150 research outputs found
Genetic diagnosis in Lafora disease: Genotype-phenotype correlations and diagnostic pitfalls
No full textLafora disease (LD) can be diagnosed by skin biopsy, but this approach has both false negatives and false positives. Biopsies of other organs can also be diagnostic but are more invasive. Genetic diagnosis is also possible but can be inconclusive, for example, in patients with only one heterozygous EPM2A mutation and patients with apparently homozygous EPM2B mutations where one parent is not a carrier of the mutation. We sought to identify occult mutations and clarify the genotypes and confirm the diagnosis of LD in patients with apparent nonrecessive disease inheritance. We used single nucleotide polymorphism, quantitative PCR, and fluorescent in situ hybridization analyses. We identified large EPM2A and EPM2B deletions undetectable by PCR in the heterozygous state and describe simple methods for their routine detection. We report a coding sequence change in several patients and describe why the pathogenic role of this change remains unclear. We confirm that adult-onset LD is due to EPM2B mutations. Finally, we report major intrafamilial heterogeneity in age at onset in LD. ©2007AAN Enterprises, Inc.Andrade DM, 2003, NEUROLOGY, V61, P1611; Baykan B, 2005, EPILEPSIA, V46, P1695, DOI 10.1111-j.1528-1167.2005.00272.x; BUSARD HLSM, 1987, ANN NEUROL, V21, P599, DOI 10.1002-ana.410210613; CARPENTER S, 1981, ANN NEUROL, V10, P63, DOI 10.1002-ana.410100116; Chan EM, 2004, NEUROLOGY, V63, P565; Chan EM, 2003, NAT GENET, V35, P125, DOI 10.1038-ng1238; Chan EM, 2004, HUM MOL GENET, V13, P1117, DOI 10.1093-hmg-ddh130; Fernandez-Barreiro A, 1999, J NEUROL NEUROSUR PS, V66, P114; Fernandez-Sanchez ME, 2003, HUM MOL GENET, V12, P3161, DOI 10.1093-hmg-ddg340; Footitt DR, 1997, J NEUROL, V244, P40; Franceschetti S, 2006, EPILEPSIA, V47, P640, DOI 10.1111-j.1528-1167.2006.00479.x; Ganesh S, 2002, HUM MOL GENET, V11, P1263, DOI 10.1093-hmg-11.11.1263; Ganesh S, 2004, BIOCHEM BIOPH RES CO, V313, P1101, DOI 10.1016-j.bbrc.2003.12.043; Ganesh S, 2000, HUM MOL GENET, V9, P2251; Gentry MS, 2005, P NATL ACAD SCI USA, V102, P8501, DOI 10.1073-pnas.0503285102; Gomez-Abad C, 2005, NEUROLOGY, V64, P982; Gomez-Garre P, 2000, EUR J HUM GENET, V8, P946, DOI 10.1038-sj.ejhg.5200571; Ianzano Leonarda, 2005, Hum Mutat, V26, P397, DOI 10.1002-humu.9376; KAUFMAN MA, 1993, NEUROLOGY, V43, P1246; Lafora GR, 1911, Z GESAMTE NEUROL PSY, V6, P1, DOI 10.1007-BF02863929; Lohi H, 2005, HUM MOL GENET, V14, P2727, DOI 10.1093-hmg-ddi306; Lohi Hannes, 2006, Adv Neurol, V97, P399; Messouak O, 2002, REV NEUROL-FRANCE, V158, P74; Minassian BA, 1998, NAT GENET, V20, P171, DOI 10.1038-2470; Minassian BA, 2001, PEDIATR NEUROL, V25, P21, DOI 10.1016-S0887-8994(00)00276-9; Minassian BA, 2000, NEUROLOGY, V55, P341; Minassian BA, 2000, NEUROLOGY, V54, P488; Singh S, 2005, J HUM GENET, V50, P347, DOI 10.1007-s10038-005-0263-7; Van Heycop Ten Ham MV, 1974, HDB CLIN NEUROLOGY, V15, P382; Wang JY, 2002, J BIOL CHEM, V277, P2377, DOI 10.1074-jbc.C100686200; Wang W, 2004, BIOCHEM BIOPH RES CO, V325, P726, DOI 10.1016-j.bbrc.2004.10.08321211
Le paysage de la gentrification à Barcelone
