Peripheral blood mononuclear cell response to YKL-40 and Galectin-3 in cystic fibrosis.

BACKGROUND: Elevated circulating levels of YKL-40 correlate with disease severity in Cystic Fibrosis (CF), but the role of YKL-40 in the inflammatory response in CF is still under investigation. Our main goal was to evaluate if YKL-40 can modulate the expression of major cytokines (IL-6, IL-10, IL-13) implicated in the inflammatory response in CF. A secondary goal was to explore the interactions between YKL-40 and other circulating proteins to determine the impacts on cytokine modulation. METHOD: Peripheral blood mononuclear cells (PBMCs) were isolated from the blood of 83 adult CF patients in stable clinical condition. PBMCs were treated with human YKL-40 followed by the measure of IL-6, IL-10 and IL-13 gene expression. Protein arrays were used to explore the interactions between YKL-40 and circulating proteins. Interaction with Galectin-3 (GAL3) was identified, and confirmed by binding assay. Cytokine gene expressions were again monitored by RT-qPCR after PBMC treatment with GAL3, with or without YKL-40 co-stimulation. RESULTS: Following YKL-40 stimulation, PBMC gene expression of IL-6, IL-10 and IL-13 varies across patients. IL-6 and IL-13 are coexpressed, but this response was different in male and female patients. GAL3 protein was detected in the blood of CF patients, and a molecular interaction with YKL-40 was identified. GAL3 did not interfere with the YKL-40 stimulation of IL-6, IL-10 and IL-13 but may modulate the coexpression. CONCLUSION: We observed that YKL-40 stimulation had a variable impact on IL-6, IL-10, and IL-13 gene expression in CF PBMCs and uncovered an interaction between GAL3 and YKL-40 in the serum of CF patients. Our findings suggest that YKL-40 is not only a biomarker of disease severity in CF, but it might play an active role in the inflammatory pathophysiology of the disease.

[Hospital pharmacy residency in France in 2014: to a recognition of the specialization?]. / L'internat en pharmacie hospitalière en France à l'horizon 2014 : vers une formation reconnue ?

The current format of French residency in hospital pharmacy was created in 1983 and is a 4-year specialized training. So far, training has not been recognized as a prerequisite for hospital pharmacy practice. Since 2011, pharmacy residents and hospital pharmacists representative structures have lobbied for that recognition and the government has worked in that direction. The ideology of the concept was validated after a period of probation and the regulatory procedure began late 2012. Two key elements were initially identified as obstacles: first the European legislation on recognition of professional qualifications and then the fear that there might not be enough hospital pharmacists trained in order to complete the care missions in hospital pharmacies in France. The European legislation has now been amended in order to recognize professional qualifications and a demographic analysis of hospital pharmacists leads to the conclusion that these items are no longer obstacles. In 2014, hospital pharmacy residency, through the Specialized Studies degree, should be recognized as a prerequisite for hospital pharmacy practice.

[Evaluation of amoxicillin-clavulanic acid prescriptions in a teaching hospital of Parisian suburb]. / Evaluation des prescriptions d'amoxicilline-acide clavulanique dans un CHU de la région parisienne.

OBJECTIVE: Prospective study of amoxicillin-clavulanic acid (amox-clav) prescriptions in the medical departments of a teaching hospital that prescribes this antibiotic very often. DESIGN: From April to May 2004, each patient treated by amox-clav was included. Data were collected (age, sex, past diseases, associated-diseases, reason for hospitalization, prior antibiotic therapy, date of amox-clav prescription, indication for amox-clav prescription, other associated antibiotics, nosocomial or community-acquired infection, site of infection, bacteriologic samples and bacterial identification, treatment duration and status of the physician). Data were analysed by a muldisciplinary group and compared with a referential used for antibiotic prescriptions in our hospital. RESULTS: One hundred and two medical files were analysed. Seventy-one percent of amox-clav prescriptions were in adequation with the referential. Combination of three criteria (indication of antibiotic therapy, choice of amox-clav and of an antibiotic combination) showed that 58 (57%) was acceptable, 29 (28%) was debatable and 15 (15%) was unacceptable. Unacceptable prescriptions were often made by a junior. The majority of inadequate antibiotic prescriptions referred to acute pulmonary infections. Antibiotic combinations were often inadequate and treatment duration was too long. The quality of the prescription was more accurate when made by a senior. CONCLUSION: An effort should be made in our teaching hospital to optimize antibiotic prescriptions.

