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1.  Immunotoxicity of zinc oxide nanoparticles with different size and electrostatic charge 
International Journal of Nanomedicine  2014;9(Suppl 2):195-205.
While zinc oxide (ZnO) nanoparticles (NPs) have been recognized to have promising applications in biomedicine, their immunotoxicity has been inconsistent and even contradictory. To address this issue, we investigated whether ZnO NPs with different size (20 or 100 nm) and electrostatic charge (positive or negative) would cause immunotoxicity in vitro and in vivo, and explored their underlying molecular mechanism. Using Raw 264.7 cell line, we examined the immunotoxicity mechanism of ZnO NPs as cell viability. We found that in a cell viability assay, ZnO NPs with different size and charge could induce differential cytotoxicity to Raw 264.7 cells. Specifically, the positively charged ZnO NPs exerted higher cytotoxicity than the negatively charged ones. Next, to gauge systemic immunotoxicity, we assessed immune responses of C57BL/6 mice after oral administration of 750 mg/kg/day dose of ZnO NPs for 2 weeks. In parallel, ZnO NPs did not alter the cell-mediated immune response in mice but suppressed innate immunity such as natural killer cell activity. The CD4+/CD8+ ratio, a marker for matured T-cells was slightly reduced, which implies the alteration of immune status induced by ZnO NPs. Accordingly, nitric oxide production from splenocyte culture supernatant in ZnO NP-fed mice was lower than control. Consistently, serum levels of pro/anti-inflammatory (interleukin [IL]-1β, tumor necrosis factor-α, and IL-10) and T helper-1 cytokines (interferon-γ and IL-12p70) in ZnO NP-fed mice were significantly suppressed. Collectively, our results indicate that different sized and charged ZnO NPs would cause in vitro and in vivo immunotoxicity, of which nature is an immunosuppression.
PMCID: PMC4279726  PMID: 25565837
immunosuppression; cytokine; ZnO; immune response; cytotoxicity; innate immunity
2.  A Systematic Review of the Literature on Cystic Echinococcosis Frequency Worldwide and Its Associated Clinical Manifestations 
A systematic literature review of cystic echinoccocosis (CE) frequency and symptoms was conducted. Studies without denominators, original data, or using one serological test were excluded. Random-effect log-binomial models were run for CE frequency and proportion of reported symptoms where appropriate. A total of 45 and 25 articles on CE frequency and symptoms met all inclusion criteria. Prevalence of CE ranged from 1% to 7% in community-based studies and incidence rates ranged from 0 to 32 cases per 100,000 in hospital-based studies. The CE prevalence was higher in females (Prevalence Proportion Ratio: 1.35 [95% Bayesian Credible Interval: 1.16–1.53]) and increased with age. The most common manifestations of hepatic and pulmonary CE were abdominal pain (57.3% [95% confidence interval [CI]: 37.3–76.1%]) and cough (51.3% [95% CI: 35.7–66.7%]), respectively. The results are limited by the small number of unbiased studies. Nonetheless, the age/gender prevalence differences could be used to inform future models of CE burden.
PMCID: PMC3752796  PMID: 23546806
3.  Methanol extract from Vietnamese Caesalpinia sappan induces apoptosis in HeLa cells 
Biological Research  2014;47(1):20.
This study evaluated the cytotoxic activity of extracts from Caesalpinia sappan heartwood against multiple cancer cell lines using an MTT cell viability assay. The cell death though induction of apoptosis was as indicated by DNA fragmentation and caspase-3 enzyme activation.
A methanol extract from C. sappan (MECS) showed cytotoxic activity against several of the cancer cell lines. The most potent activity exhibited by the MECS was against HeLa cells with an IC50 value of 26.5 ± 3.2 μg/mL. Treatment of HeLa cells with various MECS concentrations resulted in growth inhibition and induction of apoptosis, as indicated by DNA fragmentation and caspase-3 enzyme activation.
This study is the first report of the anticancer properties of the heartwood of C. sappan native to Vietnam. Our findings demonstrate that C. sappan heartwood may have beneficial applications in the field of anticancer drug discovery.
