative disorder, and cancers. A major signaling complex in the death receptor signaling pathway leading to apoptosis is death-induced signaling complex (DISC), which is regulated mainly by death effector domain (DED)-containing proteins. There are seven DED-containing proteins in human, including FADD, c-FLIP, caspase-8, caspase-10, DEDD, DEDD2, and PEA-15. The main players in DISC formation employ tandem DEDs for regulating signaling complex formation. The regulatory mechanism of signaling complex formation is important and yet remains unclear. Interestingly, three caspase recruitment domain (CARD)-containing members, which belong to the same DD superfamily as DED-containing proteins, also contains similar tandem CARDs. Recent structural studies have shown that tandem CARDs are essential for the formation of a helical signaling complex. This review summarizes recent structural studies on DED-containing proteins and especially discusses the studies on tandem DEDs and tandem CARDs, which suggest new mechanisms of signaling complex assembly.
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Maternal Citrulline Supplementation Prevents Prenatal NG-Nitro-L-Arginine-Methyl ester (L-NAME)-Induced Programmed Hypertension in Rats.
Biol. Reprod.
PUBLISHED: 11-15-2014
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Nitric oxide (NO) deficiency induced by the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine-methyl ester (L-NAME) resulted in hypertension. L-citrulline (CIT) can be converted to L-arginine to generate NO. We examined whether maternal CIT supplementation can prevent L-NAME-induced programmed hypertension. Pregnant Sprague-Dawley rats were assigned to four groups: control, L-NAME, control + citrulline (CIT), and L-NAME + citrulline (L-NAME+CIT). Pregnant rats received L-NAME administration at 60 mg/kg per day subcutaneously during pregnancy alone or with additional 0.25% L-citrulline solution in drinking water during the whole period of pregnancy and lactation. Male offspring were sacrificed at 12 wk of age. L-NAME exposure during pregnancy induces hypertension in the 12-wk-old offspring. Maternal CIT therapy prevented L-NAME-induced programmed hypertension, which was associated with decreased asymmetric dimethylarginine (ADMA) concentration and increased L-arginine-to-ADMA ratio in the kidney, increased urinary cGMP levels, and decreased renal protein levels of type 3 sodium hydrogen exchanger (NHE3). Together, our data suggests that the beneficial effects of CIT supplementation are attributed to its ability to increase NO level in the kidney, and inhibition of NHE3 expression. Our results suggest that supplementing CIT to pregnant women with NO deficiency can improve fetal development and prevent programmed hypertension.
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Hyperactive Human Glucocorticoid Receptor Isoforms and Their Implications for the Stress Response.
Shock
PUBLISHED: 11-14-2014
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Glucocorticoids are indispensable therapeutic agents in diseases of inflammation, but their effectiveness in treating advanced septic shock has been inconsistent. Our understanding of the mechanisms causing this variability to steroid therapy remains limited. Previous studies in our laboratory have implicated human glucocorticoid receptor (hGR) polymorphisms as one of the likely reasons for this variability. We examined the effect of two single nucleotide polymorphisms (SNPs) on the transactivation potential of the hGR in the absence and presence of exogenous steroids. An isoform containing a novel naturally-occurring human SNP, T1463C, was found to have a hyperactive response with treatment of all three steroids examined, while maintaining low activity in the absence of steroids, relative to reference hGR. In comparison, another hGR isoform with the A2297G SNP, previously identified in our laboratory, demonstrated hyperactive transactivational response in the absence of steroids, however, it had a significant increase in activity after treatment with only one of the glucocorticoids (hydrocortisone) tested. These results offer a possible explanation for the clinical variability seen amongst individuals in response to stress or shock.
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Quality of life comparing dor and toupet after heller myotomy for achalasia.
JSLS
PUBLISHED: 11-14-2014
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Laparoscopic Heller cardiomyotomy (LHC) is standard therapy for achalasia. Traditionally, an antireflux procedure has accompanied the myotomy. This study was undertaken to compare quality-of-life outcomes between patients undergoing myotomy with Toupet versus Dor fundoplication. In addition, we investigated overall patient satisfaction after LHC in the treatment of achalasia.
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Advanced Hepatic Fibrosis and Steatosis Are Associated with Persistently Alanine Aminotransferase Elevation in Chronic Hepatitis C Patients Negative for HCV RNA During Pegylated Interferon Plus Ribavirin Therapy.
J. Infect. Dis.
PUBLISHED: 11-13-2014
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?Clinical implications of persistently alanine aminotransferase (ALT) elevation and associated factors in chronic hepatitis C (CHC) patients who achieved undetectable hepatitis C virus (HCV) RNA during pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy remain unknown.
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Conjugation of Monocarboxybetaine Molecules on Amino-Poly-p-xylylene Films to Reduce Protein Adsorption and Cell Adhesion.
Langmuir
PUBLISHED: 11-08-2014
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A surface that resists protein adsorption and cell adhesion is highly desirable for many biomedical applications such as blood-contact devices and biosensors. In this study, we fabricated a carboxybetaine-containing surface and evaluated its antifouling efficacy. First, an amine-containing substrate was created by chemical vapor deposition of 4-aminomethyl-p-xylylene-co-p-xylylene (Amino-PPX). Aldehyde-ended carboxybetaine molecules were synthesized and conjugated onto Amino-PPX. The carboxybetaine-PPX surface greatly reduced protein adsorption and cell adhesion. The attachment of L929 cells on the carboxybetaine-PPX surface was reduced by 87% compared to the cell adhesion on Amino-PPX. Furthermore, RGD peptides could be conjugated on carboxybetaine-PPX to mediate specific cell adhesion. In conclusion, we demonstrate that a surface decoration with monocarboxybetaine molecules is useful for antifouling applications.
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Clinical significance of pathological complete response in patients with metastatic gastrointestinal stromal tumors after imatinib mesylate treatment - lessons learned.
Anticancer Res.
PUBLISHED: 11-05-2014
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Imatinib mesylate (IM) has substantial efficacy in patients with metastatic gastrointestinal stromal tumors (GISTs), and pathological complete response (pCR) following IM treatment has been sporadically reported; however, its clinical significance for GIST needs to be clarified.
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Serum Biomarkers Predictive of Significant Fibrosis and Cirrhosis in Chronic Hepatitis B.
J. Clin. Gastroenterol.
PUBLISHED: 10-17-2014
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Aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 index are noninvasive biomarkers to evaluate hepatic fibrosis. However, their usefulness in chronic hepatitis B (CHB) patients remains unclear.
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Structural and functional characterization of ybr137wp implicates its involvement in the targeting of tail-anchored proteins to membranes.
Mol. Cell. Biol.
PUBLISHED: 10-06-2014
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Nearly 5% of membrane proteins are guided to nuclear, endoplasmic reticulum (ER), mitochondrial, Golgi, or peroxisome membranes by their C-terminal transmembrane domain and are classified as tail-anchored (TA) membrane proteins. In Saccharomyces cerevisiae, the guided entry of TA protein (GET) pathway has been shown to function in the delivery of TA proteins to the ER. The sorting complex for this pathway is comprised of Sgt2, Get4, and Get5 and facilitates the loading of nascent tail-anchored proteins onto the Get3 ATPase. Multiple pulldown assays also indicated that Ybr137wp associates with this complex in vivo. Here, we report a 2.8-Å-resolution crystal structure for Ybr137wp from Saccharomyces cerevisiae. The protein is a decamer in the crystal and also in solution, as observed by size exclusion chromatography and analytical ultracentrifugation. In addition, isothermal titration calorimetry indicated that the C-terminal acidic motif of Ybr137wp interacts with the tetratricopeptide repeat (TPR) domain of Sgt2. Moreover, an in vivo study demonstrated that Ybr137wp is induced in yeast exiting the log phase and ameliorates the defect of TA protein delivery and cell viability derived by the impaired GET system under starvation conditions. Therefore, this study suggests a possible role for Ybr137wp related to targeting of tail-anchored proteins.
