Thromboembolic events and thromboprophylaxis associated with immunomodulators in multiple myeloma patients: a real-life study.

PURPOSE: The aim of this study is to assess international guidelines implementation concerning thromboprophylaxis strategy in myeloma patients treated with immunomodulatory drugs. METHODS: This retrospective study includes multiple myeloma patients treated with immunomodulatory drugs between 2014 and 2017 in the Hematology department of a teaching hospital (Hospices Civils de Lyon, France) and followed by the multidisciplinary care plan for cancer outpatients ONCORAL (ONCological care for outpatients with ORAL anticancer drugs). Data from immunomodulatory drugs administration, thromboprophylaxis strategy and thrombotic events were collected from medical files. Adherence to 2010 International Myeloma Working Group (IMWG) guidelines was assessed. RESULTS: 213 patients received at least one immunomodulatory drug: lenalidomide (60.9%), pomalidomide (24.0%) and thalidomide (15.1%). About two third of treatment lines (66.2%) were in accordance with IMWG recommendations. Among the others, 30.5% and 69.5% had thromboprophylaxis, respectively, superior or inferior to IMWG recommendations. 37 venous thrombotic events and 4 arterial thromboembolisms (one patient experienced both a stroke and deep venous thrombosis simultaneously) were reported. CONCLUSION: Thromboprophylaxis was systematically performed in myeloma patients treated with immunomodulatory drugs in this real-life retrospective cohort. However, the choice of anticoagulant or anti-platelet agent remains debatable, as adherence to existing guidelines was variable.

Detection, isolation and characterization of Shiga toxin-producing Escherichia coli in retail-minced beef using PCR-based techniques, immunoassays and colony hybridization.

AIMS: To provide information on detection of Shiga toxin-producing Escherichia coli (STEC) in retail-minced beef using an approach combining (i) PCR-based techniques and automated immunoassay for stx screening and detection of the five major serogroups associated with human infection, and (ii) immunomagnetic separation (IMS) and colony hybridization assays for bacterial strain isolation. METHODS AND RESULTS: Twenty-seven out of 164 minced beef samples were stx-positive by PCR-ELISA, nine of which were also positive by real-time PCR for at least one marker of the five main serogroups tested (O26, O103, O111, O145 and O157). Two E. coli O103 stx-negative strains were isolated from two out of 10 IMS and nine STEC strains that did not belong to the five main serogroups were isolated by colony hybridization. CONCLUSIONS: PCR techniques are applicable for rapid screening of samples containing both an stx gene and an O-group marker of the five main pathogenic STEC serogroups. Isolation of STEC strains belonging to the main non-O157 serogroups remains difficult. SIGNIFICANCE AND IMPACT OF THE STUDY: This study presents an evaluation of a multi-faceted approach for the detection of the most frequently reported human pathogenic STEC serogroups. The advantages and limits of this strategy are presented.

Acute local tolerability of acidic aqueous vehicles delivered via Respimat Soft Mist Inhaler in hyperreactive asthma patients.

BACKGROUND: Acidic inhalers can be associated with increased adverse reactions. OBJECTIVES: This study aimed to determine the acute local tolerability of acidic aqueous placebo formulations delivered via Respimat Soft Mist Inhaler (SMI) and placebo chlorofluorocarbon metered dose inhaler (CFC-MDI). METHODS: A single-dose (four inhalations), randomized, double-blind within Respimat SMI device, four-way crossover study in asthma patients with documented bronchial hyperresponsiveness was used. Patients received acidic placebo solutions [pH 2.7, 3.4 or 7.0 (neutral)], delivered via Respimat SMI or placebo CFC-MDI. The primary endpoint was the largest decrease in forced expiratory volume in 1 s (FEV(1)) from baseline to 0-30 min after dosing. Secondary endpoints included spirometry, paradoxical bronchoconstriction (defined as a fall in FEV(1) >or=15% below baseline within 30 min of dosing), cough episodes and adverse events. RESULTS: Thirty-two patients were included in the per-protocol population (mean age 27 years, 62.5% males). The mean percentage decrease in FEV(1) was comparable between treatment groups: -1.6% (Respimat SMI pH 2.7), -1.8% (Respimat SMI pH 7.0), -1.9% (CFC-MDI), and -2.3% (Respimat SMI pH 3.4); no patient experienced paradoxical bronchoconstriction. The mean number of cough episodes was significantly lower in the Respimat SMI pH 2.7 group versus CFC-MDI (p = 0.0165). No patient used rescue medication. Only 3 patients experienced at least one adverse event. CONCLUSIONS: The Respimat SMI pH 2.7 placebo solution does not induce adverse events in these patients. Compared with the CFC-MDI placebo suspension, Respimat SMI is a well-tolerated inhaled medication delivery system that can accommodate medication formulations with a wide range of pH solutions.