PMCID: PMC4101718  PMID: 25028057
Caesalpinia sappan; Leguminosae; MTT assay; DNA fragmentation; Caspase-3
4.  sLORETA current source density analysis of evoked potentials for spatial updating in a virtual navigation task 
Previous studies have reported that multiple brain regions are activated during spatial navigation. However, it is unclear whether these activated brain regions are specifically associated with spatial updating or whether some regions are recruited for parallel cognitive processes. The present study aimed to localize current sources of event related potentials (ERPs) associated with spatial updating specifically. In the control phase of the experiment, electroencephalograms (EEGs) were recorded while subjects sequentially traced 10 blue checkpoints on the streets of a virtual town, which were sequentially connected by a green line, by manipulating a joystick. In the test phase of the experiment, the checkpoints and green line were not indicated. Instead, a tone was presented when the subjects entered the reference points where they were then required to trace the 10 invisible spatial reference points corresponding to the checkpoints. The vertex-positive ERPs with latencies of approximately 340 ms from the moment when the subjects entered the unmarked reference points were significantly larger in the test than in the control phases. Current source density analysis of the ERPs by standardized low-resolution brain electromagnetic tomography (sLORETA) indicated activation of brain regions in the test phase that are associated with place and landmark recognition (entorhinal cortex/hippocampus, parahippocampal and retrosplenial cortices, fusiform, and lingual gyri), detecting self-motion (posterior cingulate and posterior insular cortices), motor planning (superior frontal gyrus, including the medial frontal cortex), and regions that process spatial attention (inferior parietal lobule). The present results provide the first identification of the current sources of ERPs associated with spatial updating, and suggest that multiple systems are active in parallel during spatial updating.
PMCID: PMC3941310  PMID: 24624067
virtual navigation; ERPs; current source density; place recognition; spatial updating
5.  Unligated Okazaki Fragments Induce PCNA Ubiquitination and a Requirement for Rad59-Dependent Replication Fork Progression 
PLoS ONE  2013;8(6):e66379.
Deficiency in DNA ligase I, encoded by CDC9 in budding yeast, leads to the accumulation of unligated Okazaki fragments and triggers PCNA ubiquitination at a non-canonical lysine residue. This signal is crucial to activate the S phase checkpoint, which promotes cell cycle delay. We report here that a pol30-K107 mutation alleviated cell cycle delay in cdc9 mutants, consistent with the idea that the modification of PCNA at K107 affects the rate of DNA synthesis at replication forks. To determine whether PCNA ubiquitination occurred in response to nicks or was triggered by the lack of PCNA-DNA ligase interaction, we complemented cdc9 cells with either wild-type DNA ligase I or a mutant form, which fails to interact with PCNA. Both enzymes reversed PCNA ubiquitination, arguing that the modification is likely an integral part of a novel nick-sensory mechanism and not due to non-specific secondary mutations that could have occurred spontaneously in cdc9 mutants. To further understand how cells cope with the accumulation of nicks during DNA replication, we utilized cdc9-1 in a genome-wide synthetic lethality screen, which identified RAD59 as a strong negative interactor. In comparison to cdc9 single mutants, cdc9 rad59Δ double mutants did not alter PCNA ubiquitination but enhanced phosphorylation of the mediator of the replication checkpoint, Mrc1. Since Mrc1 resides at the replication fork and is phosphorylated in response to fork stalling, these results indicate that Rad59 alleviates nick-induced replication fork slowdown. Thus, we propose that Rad59 promotes fork progression when Okazaki fragment processing is compromised and counteracts PCNA-K107 mediated cell cycle arrest.
PMCID: PMC3688925  PMID: 23824283
6.  Design and validation of an intelligent wheelchair towards a clinically-functional outcome 
Many people with mobility impairments, who require the use of powered wheelchairs, have difficulty completing basic maneuvering tasks during their activities of daily living (ADL). In order to provide assistance to this population, robotic and intelligent system technologies have been used to design an intelligent powered wheelchair (IPW). This paper provides a comprehensive overview of the design and validation of the IPW.
The main contributions of this work are three-fold. First, we present a software architecture for robot navigation and control in constrained spaces. Second, we describe a decision-theoretic approach for achieving robust speech-based control of the intelligent wheelchair. Third, we present an evaluation protocol motivated by a meaningful clinical outcome, in the form of the Robotic Wheelchair Skills Test (RWST). This allows us to perform a thorough characterization of the performance and safety of the system, involving 17 test subjects (8 non-PW users, 9 regular PW users), 32 complete RWST sessions, 25 total hours of testing, and 9 kilometers of total running distance.
User tests with the RWST show that the navigation architecture reduced collisions by more than 60% compared to other recent intelligent wheelchair platforms. On the tasks of the RWST, we measured an average decrease of 4% in performance score and 3% in safety score (not statistically significant), compared to the scores obtained with conventional driving model. This analysis was performed with regular users that had over 6 years of wheelchair driving experience, compared to approximately one half-hour of training with the autonomous mode.
