1,721,000 research outputs found
Do anti-amyloid-β drugs affect neuropsychiatric status in Alzheimer's disease patients?
No full textIn the Alzheimer's disease (AD) brain, accumulation of the amyloid-β (Aβ) peptide starts 15–20 years before clinical symptoms become apparent and is believed to be the initial event of the pathological process. Unfortunately, candidate drugs targeting production, clearance and deposition of Aβ have failed to show clinical benefit in patients with established or prodromal disease, or in cognitively normal subjects with high risk of developing AD. Surprisingly, several potent anti-Aβ drugs accelerated cognitive decline of AD and, in some cases, worsened neuropsychiatric symptoms (NPS) and triggered suicidal ideation. Clarifying the relationships between the AD-related pathology and NPS of AD patients may be useful for elucidating the underlying pathophysiological process. We believe that steady overproduction of Aβ in AD may represent an attempt of the brain to mitigate or repair neuronal damage/insult. Sudden reductions of brain Aβ levels with potent anti-Aβ drugs may worsen cognition and exacerbate NPS
Structural evidence for native state stabilization of a conformationally labile amyloidogenic transthyretin variant by fibrillogenesis inhibitors
No full textSeveral classes of chemicals are able to bind to the thyroxine binding sites of transthyretin (TTR), stabilizing its native state and inhibiting in vitro the amyloidogenic process. The amyloidogenic I84S TTR variant undergoes a large conformational change at moderately acidic pH. Structural evidence has been obtained by X-ray analysis for the native state stabilization of I84S TTR by two chemically distinct fibrillogenesis inhibitors. In fact, they fully prevent the acidic pH-induced protein conformational change as a result of a long-range stabilizing effect. This study provides further support to the therapeutic strategy based on the use of TTR stabilizers as anti-amyloidogenic drugs
Amyloid-related imaging abnormalities associated with immunotherapy in Alzheimer's disease patients
No full text
Structure-activity relationships of flurbiprofen analogues as stabilizers of the amyloidogenic protein transthyretin
No full textThe inherent amyloidogenic potential of wild type transthyretin (TTR) is enhanced by a large number of point
mutations, which destabilize the TTR tetramer, thereby promoting its disassembly and pathological aggregation
responsible for TTR-related amyloidosis. TTR stabilizers are able to interact with the thyroxine-binding sites of
TTR, stabilizing its tetrameric native state and inhibiting amyloidogenesis. Herein, we report on in vitro, ex vivo,
and X-ray analyses to assess the TTR structural stabilization by analogues of flurbiprofen, a non-steroidal antiinflammatory
drug (NSAID). Overall, considering together binding selectivity and protective effects on TTR
native structure by flurbiprofen analogues in the presence of plasma proteins, as determined by Western Blot, the
aforementioned properties of analyzed compounds appear to be better (CHF5075 and CHF4802) or similar
(CHF4795) or worse (CHF5074, also known as CSP-1103) as compared to those of diflunisal, used as a reference
TTR stabilizer. Molecular details of the determinants affecting the interactions of CHF5075, CHF4802, and
CHF4795 with wild type TTR and of CHF5074 with the amyloidogenic A25T TTR variant have been elucidated
by X-ray analysis. Distinct interactions with TTR appear to characterize flurbiprofen analogues and the NSAID
diflunisal and its analogues as TTR stabilizers. Relationships between stabilizing effect on TTR by flurbiprofen
analogues determined experimentally and molecular details of their interactions with TTR have been established,
providing the rationale for their protective effects on the native protein structure
Different effects of atropine and cimetropium bromide on gastric emptying of liquids and antroduodenal motor activity in man
No full textAtropine (1 mg intravenously) and a new antimuscarinic compound, cimetropium bromide (5 mg intravenously), as well as placebo (physiological saline) were tested for their effects on gastric emptying and antroduodenal motility in healthy humans. In a first single-blind cross-over study, the emptying rate was assessed in 12 subjects by measuring paracetamol absorption. In a second single-blind parallel-group study, antroduodenal motor activity was measured in 20 subjects through four perfused open tip catheters with orifices positioned in the antroduodenal region. Atropine, unlike cimetropium bromide, significantly delayed gastric emptying. Antral and duodenal motility index was reduced significantly by atropine, but not by cimetropium bromide. Heart rate significantly increased only after atropine. Three subjects taking atropine complained of dry mouth and one of blurred vision. In conclusion, the results of these studies show that atropine, unlike cimetropium bromide, strongly inhibits gastric emptying of liquids and reduces antroduodenal motor activity in man
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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