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Find video protocols related to scientific articles indexed in Pubmed.
New approaches to manipulating the epigenome.
Dialogues Clin Neurosci
PUBLISHED: 11-04-2014
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Cellular processes that control transcription of genetic information are critical for cellular function, and are often implicated in psychiatric and neurological disease states. Among the most critical of these processes are epigenetic mechanisms, which serve to link the cellular environment with genomic material. Until recently our understanding of epigenetic mechanisms has been limited by the lack of tools that can selectively manipulate the epigenome with genetic, cellular, and temporal precision, which in turn diminishes the potential impact of epigenetic processes as therapeutic targets. This review highlights an emerging suite of tools that enable robust yet selective interrogation of the epigenome. In addition to allowing site-specific epigenetic editing, these tools can be paired with optogenetic approaches to provide temporal control over epigenetic processes, allowing unparalleled insight into the function of these mechanisms. This improved control promises to revolutionize our understanding of epigenetic modifications in human health and disease states.
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DNA Methylation and Its Implications and Accessibility for Neuropsychiatric Therapeutics.
Annu. Rev. Pharmacol. Toxicol.
PUBLISHED: 10-24-2014
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In this review, we discuss the potential pharmacological targeting of a set of powerful epigenetic mechanisms: DNA methylation control systems in the central nervous system (CNS). Specifically, we focus on the possible use of these targets for novel future treatments of learning and memory disorders. We first describe several unique pharmacological attributes of epigenetic mechanisms, especially DNA cytosine methylation, as potential drug targets.Wethen present an overview of the existing literature regarding DNA methylation control pathways and enzymes in the nervous system, particularly as related to synaptic function, plasticity, learning and memory. Lastly, we speculate upon potential categories of CNS cognitive disorders that might be amenable to methylomic targeting. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 55 is January 06, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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Viral aetiology of central nervous system infections in adults admitted to a tertiary referral hospital in southern Vietnam over 12 years.
PLoS Negl Trop Dis
PUBLISHED: 08-28-2014
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Central nervous system (CNS) infections are important diseases in both children and adults worldwide. The spectrum of infections is broad, encompassing bacterial/aseptic meningitis and encephalitis. Viruses are regarded as the most common causes of encephalitis and aseptic meningitis. Better understanding of the viral causes of the diseases is of public health importance, in order to better inform immunization policy, and may influence clinical management.
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CryptoDex: A randomised, double-blind, placebo-controlled phase III trial of adjunctive dexamethasone in HIV-infected adults with cryptococcal meningitis: study protocol for a randomised control trial.
Trials
PUBLISHED: 05-16-2014
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Cryptococcal meningitis (CM) is a severe AIDS-defining illness with 90-day case mortality as high as 70% in sub-Saharan Africa, despite treatment. It is the leading cause of death in HIV patients in Asia and Africa.No major advance has been made in the treatment of CM since the 1970s. The mainstays of induction therapy are amphotericin B and flucytosine, but these are often poorly available where the disease burden is highest. Adjunctive treatments, such as dexamethasone, have had dramatic effects on mortality in other neurologic infections, but are untested in CM. Given the high death rates in patients receiving current optimal treatment, and the lack of new agents on the horizon, adjuvant treatments, which offer the potential to reduce mortality in CM, should be tested.The principal research question posed by this study is as follows: does adding dexamethasone to standard antifungal therapy for CM reduce mortality? Dexamethasone is a cheap, readily available, and practicable intervention.
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Histone H2A.Z subunit exchange controls consolidation of recent and remote memory.
Nature
PUBLISHED: 05-12-2014
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Memory formation is a multi-stage process that initially requires cellular consolidation in the hippocampus, after which memories are downloaded to the cortex for maintenance, in a process termed systems consolidation. Epigenetic mechanisms regulate both types of consolidation, but histone variant exchange, in which canonical histones are replaced with their variant counterparts, is an entire branch of epigenetics that has received limited attention in the brain and has never, to our knowledge, been studied in relation to cognitive function. Here we show that histone H2A.Z, a variant of histone H2A, is actively exchanged in response to fear conditioning in the hippocampus and the cortex, where it mediates gene expression and restrains the formation of recent and remote memory. Our data provide evidence for H2A.Z involvement in cognitive function and specifically implicate H2A.Z as a negative regulator of hippocampal consolidation and systems consolidation, probably through downstream effects on gene expression. Moreover, alterations in H2A.Z binding at later stages of systems consolidation suggest that this histone has the capacity to mediate stable molecular modifications required for memory retention. Overall, our data introduce histone variant exchange as a novel mechanism contributing to the molecular basis of cognitive function and implicate H2A.Z as a potential therapeutic target for memory disorders.
