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L’approche rahnerienne de la vie spirituelle « dans la grâce » presente une veritable theologie de l’experience spirituelle qui prend en charge les questions de fond que rencontrent toute vie et toute theologie spirituelle ; tout en etant theologique, elle respecte le caractere propre de l’experience spirituelle en sa difference d’avec la theologie systematique. La fluidite de la grâce, sa capacite a articuler transcendance et immanence mais aussi initiative de Dieu et liberte humaine, le rapport qu’elle entretient avec les affirmations dogmatiques de la foi chretienne sont des atouts precieux pour une theologie spirituelle fondamentale dans un contexte ou le spirituel est sorti de la seule sphere chretienne.

espanolEscrito en Paris entre 1260 y 1267 por Brunetto Latini, el Libro del Tesoro es una obra de caracter enciclopedico que habla de los hombres, de Dios o de la historia de los pueblos; sin embargo, no puede considerarse como una mera recopilacion de textos. En el prologo, Latini explica su voluntad de seguir las diferentes partes de la filosofia, centrandose el segundo libro en la Etica a Nicomaco de Aristoteles. Esta obra se propone hacer el retrato del monarca ideal, honrado, prudente y sabio gracias al estudio de los vicios y de las virtudes. Por fin, el Tesoro hace hincapie en la importancia del amor a Dios, tambien promovido por Sancho IV. Podemos considerar el Tesoro como un verdadero tratado de conducta real, recordando asi la voluntad del rey Sancho: imponer una monarquia cristiana fuerte. francaisRedige a Paris entre 1260 et 1267 par Brunet Latin, le Libro del Tesoro est une œuvre a caractere encyclopedique qui traite de l’homme, de Dieu, ou de l’histoire des peuples, mais elle ne peut se resumer a une simple compilation. Le prologue annonce que les trois livres qui constituent le Libro del Tesoro suivent les differentes parties de la philosophie, et le deuxieme se centre sur l’Ethique a Nicomaque d’Aristote. Cet ouvrage entend dresser le portrait d’un monarque ideal, juste, savant et sage a travers l’exposition des vices et des vertus. Enfin, le Tesoro reaffirme l’importance du lien a Dieu promu par Sanche IV. On peut donc considerer l’œuvre de Latin comme un veritable manuel de comportement royal, rappelant ainsi la volonte du roi Sanche : asseoir une monarchie forte et chretienne.

The rapid progression of COVID-19 is an organizational challenge for all hospitals. To secure the patient overflow, the Department internal medicine of the University Hospital of Lausanne increased nurse and medical workforces as well as bed capacity by 65 %, with extraordinary help from other departments. The implemented crisis management stood upon three pillars : a crisis management team, steering documents and internal communication. In this new form, the Department had already taken care of 442 COVID-19 admissions by April 16, 2020. Alongside organizational challenges, clinical issues such as rapid respiratory distress, clinical suspicions with negative PCR and treatment uncertainties in the absence of sufficient evidence were overcome. Despite the peak of the pandemic appearing to have passed, the next phase could be just as complicated.La progression rapide du COVID-19 constitue un défi organisationnel pour tous les hôpitaux. Pour anticiper un afflux important de patients, le service de médecine interne du CHUV a ainsi augmenté ses forces de travail médico-soignantes et son nombre de lits de 65 % avec un soutien extraordinaire de toute l’institution. Pour opérer ces changements majeurs, l’organisation de crise mise en place s’est appuyée sur trois piliers : une cellule de conduite, des documents de pilotage et une communication interne. Sous cette nouvelle forme, le service a pris en charge 442 hospitalisations COVID-19 jusqu’au 16 avril 2020. Si les enjeux organisationnels ont été majeurs, la gestion des situations complexes, comme les manifestations respiratoires et les multiples incertitudes cliniques diagnostiques et thérapeutiques, ont été également une gageure. Le pic de la pandémie semble passé, mais la prochaine phase pourrait constituer un nouveau défi organisationnel.

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Highlights • Pulmonary samples and nasopharyngeal aspirates have a similar diagnostic sensitivity for viruses detection by multiplex PCR. • Pulmonary samples have a higher efficiency for detection of Legionella pneumophila., Background PCR-based techniques for the diagnosis of community- acquired severe lower respiratory tract infections are becoming the standard of care. However, their relative ability to identify either atypical bacteria or viruses that cause LRTI from clinical samples from various sources is yet to be determined. Objectives and study design The aim of our study was to compare the diagnostic yield of nasopharyngeal aspirates with that of pulmonary samples for the etiological diagnosis of severe acute lower respiratory tract infections by multiplex PCR. Patients were adults with community-acquired pneumonia or acute exacerbation of chronic obstructive pulmonary disease. Results We obtained concordant results for 81 (79%) of the 103 pairs of samples. In 14 of the 22 discordant results, more pathogens were evidenced in the lower respiratory tract samples. Conclusions Pulmonary samples had a similar diagnostic sensitivity for virus detection by multiplex PCR as nasopharyngeal aspirates. In contrast, in our study, the diagnostic efficacy of pulmonary samples for Legionella pneumophila over simple aspirates was clearly superior.