The platform tested in these experiments is among the most experimentally validated robotic wheelchairs in realistic contexts. The results establish that proficient powered wheelchair users can achieve the same level of performance with the intelligent command mode, as with the conventional command mode.
PMCID: PMC3691756  PMID: 23773851
Assistive robotics; Intelligent powered wheelchairs; Wheelchair skills test
7.  Kv1.3 deletion biases T cells towards an immuno-regulatory phenotype and renders mice resistant to autoimmune encephalomyelitis1 
Increasing evidence suggests ion channels have critical functions in the differentiation and plasticity of T cells. Kv1.3, a voltage-gated K+ channel, is a functional marker and a pharmacological target for activated effector memory T cells. Selective Kv1.3 blockers have been shown to inhibit proliferation and cytokine production by human and rat effector memory T cells. We utilized Kv1.3 knockout mice to investigate the mechanism by which Kv1.3 blockade affects CD4+ T cell differentiation during an inflammatory immune-mediated disease. Kv1.3 knockout animals displayed significantly lower incidence and severity of MOG peptide-induced experimental autoimmune encephalomyelitis. Kv1.3 was the only KV channel expressed in MOG 35–55-specific CD4+ T cell-blasts, and no KV current was present in MOG-specific CD4+ T cell-blasts from Kv1.3 knockout mice. Fewer CD4+ T cells migrated to the CNS in Kv1.3 knockout mice following disease induction, and antigen-specific proliferation of CD4+ T cells from these mice was impaired with a corresponding cell cycle delay. Kv1.3 was required for optimal expression of IFN-γ and IL-17, while its absence led to increased IL-10 production. Dendritic cells from Kv1.3 knockout mice fully activated WT CD4+ T cells, indicating a T cell intrinsic defect in Kv1.3 knockout mice. The loss of Kv1.3 led to a suppressive phenotype, which may contribute to the mechanism by which deletion of Kv1.3 produces an immunotherapeutic effect. Skewing of CD4+ T cell differentiation towards antigen-specific regulatory T cells by pharmacological blockade or genetic suppression of Kv1.3 might be beneficial for therapy of immune-mediated diseases such as multiple sclerosis.
PMCID: PMC3370138  PMID: 22581856
potassium channels; Kv1.3 knockout; CD4+ T cells; autoimmunity; experimental autoimmune encephalomyelitis (EAE)
8.  Two Distinct Modes of ATR Activation Orchestrated by Rad17 and Nbs1 
Cell reports  2013;3(5):1651-1662.
The ATR kinase is a master regulator of the DNA damage response. Yet, how ATR is activated towards different substrates is still poorly understood. Here, we show that ATR phosphorylates Chk1 and RPA32 through distinct mechanisms at replication-associated DNA double-stranded breaks (DSBs). In contrast to the rapid phosphorylation of Chk1, RPA32 is progressively phosphorylated by ATR at Ser33 during DSB resection prior to the phosphorylation of Ser4/Ser8 by DNA-PKcs. Surprisingly, despite its reliance on ATR and TopBP1, substantial RPA32 Ser33 phosphorylation occurs in a Rad17-independent but Nbs1-dependent manner in vivo and in vitro. Importantly, the role of Nbs1 in RPA32 phosphorylation can be separated from ATM activation and DSB resection, and is dependent upon its interaction with RPA. An Nbs1 mutant unable to bind RPA fails to support proper recovery of collapsed replication forks, suggesting that the Nbs1-mediated mode of ATR activation is important for the repair of replication-associated DSBs.
PMCID: PMC3680100  PMID: 23684611
9.  Estimating the payoffs from cardiovascular disease research in Canada: an economic analysis 
CMAJ Open  2013;1(2):E83-E90.
Investments in medical research can result in health improvements, reductions in health expenditures and secondary economic benefits. These “returns” have not been quantified in Canada. Our objective was to estimate the return on cardiovascular disease research funded by public or charitable organizations.
Our primary outcome was the internal rate of return on cardiovascular disease research funded by public or charitable sources. The internal rate of return is the annual monetary benefit to the economy for each dollar invested in cardiovascular disease research. Calculation of the internal rate of return involved the following: measuring expenditures on cardiovascular disease research, estimating the health gains accrued from new treatments for cardiovascular disease, determining the proportion of health gains attributable to cardiovascular disease research and the time lag between research expenditures and health gains, and estimating the spillovers from public- or charitable-sector investments to other sectors of the economy.