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AIDS-related mycoses: the way forward.
Trends Microbiol.
PUBLISHED: 03-04-2014
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The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries.
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Evaluation of GeneXpert MTB/RIF for Diagnosis of Tuberculous Meningitis.
J. Clin. Microbiol.
PUBLISHED: 11-06-2013
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Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Microbiological confirmation is rare, and treatment is often delayed, increasing mortality and morbidity. The GeneXpert MTB/RIF test was evaluated in a large cohort of patients with suspected tuberculous meningitis. Three hundred seventy-nine patients presenting with suspected tuberculous meningitis to the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, between 17 April 2011 and 31 December 2012 were included in the study. Cerebrospinal fluid samples were tested by Ziehl-Neelsen smear, mycobacterial growth indicator tube (MGIT) culture, and Xpert MTB/RIF. Rifampin (RIF) resistance results by Xpert were confirmed by an MTBDR-Plus line probe assay and all positive cultures were tested by phenotypic MGIT drug susceptibility testing. Overall, 182/379 included patients (48.0%) were diagnosed with tuberculous meningitis. Sensitivities of Xpert, smear, and MGIT culture among patients diagnosed with TBM were 59.3% (108/182 [95% confidence interval {CI}, 51.8 to 66.5%]), 78.6% (143/182 [95% CI, 71.9 to 84.3%]) and 66.5% (121/182 [95% CI, 59.1 to 73.3%]), respectively. There was one false-positive Xpert MTB/RIF test (99.5% specificity). Four cases of RIF resistance (4/109; 3.7%) were identified by Xpert, of which 3 were confirmed to be multidrug-resistant (MDR) TBM and one was culture negative. Xpert MTB/RIF is a rapid and specific test for the diagnosis of tuberculous meningitis. The addition of a vortexing step to sample processing increased sensitivity for confirmed TBM by 20% (P = 0.04). Meticulous examination of a smear from a large volume of cerebrospinal fluid (CSF) remains the most sensitive technique but is not practical in most laboratories. The Xpert MTB/RIF represents a significant advance in the early diagnosis of this devastating condition.
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Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal.
J. Antimicrob. Chemother.
PUBLISHED: 06-20-2013
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Current, widely accepted guidelines for the management of HIV-associated cryptococcal meningoencephalitis (CM) recommend amphotericin B combined with flucytosine (5-FC) for ?2 weeks as the initial induction treatment of choice. However, access to flucytosine in Africa and Asia, where disease burden is greatest, is inadequate at present. While research into identifying effective and well-tolerated antifungal combinations that do not contain flucytosine continues, an ever-increasing body of evidence from in vitro, in vivo and clinical studies points to the benefits of flucytosine in the treatment of CM in both intravenous combinations with amphotericin B and oral combinations with high-dose fluconazole. This article provides an up-to-date review of this evidence, and the current issues and challenges regarding increasing access to this key component of combination antifungal therapy for cryptococcosis.
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DNA methylation regulates associative reward learning.
Nat. Neurosci.
PUBLISHED: 04-18-2013
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Reward-related memories are essential for adaptive behavior and evolutionary fitness, but they are also a core component of maladaptive brain diseases such as addiction. Reward learning requires dopamine neurons located in the ventral tegmental area (VTA), which encode relationships between predictive cues and future rewards. Recent evidence suggests that epigenetic mechanisms, including DNA methylation, are essential regulators of neuronal plasticity and experience-driven behavioral change. However, the role of epigenetic mechanisms in reward learning is poorly understood. Here we show that the formation of reward-related associative memories in rats upregulates key plasticity genes in the VTA, which are correlated with memory strength and associated with gene-specific changes in DNA methylation. Moreover, DNA methylation in the VTA is required for the formation of stimulus-reward associations. These results provide the first evidence that that activity-dependent methylation and demethylation of DNA is an essential substrate for the behavioral and neuronal plasticity driven by reward-related experiences.
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Development of behavioral preferences for the optimal choice following unexpected reward omission is mediated by a reduction of D2-like receptor tone in the nucleus accumbens.
Eur. J. Neurosci.
