[Characteristics of patients with connective tissue disease-associated pulmonary arterial hypertension treated with prostanoids: A multicenter retrospective study]. / Caractéristiques des patients traités par prostanoïdes pour une hypertension artérielle pulmonaire associée à une connectivite : étude multicentrique rétrospective.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue disease (CTD). Data on use of prostanoids in this particular subset of patients are lacking. We aimed to describe the characteristics of patients with PAH-CTD treated with prostanoids and the outcomes under treatment. METHODS: In this multicenter retrospective study, all patients treated with prostanoids since 2006 were included. Data on PAH and CTD were collected at the time of prostanoid introduction and under treatment. RESULTS: Twenty-one patients were included, of whom 20 (95%) had limited cutaneous systemic sclerosis. Nineteen patients were treated with oral monotherapy or combination before addition of prostanoid. Treprostinil was the most used molecule (57% of patients). At the time of prostanoid introduction, 90% of patients were considered at high risk for death. Among patients who had right heart catheterization during follow-up, there was no significant difference in haemodynamics. No extrarespiratory worsening of the CTD was reported. The 1-year survival under prostanoid was 62%. In univariate analysis, NYHA functional class was associated with survival under treatment. CONCLUSION: This study provides original data on use of prostanoids in a cohort consisting mainly of systemic sclerosis. It underlines the difficulty to achieve a standardized assessment in this subset of patients. Safety profile was comparable with data reported in idiopathic PAH.

[Paraneoplastic pemphigus: Retrospective study of a case series]. / Étude rétrospective d'une série de pemphigus paranéoplasiques.

CONTEXT: Paraneoplastic pemphigus (PNP) is a rare condition associated with poor prognosis. It associates polymorphic mucocutaneous manifestations with neoplasia. Diagnosis is difficult because of the various clinical and histological features involved and the lack of specificity of immunological examinations. METHODS: We retrospectively analyzed the records of patients presenting with PNP in the Poitou-Charentes region between 2000 and 2015. RESULTS: Seven patients were included. They presented 9 neoplasias (1 lymphoma, 1 melanoma, and 7 carcinomas) diagnosed from 4 months before to 25 months after the occurrence of cutaneous (6/7) and/or mucosal (6/7) polymorphic lesions. Histological examination revealed epidermal acantholysis (7/7), keratinocytic necrosis (4/7), and interface lichenoid dermatitis (5/7). Intercellular deposits of IgG and C3 or along the dermo-epidermal junction were detected with direct immunofluorescence (IF) (7/7). Four of 6 patients tested had positive indirect IF on rat bladder epithelium. Follow-up ranged from 1-132 months with a one-year survival of 85.7%. DISCUSSION: The clinical and histopathological presentations observed in our patients were polymorphic, with overlap between the clinical and histological features of PNP and classical pemphigus. Prognosis and survival appear better in our series than in the literature. It is possible that in some cases, the association of pemphigus with neoplasia was fortuitous, which might account for the better prognosis. A new consensus on the diagnostic criteria for PNP is needed to help practitioners to consensually diagnose it for prognostic or therapeutic trials.

[Screening for pulmonary arterial hypertension in patients with systemic sclerosis: Comparison of DETECT algorithm to decisions of a multidisciplinary team, in a competence centre]. / Dépistage de l'hypertension artérielle pulmonaire au cours de la sclérodermie systémique : comparaison de l'algorithme DETECT à une discussion pluridisciplinaire en centre de compétence.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis and detecting PAH efficiently remains challenging. The DETECT study has offered in 2013 a composite screening tool for PAH. The objective of our study was to compare the indication of right heart catheterisation (RHC) as suggested by the DETECT algorithm with the decisions of a multidisciplinary team. METHODS: This prospective monocentric non-interventional study consecutively included systemic sclerosis patients when data required to apply DETECT algorithm were available. We evaluate the number of RHC as requested by this algorithm and confronted it with the indications of RHC suggested by a multidisciplinary group blinded for the result of DETECT algorithm. RESULTS: In total, 117 systemic sclerosis patients were included. When DETECT algorithm was applied to all patients, RHC was suggested by this algorithm for 70 patients, whereas only 15 indications were required by the multidisciplinary group; among those patients only 7 had PAH. When DETECT algorithm was applied only to the 42 patients with DLCO<60% and disease duration of more than 3 years, RHC was suggested for 31 patients whereas only 13 were indicated by the multidisciplinary group; among those patients only 7 had PAH. CONCLUSION: The DETECT algorithm is able to efficiently detect all PAH patients finally diagnosed by our multidisciplinary team. However, it increases by 3 the number of RHC that should be performed.