Expenditures by public or charitable organizations on cardiovascular disease research from 1981 to 1992 amounted to $392 million (2005 dollars). Health gains associated with new treatments from 1994 to 2005 (13-yr lag) amounted to 2.2 million quality-adjusted life-years. We calculated an internal rate of return of 20.6%.
Canadians obtain relatively high health and economic gains from investments in cardiovascular disease research. Every $1 invested in cardiovascular disease research by public or charitable sources yields a stream of benefits of roughly $0.21 to the Canadian economy per year, in perpetuity.
PMCID: PMC3986018  PMID: 25077108
10.  Activation of Inflammasomes by Tumor Cell Death Mediated by Gold Nanoshells 
Biomaterials  2011;33(7):2197-2205.
Gold nanoshell enabled photothermal therapy (NEPTT) utilizes the efficient thermal conversion of near infrared (NIR) light for the ablation of cancer cells. Cancer therapies that combine cell killing with the induction of a strong immune response against the dying tumor cells have been shown to increase therapeutic efficacy in the clearance and regression of cancers. In this study, we assessed the ability of dying cells generated by in vitro NEPTT to activate inflammasome complexes. We quantified levels of major danger-associated molecular patterns (DAMPs), including adenosine triphosphate (ATP), adenosine diphosphate (ADP), and uric acid, released from tumor cells treated by NEPTT. The amount of DAMPs released was dependent on the dose of nanoshells internalized by cells. However, under all the employed conditions, the levels of generated DAMPs were insufficient to activate inflammasome complexes and to induce the production of pro-inflammatory cytokines (i.e. IL-1β). The results from this study provide insights into the development of nanoplasmonics for combining both photothermal therapy and immunotherapy to eradicate cancers.
PMCID: PMC3259204  PMID: 22177288
gold nanoshell; nanoplamonics; apoptosis; necrosis; NALP3 inflammasome; DAMPs; immunotherapy
11.  Effect of Surface Chemistry on Gene Transfer Efficiency Mediated by Surface-induced DNA-doped Nanocomposites 
Acta Biomaterialia  2011;8(3):1109-1116.
Surface-induced biomineralization represents an effective way to immobilize DNA molecules onto biomaterial surfaces for introducing DNA into cells in contact with or in an approximate distance to biomaterial surfaces. Our previous studies have investigated how the composition of mineralizing solutions affects the composition and pH responsiveness of nanocomposites and thus gene transfer efficiency in different cell types. In this study, we investigated how the functional groups of a biomaterial surface would affect the induction and crystallographic properties of nanocomposites and thus the gene transfer efficiency. Self-assembled monolayers (SAMs) with different terminus were used to control the functional groups of a surface. We demonstrated that the induction of DNA-doped nanocomposites depended on the surface functional groups, which is consistent with previous studies. The crystallographic properties did not vary significantly with the functional groups. DNA-doped nanocomposites induced by different surface functional groups resulted in different cellular uptake of DNA and thus gene transfer efficiency. The differential cellular uptake may be attributed to the interactions between nanocomposites and functional groups. The weaker inducer resulted in higher cellular uptake thus higher gene transfer efficiency. Together with others and our previous studies, our current results suggest that surface-mediated gene transfer by DNA-doped nanocomposites can be modulated through both mineralizing solutions and surface chemistries.
PMCID: PMC3272147  PMID: 22198137
Tissue engineering; Gene therapy; Surface-mediated gene delivery; Nanocomposites
12.  Outcomes of Antiretroviral Therapy in Vietnam: Results from a National Evaluation 
PLoS ONE  2013;8(2):e55750.
Vietnam has significantly scaled up its national antiretroviral therapy (ART) program since 2005. With the aim of improving Vietnam’s national ART program, we conducted an outcome evaluation of the first five years of the program in this concentrated HIV epidemic where the majority of persons enrolled in HIV care and treatment services are people who inject drugs (PWID). The results of this evaluation may have relevance for other national ART programs with significant PWID populations.
Retrospective cohort analysis of patients at 30 clinics randomly selected with probability proportional to size among 120 clinics with at least 50 patients on ART.
Charts of patients whose ART initiation was at least 6 months prior to the study date were abstracted. Depending on clinic size, either all charts or a random sample of 300 charts were selected. Analyses were limited to treatment-naïve patients. Multiple imputations were used for missing data.