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Early failure of the Biotronik Linox implantable cardioverter defibrillator lead.
J. Cardiovasc. Electrophysiol.
PUBLISHED: 10-03-2014
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The Linox and Durata implantable cardioverter defibrillator (ICD) leads were introduced to British Columbia (BC) in 2008. We determined their performance and the potential risk factors for lead failure in a large population-based patient registry.
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Fractioned dose regimen of sunitinib for patients with gastrointestinal stromal tumor: a pharmacokinetic and treatment efficacy study.
Transl Oncol
PUBLISHED: 10-01-2014
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Sunitinib has shown benefit in patients with imatinib (IM)-resistant gastrointestinal stromal tumor (GIST). However, its advantages are somewhat diminished because of associated toxicities. Herein, we clarify the efficacy and safety of fractioned dose regimen of sunitinib by a pharmacokinetic and efficacy study.
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G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases A?42/A?40 Ratio and Elevates ER Ca(2+) Accumulation.
Mol. Neurobiol.
PUBLISHED: 09-24-2014
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Early-onset familial Alzheimer's disease (AD) is most commonly associated with the mutations in presenilin-1 (PS1). PS1 is the catalytic component of the ?-secretase complex, which cleaves amyloid precursor protein to produce amyloid-? (A?), the major cause of AD. Presenilin enhancer 2 (Pen2) is critical for activating ?-secretase and exporting PS1 from endoplasmic reticulum (ER). Among all the familial AD-linked PS1 mutations, mutations at the G206 amino acid are the most adjacent position to the Pen2 binding site. Here, we characterized the effect of a familial AD-linked PS1 G206D mutation on the PS1-Pen2 interaction and the accompanied alteration in ?-secretase-dependent and -independent functions. We found that the G206D mutation reduced PS1-Pen2 interaction, but did not abolish ?-secretase formation and PS1 endoproteolysis. For ?-secretase-dependent function, the G206D mutation increased A?42 production but not Notch cleavage. For ?-secretase-independent function, this mutation disrupted the ER calcium homeostasis but not lysosomal calcium homeostasis and autophagosome maturation. Impaired ER calcium homeostasis may due to the reduced mutant PS1 level in the ER. Although this mutation did not alter the cell survival under stress, both increased A?42 ratio and disturbed ER calcium regulation could be the mechanisms underlying the pathogenesis of the familial AD-linked PS1 G206D mutation.
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Improving clinical outcomes of chronic hepatitis B virus infection.
Expert Rev Gastroenterol Hepatol
PUBLISHED: 09-23-2014
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Chronic hepatitis B virus (HBV) infection is a global health problem, leading to cirrhosis, hepatocellular carcinoma (HCC) and liver-related deaths. Universal hepatitis B vaccination is the most cost-effective way to eradicate HBV infection with the remarkable reduction of chronic carriage, neonatal fulminant hepatitis and childhood HCC. The introduction of highly effective antiviral agents, including lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir disoproxil fumarate and pegylated interferons further improve short-, medium- and long-term outcomes of chronic HBV infection, such as ALT normalization, HBV DNA suppression, HBeAg seroconversion, HBsAg seroclearance, fibrosis regression, reduction of cirrhosis, HCC, liver-related deaths and the need for liver transplantation. Above all, sustained and profound viral suppression is the key to improve the clinical outcomes of chronic hepatitis B.
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Imatinib escalation or sunitinib treatment after first-line imatinib in metastatic gastrointestinal stromal tumor patients.
Anticancer Res.
PUBLISHED: 09-10-2014
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Imatinib mesylate (IM) is effective in metastatic gastrointestinal stromal tumor (GIST) patients; however, disease progression eventually occurs due to IM resistance or intolerance. Treatment options include IM escalation or a direct shift to sunitinib, but comparison of these strategies is required.
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Diatomological investigation in sphenoid sinus fluid and lung tissue from cases of suspected drowning.
Forensic Sci. Int.
PUBLISHED: 08-20-2014
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We report on the presence, distribution and numbers of diatoms within specific organs as a result of drowning in fresh, treated and seawater. Specimens of sphenoid sinus fluid and lung tissue from 100 cases of suspected drowning and 20 cases where death was by natural causes, to act as a control, were examined for the presence of diatoms. In the 100 cases where the deceased was suspected to have drowned, 94 were confirmed as a death by drowning after autopsy with the other six being reported as death by another cause. No diatoms were found in cases confirmed as death by causes unrelated to drowning, with the exception of possible contamination via open wounds and through decomposition. In 94 cases, where all fatalities were confirmed as death by drowning, there were 81 cases in which diatoms were detected in samples taken from the sphenoid sinus fluid and/or lung tissue. No, or only few, diatoms were observed from the samples where the deceased drowned in treated waters such as spa or swimming pools. A significantly higher number of diatoms were detected in the sphenoid sinus fluid and lung tissue of confirmed drowning cases in fresh water compared to seawater. More diatoms were observed in sphenoid sinus fluid compared to lung tissue regardless of the water in which the deceased drowned. This study illustrates the potential use of diatom screening using both sphenoid sinus fluid and lung tissue to determine the cause of death in suspected cases of drowning. This report also highlights specific variables that need to be considered prior to such as conclusion being reached.
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Metformin reduces asymmetric dimethylarginine and prevents hypertension in spontaneously hypertensive rats.
Transl Res
PUBLISHED: 08-07-2014
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Elevated asymmetric dimethylarginine (ADMA) levels and nitric oxide (NO) deficiency are associated with the development of hypertension. Metformin, an antidiabetic agent, is a structural analog of ADMA. We examined whether metformin can prevent the development of hypertension in spontaneously hypertensive rats (SHRs) by restoration of ADMA-NO balance. SHRs and control normotensive Wistar-Kyoto (WKY) rats were assigned to 4 groups (N = 8 for each group): untreated SHRs and WKY rats, metformin-treated SHRs and WKY rats. Metformin-treated rats received metformin 500 mg/kg per day via oral gavage for 8 weeks. All rats were sacrificed at the age of 12 weeks. We found an increase in the blood pressure of SHRs was prevented by metformin. ADMA levels in the plasma and lung were elevated in SHRs, which metformin prevented. Lung dimethylarginine dimethylaminohydrolase (DDAH, ADMA-metabolizing enzyme) activity was lower in SHRs than WKY rats. Next, metformin had no effect on protein arginine methyltransferase 1 (ADMA-synthesizing enzyme), DDAH-1, DDAH-2, NO synthase enzymes, and DDAH activity in the kidney. Moreover, metformin increased the levels of NO in kidney. Conclusively, the observed antihypertensive effect of metformin in SHRs is because of the restoration of the ADMA-NO pathway. Our findings support the consideration of metformin as an antihypertensive agent for diabetic patients with prehypertension.
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Transcriptional Regulation of Programmed Hypertension by Melatonin: An Epigenetic Perspective.
Int J Mol Sci
PUBLISHED: 07-13-2014
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Melatonin is an endogenously produced indoleamine and secreted by the pineal gland. Melatonin has pleiotropic bioactivities and is involved in epigenetic regulation. Suboptimal conditions during maternal and perinatal phases can elicit epigenetic regulation of genes for nephrogenesis and reset physiological responses to develop programmed hypertension. This review discusses the early utility of melatonin to prevent programmed hypertension in later life by epigenetic regulation in the kidney, with an emphasis on: (1) the role of melatonin in epigenetic regulation; (2) the beneficial effects of melatonin on programmed hypertension; (3) epigenetic regulation of maternal melatonin therapy in different developmental windows of offspring kidneys analyzed by whole-genome RNA next-generation sequencing; and (4) current blocks in the application of melatonin in preventing programmed hypertension.
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Hyperplastic polyps identified during screening endoscopy: reevaluated by histological examinations and genetic alterations.