Prognostic value of left atrial reservoir function in patients with severe aortic stenosis: a 2D speckle-tracking echocardiographic study.

AIMS: The aim of this article is to assess the left atrial (LA) reservoir function in patients with severe aortic stenosis (AS) and to evaluate its impact on the recurrence of major adverse cardiac events (MACEs). METHODS AND RESULTS: About 128 patients (mean age 79 ± 9 years) with severe AS were included in the study. Global peak LA strain (PLAS) measured by two-dimensional speckle-tracking echocardiography (STE) during left ventricular (LV) systole represented the LA reservoir function. Overall death, hospitalization for cardiac cause, and worsening heart failure were defined as MACEs. With respect to the values observed in a control group of 20 healthy patients, PLAS resulted significantly reduced in AS. According to the multivariate linear regression analysis, LV global longitudinal strain, mitral E/e' ratio, and systolic pulmonary arterial pressure (sPAP) were the best correlates to PLAS. During follow-up, the predefined MACEs occurred in 39 patients. According to the multivariate Cox regression analysis, a PLAS <21% was a significant predictor of MACEs [hazard ratio (HR) 2.88, P = 0.04], as was coronary artery disease (HR 2.68, P = 0.004) and the New York Heart Association functional class (HR 2.08, P = 0.03). CONCLUSION: In patients with severe AS, a global PLAS <21% is an independent predictor of prognosis. Given the combined influence of LV diastolic and systolic function and of LA performance on sPAP, the decline of PLAS might be considered a marker of global myocardial impairment in AS. Further studies are needed to confirm the critical role of LA relaxation in prognosis and to validate its relevance in routine clinical practice.

Variation of strand break yield for plasmid DNA irradiated with high-Z metal nanoparticles.

Using agarose gel electrophoresis, we measured the effectiveness of high-Z metal particles of different sizes on SSB and DSB yields for plasmid DNA irradiated with 160 kVp X rays. For plasmid samples prepared in Tris-EDTA buffer, gold nanoparticles were shown to increase G'(SSB) typically by a factor of greater than 2 while G'(DSB) increased by a factor of less than 2. Similar dose-modifying effects were also observed using gold microspheres. Addition of 10(-1) M DMSO typically decreased damage yields by a factor of less than 0.5. Plasmid samples prepared in PBS showed significantly different damage yields compared to those prepared in Tris-EDTA (P < 0.001) with G'(SSB) and G'(DSB) increasing by factors of 100 and 48, respectively. Furthermore, addition of gold nanoparticles to samples prepared in PBS decreased G'(SSB) and G'(DSB) by factors of 0.2 and 0.3, respectively. The results show plasmid damage yields to be highly dependent on differences in particle size between the micro- and nanometer scale, atomic number (Z) of the particle, and scavenging capacity of preparation buffers. This study provides further evidence using a plasmid DNA model system for the potential of high-Z metal nanoparticles as local dose-modifying agents.

[Creating a local collection of professional reports. A stake in the engineering of diploma education and research in continuing education]. / La création d'un observatoire local des mémoires professionnels. Un enjeu pour l'ingénierie de formation diplômante et la recherche en formation continue.

The question of the dissertation written during the training is tackled through the entry key offered by the professional dissertations written during the training courses leading to qualification in the framework of a university department of vocational training. 72 professional dissertations, defended between 1993 and 1996, were analysed on the basis of observation sheets filled out by the directors. In reference to the semiotic approach which provides relevant theoretical and methodological materials for the problem posed, we shall show the interest of considering that these documents are, above all, "object-speeches" and must therefore be studied as such. According to the demands to be determined, related to the types of speeches to deliver, the professional dissertations considered as written traces reconstituting the practices and praxis which found them, as well on the professional as on the scientific level, can provide indications for training, in the area of research as well as in the one of praxeology. The written document is thought of as an object of transition from practice to professional praxis, rallying the scientific praxis which is expressed particularly in the writing work.

Insulin binding to Leydig cells and insulin levels in testicular interstitial fluid at different stages of development in the rat.