PUBLISHED: 04-09-2013
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To survive in a dynamic environment, animals must identify changes in resource availability and rapidly apply adaptive strategies to obtain resources that promote survival. We have utilised a behavioral paradigm to assess differences in foraging strategy when resource (reward) availability unexpectedly changes. When reward magnitude was reduced by 50% (receive one reward pellet instead of two), male and female rats developed a preference for the optimal choice by the second session. However, when an expected reward was omitted (receive no reward pellets instead of one), subjects displayed a robust preference for the optimal choice during the very first session. Previous research shows that, when an expected reward is omitted, dopamine neurons phasically decrease their firing rate, which is hypothesised to decrease dopamine release preferentially affecting D2-like receptors. As robust changes in behavioral preference were specific to reward omission, we tested this hypothesis and the functional role of D1- and D2-like receptors in the nucleus accumbens in mediating the rapid development of a behavioral preference for the rewarded option during reward omission in male rats. Blockade of both receptor types had no effect on this behavior; however, holding D2-like, but not D1-like, receptor tone via infusion of dopamine receptor agonists prevented the development of the preference for the rewarded option during reward omission. These results demonstrate that avoiding an outcome that has been tagged with aversive motivational properties is facilitated through decreased dopamine transmission and subsequent functional disruption of D2-like, but not D1-like, receptor tone in the nucleus accumbens.
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Combination antifungal therapy for cryptococcal meningitis.
N. Engl. J. Med.
PUBLISHED: 04-05-2013
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Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days.
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Epigenetic mechanisms in memory and synaptic function.
Epigenomics
PUBLISHED: 11-30-2011
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Although the term epigenetics was coined nearly seventy years ago, its critical function in memory processing by the adult CNS has only recently been appreciated. The hypothesis that epigenetic mechanisms regulate memory and behavior was motivated by the need for stable molecular processes that evade turnover of the neuronal proteome. In this article, we discuss evidence that supports a role for neural epigenetic modifications in the formation, consolidation and storage of memory. In addition, we will review the evidence that epigenetic mechanisms regulate synaptic plasticity, a cellular correlate of memory. We will also examine how the concerted action of multiple epigenetic mechanisms with varying spatiotemporal profiles influence selective gene expression in response to behavioral experience. Finally, we will suggest key areas for future research that will help elucidate the complex, vital and still mysterious, role of epigenetic mechanisms in neural function and behavior.
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Phasic nucleus accumbens dopamine encodes risk-based decision-making behavior.
Biol. Psychiatry
PUBLISHED: 06-07-2011
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To optimize behavior, organisms evaluate the risks and benefits of available choices. The mesolimbic dopamine (DA) system encodes information about response costs and reward delays that bias choices. However, it remains unclear whether subjective value associated with risk-taking behavior is encoded by DA release.
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The RNR motif of B. subtilis RNase P protein interacts with both PRNA and pre-tRNA to stabilize an active conformer.
RNA
PUBLISHED: 05-27-2011
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Ribonuclease P (RNase P) catalyzes the metal-dependent 5 end maturation of precursor tRNAs (pre-tRNAs). In Bacteria, RNase P is composed of a catalytic RNA (PRNA) and a protein subunit (P protein) necessary for function in vivo. The P protein enhances pre-tRNA affinity, selectivity, and cleavage efficiency, as well as modulates the cation requirement for RNase P function. Bacterial P proteins share little sequence conservation although the protein structures are homologous. Here we combine site-directed mutagenesis, affinity measurements, and single turnover kinetics to demonstrate that two residues (R60 and R62) in the most highly conserved region of the P protein, the RNR motif (R60-R68 in Bacillus subtilis), stabilize PRNA complexes with both P protein (PRNA•P protein) and pre-tRNA (PRNA•P protein•pre-tRNA). Additionally, these data indicate that the RNR motif enhances a metal-stabilized conformational change in RNase P that accompanies substrate binding and is essential for efficient catalysis. Stabilization of this conformational change contributes to both the decreased metal requirement and the enhanced substrate recognition of the RNase P holoenzyme, illuminating the role of the most highly conserved region of P protein in the RNase P reaction pathway.
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Epigenetic treatments for cognitive impairments.
Neuropsychopharmacology
PUBLISHED: 05-18-2011
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Epigenetic mechanisms integrate signals from diverse intracellular transduction cascades and in turn regulate genetic readout. Accumulating evidence has revealed that these mechanisms are critical components of ongoing physiology and function in the adult nervous system, and are essential for many cognitive processes, including learning and memory. Moreover, a number of psychiatric disorders and syndromes that involve cognitive impairments are associated with altered epigenetic function. In this review, we will examine how epigenetic mechanisms contribute to cognition, consider how changes in these mechanisms may lead to cognitive impairments in a range of disorders and discuss the potential utility of therapeutic treatments that target epigenetic machinery. Finally, we will comment on a number of caveats associated with interpreting epigenetic changes and using epigenetic treatments, and suggest future directions for research in this area that will expand our understanding of the epigenetic changes underlying cognitive disorders.