International audience; Guinea pig pancreatic lipase-related protein 2 (GPLRP2) is an interesting model enzyme that can hydrolyze a large set of acylglycerols in vitro but displays however some selectivity depending on the supramolecular structure of substrate and the presence of surfactants like bile salts. We showed that GPLRP2 hydrolyzes 1,2-Dipalmitoyl phosphatidylcholine (DPPC) present in mixed micelles with sodium taurodeoxycholate (NaTDC) but not in multilamellar (MLV) and large unilamellar (LUV) vesicles of DPPC. After characterization of these lipid aggregates by dynamic light scattering (DLS), the discriminative recognition of DPPC in DPPC/NaTDC micelles versus MLV and LUV by an inactive variant (S152G) of GPLRP2 to avoid the effect of substrate hydrolysis was investigated using Fourier transform infrared spectroscopy (FTIR). IR spectra were recorded after hydrogen/deuterium exchange, at pD 6 and various temperatures to study phase transitions. We analyzed the methylene asymmetric stretching ((CH2)as), the carbonyl stretching ((CO)) and the composite polar head-group vibration bands, first to characterized differences in DPPC micelles and vesicles, and second to estimate the degree of interaction of GPLRP2 S152G with phospholipid. Our results indicate that a significant interaction between GPLRP2 S152G and DPPC is only observed when NaTDC is added to the system to form micelles and this can be explained by the different organization of DPPC in mixed micelles compared to lamellar vesicles (higher hydration of polar head, higher mobility of alkyl chains) that favors GPLRP2 penetration into the phospholipid layer.

Background Community-acquired pneumonia (CAP) requires urgent and specific antimicrobial therapy. However, the causal pathogen is typically unknown at the point when anti-infective therapeutics must be initiated. Physicians synthesize information from diverse data streams to make appropriate decisions. Artificial intelligence (AI) excels at finding complex relationships in large volumes of data. We aimed to evaluate the abilities of experienced physicians and AI to answer this question at patient admission: is it a viral or a bacterial pneumonia? Methods We included patients hospitalized for CAP and recorded all data available in the first 3-h period of care (clinical, biological and radiological information). For this proof-of-concept investigation, we decided to study only CAP caused by a singular and identified pathogen. We built a machine learning model prediction using all collected data. Finally, an independent validation set of samples was used to test the pathogen prediction performance of: (i) a panel of three experts and (ii) the AI algorithm. Both were blinded regarding the final microbial diagnosis. Positive likelihood ratio (LR) values > 10 and negative LR values Results We included 153 patients with CAP (70.6% men; 62 [51–73] years old; mean SAPSII, 37 [27–47]), 37% had viral pneumonia, 24% had bacterial pneumonia, 20% had a co-infection and 19% had no identified respiratory pathogen. We performed the analysis on 93 patients as co-pathogen and no-pathogen cases were excluded. The discriminant abilities of the AI approach were low to moderate (LR+ = 2.12 for viral and 6.29 for bacterial pneumonia), and the discriminant abilities of the experts were very low to low (LR+ = 3.81 for viral and 1.89 for bacterial pneumonia). Conclusion Neither experts nor an AI algorithm can predict the microbial etiology of CAP within the first hours of hospitalization when there is an urgent need to define the anti-infective therapeutic strategy.

Il y a plus de 2300 ans qu’a été décrite en Inde une maladiefaisant suite à une morsure de rat. Cette maladie a plus récemment été retrouvée un peu partout dans le monde et nommée « lafièvre par morsure de rat » ou « rat-bite fever » en anglais. Ceterme désigne deux maladies infectieuses distinctes: une zoonosedue à Streptobacillus moniliformis ou Streptobacillose, la plusfréquente et retrouvée sur tous les continents et l’autre, plus raredue à Spirillum minus ou « sodoku » retrouvée surtout en Asie(Washburn et al., 2005).