Of 7,587 patient charts sampled, 6,875 were those of treatment-naïve patients (74.4% male, 95% confidence interval [CI]: 72.4–76.5, median age 30, interquartile range [IQR]: 26–34, 62.0% reported a history of intravenous drug use, CI: 58.6–65.3). Median baseline CD4 cell count was 78 cells/mm3 (IQR: 30–162) and 30.4% (CI: 25.8–35.1) of patients were at WHO stage IV. The majority of patients started d4T/3TC/NVP (74.3%) or d4T/3TC/EFV (18.6%). Retention rates after 6, 12, 24, and 36 months were 88.4% (CI: 86.8–89.9), 84.0% (CI: 81.8–86.0), 78.8% (CI: 75.7–81.6), and 74.6% (CI: 69.6–79.0). Median CD4 cell count gains after 6, 12, 24, and 36 months were 94 (IQR: 45–153), 142 (IQR: 78–217), 213 (IQR: 120–329), and 254 (IQR: 135–391) cells/mm3. Patients who were PWID showed significantly poorer retention.
The study showed good retention and immunological response to ART among a predominantly PWID group of patients despite advanced HIV infections at baseline.
PMCID: PMC3574016  PMID: 23457477
13.  Litchi–associated Acute Encephalitis in Children, Northern Vietnam, 2004–2009 
Emerging Infectious Diseases  2012;18(11):1817-1824.
Outbreaks are spatiotemporally associated with litchi harvest, but the causative agent remains unknown.
Since the end of the 1990s, unexplained outbreaks of acute encephalitis in children coinciding with litchi harvesting (May–July) have been documented in the Bac Giang Province in northern Vietnam. A retrospective ecologic analysis of data for 2004–2009 involving environmental, agronomic, and climatic factors was conducted to investigate the suspected association between the outbreaks and litchi harvesting. The clinical, biological, and immunologic characteristics of the patients suggested a viral etiology. The ecologic study revealed an independent association between litchi plantation surface proportion and acute encephalitis incidence: Incidence rate ratios were 1.52 (95% CI 0.90–2.57), 2.94 (95% CI 1.88–4.60), and 2.76 (95% CI 1.76–4.32) for second, third, and fourth quartiles, respectively, compared with the lowest quartile. This ecologic study confirmed the suspected association between incidence of acute encephalitis and litchi plantations and should be followed by other studies to identify the causative agent for this syndrome.
PMCID: PMC3559149  PMID: 23092599
Encephalitis; epidemics; disease outbreaks; epidemiology; risk factors; litchi; retrospective studies; Vietnam; Asia; viruses; vector-borne infections
14.  Improving the Description of Salt Bridge Strength and Geometry in a Generalized Born Model 
The Generalized Born (GB) solvent model is widely used in molecular dynamics simulations because it can be less computationally expensive and it samples conformational changes more efficiently than explicit solvent simulations. Meanwhile, great efforts have been made in the past to improve its precision and accuracy. Previous studies have shown that reducing intrinsic GB radii of some hydrogen atoms would improve AMBER GB-HCT solvent model's accuracy on salt bridges. Here we present our finding that similar correction also shows dramatic improvement for the AMBER GB-OBC solvent model. Potential of mean force and cluster analysis for small peptide replica exchange molecular dynamics simulations suggested that new radii GB simulation with ff99SB/GB-OBC corrected salt bridge strength and achieved significantly higher geometry similarity with TIP3P simulation. Improved performance in 60 ns HIV-1 protease GB simulation further validated this approach for large systems.
PMCID: PMC3390179  PMID: 21168352
intrinsic radii; salt bridge; PMF; cluster analysis; HIV-1 protease; HIVPR
15.  Role of Maltose Enzymes in Glycogen Synthesis by Escherichia coli▿ 
Journal of Bacteriology  2011;193(10):2517-2526.
Mutants with deletion mutations in the glg and mal gene clusters of Escherichia coli MC4100 were used to gain insight into glycogen and maltodextrin metabolism. Glycogen content, molecular mass, and branch chain distribution were analyzed in the wild type and in ΔmalP (encoding maltodextrin phosphorylase), ΔmalQ (encoding amylomaltase), ΔglgA (encoding glycogen synthase), and ΔglgA ΔmalP derivatives. The wild type showed increasing amounts of glycogen when grown on glucose, maltose, or maltodextrin. When strains were grown on maltose, the glycogen content was 20 times higher in the ΔmalP strain (0.97 mg/mg protein) than in the wild type (0.05 mg/mg protein). When strains were grown on glucose, the ΔmalP strain and the wild type had similar glycogen contents (0.04 mg/mg and 0.03 mg/mg protein, respectively). The ΔmalQ mutant did not grow on maltose but showed wild-type amounts of glycogen when grown on glucose, demonstrating the exclusive function of GlgA for glycogen synthesis in the absence of maltose metabolism. No glycogen was found in the ΔglgA and ΔglgA ΔmalP strains grown on glucose, but substantial amounts (0.18 and 1.0 mg/mg protein, respectively) were found when they were grown on maltodextrin. This demonstrates that the action of MalQ on maltose or maltodextrin can lead to the formation of glycogen and that MalP controls (inhibits) this pathway. In vitro, MalQ in the presence of GlgB (a branching enzyme) was able to form glycogen from maltose or linear maltodextrins. We propose a model of maltodextrin utilization for the formation of glycogen in the absence of glycogen synthase.