A randomized, double-blind, double-dummy, single-dose, efficacy crossover trial comparing formoterol-HFA (pMDI) versus formoterol-DPI (Aerolizer) and placebo (pMDI or Aerolizer) in asthmatic patients.

BACKGROUND: Chlorofluorocarbons (CFCs) have traditionally been used as propellants in pressurized metered-dose inhalers (pMDIs), which are often used to deliver drugs to the lungs for the treatment of reversible obstructive airways diseases. However, CFCs are harmful to the environment and need to be phased out. Hydrofluoroalkanes (HFAs), such as HFA-134a, represent a safe alternative to CFC propellants for use with pMDIs. Formoterol fumarate has been recently formulated in an HFA-134a-containing pMDI and is undergoing clinical testing with the aim of providing an effective, safe and environmentally-friendly alternative to currently existing formulations. OBJECTIVES: The study objective was to demonstrate the non-inferiority (clinical equivalence) of the HFA-134a-propelled formoterol pMDI versus the formoterol Aerolizer dry powder inhaler (DPI). METHODS: The study was a single dose, double-blind, double-dummy, randomized, placebo and reference product controlled, three-periods, crossover trial in 49 patients with moderate-to-severe stable asthma. The active treatments involved a single 12-microg dose of formoterol delivered from an HFA-134a-propelled pMDI and an Aerolizer DPI. The primary efficacy parameter was the average 12-hour forced expiratory volume in 1 s (FEV1), calculated as area under the 12-hour post-morning dose FEV1 time curve divided by time (hours). RESULTS: Mean 12-hour average FEV1 was 2.28 liters for placebo, 2.60 liters for formoterol pMDI and 2.60 liters for the formoterol DPI. Contrast analysis showed that the HFA-propelled formoterol pMDI was significantly superior to placebo in terms of 12-hour average FEV1. Further statistical analysis confirmed bronchodilation with the pMDI formoterol formulation which was clinically equivalent to that seen with the DPI formoterol formulation. All treatments were well tolerated. CONCLUSIONS: The bronchodilatory effect of a 12-microg dose of formoterol inhaled from a CFC-free, HFA-propelled pMDI is significantly superior to placebo and equivalent to a commercially available formoterol DPI.

Rapid onset of bronchodilation in COPD: a placebo-controlled study comparing formoterol (Foradil Aerolizer) with salbutamol (Ventodisk).

Formoterol fumarate is a beta2-agonist bronchodilator that combines a fast onset of action with a long duration of action. Its fast onset of action is well documented in asthma but has not been directly compared with that of salbutamol in patients with chronic obstructive pulmonary disease (COPD). This randomized, double-blind, placebo-controlled study was conducted to assess the bronchodilatory effects over the first 3 h after inhalation of single doses of formoterol 24 microg delivered via the Aerolizer dry powder inhaler device (double-blind), or salbutamol 400 microg delivered by a Diskhaler dry powder inhaler (single-blind) in patients with COPD. A total of 24 patients with COPD were randomized [mean age 61.6 +/- 7.8 years, mean forced expiratory volume in 1 sec (FEV1) 1.38 +/- 0.32 l and 45.8 +/- 9.6% of predicted]. Inhalation of formoterol or salbutamol resulted in similar increases in FEV from 0 to 3 h post-dose. Both drugs produced similar bronchodilation by 5 min, which became almost maximal by 30 min. The primary efficacy variable, the area under the curve (AUC) of the FEV increase above predose baseline from 0 to 30 min (AUC(0-30 min)), demonstrated significant effects for formoterol (mean 5.89 +/- 4.67 l min(-1)), and salbutamol (mean 6.06 +/- 4.34 l min(-1)), which were not statistically different from each other but statistically significantly higher (P<0.0001) than that observed with placebo (-0.32 +/- 2.59 l min(-1)). In addition, both formoterol and salbutamol produced similar and rapid increases in forced vital capacity (FVC). In summary, this study confirms the rapid onset of action of formoterol and indicates that the onset of action of formoterol and salbutamol are similar in patients with COPD.