Resume Introduction Les avancees technologiques effectuees ces dernieres annees en identification bacterienne grâce a la biologie moleculaire et la spectrometrie de masse ou Matrix Assisted Laser Desorption Ionisation-Time of Flight (MALDI-TOF) ont permis de mettre en evidence de nouvelles bacteries impliquees dans les infections du tractus urinaire. Le but de cette revue est de faire connaitre aux cliniciens ces differents germes afin qu’ils pensent a les rechercher specifiquement chez une population ciblee et d’aider les biologistes a les suspecter et les identifier. Methode Une recherche bibliographique a ete effectuee sur la base MEDLINE a l’aide des mots cles Aerococcus, Actinobaculum, Alloscardovia, Trueperella . Resultats Si Aerococcus sp. est maintenant bien connu, Actinobaculum sp., Alloscardovia sp. et Trueperella sp. sont rarement isoles et sont meconnus des cliniciens. Ces germes pourraient avoir une importance sous-estimee du fait des difficultes d’identification et d’isolement qui existaient au prealable. On les retrouve plus particulierement chez des personnes âgees, presentant des pathologies sous-jacentes ou des facteurs de risque urologiques favorisants des infections du tractus urinaire. Actinobaculum schaalii peut egalement etre retrouve chez les jeunes enfants. Conclusion Aerococcus sp. et A. schaalii sont de veritables uropathogenes a ne pas meconnaitre. Des etudes complementaires demeurent cependant necessaires pour affirmer l’implication particuliere de Trueperella sp. et Alloscardovia sp. en pathologie urinaire.

Les ouvrages sapientiels écrits sous l’égide de Sanche IV sont des traités à caractère politico-moral réunissant un certain nombre de préceptes moraux et de conseils destinés à guider l’action du roi qui est considéré comme un modèle pour ses sujets. Devenus des guides de comportement pour tout noble souhaitant bien se comporter ou devenir conseiller du roi, ces textes, bien que de facture très diverse, présentent des similitudes, se recoupent, créant ainsi un maillage idéologique particulier, fruit de la pensée de Sanche IV, qui préconise une vision théologique du monde s’opposant ainsi aux choix opérés par son père, Alphonse X. Las obras sapienciales escritas bajo la tutela de Sancho IV son tratados políticos y morales que encierran cierto número de preceptos y consejos enfocados a guiar la acción del rey, el cual es considerado como un modelo para sus súbditos. Convertidos en guías de comportamiento para los nobles que quieren comportarse bien o llegar a ser consejero real, esos textos, aunque de factura muy diferente, presentan semejanzas y coinciden unos con otros, creando así un peculiar entramado ideológico, fruto del pensamiento de Sancho IV, el cual promueve una visión teológica del mundo oponiéndose a las opciones escogidas por su padre Alfonso X.

To the Editor: Ignatzschineria is a recently described genus of bacteria that have been rarely implicated in human disease (1–3). We report a patient in France with septicemia caused by I. ureiclastica.

SummaryLeptospirosis is a zoonotic infection for which diagnosis is difficult. It has appeared as a global emerging infectious disease over recent years. Genotype determination often requires a Leptospira strain obtained by culture, which is a long and fastidious technique. A method based on multilocus variable number tandem repeat analysis (MLVA) to determine the genotype of Leptospira interrogans, performed directly on blood or urine samples, is proposed. This method was applied to a fatal case of leptospirosis for which the geographical origin of infection was unknown. This technique will allow a genotype to be obtained for L. interrogans, even when cultures remain negative.

Immobilization of membrane bound enzymes onto electrodes is of great interest for studying physiological electron transfer processes and for biotechnological devices. Hydrogenases are the key enzymes for hydrogen metabolism in many microorganisms. Due to the high efficiency and specificity they develop for H2 oxidation, research in the last 5 years has aimed towards their use as biocatalysts for H2/O2 biofuel cells to replace platinum-based bioanodes. We demonstrate in this work that the O2-, CO- and T°-resistant membrane-bound [NiFe] hydrogenase purified from the hyperthermophilic bacterium Aquifex aeolicus can be efficiently immobilized onto electrodes. Both pyrolytic graphite (PG) and hydrophobic Self-Assembled-Monolayers (SAMs) on gold electrodes are used for hydrogenase immobilization. According to the chemistry and structure of the electrochemical interface, a different process for H2 oxidation is observed, from direct to mediated electron transfer process. To gain new insight in the catalytic process, a quantification of the remaining detergent surrounding the membrane protein is performed. Adsorption isotherms of hydrogenase are determined as a function of the electrode material and the amount of detergent. Competitive adsorption of free detergent and hydrogenase is demonstrated coupling electrochemistry and Polarization Modulation Infrared Reflexion Adsorption Spectroscopy (PM-IRRAS). The efficiency of the enzymatic process is then analyzed according to the tiny interaction between the lipophilic redox mediator (methylene blue), the detergent, the enzyme and the electrochemical interface.