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Epigenetic mechanisms in cognition.
Neuron
PUBLISHED: 05-06-2011
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Although the critical role for epigenetic mechanisms in development and cell differentiation has long been appreciated, recent evidence reveals that these mechanisms are also employed in postmitotic neurons as a means of consolidating and stabilizing cognitive-behavioral memories. In this review, we discuss evidence for an "epigenetic code" in the central nervous system that mediates synaptic plasticity, learning, and memory. We consider how specific epigenetic changes are regulated and may interact with each other during memory formation and how these changes manifest functionally at the cellular and circuit levels. We also describe a central role for mitogen-activated protein kinases in controlling chromatin signaling in plasticity and memory. Finally, we consider how aberrant epigenetic modifications may lead to cognitive disorders that affect learning and memory, and we review the therapeutic potential of epigenetic treatments for the amelioration of these conditions.
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A multi-center randomized trial to assess the efficacy of gatifloxacin versus ciprofloxacin for the treatment of shigellosis in Vietnamese children.
PLoS Negl Trop Dis
PUBLISHED: 03-28-2011
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The bacterial genus Shigella is the leading cause of dysentery. There have been significant increases in the proportion of Shigella isolated that demonstrate resistance to nalidixic acid. While nalidixic acid is no longer considered as a therapeutic agent for shigellosis, the fluoroquinolone ciprofloxacin is the current recommendation of the World Health Organization. Resistance to nalidixic acid is a marker of reduced susceptibility to older generation fluoroquinolones, such as ciprofloxacin. We aimed to assess the efficacy of gatifloxacin versus ciprofloxacin in the treatment of uncomplicated shigellosis in children.
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Epidemiology, seasonality, and predictors of outcome of AIDS-associated Penicillium marneffei infection in Ho Chi Minh City, Viet Nam.
Clin. Infect. Dis.
PUBLISHED: 03-24-2011
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Penicillium marneffei is an important human immunodeficiency virus (HIV)-associated opportunistic pathogen in Southeast Asia. The epidemiology and the predictors of penicilliosis outcome are poorly understood.
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Sample size requirements for separating out the effects of combination treatments: randomised controlled trials of combination therapy vs. standard treatment compared to factorial designs for patients with tuberculous meningitis.
Trials
PUBLISHED: 02-02-2011
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In certain diseases clinical experts may judge that the intervention with the best prospects is the addition of two treatments to the standard of care. This can either be tested with a simple randomized trial of combination versus standard treatment or with a 2 x 2 factorial design.
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Intensified treatment with high dose rifampicin and levofloxacin compared to standard treatment for adult patients with tuberculous meningitis (TBM-IT): protocol for a randomized controlled trial.
Trials
PUBLISHED: 02-02-2011
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Tuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against Mycobacterium tuberculosis. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin.
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Cocaine cues drive opposing context-dependent shifts in reward processing and emotional state.
Biol. Psychiatry
PUBLISHED: 01-21-2011
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Prominent neurobiological theories of addiction posit a central role for aberrant mesolimbic dopamine release but disagree as to whether repeated drug experience blunts or enhances this system. Although drug withdrawal diminishes dopamine release, drug sensitization augments mesolimbic function, and both processes have been linked to drug seeking. One possibility is that the dopamine system can rapidly switch from dampened to enhanced release depending on the specific drug-predictive environment. To test this, we examined dopamine release when cues signaled delayed cocaine delivery versus imminent cocaine self-administration.
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Nucleus accumbens neurons encode predicted and ongoing reward costs in rats.
Eur. J. Neurosci.
PUBLISHED: 12-29-2010
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Efficient decision-making requires that animals consider both the benefits and the costs of potential actions, such as the amount of effort or temporal delay involved in reward seeking. The nucleus accumbens (NAc) has been implicated in the ability to choose between options with different costs and overcome high costs when necessary, but it is not clear how NAc processing contributes to this role. Here, neuronal activity in the rat NAc was monitored using multi-neuron electrophysiology during two cost-based decision tasks in which either reward effort or reward delay was manipulated. In each task, distinct visual cues predicted high-value (low effort/immediate) and low-value (high effort/delayed) rewards. After training, animals exhibited a behavioral preference for high-value rewards, yet overcame high costs when necessary to obtain rewards. Electrophysiological analysis indicated that a subgroup of NAc neurons exhibited phasic increases in firing rate during cue presentations. In the effort-based decision task (but not the delay-based task), this population reflected the cost-discounted value of the future response. In contrast, other subgroups of cells were activated during response initiation or reward delivery, but activity did not differ on the basis of reward cost. Finally, another population of cells exhibited sustained changes in firing rate while animals completed high-effort requirements or waited for delayed rewards. These findings are consistent with previous reports that implicate NAc function in reward prediction and behavioral allocation during reward-seeking behavior, and suggest a mechanism by which NAc activity contributes to both cost-based decisions and actual cost expenditure.
