The Inhibitory Effect of Kakkonto, Japanese Traditional (Kampo) Medicine, on Brain Penetration of Oseltamivir Carboxylate in Mice with Reduced Blood-Brain Barrier Function

Oseltamivir phosphate (OP) is used to treat influenza virus infections. However, its use may result in central nervous system (CNS) adverse effects. In Japan, OP is used with Kampo formulations to improve clinical effectiveness. We evaluated the potential for using Kampo formulations to reduce CNS adverse effects by quantifying the CNS distribution of oseltamivir and its active metabolite oseltamivir carboxylate (OC) when administered with maoto and kakkonto. We administered lipopolysaccharide (LPS) by intraperitoneal injection to C57BL/6 mice to reduce blood-brain barrier function. Saline, maoto, and kakkonto were administered orally at the same time as LPS. OP was orally administered 4 hours after the last LPS injection and the migration of oseltamivir and OC was examined. Additionally, we examined the brain distribution of OC following intravenous administration. Changes in OC concentrations in the brain suggest that, in comparison to LPS-treated control mice, both Kampo formulations increased plasma levels of OC, thereby enhancing its therapeutic effect. Additionally, our findings suggest kakkonto may not only improve the therapeutic effect of oseltamivir but also reduce the risk of CNS-based adverse effects. Considering these findings, it should be noted that administration of kakkonto during periods of inflammation has led to increased OAT3 expression

Proteomic Biomarkers for Acute Interstitial Lung Disease in Gefitinib-Treated Japanese Lung Cancer Patients

Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

La bataille de Guillaume Budé, princeps de la République des Lettres, contre la barbarie des gens de justice

This article focuses on the battle that Guillaume Budé waged against the barbarity of the magistrates of the French sovereign court, who, despising the study of letters and prone to the pursuit of gain, relied solely on the Bartolist science of law. I argue that, at the court of Francis I, Budé, already recognised as princeps of the Republic of Letters, assumed the political role of “advocate of the Philologists’ nation” and proposed, based on his idea of encyclopaedia, the ideal of the orator-philosopher able to achieve justice

The Naissance of Modern Political in the Methodus of Jean Bodin : heritage of Budé and Connan, from law to politics

L’objectif de notre recherche est de préciser comment la conception novatrice de la science politique développée par Jean Bodin (1529/30-1596) dans sa Methodus ad facilem historiarum cognitionem(1566 ; 1572) s’inscrit dans le cadre d’un programme humaniste de restauration juridique de la «science civile». Pour cela, nous dégageons une ligne de réflexions sur cette «science» dans les œuvres de deux de ses prédécesseurs, Guillaume Budé et François Connan, qui la développent, à l’adresse des gens de justice, en élaborant un dispositif théorique, la «méthode», destiné à unifier la théorie juridique avec la connaissance pratique. Ces réflexions les amènent à ériger un nouveau paradigme du jusnaturalisme et à rétablir le droit tout entier sur la base de la droite raison, voire sur la base de la communauté de droit dominée par la seule raison: la civitas universa. Nous montrons que lorsque cette communauté est identifiée à la société mondiale de son temps, censée être régie par le ius gentiumqui incarne la raison, Bodin confère à la «science civile» un caractère politique. Le paradigme du jusnaturalisme le conduit à envisager le passage d’un état sauvage à la société humaine juridique (la communauté de droit), mais c’est la fameuse théorie de la souveraineté (summum imperium) qui permet aux magistrats des parlements d’opérer ce passage, en définissant leur pouvoir coercitif. Nous avançons que la science politique se concrétise dans la «méthode» de lecture de l’histoire et qu’elle détermine, au-delà des limites du droit, le rôle du gouvernement de la «République» comme ce qui réalise la société politique, c’est-à-dire la civitas universa régie par le ius gentium.Our research aims to examine how the innovative conception of “political science”, developed by Jean Bodin (1529/30-1596) in his Methodus ad facilem historiarum cognitionem (1566; 1572), falls within the scope of a humanist program which restores legal science in the name of scientia civilis. We therefore propose to investigate the line of thoughts which regard the scientia civilisin the works oftwo of his predecessors, Guillaume Budé and François Connan, who develop this “science” for the sake of magistrates-judges of the Parlements by devising a “method” which intends to unify legal theory with practical knowledge. Their considerations lead them to establish a new paradigm of jusnaturalism and to re-establish, in modern times, the very notion of law on the basis of right reason, id est, on the basis of a community of laws dominated only by reason: civitas universa. We bring light to the fact that, when this community is identified with the international society of his time, supposedly ruled by the ius gentiumwhich incarnates reason, Bodin bestows upon his scientia civilis a political character. If the jusnaturalist paradigm allows him to assume the transition from a barbarous state to ahuman society, it is his famous theory of sovereignty (summum imperium) that,by defining the coercive power delegated tothe magistrates of Parlements, allowsthem to realize this transition. We propose that his “method” of reading the history enables him to materialize the political science, which determines, beyond the limits of legal science, the role thegovernment plays in realizing the human society, or in other words, the new civitas universa, governed by the ius gentium

La naissance de la science politique moderne dans la Methodus de Jean Bodin : l'héritage de Budé et Connan, du droit à la politique

Our research aims to examine how the innovative conception of "political science", developed by Jean Bodin (1529/30-1596) in his Methodus ad facilem historiarum cognitionem (1566; 1572), falls within the scope of a humanist program which restores legal science in the name of scientia civilis. We therefore propose to investigate the line of thoughts which regard the scientia civilis in the works of two of his predecessors, Guillaume Budé and François Connan, who develop this "science" for the sake of magistrates-judges of the Parlements by devising a "method" which intends to unify legal theory with practical knowledge. Their considerations lead them to establish a new paradigm of jusnaturalism and to re-establish, in modern times, the very notion of law on the basis of right reason, id est, on the basis of a community of laws dominated only by reason: civitas universa. We bring light to the fact that, when this community is identified with the international society of his time, supposedly ruled by the ius gentium which incarnates reason, Bodin bestows upon his scientia civilis a political character. If the jusnaturalist paradigm allows him to assume the transition from a barbarous state to a human society, it is his famous theory of sovereignty (summum imperium) that, by defining the coercive power delegated to the magistrates of Parlements, allows them to realize this transition. We propose that his "method" of reading the history enables him to materialize the political science, which determines, beyond the limits of legal science, the role the government plays in realizing the human society, or in other words, the new civitas universa, governed by the ius gentium