International audience; Lipase secretion, extracellular lipolysis, and fatty acid uptake were quantified in the yeast Yarrowia lipolytica grown in the presence of olive oil and/or glucose. Specific lipase assays, Western blot analysis, and ELISA indicated that most of the lipase activity measured in Y. lipolytica cultures resulted from the YLLIP2 lipase. Lipase production was triggered by olive oil and, during the first hours of culture, most of the lipase activity and YLLIP2 immunodetection remained associated with the yeast cells. YLLIP2 was then released in the culture medium before it was totally degraded by proteases. Olive oil triglycerides were largely degraded when the lipase was still attached to the cell wall. The fate of lipolysis products in the culture medium and inside the yeast cell, as well as lipid storage, was investigated simultaneously by quantitative TLC-FID and GC analysis. The intracellular levels of free fatty acids (FFA) and triglycerides increased transiently and were dependent on the carbon sources. A maximum fat storage of 37.8% w/w of yeast dry mass was observed with olive oil alone. A transient accumulation of saturated FFA was observed whereas intracellular triglycerides became enriched in unsaturated fatty acids. So far, yeasts have been mainly used for studying the intracellular synthesis, storage, and mobilization of neutral lipids. The present study shows that yeasts are also interesting models for studying extracellular lipolysis and fat uptake by the cell. The quantitative data obtained here allow for the first time to establish interesting analogies with gastrointestinal and vascular lipolysis in humans.

Chirality of biomolecules is one of the major characteristics of living systems. Molecular asymmetry can be detected in the earliest prokaryotes and stereoselective synthesis of proteins and polysaccharides was recognized since Pasteur’s time. More recently much attention was paid to the molecular origin of asymmetric development of organs. This asymmetry can be followed up to the cellular and tissue levels. We compared the periorbital wrinkle pattern (crow’s feet) around the left and right eyes, as well as the microdepressional skin surface relief on the left and right arms. The pattern of these reliefs was shown to change with age in a typical manner. Apparently this age-dependent modification of the skin surface micro-relief as well as wrinkle formation is largely determined by the progressive modifications of the dermal extracellular matrix (ECM) and especially of the elastic fiber network as the result of the oriented (vectorial) biosynthetic activity of dermal fibroblasts. These cells do not form a homogeneous population as shown by their proliferation pattern. The reaction of these cells to receptor-mediated stimuli—by growth factors, cytokines, and hormones also exhibit microheterogeneity. Cell–cell interactions, especially between the keratinocyte layers of the epidermis and dermal fibroblasts might also play an important role in the regulation of cell-patterning. These mechanisms might well explain the asymmetry detected by our semi-automated image analysis program on left–right microdepressionary skin surface relief, as well as periorbital wrinkle formation.

Équipe 104 : Nanomatériaux; International audience; We investigated the nickel doped TiO2 layer and annealing duration effects on SiO2/TiO2 Bragg reflectors. The films crystallize in pure anatase phase whatever is the Ni content and the annealing duration. In UV-vis-NIR analyses, variations of width, position and transmission coefficient of the stop-band were observed. The PL spectra red-shifted when the Ni content and annealing duration increased. As the annealing duration increases, an additional sharp emission peak appears around 867 nm, indicating a reduced number of defects. As Ni content increased, the M-lines spectroscopy shows two transverse electric polarization guided modes TE0 and TE1, which indicates a decreased refractive index and an increased film thickness.

International audience; A detailed analysis of triacylglycerols (TAGs) contents, fatty acid patterns and key enzyme activities in the freshwater diatom Asterionella formosa was performed under various conditions, including nitrate, iron and silicon limitation (stress conditions), or bicarbonate and phytohormones supplementation (stimulation conditions). Of all the conditions tested, the addition of bicarbonate produced the greatest increase (5-fold) in TAGs contents compared to the control while the biomass increased. The addition of phytohormones also allowed a significant increase in TAGs of about 3-fold while the biomass increased. Silicon, unlike iron and nitrate limitation, also triggered a significant increase in TAGs contents of 3.5-fold but negatively affected the biomass. Analysis of fatty acid profiles showed that the mono-unsaturated C16:1 fatty acid was the most abundant in A. formosa, followed by C16:0, C14:0 and eicosapentaenoic acid (EPA; C20:5 n-3). EPA levels were found to increase under nitrate and iron limitation. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoribulokinase (PRK), phosphofructokinase (PFK), glucose-6-phosphate dehydrogenase (G6PDH) and malate dehydrogenase (MDH) activities differed with growth conditions. Most enzymes were up-regulated in stimulated cells while in the case of stressed cells, the pattern of activities was more variable. Detailed analysis of all enzyme activities showed that the most important enzyme among those tested was GAPDH which could be a good candidate for genetic engineering of high lipid-producing algae. This study provides a better understanding of key enzymes and biochemical pathways involved in lipid accumulation processes in diatoms.

CITREM is an emulsifier used in the food industry and contains citric acid esters of mono- and diglycerides (GCFE). It is generally recognized as safe but no publication on its digestibility under gastrointestinal conditions and impact on fat digestion was available. It was shown here that fatty acids are released from CITREM by gastric lipase, pancreatic lipase, pancreatic-lipase-related protein 2 and carboxyl ester hydrolase. A two-step in vitro digestion model mimicking lipolysis in the stomach and upper small intestine of term and preterm infants was then used to evaluate the digestibility of CITREM alone, CITREM-containing infant formula and fat emulsions, and isolated GCFE fractions. Overall, it was shown that fat digestion is not significantly changed by the presence of CITREM, and fatty acids contained in CITREM compounds are released to a large extent by lipases. Nevertheless, undigestible water-soluble compounds containing glycerol and citric acid units were identified, indicating that the ester bond between citric acid and glycerol is not fully hydrolyzed throughout the proposed digestion.