PMCID: PMC3133173  PMID: 21421758
16.  Damage-specific modification of PCNA 
Cell Cycle  2010;9(18):3674-3679.
Okazaki fragment processing is an integral part of DNA replication. For a long time, we assumed that the maturation of these small RNA-primed DNA fragments did not necessarily have to occur during S phase, but could be postponed to late in S phase after the bulk of DNA synthesis had been completed. This view was primarily based on the arrest phenotype of temperature-sensitive DNA ligase I mutants in yeast, which accumulated with an almost fully duplicated set of chromosomes. However, many temperature-sensitive alleles can be leaky and the re-evaluation of DNA ligase I-deficient cells has offered new and unexpected insights into how cells keep track of lagging strand synthesis. It turns out that if Okazaki fragment joining goes awry, cells have their own alarm system in the form of ubiquitin that is conjugated to the replication clamp PCNA. Although this modification results in mono- and poly-ubiquitination of PCNA, it is genetically distinct from the known post-replicative repair mark at lysine 164. In this Extra View, we discuss the possibility that eukaryotic cells utilize different enzymatic pathways and ubiquitin attachment sites on PCNA to alert the replication machinery to the accumulation of single-stranded gaps or nicks behind the fork.
PMCID: PMC3047796  PMID: 20930510
DNA ligase I; DNA replication; Okazaki fragment processing; PCNA; ubiquitin; SUMO
17.  Analysis of the Waggle Dance Motion of Honeybees for the Design of a Biomimetic Honeybee Robot 
PLoS ONE  2011;6(8):e21354.
The honeybee dance “language” is one of the most popular examples of information transfer in the animal world. Today, more than 60 years after its discovery it still remains unknown how follower bees decode the information contained in the dance. In order to build a robotic honeybee that allows a deeper investigation of the communication process we have recorded hundreds of videos of waggle dances. In this paper we analyze the statistics of visually captured high-precision dance trajectories of European honeybees (Apis mellifera carnica). The trajectories were produced using a novel automatic tracking system and represent the most detailed honeybee dance motion information available. Although honeybee dances seem very variable, some properties turned out to be invariant. We use these properties as a minimal set of parameters that enables us to model the honeybee dance motion. We provide a detailed statistical description of various dance properties that have not been characterized before and discuss the role of particular dance components in the commmunication process.
PMCID: PMC3153927  PMID: 21857906
18.  Clinical Manifestations Associated with Neurocysticercosis: A Systematic Review 
The clinical manifestations of neurocysticercosis (NCC) are poorly understood. This systematic review aims to estimate the frequencies of different manifestations, complications and disabilities associated with NCC.
A systematic search of the literature published from January 1, 1990, to June 1, 2008, in 24 different electronic databases and 8 languages was conducted. Meta-analyses were conducted when appropriate.
A total of 1569 documents were identified, and 21 included in the analysis. Among patients seen in neurology clinics, seizures/epilepsy were the most common manifestations (78.8%, 95%CI: 65.1%–89.7%) followed by headaches (37.9%, 95%CI: 23.3%–53.7%), focal deficits (16.0%, 95%CI: 9.7%–23.6%) and signs of increased intracranial pressure (11.7%, 95%CI: 6.0%–18.9%). All other manifestations occurred in less than 10% of symptomatic NCC patients. Only four studies reported on the mortality rate of NCC.
NCC is a pleomorphic disease linked to a range of manifestations. Although definitions of manifestations were very rarely provided, and varied from study to study, the proportion of NCC cases with seizures/epilepsy and the proportion of headaches were consistent across studies. These estimates are only applicable to patients who are ill enough to seek care in neurology clinics and likely over estimate the frequency of manifestations among all NCC cases.