J. Formos. Med. Assoc.
PUBLISHED: 06-26-2014
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Screening colonoscopy is one of the most effective methods to detect and prevent colorectal cancer by removing neoplastic polyps. The recent discovery of serrated polyps with neoplastic potential has reclassified these polyps into hyperplastic polyps (HPs), sessile serrated adenoma (SSA), and traditional serrated adenoma (TSA) on the basis of macroscopic morphology and microscopic histology. In this study, we aimed to revisit HPs identified during screening endoscopy by histological reevaluation and genetic alterations.
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Identification of aurora kinase A as an unfavorable prognostic factor and potential treatment target for metastatic gastrointestinal stromal tumors.
Oncotarget
PUBLISHED: 06-06-2014
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Although imatinib mesylate (IM) has revolutionized the management of gastrointestinal stromal tumors (GISTs), drug resistance remains a challenge. Previous studies have shown that the expression of aurora kinase A (AURKA) predicts recurrence in patients with primary, surgically resected GISTs. The current study aimed to evaluate the significance of AURKA expression as an unfavorable prognostic marker for advanced GISTs, and provide evidence that AURKA could be a potential therapeutic target in GISTs. The prognostic significance of the expression of AURKA, along with other clinicopathological factors, was analyzed in a cohort of 99 IM-treated patients with advanced GISTs. The potential use of an inhibitor of AURKA as a therapeutic agent against GISTs was also tested in GIST cell lines. Among 99 enrolled patients, poor performance status, large tumor size, drug response, and AURKA overexpression were independent prognostic factors for poor progression-free survival (PFS). For overall survival (OS), only large tumor size and AURKA overexpression were identified as independent unfavorable factors. In an in vitro study, MLN8237, an AURKA inhibitor, inhibited growth of both IM-sensitive and IM-resistant GIST cells in a concentration-dependent manner, and exhibited synergistic cytotoxicity with IM in GIST cells. The inhibitory effect of MLN8237 in GIST cells could be attributed to the induction of G2/M arrest, apoptosis, and senescence. Our study shows that AURKA expression independently predicted poor PFS and OS in patients with advanced GISTs who were treated with IM. An AURKA inhibitor may have potential as a therapeutic agent for both IM-sensitive and IM-resistant GISTs.
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Neoadjuvant bevacizumab and chemoradiotherapy in locally advanced rectal cancer: early outcome and technical impact on toxicity.
World J Surg Oncol
PUBLISHED: 06-05-2014
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We aimed to evaluate early clinical and pathological results for treating locally advanced rectal cancer with bevacizumab and neoadjuvant concurrent chemoradiotherapy using the technique of prone-position volumetric modulated arc therapy and to compare the toxicity of volumetric modulated arc therapy with that of supine-position four-field box radiotherapy.
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Electrochemical OFF-ON ratiometric chemodosimeters for the selective and rapid detection of fluoride.
Talanta
PUBLISHED: 05-27-2014
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We have described two "OFF-ON electrochemical latent ratiometric redox chemodosimeters", 1,4-Bis(tert-butyldimethylsiloxy)benzene (H2Q') and 1,4-Bis (tert-butyldimet hylsiloxy)-2-methoxybenzene (MH2Q') for the selective detection of inorganic fluoride. The electrochemical signals of hydroquinone (H2Q) and o-methoxy hydroquinone (MH2Q) within this latent redox probes (H2Q' and MH2Q') were completely masked by protecting their hydroxyl group as silylether (OFF state). The externally added fluoride ions triggered the deprotection of H2Q' and MH2Q' and unmasked the electrochemical properties of H2Q and MH2Q respectively. The electrochemical reporters (H2Q and MH2Q) presented a pair of redox peaks at the electrode surface (ON state) and the peak currents are linearly dependent with the concentration of fluoride which leading to the ratiometric detection of fluoride. The limit of detection (signal-to-noise ratio=3) observed for the probes are 23.8 µM and 2.38 µM for H2Q' and MH2Q' respectively. The deprotection is highly selective for fluoride over other anions investigated. The probes are highly stable and the proposed approach offers rapid response time and promising practical applicability. The proposed strategy holds great promise for the commencement of new H2Q based electrochemical probes by tuning the electrochemical behavior of H2Q.
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Restoration of asymmetric dimethylarginine-nitric oxide balance to prevent the development of hypertension.
Int J Mol Sci
PUBLISHED: 05-27-2014
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Despite the use of extensive antihypertensive therapy in patients with hypertension, little attention has been paid to early identification and intervention of individuals at risk for developing hypertension. The imbalance between nitric oxide (NO) and reactive oxygen species (ROS) resulting in oxidative stress has been implicated in the pathophysiology of hypertension. NO deficiency can precede the development of hypertension. Asymmetric dimethylarginine (ADMA) can inhibit nitric oxide synthase (NOS) and regulate local NO/ROS balance. Emerging evidence supports the hypothesis that ADMA-induced NO-ROS imbalance is involved in the development and progression of hypertension. Thus, this review summarizes recent experimental approaches to restore ADMA-NO balance in order to prevent the development of hypertension. Since hypertension might originate in early life, we also discuss the putative role of the ADMA-NO pathway in programmed hypertension. Better understanding of manipulations of the ADMA-NO pathway prior to hypertension in favor of NO will pave the way for the development of more effective medicine for the treatment prehypertension and programmed hypertension. However, more studies are needed to confirm the clinical benefit of these interventions.
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Aliskiren in early postnatal life prevents hypertension and reduces asymmetric dimethylarginine in offspring exposed to maternal caloric restriction.
J Renin Angiotensin Aldosterone Syst
PUBLISHED: 05-15-2014
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Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is involved in hypertension. We tested whether aliskiren treatment in early postnatal life can reduce ADMA and regulate the renin-angiotensin system to prevent hypertension in rat offspring exposed to maternal caloric restriction (CR).
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Melatonin prevents neonatal dexamethasone induced programmed hypertension: Histone deacetylase inhibition.
J. Steroid Biochem. Mol. Biol.
PUBLISHED: 05-11-2014
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Adulthood hypertension can be programmed by corticosteroid exposure in early life. Oxidative stress, epigenetic regulation by histone deacetylases (HDACs), and alterations of renin-angiotensin system (RAS) are involved in the developmental programming of hypertension. We examined whether melatonin prevented neonatal dexamethasone (DEX)-induced programmed hypertension and how melatonin prevented these processes. We also examined whether HDAC inhibition by trichostatin A (TSA, a HDAC inhibitor) had similar effects. Male offspring were assigned to 5 groups (n=6/group): control, DEX, melatonin, DEX+melatonin, and DEX+TSA. Male rat pups were injected i.p. with DEX on day 1 (0.5mg/kg BW), day 2 (0.3mg/kg BW), and day 3 (0.1mg/kg BW) after birth. Melatonin was administered in drinking water at the dose of 0.01% during the lactation period. The DEX+TSA group received DEX and 0.5mg/kg TSA subcutaneous injection once daily for 1 week. All rats were killed at 16 weeks of age. Neonatal DEX exposure induced hypertension in male offspring at 16 weeks of age, which melatonin prevented. Neonatal DEX exposure decreased gene expression related to apoptosis, nephrogenesis, RAS, and sodium transporters. Yet DEX treatment increased protein levels of HDAC-1, -2, and -3 in the kidney. Melatonin therapy preserved the decreases of gene expression and decreased HDACs. Similarly, HDAC inhibition prevented DEX-induced programmed hypertension. In conclusion, melatonin therapy exerts a long-term protection against neonatal DEX-induced programmed hypertension. Its beneficial effects include alterations of RAS components and inhibition of class I HDACs. Given that the similar protective effects of melatonin and TSA, melatonin might inhibit HDACs to epigenetic regulation of hypertension-related genes to prevent programmed hypertension.