Total synthesis of (+)-lactacystin.

A double stereodifferentiating crotylation between aldehyde 1 and silane (S)-2 to afford homoallylic alcohol 3 is the key diastereoselective step (anti:syn >30:1) in an efficient asymmetric synthesis of (+)-lactacystin. This compound is a metabolite isolated from Streptomyces sp. OM-6519 that exhibits significant neurotrophic activity. An additional important step in the synthesis is a catalytic asymmetric aminohydroxylation used as the key step in the synthesis of the (2R,3S)-hydroxyleucine synthon.

Electrophysiologic effects of bepridil in the anesthetized dog studied by endocardiac electrodes.

The electrophysiologic effects of bepridil in the anesthetized closed-chest dog were studied with intracardiac electrodes using the extrastimulus technique to measure the refractory periods of atria, atrioventricular (AV) junction and ventricles. Intravenous administration of 5 mg/kg of bepridil caused a reduction in sinus node rate and prolonged the sinus node recovery time. Refractory periods in the atrium, especially the effective refractory period, increased. Anterograde AV nodal conduction was slowed and refractoriness increased, often resulting in AV nodal Wenckebach periods, during atrial pacing, and retrograde conduction was always completely abolished. Refractory periods of the AV junction were altered in a comparable fashion to conduction through the AV node. No significant actions on conduction or the refractory period were noticed in the His-Purkinje system or the ventricle. The mechanism of action of bepridil seems to be correlated to its membrane effects, namely, inhibition of pathways responsible for the slow inward current, which explains its selective action on myocardial sites where this current is particularly involved.

An asymmetric aminohydroxylation approach to the azepine core of (-)-balanol.

[reaction: see text]An efficient formal synthesis of the potent protein kinase C inhibitor (-)-balanol that relies on a modified asymmetric aminohydroxylation of the alpha,beta-unsaturated aryl ester (1) is reported. The aryl ester functionality and the dihydroquinyl alkaloid ligand system (DHQ)2-AQN are used to control the regio- and enantioselectivity of the process.

Reversal of regioselection in the sharpless asymmetric aminohydroxylation of aryl ester substrates.

[formula: see text] The asymmetric synthesis of beta-hydroxy-alpha-amino acids is reported which relies on the use of alpha,beta-unsaturated aryl ester substrates and the dihydroquinyl alkaloid ligand system (DHQ)2-AQN to control the regio- and enantioselectivity of the asymmetric aminohydroxylation (AA) process. alpha,beta-Unsaturated ester substrates of type 1 have a significant effect on the substrate-ligand recognition event which results in a reversal of regioselectivity in the AA reaction.

The increased susceptibility of women to multiple sclerosis.

Many diseases with an auto-immune etiology have a skewed sex distribution. In the majority of instances, women are affected more frequently than men. A review of population studies demonstrates that the preponderance of women in multiple sclerosis (MS) is almost constant. We show that this preponderance is further increased in early as well as in late-onset cases, in familial cases as well as in MS twin pairs and that the HLA-DR2 allele, which has been associated with MS in Caucasian populations, is significantly more frequent in women than in men with MS. "Rules" have been established for multifactorial diseases; MS contravenes most of those rules. The skewed sex distribution in MS could be attributed to the known hormonal and gender influences on the immune response, as well as to genetic influences.

Electrophysiological effects of penticainide in the anaesthetized dog.

The cardiac electrophysiological effects of Penticainide, a new antiarrhythmic agent, were studied by means of intracardiac electrodes in the anaesthetized dog. Intravenous administration of 5 mg/kg of Penticainide reduced the sinus rate and prolonged the sinus node recovery time. Atrial refractory periods increased. Anterograde intranodal conduction slowed and nodal refractoriness increased. Conduction time in the His-Purkinje tissue and ventricle increased, as did the ventricular refractory periods. Monophasic action potential duration was not altered by the drug in the atrium or the ventricle. The mechanism of action of Penticainide as an antiarrhythmic drug seems to be correlated to its membrane effects: inhibition of the fast-inward current, responsible for the marked effects on His-Purkinje and ventricular tissues; and inhibition of the slow-inward current, suggested by its effects on sinus node and atrio-ventricular node.