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Most cases of cryptococcal meningitis in HIV-uninfected patients in Vietnam are due to a distinct amplified fragment length polymorphism-defined cluster of Cryptococcus neoformans var. grubii VN1.
J. Clin. Microbiol.
PUBLISHED: 12-15-2010
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Cryptococcal disease most commonly occurs in patients with an underlying immune deficit, most commonly HIV infection, and is due to Cryptococcus neoformans var. grubii. Occasionally disease due to this variety occurs in apparently immunocompetent patients. The relationship between strains infecting immunosuppressed and immunocompetent patients is not clear. Amplified fragment length polymorphism (AFLP) analysis was used to characterize the relationship between strains infecting HIV-infected and uninfected patients. Isolates from 51 HIV-uninfected patients and 100 HIV-infected patients with cryptococcal meningitis were compared. C. neoformans var. grubii VNI was responsible for infections in 73% of HIV-uninfected and 100% of HIV-infected patients. AFLP analysis defined two distinct clusters, VNI? and VNI?. The majority (84%) of isolates from HIV-uninfected patients were VNI?, compared with only 38% of isolates from HIV-infected patients (odds ratio, 8.30; 95% confidence interval [CI], 3.04 to 26.6; P < 0.0001). In HIV-uninfected patients, underlying disease was less frequent in those with VNI? infections. Two clusters of C. neoformans var. grubii VN1 are responsible for the majority of cases of cryptococcal meningitis in Vietnam. The distribution of these clusters differs according to the immune status of the host.
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AIDS-associated Penicillium marneffei infection of the central nervous system.
Clin. Infect. Dis.
PUBLISHED: 11-05-2010
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Penicillium marneffei is an important human immunodeficiency virus-associated opportunistic infection endemic in Southeast Asia. Central nervous system infection has not been described. We report the first case series of 21 human immunodeficiency virus-infected patients who presented with a syndrome consistent with acute central nervous system infection and who had Penicillium marneffei isolated from cerebrospinal fluid.
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Cognitive neuroepigenetics: a role for epigenetic mechanisms in learning and memory.
Neurobiol Learn Mem
PUBLISHED: 11-04-2010
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Although long-lasting behavioral memories have long been thought to require equally persistent molecular changes, little is known about the biochemical underpinnings of memory storage and maintenance. Increasing evidence now suggests that long-term behavioral change may be associated with epigenetic regulation of transcription in the central nervous system. In this review, we present evidence that changes in DNA methylation contribute to memory formation and maintenance, consider how DNA methylation affects readout of memory-related genes, and discuss how these changes may be important in the large-scale context of memory circuits. Finally, we discuss potential challenges involved in examining epigenetic changes in the brain and highlight how epigenetic mechanisms may be relevant for other cognitive processes.
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DNA methylation and memory formation.
Nat. Neurosci.
PUBLISHED: 10-27-2010
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Memory formation and storage require long-lasting changes in memory-related neuronal circuits. Recent evidence indicates that DNA methylation may serve as a contributing mechanism in memory formation and storage. These emerging findings suggest a role for an epigenetic mechanism in learning and long-term memory maintenance and raise apparent conundrums and questions. For example, it is unclear how DNA methylation might be reversed during the formation of a memory, how changes in DNA methylation alter neuronal function to promote memory formation, and how DNA methylation patterns differ between neuronal structures to enable both consolidation and storage of memories. Here we evaluate the existing evidence supporting a role for DNA methylation in memory, discuss how DNA methylation may affect genetic and neuronal function to contribute to behavior, propose several future directions for the emerging subfield of neuroepigenetics, and begin to address some of the broader implications of this work.
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Diagnosis of pulmonary tuberculosis in HIV-positive patients by microscopic observation drug susceptibility assay.