No full textCet article présente en quoi le paysage urbain permet d’appréhender le phénomène de gentrification. En mettant en évidence la rareté des travaux espagnols sur la gentrification et en s’appuyant sur un corpus photographique de Ciutat Vella (le centre médiéval et pré-XIXe siècle de Barcelone), l’auteur cherche à souligner l’apport de cette méthodologie pour comprendre un phénomène qui modifie en profondeur le paysage urbain et social. L’article s’appuie sur la lecture du paysage urbain élaborée par S. Rimbert et les réflexions de D. Mendibil et J.-M. Schaeffer sur la photographie. Il propose un parcours photographique autour de l’opération de rénovation de la « Rambla del Raval » dans le quartier du Raval (district de Ciutat Vella), spécifique par son histoire, son contexte socio-économique et son rôle dans l’imaginaire collectif à l’échelle de l’agglomération. Cette lecture complète l’approche quantitative et met en évidence la juxtaposition de phénomènes contradictoires autour de la Rambla del Raval, entre dégradation et gentrification en cours.Hovig Ter Minassian, The landscape of gentrification in Barcelona This article examines the way in which the urban landscape makes it possible to apprehend the phenomenon of gentrification. Pointing to the scarcity of Spanish studies on issues of gentrification and drawing on a corpus of photographs of Ciutat Vella, i.e. the medieval and pre-19th century centre of Barcelona, the author seeks to underline the contribution of this methodology to understand a phenomenon which deeply modifies the urban and social landscape. The article draws on S. Rimbert’s conceptualization of urban landscape and on the writings of D. Mendibil and J.-M. Schaeffer on photography. It offers a photographic route around the operation of renovation of the “Rambla del Raval” in the area of the Raval (district of Ciutat Vella), specific by its history, its socio-economic context and its role in the collective imaginary of the whole agglomeration. This methodology is conceived of as complementary to the quantitative approach and highlights the juxtaposition of contradictory phenomena around the “Rambla del Raval”, between degradation and gentrification in progress
Le paysage de la gentrification à Barcelone
No full textCet article présente en quoi le paysage urbain permet d’appréhender le phénomène de gentrification. En mettant en évidence la rareté des travaux espagnols sur la gentrification et en s’appuyant sur un corpus photographique de Ciutat Vella (le centre médiéval et pré-XIXe siècle de Barcelone), l’auteur cherche à souligner l’apport de cette méthodologie pour comprendre un phénomène qui modifie en profondeur le paysage urbain et social. L’article s’appuie sur la lecture du paysage urbain élaborée par S. Rimbert et les réflexions de D. Mendibil et J.-M. Schaeffer sur la photographie. Il propose un parcours photographique autour de l’opération de rénovation de la « Rambla del Raval » dans le quartier du Raval (district de Ciutat Vella), spécifique par son histoire, son contexte socio-économique et son rôle dans l’imaginaire collectif à l’échelle de l’agglomération. Cette lecture complète l’approche quantitative et met en évidence la juxtaposition de phénomènes contradictoires autour de la Rambla del Raval, entre dégradation et gentrification en cours.Hovig Ter Minassian, The landscape of gentrification in Barcelona This article examines the way in which the urban landscape makes it possible to apprehend the phenomenon of gentrification. Pointing to the scarcity of Spanish studies on issues of gentrification and drawing on a corpus of photographs of Ciutat Vella, i.e. the medieval and pre-19th century centre of Barcelona, the author seeks to underline the contribution of this methodology to understand a phenomenon which deeply modifies the urban and social landscape. The article draws on S. Rimbert’s conceptualization of urban landscape and on the writings of D. Mendibil and J.-M. Schaeffer on photography. It offers a photographic route around the operation of renovation of the “Rambla del Raval” in the area of the Raval (district of Ciutat Vella), specific by its history, its socio-economic context and its role in the collective imaginary of the whole agglomeration. This methodology is conceived of as complementary to the quantitative approach and highlights the juxtaposition of contradictory phenomena around the “Rambla del Raval”, between degradation and gentrification in progress