Electrophysiological effects of the new cardioactive drug CERM 4205: a comparative study in an animal model and in man.

The cardiac electrophysiological effects of CERM 4205, a new cardioactive agent, were studied by means of intracardiac electrodes in man and in anaesthetized dogs. The results show that CERM 4205 is a cardioactive drug with a main inhibitory effect on slow-response structures (sinus and atrioventricular node) with an associated effect on fast-response structures (atrial, His-Purkinje and ventricular tissues). No qualitative differences were observed between the effects observed in man and dogs. In conclusion, the present study confirms that CERM 4205 is a compound with combined class IV and class I electrophysiological effects in dogs and man. The anaesthetized dog appears to be a satisfactory model for the evaluation of the electrophysiological effects of cardioactive drugs.

[The supernormal phase of cardiac conduction. An experimental study in the dog]. / La phase supernormale de conduction cardiaque. Etude expérimentale chez le chien.

The existence of a cardiac phase of supernormal excitability is not fully proved at the cellular level. As far as the whole heart is concerned, the phenomenon of supernormal conduction is still under discussion. Intracardiac conduction has been studied both in the right atrium (13 dogs) and in the right ventricle (14 dogs) by programmed stimulation (extrastimulus technique), while monophasic action potential (MAP) was recorded. The phenomenon of supernormal conduction was noted in 67.7% of cases, starting at 59.0% and ending at 78.0% of the basic cycle, hence occuring shortly after phase 3 of the MAP. In the ventricle, a phase of supernormal conduction was present in 52.4% of cases, starting at 66.1% and ending at 77.9% of the basic cycle. After ajmaline, the supernormal conduction was moved towards the end of the cycle. The mechanism of supernormal conduction, and its implications in the study of arrhythmias are discussed.

[Cardiac toxicity of bupivacaine and diazepam. Experimental study in the anesthetized dog]. / Toxicité cardiaque de la bupivacaïne et diazépam. Etude expérimentale chez le chien anesthésié.

The use of diazepam has been suggested for the treatment of convulsions resulting from accidental high plasma levels of local anaesthetics. However, it has been reported that this drug may increase the cardiac effects of bupivacaine in dogs. The present study aimed to assess the effects of diazepam on the electrophysiological signs of a high-dose intravenous bolus of bupivacaine in fourteen dogs, divided into two groups, and anaesthetized with thiopentone and ventilated. All the animals were given a bolus dose of 4 mg.kg-1 bupivacaine. Immediately afterwards, group I (n = 7) received 0.8 ml.kg-1 normal saline solution and group II (n = 7) was given 4 mg.kg-1 diazepam over 1 min. The parameters measured on lead II of the electrocardiogram were: cycle length (R-R interval), QRS length (QRS) and QT interval corrected for heart rate (cQT). Intranodal (AH) and His-Purkinje (HV) conduction times were measured with recording bipolar stimulation electrodes (USCI 6F). Mean aortic pressure (Pao) was measured via a femoral arterial line. In the two groups, the parameters were recorded before and 2, 5, 10 and 15 min after the bupivacaine bolus. Arterial blood samples for measurement of bupivacaine and diazepam serum levels were obtained before and 3, 15 and 30 min after the bupivacaine bolus. There was no significant difference between the two groups in the electrophysiological or haemodynamic parameters at any time. However, the increase in HV and QRS length was a little higher in group I than in group II.(ABSTRACT TRUNCATED AT 250 WORDS)

[Non-surgical treatment of Dupuytren disease using needle fasciotomy]. / Traitement non chirurgical de la maladie de Dupuytren par aponévrotomie à l'aiguille.

Short-term and five-year outcomes after nonsurgical treatment of Dupuytren's contracture by needle fasciotomy were studied. Among the 138 patients who were evaluated, 90 (123 hands) were seen five years after the procedure. Outcome was excellent or good in 81% of cases in the short term and 69% of cases after 5 years. Adverse events included skin breaks (20 hands, 16% of cases), digital dysesthesia due to nerve damage (3 patients, 2% of cases), and local infection (3 patients, 2% of cases). Five-year recurrence rate was 50.4%. These findings demonstrate the value of needle fasciotomy especially in the early stages of Dupuytren's disease.