J. Clin. Microbiol.
PUBLISHED: 10-06-2010
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The microscopic observation drug susceptibility assay (MODS) is a novel and promising test for the early diagnosis of tuberculosis (TB). We evaluated the MODS assay for the early diagnosis of TB in HIV-positive patients presenting to Pham Ngoc Thach Hospital for Tuberculosis and Lung Diseases in southern Vietnam. A total of 738 consecutive sputum samples collected from 307 HIV-positive individuals suspected of TB were tested by smear, MODS, and the mycobacteria growth indicator tube method (MGIT). The diagnostic sensitivity and specificity of MODS compared to the microbiological gold standard (either smear or MGIT) were 87 and 93%, respectively. The sensitivities of smear, MODS, and MGIT were 57, 71, and 75%, respectively, against clinical gold standard (MODS versus smear, P<0.001; MODS versus MGIT, P=0.03). The clinical gold standard was defined as patients who had a clinical examination and treatment consistent with TB, with or without microbiological confirmation. For the diagnosis of smear-negative patients, the sensitivities of MODS and MGIT were 38 and 45%, respectively (P=0.08). The median times to detection using MODS and MGIT were 8 and 11 days, respectively, and they were 11 and 17 days, respectively, for smear-negative samples. The original bacterial/fungal contamination rate of MODS was 1.1%, while it was 2.6% for MGIT. The cross-contamination rate of MODS was 4.7%. In conclusion, MODS is a sensitive, specific, and rapid test that is appropriate for the detection of HIV-associated TB; its cost and ease of use make it particularly useful in resource-limited settings.
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AIDS?associated Cryptococcus neoformans and Penicillium marneffei coinfection: a therapeutic dilemma in resource?limited settings.
Clin. Infect. Dis.
PUBLISHED: 10-05-2010
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AIDS‐associated Cryptococcus neoformans and Penicillium marneffei coinfection has not been adequately studied and poses unique therapeutic challenges in resource‐limited settings. Itraconazole poorly penetrates the central nervous system, whereas fluconazole has poor activity against P. marneffei. We prospectively report management of 1 patient and retrospectively review 7 coinfection cases from Vietnam.
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A prospective descriptive study of cryptococcal meningitis in HIV uninfected patients in Vietnam - high prevalence of Cryptococcus neoformans var grubii in the absence of underlying disease.
BMC Infect. Dis.
PUBLISHED: 07-09-2010
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Most cases of cryptococcal meningitis occur in patients with HIV infection: the course and outcome of disease in the apparently immunocompetent is much more poorly understood. We describe a cohort of HIV uninfected Vietnamese patients with cryptococcal meningitis in whom underlying disease is uncommon, and relate presenting features of patients and the characteristics of the infecting species to outcome.
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The burden and characteristics of enteric fever at a healthcare facility in a densely populated area of Kathmandu.
PLoS ONE
PUBLISHED: 07-01-2010
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Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi A (S. Typhi and S. Paratyphi A) remains a major public health problem in many settings. The disease is limited to locations with poor sanitation which facilitates the transmission of the infecting organisms. Efficacious and inexpensive vaccines are available for S. Typhi, yet are not commonly deployed to control the disease. Lack of vaccination is due partly to uncertainty of the disease burden arising from a paucity of epidemiological information in key locations. We have collected and analyzed data from 3,898 cases of blood culture-confirmed enteric fever from Patan Hospital in Lalitpur Sub-Metropolitan City (LSMC), between June 2005 and May 2009. Demographic data was available for a subset of these patients (n = 527) that were resident in LSMC and who were enrolled in trials. We show a considerable burden of enteric fever caused by S. Typhi (2,672; 68.5%) and S. Paratyphi A (1,226; 31.5%) at this Hospital over a four year period, which correlate with seasonal fluctuations in rainfall. We found that local population density was not related to incidence and we identified a focus of infections in the east of LSMC. With data from patients resident in LSMC we found that the median age of those with S. Typhi (16 years) was significantly less than S. Paratyphi A (20 years) and that males aged 15 to 25 were disproportionately infected. Our findings provide a snapshot into the epidemiological patterns of enteric fever in Kathmandu. The uneven distribution of enteric fever patients within the population suggests local variation in risk factors, such as contaminated drinking water. These findings are important for initiating a vaccination scheme and improvements in sanitation. We suggest any such intervention should be implemented throughout the LSMC area.
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Phasic nucleus accumbens dopamine release encodes effort- and delay-related costs.
Biol. Psychiatry
PUBLISHED: 01-28-2010
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Optimal decision-making requires that organisms correctly evaluate both the costs and benefits of potential choices. Dopamine transmission within the nucleus accumbens (NAc) has been heavily implicated in reward-learning and decision-making, but it is unclear how dopamine release might contribute to decisions that involve costs.