Effect of various environmental parameters on the recovery of sublethally salt-damaged and acid-damaged Listeria monocytogenes.

The influence of supplementing the culture medium with magnesium sulphate, D-glucose, L-cysteine, catalase or lithium chloride, of incubation temperature and of oxygen availability on the recovery of salt- or acid-damaged Listeria monocytogenes, was studied on a solid repair medium according to a Hadamard matrix, with seven parameters varying between a high and a low level. The most important factors for repair of stressed Listeria were further studied with complete factorial design experiments. Results show that conditions promoting resuscitation of acid- or salt-injured cells are stress-specific, and differ in part from those described in the literature for heat-stressed Listeria.

Pharmacokinetics of quinupristin/ dalfopristin in patients with severe chronic renal insufficiency.

OBJECTIVE: To compare the pharmacokinetic profile of a single intravenous injection of quinupristin/dalfopristin, a new injectable streptogramin, in healthy young individuals and patients with severe chronic renal insufficiency. A secondary objective was to assess the relative tolerability of this dose in these patients compared with healthy individuals. PATIENTS AND PARTICIPANTS: 13 patients with severe chronic renal insufficiency (creatinine clearance 6 to 28 ml/min/1.73m2) were individually matched for gender, bodyweight and age to a healthy volunteer. METHODS: Participants received a single dose of quinupristin/dalfopristin 7.5 mg/kg bodyweight as a continuous 1-hour intravenous infusion, followed by serial blood sampling. RESULTS: The disposition profile of unchanged quinupristin was similar in the 2 groups. However, the elimination of quinupristin derivatives in patients with renal impairment tended to be decreased: mean peak plasma drug concentration (Cmax) and area under the concentration-time curve from zero to infinity (AUCinfinity) of quinupristin plus its active derivatives were about 1.4 times higher in the patients with renal impairment compared with healthy volunteers. The mean Cmax and AUCinfinity of both unchanged dalfopristin and dalfopristin plus its active derivatives were about 1.3 times higher in renally impaired patients than in healthy volunteers. Adverse events were generally mild and transient. No severe or serious adverse events were reported and no participants prematurely discontinued the study. Venous tolerability tended to be better in healthy volunteers than in the patients with renal impairment. CONCLUSION: These results suggest that no formal reduction in the dosage of quinupristin/dalfopristin is necessary in patients with severe chronic renal impairment.

Improved delivery of ipratropium bromide using Respimat (a new soft mist inhaler) compared with a conventional metered dose inhaler: cumulative dose response study in patients with COPD.

Respimat (RMT) is a reusable, propellant-free, soft mist inhaler (SMI), a novel device for inhalation therapy. We conducted a three-period cross-over study to evaluate the safety and efficacy of cumulative doses of ipratropium bromide inhaled from RMT (Two dose levels) or from a pressurized metered dose inhaler (MDI), in 36 patients with chronic obstructive pulmonary disease (COPD). The bronchodilator effect of ipratropium bromide was greater when administered via RMT (10 or 20 microg per puff, given double-blind within device, to total doses of 160 or 320 microg) than via MDI (20 microg per puff, total dose 320 microg). The bronchodilator effects of the 160 and 320 microg doses delivered via RMT were similar. Cumulative ipratropium bromide doses of 320 microg given via MDI or RMT and 160 microg given via RMT produced similar safety profiles. Between 45 min after the first drug inhalation and 45 min after the final dose, greater bronchodilatory effect was obtained from half the cumulative dose of ipratropium (RMT 10 microg per puff) when compared with the MDI (20 microg per puff). Therefore, ipratropium bromide delivered by RMT is as safe as, and can be more effective than, the MDI on acute administration in patients with COPD.

Dominant-negative mutants reveal a role for the Cdk7 kinase at the mid-blastula transition in Drosophila embryos.

