177 research outputs found
Microwave-assisted generation and reactivity of aza- and diazafulvenium methides: heterocycles via pericyclic reactions
Azafulvenium methides and diazafulvenium methides have been generated under microwave irradiation from 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazoles and 2,2-dioxo-1H,3H-pyrazolo[1,5-c]thiazoles, respectively. Pericyclic reactions of these 1,7-dipole intermediates, namely, sigmatropic [1,8]H shifts, 1,7-electrocyclization or [8[pi]+2[pi]] cycloaddition led to the synthesis of a range of pyrrole and pyrazole derivatives. The first evidence for the azafulvenium methides by intermolecular trapping via [8[pi]+2[pi]] cycloaddition is reported.http://www.sciencedirect.com/science/article/B6THS-4SP3SM3-6/1/d6303d9db78919cfe9cd796c1a17d44
Clinical presentation and neural correlates of stroke‐associated spatial delusions
© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Background and purpose: Incongruent beliefs about self-localization in space markedly disturb patients' behavior. Spatial delusions, or reduplicative paramnesias, are characterized by a firm conviction of place reduplication, transformation, or mislocation. Evidence suggests they are frequent after right hemisphere lesions, but comprehensive information about their clinical features is lacking.
Methods: We prospectively screened 504 acute right-hemisphere stroke patients for the presence of spatial delusions. Their behavioral and clinical features were systematically assessed. Then, we analyzed the correlation of their duration with the magnitude of structural disruption of belief-associated functional networks. Finally, we described the syndrome subtypes and evaluated whether the clinical categorization would be predicted by the structural disruption of familiarity-associated functional networks using an unsupervised k-means clustering algorithm.
Results: Sixty patients with spatial delusions were identified and fully characterized. Most (93%) localized the misidentified places closer to home than the hospital. The median time duration was 3 days (interquartile range = 1-7 days), and it was moderately correlated with the magnitude of structural-functional decoupling of belief-associated functional networks (r = 0.39, p = 0.02; beta coefficient regressing for lesion volume = 3.18, p = 0.04). Each clinical subtype had characteristic response patterns, which were reported, and representative examples were provided. Clustering based on structural disruption of familiarity- and unfamiliarity-associated functional networks poorly matched the clinical categorization (lesion: Rand index = 0.47; structural disconnection: Rand index = 0.51).
Conclusions: The systematic characterization of the peculiar clinical features of stroke-associated spatial delusions may improve the syndrome diagnosis and clinical approaches. The novel evidence about their neural correlates fosters the clarification of the pathophysiology of delusional misidentifications.This work was supported by the following grants: PRÉMIO JOÃO LOBO ANTUNES 2018–SCML and Bolsa de Investigação em Doenças Vasculares Cerebrais 2017–SPAVC.info:eu-repo/semantics/publishedVersio
Avaliação da afasia: impacto do material no desempenho da nomeação
Background: Naming and lexical retrieval difficulties are common symptoms of aphasia. Naming abilities are usually evaluated by means of real objects or pictures or line drawings that are printed. Objective: The aim of this study was to investigate whether the ability to name objects among individuals with aphasia is influenced by the dimensions of the visual stimuli and to understand whether the order of presentation of the stimuli, number of years of education and length of time post-onset are involved in the success of naming. Methods: The naming abilities of healthy controls and patients with acute or chronic aphasia due to stroke were assessed through presentation of two sets of 24 stimuli consisting of real objects and color photographs of the same objects presented on a screen. The results obtained under these two conditions were compared by means of within-subject paired ANOVA, controlling for presentation order. Results: 40 patients (62.4 ± 17.3 years old; 70% females; mean education level of 