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Maria A. Silva

Other affiliations: Instituto de Medicina Molecular
Bio: Maria A. Silva is an academic researcher from University of Lisbon. The author has contributed to research in topics: Randomized controlled trial & Cadastre. The author has an hindex of 3, co-authored 4 publications receiving 146 citations. Previous affiliations of Maria A. Silva include Instituto de Medicina Molecular.

Papers
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Journal ArticleDOI
TL;DR: In this paper, the authors present a review of nine publications on cadastre and identify the methodologies used, focusing on the institutional, social, political and economic aspects of cadastral development, rather than on the technical aspects.

67 citations

Journal ArticleDOI
01 May 2002-RNA
TL;DR: It is shown that although HDV ribonucleoproteins are mainly detected in the nucleus, they are also present in the cytoplasm of cells infected with HDV or transfected withHDV cDNA, which suggests that HDV RNA mediates export of viral particles to the cy toplasm whereas the delta antigen triggers their reimport into the nucleus.
Abstract: Hepatitis delta virus (HDV) infection of individuals infected with hepatitis B virus (HBV) is associated with more severe liver damage and an increased risk of fulminant disease. HDV is a single-stranded RNA virus that encodes a single protein, the delta antigen, which is expressed in two forms, small (S-HDAg) and large (L-HDAg). Here we show that although HDV ribonucleoproteins are mainly detected in the nucleus, they are also present in the cytoplasm of cells infected with HDV or transfected with HDV cDNA. Making use of an heterokaryon assay, we demonstrate that HDV ribonucleoproteins shuttle continuously between the nucleus and the cytoplasm. In the absence of HDV RNA, both forms of the delta antigen are retained in the nucleus, whereas in the absence of the delta antigen, HDV RNA is predominantly detected in the cytoplasm. Coexpression of HDV RNA and S-HDAg (which binds to the viral RNA and contains a nuclear localization signal) results in nuclear accumulation of the viral RNA. This suggests that HDV RNA mediates export of viral particles to the cytoplasm whereas the delta antigen triggers their reimport into the nucleus.

52 citations

Journal ArticleDOI
TL;DR: The magnitude of the placebo response in RLS is above the threshold of minimal clinical important difference, and the frequency of adverse events is also considerable.
Abstract: Objective: To estimate the placebo and nocebo responses in restless legs syndrome (RLS) and explore their determinants. Methods: Databases were searched up to October 2015. Randomized, double-blind, placebo-controlled trials of patients with RLS were included if quantitative data were extractable in the placebo arm. Placebo response was defined as the within-group change from baseline, using any scale measuring RLS severity or disability. Nocebo response was defined as the proportion of patients experiencing adverse events in the placebo arm. Random-effects meta-analysis was used to pool data. Statistical heterogeneity was assessed with I2 statistic. Several predetermined subgroup and sensitivity analysis were performed. PROSPERO registration number is CRD42015027992. Results: We included 85 randomized controlled trials (5,046 participants). Pooled placebo response effect size was −1.41 (95% confidence interval [CI] −1.56 to −1.25, 64 trials, I2 = 88.1%), corresponding to −6.58 points in the International RLS Study Group Scale (IRLS). Pooled nocebo response was 45.36% (95% CI 40.47%–50.29%, 72 trials; I2 = 89.8%). The placebo and nocebo responses were greater in trials with longer duration, evaluating pharmacologic interventions and idiopathic RLS, and in industry-funded and unpublished studies. The placebo response was considerably smaller in objective as compared to subjective outcomes. In addition, the nocebo response increases proportionally with the placebo response, and has the same predictors. Conclusions: The magnitude of the placebo response in RLS is above the threshold of minimal clinical important difference, and the frequency of adverse events is also considerable. These results are relevant to inform the design and interpretation of future clinical trials.

38 citations

Journal ArticleDOI
TL;DR: The frequency of major cardiovascular events in the RLS trials is not negligible, particularly when considering the young age of these patients.