The metazoan cyclin-dependent kinase Cdk7 was purified originally as part of a biochemical activity called CAK (Cdk-activating kinase) capable of phosphorylating and activating in vitro the Cdks that promote the different cell cycle transitions. Cdk7 is also found in the transcription factor complex TFIIH, suggesting that it participates in vivo in the control of RNA polymerase II. We have examined the physiological role of Cdk7 during the course of Drosophila development. By expressing dominant-negative forms of the kinase, we were able to alter Cdk7 function at given developmental stages. Expression of Cdk7 mutants severely delayed the onset of zygotic transcription in the early embryo, but did not alter the timing of the first 13 embryonic nuclear cycles. These results implicate Cdk7 in the control of transcriptional machinery in vivo. While cell cycle regulation is not sensitive to our manipulations of Cdk7 activity, it suggests that a distinct pool of CAK activity that is unaffected by expression of the cdk7(DN) mutants is present in these embryos.

Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands.

A previous paper reported the synthesis of melatonin receptor ligands. In order to complete the structure-activity relationships and to obtain antagonists to the melatonin receptor, a new series of naphthalenic analogues of melatonin have been synthesized. Modifications include deletion of the 7-methoxy group, replacement of the ethylene moiety, replacement of the amidic function by bioisosteres, and replacement of the naphthalenic nucleus by other bicyclic rings. Almost all the structural modifications lead to decreased affinity for the melatonin receptor. However, the N-n propyl urea derivative (27) is a very potent ligand at this receptor (pKi = 14.3). Most interestingly deletion of the methoxy group resulted in the first antagonist in this series. This molecule, compound 12, or N-[2-(1-naphthyl)-ethyl]cyclobutyl carboxamide has been selected for preclinical development.

Effect of hepatic impairment on the pharmacokinetics of zolmitriptan.

Zolmitriptan, an oral 5HT1D agonist for the acute treatment of migraine, is cleared from the systemic circulation mainly by hepatic metabolism. Consequently, changes in hepatic function may result in changes in the pharmacokinetics of zolmitriptan. This open, parallel-group study was conducted to compare the pharmacokinetics and tolerability of a single 10-mg dose of zolmitriptan in healthy subjects and patients with hepatic impairment. A total of 37 participants entered and completed the study, including 10 healthy volunteers, 11 patients with moderate hepatic impairment, 10 patients with severe hepatic impairment without ascites, and 6 patients with severe hepatic impairment with ascites. The metabolism of zolmitriptan was reduced in patients with severe hepatic impairment compared with healthy subjects, resulting in higher peak plasma concentrations (47%), increased exposure (226%), and prolonged half-life (157%). The changes were similar in the presence and absence of ascites. Smaller changes were observed in patients with moderate hepatic impairment. Plasma concentrations of the three major metabolites of zolmitriptan were reduced in the patients with hepatic impairment. Patients with moderate hepatic impairment require no dosage adjustment, but the recommended daily intake of zolmitriptan may need to be reduced in patients with severe hepatic impairment.

[Behavioral psychotherapy: possibilities in the framework of general medicine]. / Psychothérapies comportementales: possibilités en médecine générale.

A SOLUTION FOR A COMMON PROBLEM: General practitioners regularly see patients with psychiatric problems. Cognitive and behavioral therapy offer reasonable complements or alternatives to drug therapy. Physicians should be aware of the possibilities and inform their patients. VARIOUS INDICATIONS: The principle indications are anxiety and depressive states, but indications can be widened to other areas such as psychological approach to health and behavioral medicine. A RECOGNIZED THERAPY: Cognitive and behavior psychotherapy offers a good cost/benefit ratio. More widespread use has been achieved by reinforcing university training.

[Melatonin, a pertinent prototype for therapeutic innovation]. / La mélatonine, prototype pertinent pour l'innovation thérapeutique.

Melatonin fulfils most of the requirements of a typical lead compound for rational drug design. We have rationally modified each of its structural features with a view to clarifying their role in drug-receptor interactions (affinity and activity) and to obtain agonist and antagonist ligands which could be used as pharmacological tools and/or as drugs. Molecular modelling studies allow us to propose a pharmacophore model. The naphthalenic bioisostere of melatonin (agomelatin) is currently under clinical (phase II) evaluation and two other compounds have been selected for development.

Drosophila Cdk8, a kinase partner of cyclin C that interacts with the large subunit of RNA polymerase II.