Binding of insulin to purified intact Leydig cells (LC) and LC membranes, and levels of insulin in plasma and testicular interstitial fluid (IF) were quantitatively evaluated in rats at three stages of development. Specific insulin binding to intact LC increased significantly with age. Scatchard analysis of the binding data always gave curvilinear plots; the number of high affinity binding sites/LC were 2590 +/- 514, 3977 +/- 701 and 8342 +/- 2039 at 21, 40 and 70 days respectively. When the results were expressed per micrograms membrane protein, the maximal specific insulin binding also increased between 21 and 40 days but did not significantly change thereafter. With ageing, insulin levels in testicular IF decreased (3.05 +/- 0.30, 2.48 +/- 0.22 and 1.66 +/- 0.13 micrograms/l in 21-, 40- and 70-day-old rats) whereas plasma insulin increased. Taken together, these results suggest (1) that the intratesticular environment in this hormone cannot be evaluated by plasma insulin levels--testicular IF insulin concentration is probably a better index and (2) that insulin may play a role in the development of LC function during sexual maturation.

Tetracycline and erythromycin distribution in pathological lungs of humans and rat.

Tetracycline and erythromycin concentrate highly in pulmonary tissues in humans as well as in the rat. Their binding to the lung, whatever the species and the pathological state, is weak. Their intrapulmonary concentrations could be explained by a passive diffusion which depends on the pH variation between the intra- and extratissue compartments, the percentage of un-ionized form present, and their liposolubility. The importance of retention of tetracycline and erythromycin by plasma proteins is demonstrated by the decrease of their pulmonary index of penetration (IP, the intra- and extratissue concentrations ratio). The IP values are, respectively, 1.09 and 1.23 for tetracycline and erythromycin. These concentrations are in excess of their minimal inhibitory concentrations for bacteria responsible for pneumopathies. The lung homogenate binding of these antibiotics is weak (5% for erythromycin and 33% for tetracycline), corresponding to a nonsaturable binding to three main subcellular fractions (nucleus, mitochondria, and cytosol). Tetracycline has the same penetration in healthy or cancerous human lungs, whereas erythromycin presents a decreased IP in cancerous tissue. However, the binding of these antibiotics to healthy or cancerous lung homogenates is similar. So, the structure of cancerous cells is solely responsible for this modification of erythromycin penetration. The intrapulmonary concentration of tetracycline is increased in rat lungs infected by Legionella pneumophila. This modification is due to a great bacteria retention. In contrast, erythromycin possesses the same IP in healthy and infected rat lungs.

Binding studies of macrolides, lincosamides and streptogramins to Streptococcus G group using [3H]-erythromycin.

Parameters of [3H]-erythromycin binding to Streptococcus are determined in vivo using both equilibrium and kinetic methods. This binding is saturable, reversible and independent of energetic systems. Whatever the methods used, the binding parameters are identical as 14 nM for the dissociation constant of the complex erythromycin-Streptococcus and a density of binding sites of 11,865 molecules/cell. Other macrolides, streptogramins and lincosamides competitively displaced bound [3H]-erythromycin suggesting that these compounds share common binding sites on the bacteria. In parallel, the MIC values of these antibiotics against Streptococcus are determined by agar dilution method in Mueller-Hinton medium with 5% of horse blood in order to compare the binding and microbiological parameters. A strong correlation (n = 0.863) has been found between the corresponding inhibition constants and MIC values. Such binding studies could be used in conjunction with microbiological assays for primary screening of active analogous or other compounds with interfere with [3H]-erythromycin binding to the bacteria.

Binding parameters and microbiological activity of macrolides, lincosamides and streptogramins against Staphylococcus aureus.

Parameters of erythromycin binding to Staphylococcus aureus were measured in-vitro using an equilibrium method with [3H]erythromycin. The dissociation constant of the complex, erythromycin-S. aureus sensitive strain, was KD = 0.11 microM. The maximal binding, representing the density of binding sites was 14,847 molecules/cell. No binding was detectable on the constitutive resistant strain. Macrolides, streptogramins and lincosamides displaced bound [3H]erythromycin by a competitive process indicating that these compounds share common binding sites on the bacteria, i.e. 50 S ribosomal subunits. A good correlation (r = 0.99) was demonstrated between the corresponding inhibition constants (Ki) and the minimal inhibitory concentration. It is proposed that knowledge of the binding parameters provides a good indication of bacterial susceptibility and may serve as a useful adjunct in developing new compounds.