7 citations


Cited by
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Journal ArticleDOI
TL;DR: It is concluded that ADAR1-S edits HDV RNA during replication and that editing occurs in the nucleus.
Abstract: Hepatitis delta virus (HDV) uses a host-encoded RNA-editing activity to express its two essential proteins from the same coding sequence. Adenosine deaminase that acts on RNA (ADAR)1 and ADAR2 are enzymes that catalyze such reactions, and each, when overexpressed, are capable of editing HDV RNA in vivo. However, the enzyme responsible for editing HDV RNA during replication has not been determined. Mammalian cells express two forms of ADAR1, a large form (ADAR1-L) that mainly localizes to the cytoplasm and a small form (ADAR1-S) that resides in the nucleus. Recently, we found that the specific activity of ADAR1-L within cells is much higher than that of ADAR1-S but only when the substrate can be edited in the cytoplasm. Here we observed that although both ADAR1-S and ADAR1-L were expressed throughout HDV replication, no ADAR2 could be observed at any time. Using expression vectors that individually overexpress either form of ADAR1, we found that ADAR1-S could stimulate editing during replication more efficiently. We next reduced ADAR1 levels during HDV replication. After transfection of an ADAR1-L-specific small interfering RNA (siRNA), we observed a significant loss of that protein and its associated cytoplasmic editing activity while the level of ADAR1-S remained unchanged. Transfection of this siRNA, however, did not reduce editing during HDV replication. In contrast, transfection of an siRNA that targets both forms of ADAR1 greatly reduced the expression of both proteins and potently inhibited editing during replication. We conclude that ADAR1-S edits HDV RNA during replication and that editing occurs in the nucleus.

170 citations

Journal ArticleDOI
TL;DR: BtA was associated with a moderate-to-large improvement in the participant's baseline clinical status as assessed by investigators, with reduction of 8.06 points in the Toronto Western Spasmodic Torticollis Rating Scale at week 4 after injection.
Abstract: Background This is an update of a Cochrane Review first published in 2005. Cervical dystonia is the most common form of focal dystonia, and is a highly disabling movement disorder, characterised by involuntary, usually painful, head posturing. Currently, botulinum toxin type A (BtA) is considered the first line therapy for this condition. Objectives To compare the efficacy, safety, and tolerability of BtA versus placebo, in people with cervical dystonia. Search methods We searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of articles, and conference proceedings in July 2020. All elements of the search, with no language restrictions, were last run in July 2020. Selection criteria Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with cervical dystonia. Data collection and analysis Two review authors independently assessed records, selected included studies, extracted data using a paper pro forma, and evaluated the risk of bias. We resolved disagreements by consensus or by consulting a third review author. We performed meta-analyses using a random-effects model, for the comparison of BtA versus placebo, to estimate pooled effects and corresponding 95% confidence intervals (95% CI). We performed preplanned subgroup analyses according to BtA dose used, the BtA formulation used, and the use (or not) of guidance for BtA injections. The primary efficacy outcome was improvement in cervical dystonia-specific impairment. The primary safety outcome was the proportion of participants with any adverse event. Main results We included nine RCTs, with moderate, overall risk of bias, that included 1144 participants with cervical dystonia. Seven studies excluded participants with poorer responses to BtA treatment, therefore, including an enriched population with a higher probability of benefiting from this therapy. Only one trial was independently funded. All RCTs evaluated the effect of a single BtA treatment session, using doses from 150 U to 500 U of onabotulinumtoxinA (Botox), 120 U to 240 U of incobotulinumtoxinA (Xeomin), and 250 U to 1000 U of abobotulinumtoxinA (Dysport). BtA resulted in a moderate to large improvement from the participant's baseline clinical status, assessed by the investigators, with a mean reduction of 8.09 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS total score) at week four after injection (95% CI 6.22 to 9.96; I² = 0%) compared to placebo. This corresponded, on average, to a 18.4% improvement from baseline. The mean difference (MD) in TWSTRS pain subscore at week four was 2.11 (95% CI 1.38 to 2.83; I² = 0%) compared to placebo. Overall, both participants and clinicians reported an improvement of subjective clinical status. It was unclear if dropouts due to adverse events differed (risk ratio (RR) 2.51; 95% CI 0.42 to 14.94; I² = 0%) However, BtA treatment increased the risk of experiencing an adverse event (R) 1.23; 95% CI 1.05 to 1.43; I² = 28%). Neck weakness (14%; RR 3.40; 95% CI 1.19 to 9.71; I² = 15%), dysphagia (11%; RR 3.19; 95% CI 1.79 to 5.70; I² = 0%), and diffuse weakness or tiredness (8%; RR 1.80; 95% CI 1.10 to 2.95; I² = 0%) were the most common treatment-related adverse events. Treatment with BtA resulted in a decreased risk of dropouts. We have moderate certainty in the evidence across all of the aforementioned outcomes, with the exception of subjective assessment and tolerability, in which we have high confidence in the evidence. We found no evidence supporting the existence of a clear dose-response relationship between BtA and improvement in cervical dystonia-specific impairment, a destinction between BtA formulations, or a variation with use of EMG-guided injection for efficacy outcomes. Due to clinical heterogeneity, we did not pool health-related quality of life data, duration of clinical effect, or the development of secondary non-responsiveness. Authors' conclusions We are moderately certain in the evidence that a single BtA treatment session resulted in a clinically relevant reduction of cervical dystonia-specific impairment, and pain, and highly certain that it is well tolerated, compared with placebo. There is moderate-certainty evidence that people treated with BtA are at an increased risk of developing adverse events, most notably, dysphagia, neckweakness and diffuse weakness or tiredness. There are no data from RCTs evaluating the effectiveness and safety of repeated BtA injection cycles. There is no evidence from RCTs to allow us to draw definitive conclusions on the optimal treatment intervals and doses, the usefulness of guidance techniques for injection, the impact on quality of life, or the duration of treatment effect.