8.5 ± 5.3 years; and 60% evaluated within the first eight days after stroke) and 50 controls that were age, gender and education-matched were included. Object naming was significantly better than naming color photographs among the patients (p = 0.001), but no differences were observed among the controls. Age, education, length of time postonset and presentation sequence did not have any impact on naming performance. Conclusion: These results suggest that use of digital color photographs for naming objects in assessment of aphasia may be associated with lower naming performance, compared with use of real objects. This needs to be taken into account when different forms of stimuli are presented in sequential aphasia evaluations.info:eu-repo/semantics/publishedVersio
New chemistry of diazafulvenium methides: one way to pyrazoles
Diazafulvenium methides generated from the solution pyrolysis of pyrazolo[1,5-c][1,3]thiazole-2,2-dioxides participate in [8[pi]+2[pi]] cycloadditions giving pyrazolo[1,5-a]pyridine derivatives. 1-Methyl-diazafulvenium, generated under flash vacuum pyrolysis reaction conditions, undergoes an intramolecular sigmatropic [1,8]H shift giving 1-vinyl-1H-pyrazoles.http://www.sciencedirect.com/science/article/B6THS-4HR7298-7/1/af0dd8d679e7977f53bc0d4af9a5b68
Synthesis and reactivity of 2-halo-2H-azirines towards nucleophiles
Nucleophilic substitution reactions of 2-halo-2H-azirine with potassium phthalimide and aniline allowed the preparation of new substituted 2H-azirines. The reactions of 2-bromo-3-phenyl-2H-azirine-2-carboxylate with methylamine led to the synthesis of [alpha]-diimines and from the reaction with water, a 3-oxazoline was obtained.http://www.sciencedirect.com/science/article/B6THS-4152YMR-K/1/e94005b66b66b6820ad27458f2562ed
Ethyl 7-Acetyl-8a-methyl-3-(1-phenyl-1H-tetrazol-5-yl)-1,4,4a,5,6,8a-hexahydro-7H-pyrano[2,3-c]pyridazine-1-carboxylate
The Diels–Alder reaction of ethyl 3-(1-phenyl-1H-tetrazol-5-yl-1,2-diaza-1,3-butadiene-1-carboxylate with 2-acetyl-6-methyl-2,3-dihydro-4H-pyran (methyl vinyl ketone dimer) regioselectively afforded the corresponding 3-(tetrazol-5-yl)-hexahydro-7H-pyrano[2,3-c]pyridazine in quantitative yield. An X-ray crystal structure of this cycloadduct is reported.info:eu-repo/semantics/publishedVersio
Seizures, electroencephalographic abnormalities, and outcome of ischemic stroke patients
© 2017 The Authors. Epilepsia Open published by Wiley Periodicals Inc. on behalf of International League Against Epilepsy. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial, and no modifications or adaptations are made.Objective: Seizures and electroencephalographic (EEG) abnormalities have been associated with unfavorable stroke functional outcome. However, this association may depend on clinical and imaging stroke severity. We set out to analyze whether epileptic seizures and early EEG abnormalities are predictors of stroke outcome after adjustment for age and clinical/imaging infarct severity.
Methods: A prospective study was made on consecutive and previously independent acute stroke patients with a National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 on admission and an acute anterior circulation ischemic lesion on brain imaging. All patients underwent standardized clinical and diagnostic assessment during admission and after discharge, and were followed for 12 months. Video-EEG (<60 min) was performed in the first 72 h. The Alberta Stroke Program Early CT Score quantified middle cerebral artery infarct size. The outcomes in this study were an unfavorable functional outcome (modified Rankin Scale [mRS] ≥ 3) and death (mRS = 6) at discharge and 12 months after stroke.
Results: Unfavorable outcome at discharge was independently associated with NIHSS score (p = 0.001), EEG background activity slowing (p < 0.001), and asymmetry (p < 0.001). Unfavorable outcome 1 year after stroke was independently associated with age (p = 0.001), NIHSS score (p < 0.001), remote symptomatic seizures (p = 0.046), EEG background activity slowing (p < 0.001), and asymmetry (p < 0.001). Death in the first year after stroke was independently associated with age (p = 0.028), NIHSS score (p = 0.001), acute symptomatic seizures (p = 0.015), and EEG suppression (p = 0.019).