Author Summary
Neurocysticercosis is an infection of the brain with the flatworm Taenia solium which is normally transmitted between humans and pigs. Sometimes, humans can infect other humans and the larva of the parasite can go the brain, causing the disease neurocysticercosis. There has never been a systematic review of what clinical signs are found among people with neurocysticercosis. We conducted a thorough review of the literature to answer this question. We reviewed 1569 and 21 were of a sufficient quality to be included in the final analysis. Among neurocysticercosis patients who are seeking care in neurology clinics, about 79% have seizures/epilepsy, 38% severe headaches, 16% focal deficits and 12% signs of increased intracranial pressure. Several other symptoms were also reported in less than 10% of patients. People with neurocysticercosis who seek care in neurology clinics show a whole range of manifestations. Clinicians should be encouraged to consider neurocysticercosis in their differential diagnosis when a patient presented with one of the symptoms described in this review. This would ultimately improve the estimates of the frequency of symptoms associated with neurocysticercosis.
PMCID: PMC3101170  PMID: 21629722
19.  The Ets-1 transcription factor controls the development and function of natural regulatory T cells 
The Journal of Experimental Medicine  2010;207(10):2113-2125.
Regulatory T cells (T reg cells) constitute a population of CD4+ T cells that limits immune responses. The transcription factor Foxp3 is important for determining the development and function of T reg cells; however, the molecular mechanisms that trigger and maintain its expression remain incompletely understood. In this study, we show that mice deficient for the Ets-1 transcription factor (Ets-1−/−) developed T cell–mediated splenomegaly and systemic autoimmunity that can be blocked by functional wild-type T reg cells. Spleens of Ets-1−/− mice contained mostly activated T cells, including Th2-polarized CD4+ cells and had reduced percentages of T reg cells. Splenic and thymic Ets-1−/− T reg cells expressed low levels of Foxp3 and displayed the CD103 marker that characterizes antigen-experienced T reg cells. Thymic development of Ets-1−/− T reg cells appeared intrinsically altered as Foxp3-expressing cells differentiate poorly in mixed fetal liver reconstituted chimera and fetal thymic organ culture. Ets-1−/− T reg cells showed decreased in vitro suppression activity and did not protect Rag2−/− hosts from naive T cell–induced inflammatory bowel disease. Furthermore, in T reg cells, Ets-1 interacted with the Foxp3 intronic enhancer and was required for demethylation of this regulatory sequence. These data demonstrate that Ets-1 is required for the development of natural T reg cells and suggest a role for this transcription factor in the regulation of Foxp3 expression.
PMCID: PMC2947068  PMID: 20855499
20.  HDM2 ERKs PCNA 
The Journal of Cell Biology  2010;190(4):487-489.
In this issue, a study by Groehler and Lannigan (2010. J. Cell Biol. doi:10.1083/jcb.201002124) sheds light on the regulation of proliferating cell nuclear antigen (PCNA) turnover and how it is counteracted by the small chromatin-bound kinase ERK8 (extracellular signal-regulated kinase 8). Importantly, inactivation of ERK8 results in genome instability and is associated with cell transformation.
PMCID: PMC2928025  PMID: 20733049
22.  A Systematic Review of the Frequency of Neurocyticercosis with a Focus on People with Epilepsy 
The objective of this study is to conduct a systematic review of studies reporting the frequency of neurocysticercosis (NCC) worldwide.
Methods/Principal Findings
PubMed, Commonwealth Agricultural Bureau (CAB) abstracts and 23 international databases were systematically searched for articles published from January 1, 1990 to June 1, 2008. Articles were evaluated for inclusion by at least two researchers focusing on study design and methods. Data were extracted independently using standardized forms. A random-effects binomial model was used to estimate the proportion of NCC among people with epilepsy (PWE). Overall, 565 articles were retrieved and 290 (51%) selected for further analysis. After a second analytic phase, only 4.5% of articles, all of which used neuroimaging for the diagnosis of NCC, were reviewed. Only two studies, both from the US, estimated an incidence rate of NCC using hospital discharge data. The prevalence of NCC in a random sample of village residents was reported from one study where 9.1% of the population harboured brain lesions of NCC. The proportion of NCC among different study populations varied widely. However, the proportion of NCC in PWE was a lot more consistent. The pooled estimate for this population was 29.0% (95%CI: 22.9%–35.5%). These results were not sensitive to the inclusion or exclusion of any particular study.
Only one study has estimated the prevalence of NCC in a random sample of all residents. Hence, the prevalence of NCC worldwide remains unknown. However, the pooled estimate for the proportion of NCC among PWE was very robust and could be used, in conjunction with estimates of the prevalence and incidence of epilepsy, to estimate this component of the burden of NCC in endemic areas. The previously recommended guidelines for the diagnostic process and for declaring NCC an international reportable disease would improve the knowledge on the global frequency of NCC.