Objective To characterize the effects of pressor doses of norepinephrine and low-dose dopamine (3 micrograms/kg/min) on renal hemodynamics in man, as well as to determine the clinical relevance of combining dopamine with norepinephrine. Design Prospective, single-blind, randomized study. Setting Clinical research unit of a tertiary care hospital. SUBJECTS. Six healthy male volunteers ranging in age between 20 and 28 yrs. Interventions The subjects were assigned randomly to four treatments (1 wk apart) in which renal hemodynamics and electrolyte excretion were assessed. Treatments consisted of 180-min infusions of the following: a) 0.9% sodium chloride (control); b) pressor doses of norepinephrine; c) dopamine at 3 micrograms/kg/min; and d) pressor doses of norepinephrine and dopamine at 3 micrograms/kg/min. Pressor doses of norepinephrine was defined as doses required to increase mean arterial pressure (MAP) by 20 mm Hg. Measurements and main results Glomerular filtration rate and renal blood flow were derived from inulin and para-aminohippurate clearances, respectively. Urine output and urine solute excretion were also determined. The mean norepinephrine dose required to increase MAP by 22 +/- 2 mm Hg was 118 +/- 30 ng/kg/min (range 76 to 164). After the addition of dopamine, similar doses of norepinephrine resulted in an MAP increase of 15 +/- 4 mm Hg. Glomerular filtration rate and urine output were comparable under all conditions. The infusion of norepinephrine decreased renal blood flow from 1241 +/- 208 to 922 +/- 143 mL/min/1.73 m2 (p = .03). The addition of dopamine returned renal blood flow to baseline values. The clearance of urine sodium increased significantly with the infusion of dopamine alone (p = .03). All subjects completed the four treatment periods. Adverse events, manifested mostly as palpitations and flushing, were rare and self-limiting. Conclusions The addition of dopamine (3 micrograms/kg/min) to pressor doses of norepinephrine normalized renal blood flow in healthy volunteers. These hemodynamic changes were not reflected in urine output and glomerular filtration rate; hence, these monitoring parameters may be unreliable indicators of renal function in the setting of vasopressor therapy. In addition, systemic effects were observed with dopamine (3 micrograms/kg/min), as indicated by a decrease in MAP.

Summary Pharmacomodulation of the non-carboxylic NSAID N -(4,6-dimethylpyridin-2-yl)benzamide 1 led to the synthesis of structurally related furan, thiophene and pyrrole carboxamides 3–14 . The derivatives benzenethiocarboxamides 15–18 and heteroaryl-thiocarboxamides 19–22 were also prepared by oxygen/sulfur exchange; this reaction was more efficiently carried out by P 4 S 10 than by Lawesson's reagent. The 20 synthesized compounds were evaluated against peripheral edema by a foot-pad carrageenin-induced edema test. Amides 3–5, 8, 9, 11, 12 and 14 were most active, exhibiting > 90% inhibition after oral administration of 0.8 mmol·kg −1 . Two amides, 3 and 5 , were selected for evaluation of their inhibitory activity in PLA 2 -induced brain edema and were found to be more potent than dexamethasone after IP administration.

The entire molecule of 5,7-dimethyl-2-phenyl-3-thioxo-3H-[1,4,2]diazaphospholo[1,5-a]pyridinium-3thiolate, C 14 H 13 N 2 PS 2 , with the exception of the two S atoms, is approximately planar. The π electrons of the N(7)-C(8) bond are partially conjugated with those of the phenyl and pyridinyl rings. The P-C and P-S bond lengths are not significantly different to distances in related compounds. However, the P-S bonds are shorter than terminal P-S bonds in thiophosphates. The P-N distance [1.819 (3) A] indicates partial ionic character

A series of borodipeptide derivatives 7–9 , which contain a 6-amino-2,4-dimethylpyridine moiety, was prepared in 3 steps. They were evaluated as hypolipidemic agents in rodents at 20 mg/kg per day. The methioninamide and phenylalaninamide derivatives were the most potent compounds demonstrating hypocholesterolemic and hypotriglyceridemic activities in rats. After 14 days, the activity of these compounds was superior to that of clofibrate, at a dose of 200 mg/kg per day.