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Pain relief from combined wound and intraperitoneal local anesthesia for patients who undergo laparoscopic cholecystectomy.
BMC Surg
PUBLISHED: 05-08-2014
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Laparoscopic cholecystectomy (LC) has become the treatment of choice for gallbladder lesions, but it is not a pain-free procedure. This study explored the pain relief provided by combined wound and intraperitoneal local anesthetic use for patients who are undergoing LC.
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Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma.
Oncotarget
PUBLISHED: 05-07-2014
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The PI3K/Akt/mTOR pathway is overactivated and heat shock protein (HSP) 90 is overexpressed in common cancers. We hypothesized that targeting both pathways can kill intrahepatic cholangiocarcinoma (CCA) cells. HSP90 and PTEN protein expression was evaluated by immunohistochemical staining of samples from 78 patients with intrahepatic CCA. CCA cell lines and a thioacetamide (TAA)-induced CCA animal model were treated with NVP-AUY922 (an HSP90 inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) alone or in combination. Both HSP90 overexpression and loss of PTEN were poor prognostic factors in patients with intrahepatic CCA. The combination of the HSP90 inhibitor NVP-AUY922 and the PI3K/mTOR inhibitor NVP-BEZ235 was synergistic in inducing cell death in CCA cells. A combination of NVP-AUY922 and NVP-BEZ235 caused tumor regression in CCA rat animal model. This combination not only inhibited the PI3K/Akt/mTOR pathway but also induced ROS, which may exacerbate the vicious cycle of ER stress. Our data suggest simultaneous targeting of the PI3K/mTOR and HSP pathways for CCA treatment.
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Molecular mechanism and treatment of viral hepatitis-related liver fibrosis.
Int J Mol Sci
PUBLISHED: 05-04-2014
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Hepatic fibrosis is a wound-healing response to various chronic stimuli, including viral hepatitis B or C infection. Activated myofibroblasts, predominantly derived from the hepatic stellate cells (HSCs), regulate the balance between matrix metalloproteinases and their tissue inhibitors to maintain extracellular matrix homeostasis. Transforming growth factor-? and platelet-derived growth factor are classic profibrogenic signals that activate HSC proliferation. In addition, proinflammatory cytokines and chemokines coordinate macrophages, T cells, NK/NKT cells, and liver sinusoidal endothelial cells in complex fibrogenic and regression processes. In addition, fibrogenesis involves angiogenesis, metabolic reprogramming, autophagy, microRNA, and epigenetic regulations. Hepatic inflammation is the driving force behind liver fibrosis; however, host single nucleotide polymorphisms and viral factors, including the genotype, viral load, viral mutation, and viral proteins, have been associated with fibrosis progression. Eliminating the underlying etiology is the most crucial antifibrotic therapy. Growing evidence has indicated that persistent viral suppression with antiviral therapy can result in fibrosis regression, reduced liver disease progression, decreased hepatocellular carcinoma, and improved chances of survival. Preclinical studies and clinical trials are currently examining several investigational agents that target key fibrogenic pathways; the results are promising and shed light on this debilitating illness.
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Formyl Peptide receptor 1 expression is associated with tumor progression and survival in gastric cancer.
Anticancer Res.
PUBLISHED: 04-30-2014
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Formyl peptide receptor 1 (FPR1) as a regulator of innate inflammatory response has been implicated in tumor progression of gliomas. The purpose of the present study was to evaluate the prognostic significance and the ligand-receptor interaction of FPR1 in gastric cancer (GC).
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Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers.
Gut
PUBLISHED: 04-26-2014
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Precore (PC) variant (G1896A) and basal core promoter (BCP) variant (A1762T/G1764A) of HBV are associated with risk of hepatocellular carcinoma in HBV carriers. However, little is known about their impact on the adverse outcomes of hepatitis B e antigen (HBeAg)-negative hepatitis and liver cirrhosis.
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A comparative study of three-year weight loss and outcomes after laparoscopic gastric bypass in patients with "yellow light" psychological clearance.
Obes Surg
PUBLISHED: 04-25-2014
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The relationship between psychological factors and bariatric surgical outcomes is unclear. While some psychological contraindications to bariatric surgery are described, there is no consensus on preoperative psychological evaluation or on factors that can predict bariatric outcomes. Our aim was to determine whether full or reserved psychological clearance predicts early weight loss or compliance with follow-up. We found no clinically significant differences in short-term weight loss outcomes or in attendance at scheduled follow-up visits between patients receiving full or "green light" clearance versus "yellow light" clearance, meaning clearance with recommendations for ongoing therapy. Further research may identify psychological predictors of success following bariatric surgery and help optimize preoperative evaluation practices.
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Peginterferon alfa-2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 2 receiving haemodialysis: a randomised trial.
Gut
PUBLISHED: 04-22-2014
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Data comparing the efficacy and safety of combination therapy with peginterferon plus low-dose ribavirin and peginterferon monotherapy in treatment-naive haemodialysis patients with hepatitis C virus genotype 2 (HCV-2) infection are limited.
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Fatal falls from height in Taiwan.
J. Forensic Sci.
PUBLISHED: 04-16-2014
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This study conducts an investigation of fatal falls from height, examines gender differences, and compares our findings with those of Western countries. We review deaths in Taiwan caused by falls from height that underwent forensic autopsy from 1994 to 2010. Among the examined cases, 182 were suicide, 156 were accidents, and 18 were homicides. Men who fell from greater heights had a lower probability of fatal head trauma (p = 0.045), and women exhibited a lower fatal head trauma rate when falling from heights of between 10 and 25 m in accident group (p = 0.003). There was no significant difference between cases of falling from greater and lower heights within the suicide group (p = 0.834). Psychiatric illness was only reported in 20.3% and 28.8% cases in suicide and accident groups. Only in male cases was the use of psychotropic substances higher in the suicide groups than in the accident groups (p = 0.047).
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Fas/Fas ligand mediates keratinocyte death in sunitinib-induced hand-foot skin reaction.
J. Invest. Dermatol.
PUBLISHED: 03-24-2014
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Sunitinib, a multitargeted receptor Y kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and gastrointestinal stromal tumor (GIST), is notorious for cutaneous adverse effects, such as hand-foot skin reaction (HFSR). To explore the underlying mechanism of HFSR, we enrolled 53 sunitinib-treated GIST patients, including 23 HFSR cases, and 30 tolerant controls. Among the 29 biomarkers examined, soluble FasL (sFasL) showed significant increase in the plasma, blister fluids, and skin lesions of HFSR patients. The plasma levels of sFasL were significantly correlated with those of sunitinib in HFSR patients. In addition to FasL, augmented expression of Fas and active caspase 3 was also detected in the epidermis of HFSR patients. The increased FasL caused keratinocyte death, as the use of anti-FasL antibody specifically blocked cell apoptosis. Oral administration of sunitinib to mice increased skin susceptibility to mechanical injuries in a dose/time-dependent manner. The administration of sunitinib (40?mg?kg(-1) per day) for 4 weeks to mice caused the maximally affected skin area with an erosion-to-ulceration response to tape-stripping. The skin biopsies of mice administered sunitinib exhibited increased expression of Fas and FasL in the apoptotic keratinocytes in the epidermis. Our data revealed that Fas/FasL interaction mediates keratinocyte death in sunitinib-induced HFSR.
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L-Arginine modulates neonatal lymphocyte proliferation through an interleukin-2 independent pathway.