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Regional specificity in the real-time development of phasic dopamine transmission patterns during acquisition of a cue-cocaine association in rats.
Eur. J. Neurosci.
PUBLISHED: 11-11-2009
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Drug seeking is significantly regulated by drug-associated cues and associative learning between environmental cues and cocaine reward is mediated by dopamine transmission within the nucleus accumbens (NAc). However, dopamine transmission during early acquisition of a cue-cocaine association has never been assessed because of the technical difficulties associated with resolving cue-evoked and cocaine-evoked dopamine release within the same conditioning trial. Here, we used fast-scan cyclic voltammetry to measure sub-second fluctuations in dopamine concentration within the NAc core and shell during the initial acquisition of a cue-cocaine Pavlovian association. Within the NAc core, cue-evoked dopamine release developed during conditioning. However, within the NAc shell, the predictive cue appeared to cause an unconditioned decrease in dopamine concentration. The pharmacological effects of cocaine also differed between sub-regions, as cocaine increased phasic dopamine release events within the NAc shell but not the core. Thus, real-time measurements not only revealed the initial development of a conditioned neurochemical response but also demonstrated differential phasic dopamine transmission patterns across NAc sub-regions during the acquisition of a cue-cocaine association.
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Basolateral amygdala modulates terminal dopamine release in the nucleus accumbens and conditioned responding.
Biol. Psychiatry
PUBLISHED: 09-01-2009
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Dopamine signaling in the nucleus accumbens (NAc) is essential for goal-directed behaviors and primarily arises from burst firing of ventral tegmental area neurons. However, the role of associative neural substrates such as the basolateral amygdala (BLA) in regulating phasic dopamine release in the NAc, particularly during reward seeking, remains unknown.
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Microscopic observation drug susceptibility assay (MODS) for early diagnosis of tuberculosis in children.
PLoS ONE
PUBLISHED: 07-20-2009
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MODS is a novel liquid culture based technique that has been shown to be effective and rapid for early diagnosis of tuberculosis (TB). We evaluated the MODS assay for diagnosis of TB in children in Viet Nam. 217 consecutive samples including sputum (n = 132), gastric fluid (n = 50), CSF (n = 32) and pleural fluid (n = 3) collected from 96 children with suspected TB, were tested by smear, MODS and MGIT. When test results were aggregated by patient, the sensitivity and specificity of smear, MGIT and MODS against "clinical diagnosis" (confirmed and probable groups) as the gold standard were 28.2% and 100%, 42.3% and 100%, 39.7% and 94.4%, respectively. The sensitivity of MGIT and MODS was not significantly different in this analysis (P = 0.5), but MGIT was more sensitive than MODS when analysed on the sample level using a marginal model (P = 0.03). The median time to detection of MODS and MGIT were 8 days and 13 days, respectively, and the time to detection was significantly shorter for MODS in samples where both tests were positive (P<0.001). An analysis of time-dependent sensitivity showed that the detection rates were significantly higher for MODS than for MGIT by day 7 or day 14 (P<0.001 and P = 0.04), respectively. MODS is a rapid and sensitive alternative method for the isolation of M.tuberculosis from children.
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Factors associated with treatment failure of patients with psychiatric diseases and injecting drug users in the treatment of genotype 2 or 3 hepatitis C chronic infection.
Liver Int.
PUBLISHED: 07-08-2009
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Genotype 2/3 hepatitis C virus (HCV) has a good response to treatment with peginterferon and ribavirin. Patients with psychiatric disorders and injecting drug users (IDUs) are considered difficult to treat and are often excluded from treatment despite the lack of evidence supporting this decision.
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Reduction in neutrophil count during hepatitis C treatment: drug toxicity or predictor of good response?
Dig. Dis. Sci.
PUBLISHED: 04-17-2009
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Bone marrow suppression is a well-recognized toxicity of the treatment of hepatitis C virus (HCV). Reduction of the peginterferon dose because of neutropenia is common in clinical practice. However, reduction of peginterferon dose during the first weeks of HCV treatment is associated with failure to achieve sustained virological response.
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Classification of voluntary cough sound and airflow patterns for detecting abnormal pulmonary function.
Cough
PUBLISHED: 03-27-2009
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Involuntary cough is a classic symptom of many respiratory diseases. The act of coughing serves a variety of functions such as clearing the airways in response to respiratory irritants or aspiration of foreign materials. It has been pointed out that a cough results in substantial stresses on the body which makes voluntary cough a useful tool in physical diagnosis.
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Clonality despite sex: the evolution of host-associated sexual neighborhoods in the pathogenic fungus Penicillium marneffei.