Benzamides I, phenylalkanamides II and cinnamamides III are structurally related to the antiinflammatory N-(4,6-dimethylpyridin-2-yl)benzamide I. These were synthesized and the transformation of the 2-aminopyridine nucleus of benzamides I into a 2-imino-1,2-dihydropyridine structure (compounds IV) was also carried out. Of the 49 new derivatives, the 3-fluorobenzamide 9 was the most potent in the oral treatment of carrageenen-induced peripheral edema; IC50 = 12.2 mg·kg−1. It was 3 times as active as benzamide 1, but the latter nevertheless had a better therapeutic index (LD50/IC50) of 52 against 23. Benzamide 1, a non-acidic antiinflammatory compound devoid of any blocking activity on cyclooxygenase, markedly reduces the production of reactive oxygen species in rat peritoneal macrophages. This compound probably acts at the membrane, perhaps by interference with transmembrane events.

This investigation compares the accuracy of calculating gentamicin pharmacokinetic parameters by a noninvasive body composition technique (bioelectrical impedance analysis; BIA) with an empiric method, against the two-point method as the criterion standard. A prospective concurrent open label design was used. The 32 medical and surgical intensive care unit beds at Henry Ford Hospital, a not-for-profit, university-affiliated teaching hospital, served as the setting. Twenty critical ill adults, Therapeutic Index Scoring System (TISS) = 4, who required gentamicin as part of their normal course of therapy for gram-negative bacillary infections, were evaluated. Gentamicin Vd and k were calculated by three methods. After measurement of body composition parameters by BIA, previously derived gentamicin dosing equations were used to predict gentamicin volume of distribution (Vd) and elimination rate constant (k) (BIA method). Empiric estimates of these parameters (Vd = 0.3L/kg and k derived from creatinine clearance) were compared with the BIA parameters against a criterion standard Vd and k determined from a two-point sampling of gentamicin serum concentrations. Measurements of BIA parameters and gentamicin serum concentrations were made in duplicate with coefficients of variation, < or = 2% and < or = 3%, respectively. The BIA and empiric methods produced resultant pharmacokinetic parameters (Vd and k) not different than those measured by the two-point method. There were no statistically significant differences in mean error (bias), or mean squared error (precision) for both Vd and k assessed by the empiric or BIA methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Derivatives of 2-amino-4,6-dimethylpyridine resulting from the integration of the amino function into a 2-imidazolidinone were synthetized via the corresponding 2-chloroethylurea. N 3 -benzylation, acylation or sulfonylation afforded the target compounds 6-14 which were evaluated for their in vitro and in vivo antileishmanial activity. Two compounds, the N 3 -benzyl derivative 7 and the N 3 -tolylsulfonyl derivative 14, exhibited potent inhibition against cultured extracellular promastigotes of Leishmania mexicana with IC 50 comparable to that of the previously studied N-(4,6-dimethylpyridin-2-yl) furan-2-carboxamide 2: 32.4, 46 and 69 µmol/l, respectively. Experimentation of their activity against mice macrophage amastigotes pointed out that IC 50 of imidazolidones 7 and 14 were 7 and 13-fold lower than that of amide 2: 13.7 and 89 µmol/l. In vivo evaluation in Balb/c mice, intradermally infested with Leishmania mexicana, confirmed that, in the lesion site, compound 14 was able to significantly reduce the parasite burden at a daily i.p. dose of 10 mg/kg. It was demonstrated that these N-pyridinylimidazolidinones could act by interference with the parasite PLA 2 activity.

Corresponding author. fax: +33 491 715 857. E-mail address: carriere@ifr88.cnrs-mrs.fr; International audience; Monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG) are the most abundant lipids in nature, mainly as important components of plant leaves and chloroplast membranes. Pancreatic lipase-related protein 2 (PLRP2) was previously found to express galactolipase activity, and it is assumed to be the main enzyme involved in the digestion of these common vegetable lipids in the gastrointestinal tract. Most of the previous in vitro studies were however performed with medium chain synthetic galactolipids as substrates. It was shown here that recombinant guinea pig (Cavia porcellus) as well as human PLRP2 hydrolyzed at high rates natural DGDG and MGDG extracted from spinach leaves. Their specific activities were estimated by combining the pH-stat technique, thin layer chromatography coupled to scanning densitometry and gas chromatography. The optimum assay conditions for hydrolysis of these natural long chain galactolipids were investigated and the optimum bile salt to substrate ratio was found to be different from that established with synthetic medium chains MGDG and DGDG. Nevertheless the length of acyl chains and the nature of the galactosyl polar head of the galactolipid did not have major effects on the specific activities of PLRP2, which were found to be very high on both medium chain [1786+/-100 to 5420+/-85U/mg] and long chain [1756+/-208 to 4167+/-167U/mg] galactolipids. Fatty acid composition analysis of natural MGDG, DGDG and their lipolysis products revealed that PLRP2 only hydrolyzed one ester bond at the sn-1 position of galactolipids. PLRP2 might be used to produce lipid and free fatty acid fractions enriched in either 16:3 n-3 or 18:3 n-3 fatty acids, both found at high levels in galactolipids.