Immunology
PUBLISHED: 03-23-2014
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In cases of arginine depletion, lymphocyte proliferation, cytokine production and CD3? chain expression are all diminished. In addition to myeloid suppressor cells, polymorphonuclear cells (PMN) also exert T-cell immune suppressive effects through arginase-induced l-arginine depletion, especially during pregnancy. In this study, we investigated how arginase/l-arginine modulates neonatal lymphocyte proliferation. Results showed that the neonatal plasma l-arginine level was lower than in adults (48·1 ± 11·3 versus 86·5 ± 14·6 ?m; P = 0·003). Neonatal PMN had a greater abundance of arginase I protein than adult PMN. Both transcriptional regulation and post-transcriptional regulation were responsible for the higher arginase I expression of neonatal PMN. Exogenous l-arginine enhanced neonate lymphocyte proliferation but not that of adult cells. The RNA-binding protein HuR was important but was not the only modulation factor in l-arginine-regulated neonatal T-cell proliferation. l-Arginine-mediated neonatal lymphocyte proliferation could not be blocked by interleukin-2 receptor blocking antibodies. These results suggest that the altered arginase/l-arginine cascade may be one of the mechanisms that contribute to altered neonatal immune responses. Exogenous l-arginine could enhance neonate lymphocyte proliferation through an interleukin-2-independent pathway.
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Serum cytokine/chemokine profiles in acute exacerbation of chronic hepatitis B: clinical and mechanistic implications.
J. Gastroenterol. Hepatol.
PUBLISHED: 03-17-2014
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Acute exacerbation (AE) of chronic hepatitis B virus (HBV) infection is common and negatively impacts the clinical outcome. Although upsurge of viral load always precedes or coincides with AE, the underlying immunological mechanisms remain unclear and were investigated.
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Immobilization of glucose oxidase on graphene and cobalt phthalocyanine composite and its application for the determination of glucose.
Enzyme Microb. Technol.
PUBLISHED: 03-13-2014
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We described a simple and facile chemical reduction strategy for the preparation of graphene (GR)-cobalt phthalocyanine (CoPc) composite and explored it for the enzymatic determination of glucose. CoPc is an active mediator and electrocatalysts for the immobilization of GOx and determination of glucose. However, it is not stable on the electrode surface and also suffers from lack of conductivity. Here, we have employed GR as the suitable support to stabilize CoPc through simple chemical reduction method and the resulting composite has been used for the glucose biosensor application. Scanning electron microscopy, X-ray diffraction and Energy-dispersive X-ray spectroscopy studies confirmed the successful formation of composite. Direct electron transfer of glucose oxidase (GOx) was observed with well defined redox peaks at the formal potential of -0.44 V. The amount of electroactive GOx (?) and electron transfer rate constant (ks) were calculated to be 3.77×10(-10) mol cm(-2) and 3.57 s(-1), respectively. The fabricated amperometric biosensor detects glucose in wide linear concentration range from 10 ?M to 14.8 mM with high sensitivity of 5.0 9?A mM(-1) cm(-2). The sensor offered very low detection limit (LOD) of 1.6 ?M. In addition, practical feasibility of the sensor has been explored in screen printing carbon electrode with accurate determination of glucose present in human blood serum and urine samples. Furthermore, the sensor exhibited appreciable stability, repeatability and reproducibility results.
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Short-stay surgery: what really happens after discharge?
Surgery
PUBLISHED: 03-11-2014
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Although duration of hospital stay commonly is used as a surrogate outcome for surgical recovery, it is not applicable in the setting of short-stay surgery (<24 hours). The objective of our study was to describe the trajectory of recovery after short-stay abdominal surgery by using measures of physical activity and health-related quality of life (HRQL) and identify predictors of prolonged, postdischarge recovery.
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Measuring postoperative recovery: what are clinically meaningful differences?
Surgery
PUBLISHED: 03-07-2014
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Surgical innovations are introduced to improve "recovery," a complex construct often operationalized by the use of patient-reported outcomes. The minimal clinically important difference (MCID) is the smallest change in an outcome sufficiently important to influence management and is crucial for designing and interpreting comparative effectiveness trials. Our objective was to generate MCID estimates for three postoperative recovery metrics.
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Left ventricular lead position and outcomes in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT).
Can J Cardiol
PUBLISHED: 02-25-2014
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Conflicting data exist regarding the association between left ventricular (LV) lead position and benefit from cardiac resynchronization therapy. We evaluated the relationships between LV lead positions and the risk of death or hospitalization for heart failure (HF) in the cardiac resynchronization therapy arm of the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT).
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Outcome of early-treated type III Gaucher disease patients.
Blood Cells Mol. Dis.
PUBLISHED: 02-06-2014
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Recombinant human acid ?-glucosidase GBA (rhGBA) infusion is an effective therapy for non-neuropathic (type I) Gaucher disease (GD), but its effect on subacute neuropathic (type III) GD is still controversial. The most common genotype for type III GD is homozygous c.1448T>C (p.L444P) mutation, and in this study, we treated seven such patients starting from an early age (median 2.1 years; range 1-2.9 years). Before the start of treatment, all patients presented hepatosplenomegaly, anemia, and thrombocytopenia, but with no neurological signs. Normalization of hemoglobin levels and platelet numbers was achieved in all patients in one year. However, after a median treatment period of 7.6 years (2.2-12.0 years), two patients developed horizontal gaze palsy, one had seizures, four demonstrated mental retardation, and five showed kyphosis. Moreover, lymphadenopathy in the neck, thorax, or abdomen was observed in four patients. Therefore, the progression of neurological symptoms in these patients probably reflected the neurologic natural history of type III GD. Residual somatic symptoms, including kyphosis and lymphadenopathy, may be more common than what we thought. An additional treatment will be necessary to improve the outcome of type III GD.
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Increased circulatory asymmetric dimethylarginine and multiple organ failure: bile duct ligation in rat as a model.
Int J Mol Sci
PUBLISHED: 02-04-2014
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Bile duct ligation (BDL)-treated rats exhibit cholestasis, increased systemic oxidative stress, and liver fibrosis, which ultimately lead to liver cirrhosis. Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of nitric oxide synthase that can decrease the synthesis of nitric oxide. BDL rats have higher plasma and hepatic ADMA levels, which may be due to increased hepatic protein arginine methyltransferase-1 and decreased dimethylarginine dimethylaminohydrolase expression. BDL rats also exhibit renal and brain damage characterized by increased tissue ADMA concentrations. The increased plasma ADMA levels and multiple organ damages seen here are also observed following multiple organ failures associated with critical illness. This review discusses the dysregulation of ADMA in major organs in BDL rats and the role of increased ADMA in multiple organ damages.
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Melatonin attenuates prenatal dexamethasone-induced blood pressure increase in a rat model.
J Am Soc Hypertens
PUBLISHED: 01-31-2014
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Although antenatal corticosteroid is recommended to accelerate fetal lung maturation, prenatal dexamethasone exposure results in hypertension in the adult offspring. Since melatonin is a potent antioxidant and has been known to regulate blood pressure, we examined the beneficial effects of melatonin therapy in preventing prenatal dexamethasone-induced programmed hypertension. Male offspring of Sprague-Dawley rats were assigned to four groups (n = 12/group): control, dexamethasone (DEX), control + melatonin, and DEX + melatonin. Pregnant rats received intraperitoneal dexamethasone (0.1 mg/kg) from gestational day 16 to 22. In the melatonin-treatment groups, rats received 0.01% melatonin in drinking water during their entire pregnancy and lactation. Blood pressure was measured by an indirect tail-cuff method. Gene expression and protein levels were analyzed by real-time quantitative polymerase chain reaction and Western blotting, respectively. At 16 weeks of age, the DEX group developed hypertension, which was partly reversed by maternal melatonin therapy. Reduced nephron numbers due to prenatal dexamethasone exposure were prevented by melatonin therapy. Renal superoxide and NO levels were similar in all groups. Prenatal dexamethasone exposure led to increased mRNA expression of renin and prorenin receptor and up-regulated histone deacetylase (HDAC)-1 expression in the kidneys of 4-month-old offspring. Maternal melatonin therapy augmented renal Mas protein levels in DEX + melatonin group, and increased renal mRNA expression of HDAC-1, HDAC-2, and HDAC-8 in control and DEX offspring. Melatonin attenuated prenatal DEX-induced hypertension by restoring nephron numbers, altering RAS components, and modulating HDACs.