PLoS Pathog.
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Molecular genetic approaches typically detect recombination in microbes regardless of assumed asexuality. However, genetic data have shown the AIDS-associated pathogen Penicillium marneffei to have extensive spatial genetic structure at local and regional scales, and although there has been some genetic evidence that a sexual cycle is possible, this haploid fungus is thought to be genetically, as well as morphologically, asexual in nature because of its highly clonal population structure. Here we use comparative genomics, experimental mixed-genotype infections, and population genetic data to elucidate the role of recombination in natural populations of P. marneffei. Genome wide comparisons reveal that all the genes required for meiosis are present in P. marneffei, mating type genes are arranged in a similar manner to that found in other heterothallic fungi, and there is evidence of a putatively meiosis-specific mutational process. Experiments suggest that recombination between isolates of compatible mating types may occur during mammal infection. Population genetic data from 34 isolates from bamboo rats in India, Thailand and Vietnam, and 273 isolates from humans in China, India, Thailand, and Vietnam show that recombination is most likely to occur across spatially and genetically limited distances in natural populations resulting in highly clonal population structure yet sexually reproducing populations. Predicted distributions of three different spatial genetic clusters within P. marneffei overlap with three different bamboo rat host distributions suggesting that recombination within hosts may act to maintain population barriers within P. marneffei.
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Direct bisulfite sequencing for examination of DNA methylation with gene and nucleotide resolution from brain tissues.
Curr Protoc Neurosci
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DNA methylation is an epigenetic modification that is essential for the development and mature function of the central nervous system. Due to the relevance of this modification to the transcriptional control of gene expression, it is often necessary to examine changes in DNA methylation patterns with both gene and single-nucleotide resolution. Here, we describe an in-depth basic protocol for direct bisulfite sequencing of DNA isolated from brain tissue, which will permit direct assessment of methylation status at individual genes as well as individual cytosine molecules/nucleotides within a genomic region. This method yields analysis of DNA methylation patterns that is robust, accurate, and reproducible, thereby allowing insights into the role of alterations in DNA methylation in brain tissue.
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Aetiologies of central nervous system infection in Viet Nam: a prospective provincial hospital-based descriptive surveillance study.
PLoS ONE
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Infectious diseases of the central nervous system (CNS) remain common and life-threatening, especially in developing countries. Knowledge of the aetiological agents responsible for these infections is essential to guide empiric therapy and develop a rational public health policy. To date most data has come from patients admitted to tertiary referral hospitals in Asia and there is limited aetiological data at the provincial hospital level where most patients are seen.
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Influence of antituberculosis drug resistance and Mycobacterium tuberculosis lineage on outcome in HIV-associated tuberculous meningitis.
Antimicrob. Agents Chemother.
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HIV-associated tuberculous meningitis (TBM) has high mortality. Aside from the devastating impact of multidrug resistance (MDR) on survival, little is understood about the influence of other bacterial factors on outcome. This study examined the influence of Mycobacterium tuberculosis drug resistance, bacterial lineage, and host vaccination status on outcome in patients with HIV-associated TBM. Mycobacterium tuberculosis isolates from the cerebrospinal fluid of 186 patients enrolled in two studies of HIV-associated TBM in Ho Chi Minh City, Vietnam, were tested for resistance to first-line antituberculosis drugs. Lineage genotyping was available for 122 patients. The influence of antituberculosis drug resistance and M. tuberculosis lineage on 9-month mortality was analyzed using Kaplan-Meier survival analysis and Cox multiple regression models. Isoniazid (INH) resistance without rifampin resistance was associated with increased mortality (adjusted hazard ratio [HR], 1.78, 95% confidence interval [CI], 1.18 to 2.66; P = 0.005), and multidrug resistance was uniformly fatal (n = 8/8; adjusted HR, 5.21, 95% CI, 2.38 to 11.42; P < 0.0001). The hazard ratio for INH-resistant cases was greatest during the continuation phase of treatment (after 3 months; HR, 5.05 [95% CI, 2.23 to 11.44]; P = 0.0001). Among drug-susceptible cases, patients infected with the "modern" Beijing lineage strains had lower mortality than patients infected with the "ancient" Indo-Oceanic lineage (HR, 0.29 [95% CI, 0.14 to 0.61]; P = 0.001). Isoniazid resistance, multidrug resistance, and M. tuberculosis lineage are important determinants of mortality in patients with HIV-associated TBM. Interventions which target these factors may help reduce the unacceptably high mortality in patients with TBM.
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