Determination of binding parameters of macrolides, lincosamides, and streptogramins to Legionella pneumophila.

Parameters of [3H]erythromycin binding to Legionella pneumophila were determined in vitro using both an equilibrium and a kinetic method. Different L. pneumophila serogroups, 1-3, and a virulent strain serogroup, 1, were tested. All strains of bacteria exhibited the same binding pattern, with a dissociation constant of 0.15 microM. Other macrolides, streptogramin B-types, and lincosamides competitively displaced bound erythromycin suggesting that these compounds share common binding sites on the bacteria. Minimum inhibitory concentration (MIC) values for macrolides, streptogramin B-types, and lincosamides were determined with buffered charcoal yeast extract (BCYE) medium. A good correlation (r = 0.994) was found between the corresponding inhibition constants of these antibiotics and their MIC. It was also noted that for lincosamides the microbiological inactivity was associated with a very low bacterium affinity. Thus, it is concluded that binding parameters of these antibiotics reflect their efficacy against L. pneumophila in vitro and may serve as a useful adjunct in developing new compounds.

Pharmacokinetics of midazolam used as an intravenous induction agent for patients over 80 years of age.

The pharmacokinetic profile of 0.2 mg kg-1 midazolam given i.v., for induction of anaesthesia, was compared in young subjects and in those who were over 80 years of age. Thirty-five patients were allocated into four groups according to their sex and age. Plasma samples were drawn before midazolam injection and at regular intervals over 24 h following injection. Plasma midazolam concentrations were measured by electron capture gas-liquid chromatography. Equilibrium dialysis was used to assess the plasma protein binding of midazolam. Distribution volume (Vdss) was significantly increased in elderly subjects when compared to young subjects of the same sex (young vs. elderly males, Vdss = 1.22 +/- 0.31 l kg-1 and 2.47 +/- 0.98 l kg-1 respectively; and young vs. elderly females, Vdss = 0.91 +/- 0.29 l kg-1 and 1.70 +/- 0.78 l kg-1 respectively). Total body clearance was significantly reduced in elderly males compared with young males (5.60 +/- 1.77 ml min-1 kg-1 vs. 8.10 +/- 3.58 ml min-1 kg-1). No significant difference in clearance was found between young and elderly females (6.08 +/- 2.04 ml min-1 kg-1 vs. 9.14 +/- 3.36 ml min-1 kg-1). As a consequence, elimination half-life (T1/2E) was significantly prolonged in elderly compared to young males (8.52 +/- 5.4 h vs. 2.77 +/- 0.80 h). In contrast, T1/2E was unchanged in elderly compared to young females (2.99 +/- 0.86 h vs. 2.86 +/- 1.04 h). Midazolam plasma protein binding was not influenced by age and sex.

[Antibacterial activity in vitro of 10 quinolones against 20 strains of Legionella pneumophila]. / Etude de l'activité antibactérienne in vitro de dix quinolones sur vingt souches de Legionella pneumophila.

Minimal inhibitory concentrations (MICs) of 10 quinolones were determined by dilution method on BCYE, for 20 strains of Legionella pneumophila. Since the BCYE Agar medium reduces the antibacterial activity of some antimicrobials, a correction factor was calculated. It was found to be 1 to 16 according to the antibiotic tested. The following mode adjusted MIC show the good in vitro antibacterial activity of quinolones on L. pneumophila: ofloxacin, pefloxacin, ciprofloxacin, norfloxacin, A 56620 cMIC: 0.06 microgram/ml), A 56619, enoxacin (cMIC: 0.12 microgram/ml), rosoxacin (cMIC: 0.25 microgram/ml). Pipemidic acid (cMIC: 2 micrograms/ml) and nalidixic acid (cMIC: 1 microgram/ml) were the least active.

In vitro [3H]-erythromycin binding to Staphylococcus aureus.

Characteristics of erythromycin binding to Staphylococcus aureus were determined by using kinetics and equilibrium binding experiments. Both methods yielded identical values of the dissociation constant, i.e. 0.1 muM. This value was in accord with that found with a bacterial extract of ribosomes which are the organelles where erythromycin exerts its action. This good agreement shows that the dissociation constant of erythromycin determined with intact bacteria is a good reflect of specific bacterial receptors of macrolides, i.e. ribosomes. In addition, mechanism of uptake of the antibiotic by Staphylococcus aureus was investigated. Passive diffusion process was shown to be mainly responsible for this phenomenon.