A review of the tolerability of the candidate TB vaccine, MVA85A compared with BCG and Yellow Fever vaccines, and correlation between MVA85A vaccine reactogenicity and cellular immunogenicity
No full text© 2012 Elsevier Ltd. All rights reservedBackground: The development of a new, more effective vaccine against tuberculosis (TB) for use in healthy and HIV-infected adults, children and infants, remains a global health priority. MVA85A is a candidate tuberculosis vaccine designed to enhance immunity to the existing vaccine, Bacillus Calmette-Guerin (BCG). MVA85A entered clinical trials in 2002 and has now progressed to Phase IIb proof-of-concept efficacy trials in infants and HIV-infected adults in Africa. Methods: A detailed analysis was conducted of the cumulative safety data of intradermal delivery of MVA85A in 112 healthy adult subjects in a series of open label, single arm, non-controlled, Phase I safety and immunogenicity clinical trials in the UK. The trials differed with respect to previous mycobacterial exposure, vaccine regime and dose. Objective safety measures (local reaction size and body temperature) were evaluated for correlations with adaptive antigen-specific immune responses. Results: All subjects in the combined mid-dose group developed a local reaction, of which 92% were mild, 8% were moderate and no reactions were severe. Around 90% of subjects in each group reported at least one systemic adverse event, most commonly headache, myalgia, malaise, feeling feverish, fatigue and arthralgia. Of all systemic adverse events in the combined mid-dose group, 96% were mild, 3% were moderate and 1% were severe (but none of these were judged to be vaccine-related). Pre-vaccination mycobacterial exposure did not affect the adverse event profile. The size of local reaction and frequency of systemic adverse events increased with MVA85A vaccine dose. There were no documented fevers in the low-dose group, whilst 3% of subjects in the combined mid-dose group and 21% in the high-dose group had documented fevers. Peak local reactions were larger after a second poxvirus vaccination, but other local and systemic adverse events were comparable to a single MVA85A vaccination. No severe systemic AEs or serious adverse events in any group were judged to be vaccine-related. Local AEs compared favourably to BCG vaccine-induced local AE and systemic AEs after MVA85A vaccination were comparable to those after the live viral Yellow Fever vaccine in similar populations. There were no correlations found between local reaction size or body temperature and adaptive immune responses (measured by ex vivo interferon gamma Enzyme Linked Immunospot). Conclusions: The candidate TB vaccine, MVA85A has been safely administered to over 100 healthy adults in the UK. Intradermal vaccination with MVA85A induced a transient, superficial reaction local to the injection site and mild short-lived viral symptoms. The local and systemic AE profile of MVA85A vaccination was comparable to published data of other intradermal vaccines and live viral vaccines respectively. Local reaction sizes and body temperature measurements did not correlate with the adaptive cellular immune response to MVA85A.Funded by charitable grants from Europe Aid;
TBVAC (EU 6th Framework Programme); The Oxford Biomedical Research Centre and the Wellcome Trus
Th1/Th17 cell induction and corresponding reduction in ATP consumption following vaccination with the novel Mycobacterium tuberculosis vaccine MVA85A.