Significance: Acute symptomatic seizures were independent predictors of vital outcome and remote symptomatic seizures of functional outcome in the first year after stroke. Therefore, their recognition and prevention strategies may be clinically relevant. Early EEG abnormalities were independent predictors and comparable to age and early clinical/imaging infarct severity in stroke functional outcome discrimination, reflecting the concept that EEG is a sensitive and robust method in the functional assessment of the brain.This work was supported by the 2012 Research Grant in Cerebrovascular Diseases (C.B.; scientific promoter: Sociedade Portuguesa do AVC; sponsor: Tecnifar).info:eu-repo/semantics/publishedVersio
11th national meeting of organic chemistry and 4th meeting of therapeutic chemistry
This work received financial support from the European Union (FEDER funds through COMPETE) and National Funds (FCT, Fundação para a Ciência e Tecnologia) through project UID/QUI/50006/2013. Fátima Fernandes (SFRH/BPD/98732/2013) and Mariana Barbosa (SFRH/BD/95861/2013) thank FCT for the grants.For the first time under the auspices of Sociedade Portuguesa de Química, the competences of two important fields of Chemistry are brought together into a single event, the 11st National Organic Chemistry Meeting and the the 4th National Medicinal Chemistry Meeting, to highlight complementarities and to promote new synergies. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report.publishersversionpublishe
Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages
Rationale: Cholesteryl hemiesters are oxidation products of polyunsaturated fatty acid esters of cholesterol. Their oxo-ester precursors have been identified as important components of the "core aldehydes" of human atheromata and in oxidized lipoproteins (Ox-LDL). We had previously shown, for the first time, that a single compound of this family, cholesteryl hemisuccinate (ChS), is sufficient to cause irreversible lysosomal lipid accumulation (lipidosis), and is toxic to macrophages. These features, coupled to others such as inflammation, are typically seen in atherosclerosis.
Objective: To obtain insights into the mechanism of cholesteryl hemiester-induced pathological changes in lysosome function and induction of inflammation in vitro and assess their impact in vivo.
Methods and results: We have examined the effects of ChS on macrophages (murine cell lines and primary cultures) in detail. Specifically, lysosomal morphology, pH, and proteolytic capacity were examined. Exposure of macrophages to sub-toxic ChS concentrations caused enlargement of the lysosomes, changes in their luminal pH, and accumulation of cargo in them. In primary mouse bone marrow-derived macrophages (BMDM), ChS-exposure increased the secretion of IL-1 beta, TNF-alpha and IL-6. In zebrafish larvae (wild-type All and PU.1:EGFP), fed with a ChS-enriched diet we observed lipid accumulation, myeloid cell-infiltration in their vasculature and decrease in larval survival. Under the same conditions the effects of ChS were more profound than the effects of free cholesterol (FC).
Conclusions: Our data strongly suggest that cholesteryl hemiesters are pro-atherogenic lipids able to mimic features of Ox-LDL both in vitro and in vivo.NOVA4Health - UID/Multi/04462/2013, a program financially supported by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement.
FCT fellowship references: SFRH/BPD/26843/2006, SFRH/BD/62126/2009, SFRH/BD/90258/2012, SFRH/BD/84685/2012, SFRH/BPD/102229/2014, SFRH/BD/52293/2013info:eu-repo/semantics/publishedVersio
High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-β-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients
Funding Information: This work was supported by Fundação para a Ciência e Tecnologia (FCT), Portugal, Aga Khan Development Network (AKDN)–Portugal Collaborative Research Network in Portuguese-speaking countries in Africa (project 332821690). CQC is supported by FCT through projects UIDB/00313/2020 and UIDP/QUI/00313/2020, co-funded by COMPETE2020-UE. iMed.ULisboa, Faculdade de Farmácia da Universidade de Lisboa, Portugal, is supported by FCT through projects UIDB/04138/2020 and UIDP/04138/2020. Inês Bártolo is supported by FCT through Norma Transitória–DL57/2016/CP1376/CT0012. Ana Rita Diniz (SFRH/BD/89140/2012), Francisco Martin (SFRH/BD/87488/2012), Inês Moranguinho (SFRH/BD/131062/2017), and Américo Alves (SFRH/BD/128910/2017) were supported by Ph.D. grants from FCT, Portugal. Publisher Copyright: © 2022 by the authors.Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.publishersversionpublishe
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