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Melatonin in the regulation of liver steatosis following prenatal glucocorticoid exposure.
Biomed Res Int
PUBLISHED: 01-27-2014
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Nonalcoholic fatty liver disease patients are characterized by hepatic steatosis. Prenatal glucocorticoid overexposure can result in steatosis. In this study, we aimed to determine the mechanism and cellular apoptosis of prenatal glucocorticoid overexposure in rats and whether melatonin can rescue the prenatal glucocorticoid-induced steatosis and apoptosis in neonatal rats. Pregnant Sprague-Dawley rats at gestational days 14 to 21 were administered dexamethasone. Acute effects of prenatal programming liver were assessed at postnatal day 7. The expression of proteins involved in the apoptotic and methylation pathways was analyzed by RT-PCR and Western blotting. Apoptosis and steatosis were examined by histology staining. The liver steatosis and apoptosis were increased in prenatal glucocorticoid group more than in control group and decreased in melatonin group. The expression of leptin decreased in prenatal glucocorticoid and increased in melatonin group by liver RT-PCR and Western blot study. Caspase 3, TNF- ? proteins expression, and TUNEL stains increased in prenatal glucocorticoid compared with control and decreased in melatonin group. The liver histone deacetylase, DNA methyltransferase activity, and DNA methylation were increased in prenatal glucocorticoid and decreased in melatonin group. The present study showed that the prenatal glucocorticoid induced programming liver steatosis at day 7 after delivery, possibly via altered leptin expression. Melatonin can reverse the methylation of leptin and decreased liver steatosis.
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Metabolic syndrome and smoking may justify earlier colorectal cancer screening in men.
Gastrointest. Endosc.
PUBLISHED: 01-25-2014
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Gender, smoking, and metabolic syndrome (MetS) are important risk factors of colorectal neoplasm. Whether presence of these factors may warrant earlier screening remains unclear.
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Current management of diminutive colorectal polyps in Taiwan.
Dig Endosc
PUBLISHED: 01-17-2014
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The majority of polyps detected during colonoscopy are diminutive polyps, for which the cost of pathological analysis is substantial. In our analysis of a screening cohort of 10737 subjects undergoing screening colonoscopy, a total of 15877 neoplastic lesions were detected, of which 10816 (68.1%) were diminutive lesions. Of those diminutive lesions, 90 (0.83%) had a villous component, 14 (0.1%) had high-grade dysplasia, and none had invasive cancer. Only 1.3% of patients were advised to decrease their surveillance interval because of unfavorable histology. Laws regulating medical practice, uncertainty regarding the accuracy of endoscopic diagnosis of diminutive polyps outside of academic centers, and the relatively low cost of pathological analysis are among the barriers to adopting a 'resect and discard' practice in Taiwan.
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Melatonin therapy prevents programmed hypertension and nitric oxide deficiency in offspring exposed to maternal caloric restriction.
Oxid Med Cell Longev
PUBLISHED: 01-06-2014
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Nitric oxide (NO) deficiency is involved in the development of hypertension, a condition that can originate early in life. We examined whether NO deficiency contributed to programmed hypertension in offspring from mothers with calorie-restricted diets and whether melatonin therapy prevented this process. We examined 3-month-old male rat offspring from four maternal groups: untreated controls, 50% calorie-restricted (CR) rats, controls treated with melatonin (0.01% in drinking water), and CR rats treated with melatonin (CR + M). The effect of melatonin on nephrogenesis was analyzed using next-generation sequencing. The CR group developed hypertension associated with elevated plasma asymmetric dimethylarginine (ADMA, a nitric oxide synthase inhibitor), decreased L-arginine, decreased L-arginine-to-ADMA ratio (AAR), and decreased renal NO production. Maternal melatonin treatment prevented these effects. Melatonin prevented CR-induced renin and prorenin receptor expression. Renal angiotensin-converting enzyme 2 protein levels in the M and CR + M groups were also significantly increased by melatonin therapy. Maternal melatonin therapy had long-term epigenetic effects on global gene expression in the kidneys of offspring. Conclusively, we attributed these protective effects of melatonin on CR-induced programmed hypertension to the reduction of plasma ADMA, restoration of plasma AAR, increase of renal NO level, alteration of renin-angiotensin system, and epigenetic changes in numerous genes.
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Hepatitis B surface antigen level complements viral load in predicting viral reactivation in spontaneous HBeAg seroconverters.
J. Gastroenterol. Hepatol.
PUBLISHED: 01-04-2014
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The level of hepatitis B surface antigen (HBsAg) has been shown to complement hepatitis B virus (HBV)-DNA level in predicting disease progression in hepatitis B e antigen (HBeAg)-negative patients, especially those with low viral loads. Whether this finding could be seen in spontaneous HBeAg seroconverters remains unclear.
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Necrotising fasciitis in systemic lupus erythematosus: a case report and literature review.
Lupus Sci Med
PUBLISHED: 01-01-2014
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Necrotising fasciitis (NF) is a rare infection of the subcutaneous tissue, known to be rapidly progressive and potentially fatal. Patients with systemic lupus erythematosus (SLE) may be predisposed to this condition, and early clinical recognition can be difficult. We report a case of necrotising fasciitis in a 26-year-old woman with SLE. She presented with painful swelling of her left leg, then developed clinical features of septic shock. Emergency debridement was performed. Intraoperative findings revealed NF and cultures grew Pseudomonas aeruginosa. The patient survived after a lengthy hospital admission, following several further debridements complicated by recurrent chest sepsis and multiorgan failure. We also review and discuss the published cases of NF in SLE patients.
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SLCO3A1, a Novel Crohn's Disease-Associated Gene, Regulates NF-?B Activity and Associates with Intestinal Perforation.
PLoS ONE
PUBLISHED: 01-01-2014
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To date, only one gene (TNFSF15) has been identified and validated as a Crohn's disease (CD)-associated gene in non-Caucasian populations. This study was designed to identify novel CD-associated single nucleotide polymorphisms (SNPs)/genes and to validate candidate genes using a functional assay.
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Early-life stress impacts the developing hippocampus and primes seizure occurrence: cellular, molecular, and epigenetic mechanisms.
Front Mol Neurosci
PUBLISHED: 01-01-2014
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Early-life stress includes prenatal, postnatal, and adolescence stress. Early-life stress can affect the development of the hypothalamic-pituitary-adrenal (HPA) axis, and cause cellular and molecular changes in the developing hippocampus that can result in neurobehavioral changes later in life. Epidemiological data implicate stress as a cause of seizures in both children and adults. Emerging evidence indicates that both prenatal and postnatal stress can prime the developing brain for seizures and an increase in epileptogenesis. This article reviews the cellular and molecular changes encountered during prenatal and postnatal stress, and assesses the possible link between these changes and increases in seizure occurrence and epileptogenesis in the developing hippocampus. In addititon, the priming effect of prenatal and postnatal stress for seizures and epileptogenesis is discussed. Finally, the roles of epigenetic modifications in hippocampus and HPA axis programming, early-life stress, and epilepsy are discussed.
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Vascular Endothelial Growth Factor-A in Lactobacillus Casei Cell Wall Extract-Induced Coronary Arteritis of a Murine Model.
Circ. J.