No full textVaccination with Bacille Calmette-Guérin (BCG) has traditionally been used for protection against disease caused by the bacterium Mycobacterium tuberculosis (M.tb). The efficacy of BCG, especially against pulmonary tuberculosis (TB) is variable. The best protection is conferred in temperate climates and there is close to zero protection in many tropical areas with a high prevalence of both tuberculous and non-tuberculous mycobacterial species. Although interferon (IFN)-γ is known to be important in protection against TB disease, data is emerging on a possible role for interleukin (IL)-17 as a key cytokine in both murine and bovine TB vaccine studies, as well as in humans. Modified Vaccinia virus Ankara expressing Antigen 85A (MVA85A) is a novel TB vaccine designed to enhance responses induced by BCG. Antigen-specific IFN-γ production has already been shown to peak one week post-MVA85A vaccination, and an inverse relationship between IL-17-producing cells and regulatory T cells expressing the ectonucleosidease CD39, which metabolises pro-inflammatory extracellular ATP has previously been described. This paper explores this relationship and finds that consumption of extracellular ATP by peripheral blood mononuclear cells from MVA85A-vaccinated subjects drops two weeks post-vaccination, corresponding to a drop in the percentage of a regulatory T cell subset expressing the ectonucleosidase CD39. Also at this time point, we report a peak in co-production of IL-17 and IFN-γ by CD4(+) T cells. These results suggest a relationship between extracellular ATP and effector responses and unveil a possible pathway that could be targeted during vaccine design
Roles for Treg expansion and HMGB1 signaling through the TLR1-2-6 axis in determining the magnitude of the antigen-specific immune response to MVA85A
No full text© 2013 Matsumiya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedA better understanding of the relationships between vaccine, immunogenicity and protection from disease would greatly facilitate vaccine development. Modified vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel tuberculosis vaccine candidate designed to enhance responses induced by BCG. Antigen-specific interferon-γ (IFN-γ) production is greatly enhanced by MVA85A, however the variability between healthy individuals is extensive. In this study we have sought to characterize the early changes in gene expression in humans following vaccination with MVA85A and relate these to long-term immunogenicity. Two days post-vaccination, MVA85A induces a strong interferon and inflammatory response. Separating volunteers into high and low responders on the basis of T cell responses to 85A peptides measured during the trial, an expansion of circulating CD4+ CD25+ Foxp3+ cells is seen in low but not high responders. Additionally, high levels of Toll-like Receptor (TLR) 1 on day of vaccination are associated with an increased response to antigen 85A. In a classification model, combined expression levels of TLR1, TICAM2 and CD14 on day of vaccination and CTLA4 and IL2Rα two days post-vaccination can classify high and low responders with over 80% accuracy. Furthermore, administering MVA85A in mice with anti-TLR2 antibodies may abrogate high responses, and neutralising antibodies to TLRs 1, 2 or 6 or HMGB1 decrease CXCL2 production during in vitro stimulation with MVA85A. HMGB1 is released into the supernatant following atimulation with MVA85A and we propose this signal may be the trigger activating the TLR pathway. This study suggests an important role for an endogenous ligand in innate sensing of MVA and demonstrates the importance of pattern recognition receptors and regulatory T cell responses in determining the magnitude of the antigen specific immune response to vaccination with MVA85A in humans.This work was funded by the Wellcome Trust. MM has a Wellcome Trust PhD studentship and HM is a Wellcome Trust Senior Fello
Malaria: Past, present and future
No full textMalaria remains a major global health problem. Transmission occurs in 84 countries across five continents, with almost 250 million cases and over 600,000 deaths each year. Primary and secondary care clinicians in the UK need to be alert to the prospect of malaria presenting in returning travellers. They must be aware of the signs of severe malaria, the need for prompt diagnosis and treatment, and the importance of seeking specialist advice. With emerging resistance, climate change and the roll-out of the first malaria vaccines, the landscape of malaria is changing. Here we discuss the past, present and future of malaria
R21 in Matrix-M adjuvant in UK malaria-naive adult men and non-pregnant women aged 18–45 years: an open-label, partially blinded, phase 1–2a controlled human malaria infection study