OBJECTIVE:The aim of this preliminary investigation was to evaluate the use of aminoglycoside serum concentrations as a surrogate measure of the glomerular filtration rate (GFR) in comparison with other measured and empiric methods against inulin, the criterion standard measure of GFR.DESIGN:A consecutive sample of all eligible patients.SETTING:An eight-bed medical intensive care unit in a university-affiliated tertiary-care teaching hospital.PATIENTS:Ten critically ill medical patients receiving gentamicin or tobramycin for presumed or documented gram-negative bacillary infection were enrolled in the study. The patients were mechanically ventilated and had underlying organ system dysfunction. All ten patients completed the study.INTERVENTION:Patients underwent renal functional assessment by measured inulin (Clin) and 24-hour urinary creatinine clearance (Clcr). Aminoglycoside serum concentrations were used to estimate GFR and were compared with the two measured methods and a creatinine clearance calculated with the Cockcroft-Gault method (ClCG). All evaluations were performed the same day.RESULTS:Clinaveraged 51.6 ± 35.0 mL/min and serum creatinine ranged from 0.3 to 5.4 mg/dL (26.5 to 477.3 μmol/L). Steady-state peak and trough aminoglycoside concentrations were 6.1 ± 1.4 and 1.3 ± 0.9 μg/mL, respectively. There were no statistically significant differences between the various methods, although the aminoglycoside-calculated GFR (Clamg) 95 percent confidence intervals were smaller man Clcrand ClCGcompared with Clin. Mean absolute errors were smaller with Clamgthan with Clcrand ClCG. Regression results indicated that only Clangand ClCGdemonstrated agreement with Clin(lines not different from y=x). However, the Clamgshowed closer agreement, with a mean square error almost half that of ClCG(9.6 vs. 18.1).CONCLUSIONS:Clamgcan be used routinely as an estimate of GFR in critically ill patients, with less error man empiric methods.

Digoxin fab antibody therapy is known to interfere with digoxin immunoassays causing spurious serum digoxin concentrations. The reliability and precision of three digoxin immunoassays--Baxter Dade Stratus (BDS), Syva affinity column enzyme-mediated immunoassay (EMIT), and the reference assay Abbott TDx fluorescence polarization immunoassay following ultrafiltration (FPIA-UF)--were compared in eight digoxin toxic patients treated with digoxin fab antibodies. Five to eight blood samples were drawn serially up to 204 h post digoxin fab therapy. The serum digoxin concentration in each sample was determined by each of the three assays. The mean (+/- SD) area under the serum digoxin concentration-time curve was significantly lower for FPIA-UF than for BDS or EMIT (86.1 +/- 58.2 vs 158.1 +/- 88.6 and 176.3 +/- 115.3 h.ng/ml p less than 0.01, respectively). BDS correlated better with FPIA-UF (r2 = 0.71) than did EMIT (r2 = 0.45). Predictive performance of the BDS and EMIT assays demonstrated that the mean prediction error (bias) (0.62 vs 0.78 ng/ml) and the mean squared prediction error (precision) (0.48 vs 0.76) differed significantly from zero (p less than 0.05). However, BDS had significantly less bias and greater precision than did EMIT (p less than 0.05). In the presence of digoxin fab antibodies, BDS is a better predictor of free serum digoxin concentration than is EMIT, but both have considerable bias. Based on these results, FPIA-UF should be the assay of choice for determining free serum digoxin concentrations during fab therapy.

OBJECTIVE:The primary objective of this article is to introduce the reader to the use of thrombolytics in the acute treatment of ischemic stroke. Theory and experimental evidence to support this approach are emphasized in addition to potential adverse effects of thrombolysis.DATA SOURCES:A MEDLINE search was used to identify pertinent literature, including reviews.STUDY SELECTION:Studies were selected for detailed review if they involved stroke patients and addressed possible toxicities of therapy. Any abstracts concerning ongoing clinical trials also were reviewed.DATA EXTRACTION:Data from animal investigations using tissue plasminogen activator for the acute treatment of several models of cerebral ischemia were used to support the importance of early treatment (within six hours of symptom onset). Also, studies performed in animal models of stroke revealed that thrombolysis could be accomplished safely in acute ischemic stroke. All human studies published to date are anecdotal case reports, but point to the safety of thrombolysis if administered early. Reviews of ongoing multicenter trials are taken from published abstracts and proceedings.DATA SYNTHESIS:Thrombolysis holds promise as a hyperacute therapy for acute stroke; however, the risk of intracerebral hemorrhage remains. Crucial to the success of this and any other therapy for acute stroke is the ability to treat patients within hours of symptom onset. Also, the importance of concomitant medications such as heparin and aspirin has not yet been addressed.CONCLUSIONS:Pharmacists need to be knowledgeable of new treatments of stroke and the risks associated with them. As patient educators, pharmacists can contribute to public awareness by promoting the early recognition of stroke symptoms. As pharmacotherapists, pharmacists need to understand the risks and the important monitoring parameters related to thrombolysis. The results of ongoing multicenter clinical trials are awaited before making a final judgment on the usefulness of thrombolysis in acute ischemic stroke.