PUBLISHED: 12-14-2013
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Background:?Vascular endothelial growth factor (VEGF) is associated with Kawasaki disease (KD), the most commonly acquired heart disease in developed countries. This study investigated the involvement of VEGF-A expression and its related signaling pathway in Lactobacillus casei cell wall extract (LCWE)-induced murine coronary artery lesions (CALs), and analyzed this in regard to the inhibition of CALs by spleen tyrosine kinase (Syk). Methods and Results:?Wild-type BALB/C mice were intraperitoneally injected with LCWE (1mg/ml) to induce CALs. The aortic roots, ventricular myocardium, peripheral blood leukocytes (PBLs), spleen, liver, kidneys, and lungs were analyzed for VEGF-A expression. Phosphate buffered saline (PBS)-, lipopolysaccharide (LPS)-, and zymosan-treated mice served as controls, and an oral Syk inhibitor served as an arteritis-ameliorated reagent. In aortic roots and PBLs, LCWE induced an early upregulation and a late downregulation of VEGF-A expression. No differential VEGF-A expression was observed in the other organs. Most importantly, Syk inhibition significantly attenuated the LCWE-induced expression of VEGF-A, dimethylarginine dimethylaminohydrolase (DDAH)-1, and endothelial nitric oxide synthase in aortic roots. However, LCWE-induced aortic DDAH-2 expression remained higher, despite Syk inhibition. Conclusions:?Local VEGF-A and its signaling pathway are associated with the development of LCWE-induced CALs. Therefore, the clinical correlation between VEGF and human KD and the role of the VEGF-A regulation and signaling pathway in murine CALs warrant further investigation.
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Low-cytotoxic synthetic bromorutaecarpine exhibits anti-inflammation and activation of transient receptor potential vanilloid type 1 activities.
Biomed Res Int
PUBLISHED: 09-12-2013
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Rutaecarpine (RUT), the major bioactive ingredient isolated from the Chinese herb Evodia rutaecarpa, possesses a wide spectrum of biological activities, including anti-inflammation and preventing cardiovascular diseases. However, its high cytotoxicity hampers pharmaceutical development. We designed and synthesized a derivative of RUT, bromo-dimethoxyrutaecarpine (Br-RUT), which showed no cytotoxicity at 20? ? M. Br-RUT suppressed nitric oxide (NO) production and tumor necrosis factor- ? release in concentration-dependent (0~20? ? M) manners in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages; protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 induced by LPS were downregulated. Br-RUT inhibited cell migration and invasion of ovarian carcinoma A2780 cells with 0~48?h of treatment. Furthermore, Br-RUT enhanced the expression of transient receptor potential vanilloid type 1 and activated endothelial NOS in human aortic endothelial cells. These results suggest that the synthetic Br-RUT possesses very low cytotoxicity but retains its activities against inflammation and vasodilation that could be beneficial for cardiovascular disease therapeutics.
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Associations of mitochondrial haplogroups b4 and e with biliary atresia and differential susceptibility to hydrophobic bile Acid.
PLoS Genet.
PUBLISHED: 08-01-2013
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Mitochondrial dysfunction has been implicated in the pathogenesis of biliary atresia (BA). This study aimed to determine whether a specific mitochondrial DNA haplogroup is implicated in the pathogenesis and prognosis of BA. We determined 40 mitochondrial single nucleotide polymorphisms in 15 major mitochondrial haplogroups by the use of 24-plex PCR and fluorescent beads combined with sequence-specific oligonucleotide probes in 71 patients with BA and in 200 controls in the Taiwanese population of ethnic Chinese background. The haplogroup B4 and E prevalence were significantly lower and higher respectively, in the patients with BA than in the controls (odds ratios, 0.82 [p = 0.007] and 7.36 [p = 0.032] respectively) in multivariate logistic-regression analysis. The 3-year survival rate with native liver was significantly lower in haplogroup E than the other haplogroups (P = 0.037). A cytoplasmic hybrid (cybrid) was obtained from human 143B osteosarcoma cells devoid of mtDNA (?(0) cell) and was fused with specific mtDNA bearing E and B4 haplogroups donated by healthy Taiwanese subjects. Chenodeoxycholic acid treatment resulted in significantly lower free radical production, higher mitochondrial membrane potential, more viable cells, and fewer apoptotic cybrid B4 cells than parental 143B and cybrid E cells. Bile acid treatment resulted in a significantly greater protective mitochondrial reaction with significantly higher mitochondrial DNA copy number and mitofusin 1 and 2 concentrations in cybrid B4 and parental cells than in cybrid E cells. The results of the study suggested that the specific mitochondrial DNA haplogroups B4 and E were not only associated with lower and higher prevalence of BA respectively, in the study population, but also with differential susceptibility to hydrophobic bile acid in the cybrid harboring different haplogroups.
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Zebularine inhibits tumorigenesis and stemness of colorectal cancer via p53-dependent endoplasmic reticulum stress.
Sci Rep
PUBLISHED: 07-15-2013
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Aberrant DNA hypermethylation is frequently found in tumor cells and inhibition of DNA methylation is an effective anticancer strategy. In this study, the therapeutic effect of DNA methyltransferase (DNMT) inhibitor zebularine (Zeb) on colorectal cancer (CRC) was investigated. Zeb exhibited anticancer activity in cell cultures, tumor xenografts and mouse colitis-associated CRC model. It stabilizes p53 through ribosomal protein S7 (RPS7)/MDM2 pathways and DNA damage. Zeb-induced cell death was dependent on p53. Microarray analysis revealed that genes related to endoplasmic reticulum (ER) stress and unfolded protein response (UPR) were affected by Zeb. Zeb induced p53-dependent ER stress and autophagy. Pro-survival markers of ER stress/UPR (GRP78) and autophagy (p62) were increased in tumor tissues of CRC patients, AOM/DSS-induced CRC mice and HCT116-derived colonospheres. Zeb downregulates GRP78 and p62, and upregulates a pro-apoptotic CHOP. Our results reveal a novel mechanism for the anticancer activity of Zeb.
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Dual-incision laparoscopic surgery for peritoneal dialysis catheter implantation and fixation: a novel, simple, and safe procedure.
J Laparoendosc Adv Surg Tech A
PUBLISHED: 07-09-2013
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Peritoneal dialysis (PD) is an alternative modality to hemodialysis and is usually used to treat patients with end-stage renal disease. Dual-incision laparoscopic surgery (DILS) had been reported in several surgical fields; however, no report was proposed about DILS in PD catheter implantation (DILS-PD). In this study, we present DILS with a novel, simple, and safe procedure for PD catheter implantation with fixation and describe the long-term outcome.
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RNA silencing targeting PIN (protein inhibitor of neuronal nitric oxide synthase) attenuates the development of hypertension in young spontaneously hypertensive rats.
J Am Soc Hypertens
PUBLISHED: 07-01-2013
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Nitric oxide (NO) deficiency contributes to hypertension. We previously showed that neuronal nitric oxide synthase (nNOS) was involved in hypertension and kidney damage in spontaneously hypertensive rats (SHRs). The protein inhibitor of nNOS (PIN) has been reported to inhibit activity of nNOS.Thus, we tested whether increased PIN in the kidney results in hypertension and whether small interfering RNA (siRNA) targeting PIN attenuates hypertension in SHRs. Four-week-old male SHRs were assigned into three groups (n = 6-7/group): SHR; SHR + PIN, SHR that received siRNA targeting PIN; and SHR + NC, SHR treated with random negative control siRNA. Rats were sacrificed at 12 weeks of age. PIN protein expression was inhibited considerably when PIN siRNA was transfected into NRK52E cells (90% siRNA at 1 nM). The increases of BP were attenuated by siRNA targeting PIN in12-week-old SHRs. Immunostaining of nNOS-? and total nNOS was greater in SHR + PIN group than SHR. Moreover, renal superoxide production and 8-hydroxydeoxyguanosine (8-OHdG) staining were more decreased in the SHR + PIN group than SHRs. We conclude that PIN siRNA reduced PIN expression in vitro and in vivo. PIN siRNA therapy attenuates hypertension in SHRs at 12 weeks of age. Our results suggest that PIN is involved in the development of hypertension.
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Two different approaches to restore renal nitric oxide and prevent hypertension in young spontaneously hypertensive rats: l-citrulline and nitrate.