No full textBackground: R21 is a novel malaria vaccine, composed of a fusion protein of the malaria circumsporozoite protein and hepatitis B surface antigen. Following favourable safety and immunogenicity in a phase 1 study, we aimed to assess the efficacy of R21 administered with Matrix-M (R21/MM) against clinical malaria in adults from the UK who were malaria naive in a controlled human malaria infection study. Methods: in this open-label, partially blinded, phase 1–2A controlled human malaria infection study undertaken in Oxford, Southampton, and London, UK, we tested five novel vaccination regimens of R21/MM. A standard three-dose regimen (groups 1 and 6) was compared with a reduced (fractional) third dose (groups 2 and 5) of R21/MM, concomitant administration with viral vectors ChAd63-MVA expressing ME-TRAP (group 3), and a two-dose R21/MM regimen (group 7). Controlled Human Malaria Infection (CHMI) was delivered by mosquito bite at Imperial College London, London, UK, 3–4 weeks after final vaccination (or 18 months after final vaccination for group 6) alongside unvaccinated controls (groups 4A and 4B). The primary outcome measures were to assess safety of the vaccines in healthy malaria-naive volunteers and the efficacy (occurrence of blood-stage malaria infection) of the different vaccine regimens compared with non-vaccinated controls after CHMI. The trial was registered with ClinicalTrials.gov (NCT02905019). Findings: 66 volunteers were enrolled with 59 undergoing subsequent CHMI. All vaccination schedules were well tolerated. The highest level of protection against CHMI was observed in participants receiving the standard three-dose regimen of R21/MM (group 1, nine of 11 volunteers protected) with protection maintained in three of five volunteers re-challenged by CHMI 7·5 months later. Protection against malaria was also seen in group 2, group 3, and group 5 compared with unvaccinated control participants. Total IgG antibody responses to the NANP repeat region of circumsporozoite protein peaked after the third dose of R21/MM in all volunteers and were well maintained to 90 days after challenge. Reducing the third dose did not affect protection or antibody concentrations. Interpretation: our study shows that R21/MM elicits high-level efficacy against clinical malaria in a controlled human infection model of malaria in adults who are malaria naive. These data supported the evaluation of R21/MM in field efficacy trials in the target population of young children in malaria-endemic areas. Funding: EU Horizon 2020, the UK Medical Research Council, the European Commission, the UK National Institute of Health Research, the Imperial NIHR Clinical Research Facility, the Oxford NIHR Biomedical Research Centre, and the Wellcome Trust.</p
The challenges of Plasmodium vivax human malaria infection models for vaccine development
No full textControlled Human Malaria Infection models (CHMI) have been critical to advancing new vaccines for malaria. Stringent and safe preparation of a challenge agent is key to the success of any CHMI. Difficulty producing the Plasmodium vivax parasite in vitro has limited production of qualified parasites for CHMI as well as the functional assays required to screen and down-select candidate vaccines for this globally distributed parasite. This and other challenges to P. vivax CHMI (PvCHMI), including scientific, logistical, and ethical obstacles, are common to P. vivax research conducted in both non-endemic and endemic countries, with additional hurdles unique to each. The challenges of using CHMI for P. vivax vaccine development and evaluation, lessons learned from previous and ongoing clinical trials, and the way forward to effectively perform PvCHMI to support vaccine development, are discussed
Community risk factors for ocular Chlamydia infection in Niger: pre-treatment results from a cluster-randomized trachoma trial.
No full textBACKGROUND: Trachoma control programs utilize mass azithromycin distributions to treat ocular Chlamydia trachomatis as part of an effort to eliminate this disease world-wide. But it remains unclear what the community-level risk factors are for infection. METHODS: This cluster-randomized, controlled trial entered 48 randomly selected communities in a 2×2 factorial design evaluating the effect of different treatment frequencies and treatment coverage levels. A pretreatment census and examination established the prevalence of risk factors for clinical trachoma and ocular chlamydia infection including years of education of household head, distance to primary water source, presence of household latrine, and facial cleanliness (ocular discharge, nasal discharge, and presence of facial flies). Univariate and multivariate associations were tested using linear regression and Bayes model averaging. FINDINGS: There were a total of 24,536 participants (4,484 children aged 0-5 years) in 6,235 households in the study. Before treatment in May to July 2010, the community-level prevalence of active trachoma (TF or TI utilizing the World Health Organization [WHO] grading system) was 26.0% (95% CI: 21.9% to 30.0%) and the mean community-level prevalence of chlamydia infection by Amplicor PCR was 20.7% (95% CI: 16.5% to 24.9%) in children aged 0-5 years. Univariate analysis showed that nasal discharge (0.29, 95% CI: 0.04 to 0.54; P = 0.03), presence of flies on the face (0.40, 95% CI: 0.17 to 0.64; P = 0.001), and years of formal education completed by the head of household (0.07, 95% CI: 0.07 to 0.13; P = 0.03) were independent risk factors for chlamydia infection. In multivariate analysis, facial flies (0.26, 95% CI: 0.02 to 0.49; P = 0.03) and years of formal education completed by the head of household (0.06, 95% CI: 0.008 to 0.11; P = 0.02) were associated risk factors for ocular chlamydial infection. INTERPRETATION: We have found that the presence of facial flies and years of education of the head of the household are risk factors for chlamydia infection when the analysis is done at the community level. TRIAL REGISTRATION: ClinicalTrials.gov NCT00792922
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