150 citations

Journal ArticleDOI
TL;DR: RNA-dependent RNA replication is a special process reserved exclusively for RNA viruses but not cellular RNAs.
Abstract: RNA-dependent RNA replication is a special process reserved exclusively for RNA viruses but not cellular RNAs. Almost all RNA viruses (except retroviruses) undergo RNA-dependent RNA replication by a virus-encoded RNA-dependent RNA polymerase (RdRP), which specifically replicates the viral RNA genome

128 citations

11 Nov 2002
TL;DR: Burdon et al. as discussed by the authors defined the extent and boundaries of land parcels as a matter of legal definition, which made a very large difference with most other types of geo-information, which depicts real life geographical phenomenon.
Abstract: concepts Land as the object of property rights is different from most other types of property. In many cases there is not a ‘logical’ object. The object has to be defined, has to be legally constructed, and can change relatively easily (compare § 2.2.5 and § 3.2.4). The objects are separated by boundaries which define where one landowner’s territory ends and the next begins. Even though there often is a reasonably high congruity between topographic boundary features and legal extent, there is no necessary identity between the topography of a parcel and the legal extent of that parcel. The extent and boundaries of land parcels are a matter of legal definition. (Burdon 1998: 152) Parcels and boundaries are abstract concepts. This makes a very large difference with most other types of geo-information, which depicts ‘real life’ geographical phenomenon. (compare van der Molen 2001: 15). Title plans and parcel maps are legal documents in a graphical form and not just another dataset for a geographical information system (GIS) (Burdon 1998: 154). Similarly the rights in land are abstract concepts. Property rights are an important example of institutions; humanly devised constraints that shape human interactions (see § 1.2.3). Rights in land are usually described in a complex system of land tenure. Through the abstract concept, land rights can grow into much more than a distribution mechanism for land use. The rights can be activated as capital, allowing inter alia for (cheaper) loans against collateral (see § 1.2.1). 78 SYSTEMS OF LAND REGISTRATION

125 citations

Journal ArticleDOI
TL;DR: Insights into the receptor-mediated entry of HDV, and the observation that HDV assembly requires farnesyltransferase, have enabled novel therapeutic strategies to be developed.
Abstract: Chronic hepatitis D is the most severe form of viral hepatitis, affecting ∼20 million HBV-infected people worldwide. The causative agent, hepatitis delta virus (HDV), is a unique human pathogen: it is the smallest known virus; it depends on HBV to disseminate its viroid-like RNA; it encodes only one protein (HDAg), which has both structural and regulatory functions; and it replicates using predominantly host proteins. The failure of HBV-specific nucleoside analogues to suppress the HBV helper function, and the limitations of experimental systems to study the HDV life cycle, have impeded the development of HDV-specific drugs. Thus, the only clinical regimen for HDV is IFNα, which shows some efficacy but long-term virological responses are rare. Insights into the receptor-mediated entry of HDV, and the observation that HDV assembly requires farnesyltransferase, have enabled novel therapeutic strategies to be developed. Interference with entry, for example through blockade of the HBV-HDV-specific receptor sodium/taurocholate cotransporting polypeptide NTCP by Myrcludex B, and inhibition of assembly by blockade of farnesyltransferase using lonafarnib or nucleic acid polymers such as REP 2139-Ca, have shown promising results in phase II studies. In this Review, we summarize our knowledge of HDV epidemiology, pathogenesis and molecular biology, with a particular emphasis on possible future developments.

125 citations