Transl Res
PUBLISHED: 06-27-2013
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Nitric oxide (NO) deficiency mediates oxidative stress in the kidney and is involved in the development of hypertension. NO synthesis occurs via 2 pathways: nitric oxide synthase (NOS) dependent and NOS-independent. We tested whether the development of hypertension is prevented by restoration of NO by dietary l-citrulline or nitrate supplementation in young spontaneously hypertensive rats (SHRs). Male SHRs and normotensive Wistar Kyoto control rats (WKYs)s age 4 weeks were assigned to 4 groups: untreated SHRs and WKYs, and SHRs and WKYs that received 0.25% l-citrulline for 8 weeks. In our second series of studies, we replaced l-citrulline with 1 mmol/kg/d sodium nitrate. All rats were sacrificed at age 12 weeks. We found an increase in the blood pressure of SHRs was prevented by dietary supplementation of l-citrulline or nitrate. Both treatments restored NO bioavailability and reduced oxidative stress in SHR kidneys. l-Citrulline therapy reduced levels of l-arginine and asymmetric dimethylarginine (ADMA)-an endogenous inhibitor of NOS-and increased the l-arginine-to-ADMA ratio in SHR kidneys. Nitrate treatment reduced plasma levels of l-arginine and ADMA concurrently in SHRs. Our findings suggest that both NOS-dependent and -independent approaches in the prehypertensive stage toward augmentation of NO can prevent the development of hypertension in young SHRs.
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Acute failure of catheter ablation for ventricular tachycardia due to structural heart disease: causes and significance.
J Am Heart Assoc
PUBLISHED: 06-04-2013
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Acute end points of catheter ablation for ventricular tachycardia (VT) remain incompletely defined. The aim of this study is to identify causes for failure in patients with structural heart disease and to assess the relation of this acute outcome to longer-term management and outcomes.
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HBV-DNA level at 6 months of entecavir treatment predicts HBeAg loss in HBeAg-positive chronic hepatitis B patients.
J. Formos. Med. Assoc.
PUBLISHED: 06-01-2013
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To evaluate whether on-treatment HBV-DNA level could predict the treatment response to entecavir in hepatitis B e antigen (HBe)-positive chronic hepatitis B (CHB) patients.
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Serum vascular adhesion protein-1 predicts all-cause mortality and cancer-related mortality in subjects with colorectal cancer.
Clin. Chim. Acta
PUBLISHED: 05-17-2013
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Vascular adhesion protein-1 (VAP-1) participates in inflammation and catalyzes the breakdown of amines to produce aldehyde, hydrogen peroxide, and ammonia. Serum VAP-1 can predict cancer mortality, including colorectal cancer (CRC) mortality, in type 2 diabetic subjects. However, it remains unknown if serum VAP-1 can predict mortality in CRC patients. This prospective cohort study investigates if serum VAP-1 is a novel biomarker for mortality prediction in CRC.
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Structure of the Sgt2 dimerization domain complexed with the Get5 UBL domain involved in the targeting of tail-anchored membrane proteins to the endoplasmic reticulum.
Acta Crystallogr. D Biol. Crystallogr.
PUBLISHED: 05-16-2013
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The insertion of tail-anchored membrane (TA) proteins into the appropriate membrane is a post-translational event that requires stabilization of the transmembrane domain and targeting to the proper destination. Sgt2, a small glutamine-rich tetratricopeptide-repeat protein, is a heat-shock protein cognate (HSC) co-chaperone that preferentially binds endoplasmic reticulum-destined TA proteins and directs them to the GET pathway via Get4 and Get5. The N-terminal domain of Sgt2 seems to exert dual functions. It mediates Get5 interaction and allows substrate delivery to Get3. Following the N-terminus of Get5 is a ubiquitin-like (Ubl) domain that interacts with the N-terminus of Sgt2. Here, the crystal structure of the Sgt2 dimerization domain complexed with the Get5 Ubl domain (Sgt2N-Get5Ubl) is reported. This complex reveals an intimate interaction between one Sgt2 dimer and one Get5 monomer. This research further demonstrates that hydrophobic residues from both Sgt2 and Get5 play an important role in cell survival under heat stress. This study provides detailed molecular insights into the specific binding of this GET-pathway complex.
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Successful treatment of chronic hepatitis B and D with pegylated-interferon plus entecavir.
J. Formos. Med. Assoc.
PUBLISHED: 05-08-2013
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Interferon-based regimen has been used to treat hepatitis D virus (HDV) super-infection on top of hepatitis B virus (HBV) carriers; however, viral relapse is frequent after stopping therapy. Recently, quantitative hepatitis B surface antigen (qHBsAg) was introduced to help the management of chronic hepatitis B (CHB). Little is known about its role in the treatment of HBV and HDV dual infection. Herein, we reported a 45-year-old male HBV carrier with HDV co-infection who received combination therapy of pegylated-interferon ?-2a plus entecavir. The qHBsAg level was adopted as the treatment guidance and a consolidation therapy of 12 months was continued after HBsAg loss. The patient achieved HBsAg seroconversion with HDV RNA undetectable after 35 months of combination therapy and sustained therapeutic response 12 months post-therapy. Therefore, personalized response-guided therapy by using qHBsAg may be an option for the treatment for HBV and HDV dual infection.
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Risk stratification of hepatocellular carcinoma in hepatitis B virus e antigen-negative carriers by combining viral biomarkers.
J. Infect. Dis.
PUBLISHED: 05-08-2013
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The serum hepatitis B virus (HBV) surface antigen (HBsAg) level can predict hepatocellular carcinoma (HCC) development in hepatitis B e antigen (HBeAg)-negative patients with an HBV DNA level of <2000 IU/mL. However, little is known regarding how well the combination of both viral biomarkers stratifies HCC risk.
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Revisional weight loss surgery after failed laparoscopic gastric banding: an institutional experience.
Surg Endosc
PUBLISHED: 05-03-2013
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Increasing experience with laparoscopic adjustable gastric banding (LAGB) has demonstrated a high rate of complications and inadequate weight loss. Laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) have been reported to be safe and effective in selected patients. The purpose of our study was to evaluate the incidence and outcomes of revisional weight loss surgery (RWLS) after laparoscopic gastric banding at our institution.
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Serum microRNA-122 level correlates with virologic responses to pegylated interferon therapy in chronic hepatitis C.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 04-23-2013
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MicroRNA-122 (miR-122) facilitates hepatitis C virus replication in vitro. Serum miR-122 has been implicated as a biomarker for various liver diseases; however, its role in chronic hepatitis C remains unclear. To address this issue, 126 patients with chronic hepatitis C who completed pegylated IFN plus ribavirin therapy with sustained virologic response (SVR) or nonresponse (NR) were retrospectively included, and their pretreatment clinical profiles and treatment responses were collected. Serum miR-122 was quantified before and during treatment. Another 51 patients in SVR and NR groups were prospectively enrolled for validation. Serum miR-122 was found to be a surrogate for hepatic miR-122 and positively correlated with hepatic necroinflammation. Patients who showed complete early virologic response and SVR had significantly higher pretreatment serum miR-122 levels than those with NR (P = 0.001 and P = 0.008, respectively), especially in subgroups of patients with hepatitis C virus genotype 2 and IL-28B rs8099917 TT genotype. Patients with IL-28B TT genotype had significantly better treatment responses and higher pretreatment serum miR-122 level than those with GT or GG genotypes. Univariate analysis showed that pretreatment body mass index, ?-glutamyl transpeptidase, triglyceride, IL-28B TT genotype, and serum miR-122 are predictors for SVR. Multivariate analysis specifically in IL-28B TT genotype demonstrated that pretreatment serum miR-122 independently predicted SVR. The validation cohort confirmed a significantly greater pretreatment serum miR-122 level in patients with SVR compared with NR (P = 0.025). In conclusion, serum miR-122 may serve as a surrogate of hepatic miR-122, and a higher pretreatment serum miR-122 level can help predict virologic responses to pegylated IFN plus ribavirin therapy.
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