Introduction In animal studies, long-term prenatal nicotinic exposure alters the development of dopaminergic neurons. To determine whether prenatal smoking exposure was associated with schizophrenia, using a retrospective design study, we compared the prevalence of tobacco use during pregnancy in mothers of subjects with and without schizophrenia. Methods One hundred patients with schizophrenia, 100 nonschizophrenic-matched subjects, and their respective mothers were interviewed. The prevalence of smoking was measured in these individuals as well as in their respective mothers during the pregnancy. Results Patients with schizophrenia smoked more often compared with controls (73% vs 57%). In contrast, the prevalence of smoking during pregnancy did not differ between the groups of mothers. Indeed, the amount of tobacco used was significantly lower in mothers of patients with schizophrenia vs mothers of nonpsychotic subjects. Conclusion This study did not show any association between prenatal tobacco exposure and further development of schizophrenia.

The inhibition of the carragenin-induced rat-paw edema by previously synthesized N-(4,6-dimethyl)-2-pyridinyl) benzamides was evaluated. Among the 29 tested compounds, secondary benzamides 1, 12 and tertiary benzamide 60 exhibited a significant anti-inflammatory activity. It prompted us to envision a pharmacomodulation in this series by structural modifications on the homocycle, the amide function and the heterocycle. Although benzamide 38, acetamide 50 and benzylamine 56 elicited marked inhibitory activity, none was more active than N-(4,6-dimethyl-2-pyridinyl) benzamide 1. The mechanism of the anti-inflammatory action of 1 was investigated. The results showed that this molecule reduced eicosanoid biosynthesis but was unable to reduce cyclooxygenase or lipoxygenase activities. Although it did not directly block phospholipase activity, however, an inhibitory process at this level is likely.

Two 3-(alpha-azolylbenzyl)indoles were evaluated against Leishmania amastigotes. Both compounds proved to be very active against intracellular and axenic amastigotes. The IC50 values of the imidazole derivative, PM17, and the triazole analogue, PM19, against L. mexicana axenic amastigotes, were 4.4 +/- 0.1 and 6.4 +/- 0.1 microM, respectively. Against intracellular amastigotes, PM17 produced a 66% decrease of leishmanial burden at 1 microM and PM19 had an IC50 of 1.3 microM. In a Balb/c mice model of L. major leishmaniasis, administration of PM17 led to a clear-cut parasite burden reduction: 98.9% in the spleen, 79.0% in the liver and 49.9% in the popliteal node draining the cutaneous lesion. As anticipated, it was brought to the fore that PM17 decreases ergosterol biosynthesis leading to membrane fungal cell alterations. Moreover it was proved that this imidazole antifungal agent induces a parasite burden-correlated decrease in interleukine-4 production both in the splenocyte and the popliteal node of the mouse.

New N1-mono and N1, N2-disubstituted imidazolidin-2-one with a significant immunosuppressive activity have been discovered. Among the 17 synthesized and tested compounds, five of them showed maximal inhibition of proliferation of concanavallin A (Con A)- stimulated splenocytes at 90 microM, identical to that obtained with cyclosporin A (CsA) at 5 microM, an optimal concentration.

N(3)-acyl, arylsulfonyl and benzyl derivatives of N(1)-(4,6-dimethylpyridin-2-yl), (5-methylthiazol-2-yl) or (3-methylisoxazol-5-yl)imidazolidin-2-ones were synthesized and evaluated as potential antileishmanial agents. Determination of their cytotoxic effect was carried out using MRC5 cells. Two compounds, 1-(4,6-dimethylpyridin-2-yl)-3-(napht-2-ylsulfonyl)imidazolidin-2-one, 18, and 1-(3-methylisoxazol-5-yl)-3-(4-bromobenzyl)imidazo-lidin-2-one, 25, exerted significant antileishmanial activity in promastigotes of Leishmania (L) mexicana and Leishmania infantum, with IC(50) in the range of 8-16 micro mol L(-1). Antiparasitical activity of the less toxic compound, 25, was confirmed against intracellular amastigote of L. mexicana, the clinical relevant stage; its low IC(50) value (2.4 micro mol L(-1)) and its favourable toxicity/activity index (11) constitute encouraging results for ongoing pharmacomodulation in the corresponding subseries.

The title compound, C 17 H 18 N 4 , is a structural analogue of N-(4,6-dimethylpyrid-2-yl)benzamide, with a triazolic heterocycle instead of the amide function, affording stronger anti-inflammatory properties. The three rings in the molecule are planar with dihedral angles between their least-squares planes of 73.4 (2), 70.7 (2) and 38.8 (4) o . The crystal structure can be regarded as a stack of molecular layers parallel to the (001) plane