Author Summary
Neurocysticercosis (NCC) is a parasitic infection of the brain caused by the tapeworm Taenia solium, which infects humans and pigs. There have been increasing case reports and epidemiological studies on this disease, but its global frequency has never been determined, partly due to the fact that blood tests are not very good for the diagnosis of NCC. We present here a systematic review of the literature on the frequency of NCC diagnosed with neuroimaging worldwide. Overall, 565 articles were retrieved and 290 (51%) selected for further review. Of those, only 26 had information valid enough to estimate the frequency of NCC in various populations. Only one study estimated the prevalence of NCC in the general population. The most striking finding was that the proportion of NCC among persons with epilepsy was very consistent and estimated at 29.6% (95%CI: 23.5%–36.1%) from 12 studies conducted in Latin America, Sub-Saharan Africa and Southeast Asia. A reinforcement of the suggested universal guidelines for the diagnostic process, declaring NCC an international reportable disease and standardizing procedures for data collection could improve our understanding of the frequency of NCC worldwide and hence its global burden.
PMCID: PMC2970544  PMID: 21072231
23.  Defects in DNA Ligase I Trigger PCNA Ubiquitination at Lysine 107 
Nature cell biology  2009;12(1):74-20.
In all eukaryotes, the ligation of newly synthesized DNA, also known as Okazaki fragments, is catalyzed by DNA ligase I1. An individual with a DNA ligase I deficiency exhibited growth retardation, sunlight sensitivity and severe immunosuppression2, likely due to accumulation of DNA damage. Surprisingly, not much is known about the DNA damage response (DDR) in DNA ligase I-deficient cells. Because DNA replication and DDR pathways are highly conserved in eukaryotes, we utilized Saccharomyces cerevisiae as a model system to address this question. We uncovered a novel pathway, which facilitates ubiquitination of lysine 107 of proliferating cell nuclear antigen (PCNA). Unlike ubiquitination at lysine 164 of PCNA in response to UV irradiation, which triggers translesion synthesis3, modification of lysine 107 is not dependent on the ubiquitin conjugating enzyme (E2) Rad64 nor the ubiquitin ligase (E3) Rad185, but requires the E2 variant Mms26 in conjunction with Ubc47 and the E3 Rad58,9. Surprisingly, DNA ligase I-deficient cdc9-1 cells that carry a PCNAK107R mutation are inviable, because they cannot activate a robust DDR. Furthermore, we show that ubiquitination of PCNA in response to DNA ligase I-deficiency is conserved in humans, yet the lysine that mediates this modification remains to be determined. We propose that PCNA ubiquitination provides a “DNA damage code” that allows cells to categorize different types of defects that arise during DNA replication.
PMCID: PMC2799194  PMID: 20010813
24.  IL-15 controls generation of the restricted TCR repertoire of γδ intestinal intraepithelial lymphocytes 
Nature immunology  2005;6(12):1263-1271.
γδT cells are prevalent in the mucosal epithelia and are postulated to act as sentries to maintain tissue integrity. What these γδT cells recognize is poorly defined, but based on the restricted T cell receptor (TCR) repertoire, the notion that they are selected by self-antigens of low complexity has been widely disseminated. We present data demonstrating that generation of the restricted TCR Vγ gene repertoire of intestinal intraepithelial lymphocytes is regulated by IL-15, which induces Vγ gene segment-specific local chromatin modifications and enhanced accessibility conducive for subsequent targeted gene rearrangement. This cytokine-directed tissue-specific TCR repertoire formation likely reflects distinct TCR repertoire selection criteria for γδ and αβT cell lineages adopted for different antigen recognition strategies.
PMCID: PMC2886802  PMID: 16273100
25.  Tethered Thiazolidinone Dimers as Inhibitors of the Bacterial Type III Secretion System 
Disruption of protein-protein interactions by small molecules is achievable but presents significant hurdles for effective compound design. In earlier work we identified a series of thiazolidinone inhibitors of the bacterial type III secretion system (T3SS) and demonstrated that this scaffold had the potential to be expanded into molecules with broad-spectrum anti-Gram negative activity. We now report on one series of thiazolidinone analogs in which the heterocycle is presented as a dimer at the termini of a series of linkers. Many of these dimers inhibited the T3SS-dependent secretion of a virulence protein at concentrations lower than that of the original monomeric compound identified in our screen.
PMCID: PMC2680725  PMID: 19195888

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