A number of cyclins have been described, most of which act together with their catalytic partners, the cyclin-dependent kinases (Cdks), to regulate events in the eukaryotic cell cycle. Cyclin C was originally identified by a genetic screen for human and Drosophila cDNAs that complement a triple knock-out of the CLN genes in Saccharomyces cerevisiae. Unlike other cyclins identified in this complementation screen, there has been no evidence that cyclin C has a cell-cycle role in the cognate organism. Here we report that cyclin C is a nuclear protein present in a multiprotein complex. It interacts both in vitro and in vivo with Cdk8, a novel protein-kinase of the Cdk family, structurally related to the yeast Srb10 kinase. We also show that Cdk8 can interact in vivo with the large subunit of RNA polymerase II and that a kinase activity that phosphorylates the RNA polymerase II large subunit is present in Cdk8 immunoprecipitates. Based on these observations and sequence similarity to the kinase/cyclin pair Srb10/Srb11 in S. cerevisiae, we suggest that cyclin C and Cdk8 control RNA polymerase II function.

The cyclin C/Cdk8 kinase.

Cyclin C was originally identified in a genetic screen for metazoan cDNAs that complement a triple knock-out of the CLN genes, involved in G1/S progression in S. cerevisiae. Unlike cyclin Ds and cyclin E, also identified in this screen, cyclin C has not been found to have a cell-cycle role in metazoa. Identified as the catalytic partner of cyclin C, Cdk8 is a novel protein-kinase of the Cdk family structurally related to the yeast Srb10 kinase. Cyclin C, Cdk8 and RNA polymerase II are found in a large multi-protein complex that shows structural as well as functional homologies with the yeast polymerase II holoenzyme. These observations and the sequence similarity to the kinase/cyclin pair Srb10/Srb11 in S. cerevisiae, suggest that cyclin C and Cdk8 control RNA polymerase II function.

The lytic cycle of Epstein-Barr virus in the nonproducer Raji line can be rescued by the expression of a 135-kilodalton protein encoded by the BALF2 open reading frame.

In Epstein-Barr virus (EBV)-carrying nonproducer Raji cells, the induction of the viral replicative cycle by chemical treatment is limited to only the early stage and viral DNA synthesis is totally inhibited. We previously showed the absence of two messenger RNAs that are encoded by the BamHI-A fragment of the EBV genome and that correspond to open reading frames BALF2 and BARF1 in chemically induced Raji cells. Since the BALF2 gene encodes a 135-kDa DNA-binding protein which was immunoprecipitated by antibody against ICP8 protein, a key protein in herpes simplex virus replication, we asked whether the lack of productive cycle in Raji cells is due to the absence of expression of the BALF2 gene. We transfected the Raji cell line with the BALF2 gene. After chemical induction, the BALF2-transfected cells expressed not only early antigens but also late antigens. In these cultures, the viral particles were detected by electron microscopy. The expression of late antigens was completely inhibited by arabinofuranosylthymine, which is a specific inhibitor of viral DNA replication. The BALF2 gene might play an essential role in the induction of the EBV-lytic cycle.

[Stabilization of the hindfoot by talonavicular arthrodesis. Results apropos of 50 cases]. / Stabilisation de l'arrière-pied par arthrodèse astragalo-scaphoïdienne. Résultats à propos de 50 cas.

UNLABELLED: Hindfoot stabilization can be obtained by an isolated talonavicular arthrodesis as well as a triple arthrodesis. MATERIAL: There were 27 cases of unstable neurological foot, 13 cases of Rhumatoid foot, 7 cases of flat feet and 3 cases of post-trauma arthritis of the talonavicular joint. The procedure was, in all cases, a talonavicular arthrodesis, associated in some cases to a lengthening of the Achilles tendon, tendon transfer and forefoot correction. METHOD: 50 cases were reviewed with a mean follow-up of 40 months. RESULTS: There were 18 per cent cases of non-union. This could be explained by 2 technical errors: bad cartilagenous resection of the surfaces and unstable bone fixation. No subtalar mobility was noted in all cases. Only one case had a midtarsal mobility associated to a non-union. 39 feet had a normal heel axation. In most cases functional improvement was significant with a painless gait. DISCUSSION: Hindfoot stabilization can be obtained by an isolated talonavicular arthrodesis. Non-union could be avoided by a better surgical technique and a cast immobilization of 2 and a half months. The pre-operative deformities should be reduced manually, because isolated fixed valgus and varus can not be corrected by an isolated talonavicular arthrodesis. In conclusion, the indications are: An early valgus deformity of the hindfoot in rhumatoid arthritis. The aim is to avoid a fixed valgus deformity. Neurological induced equino varus deformities specially after stroke and other reducible neurological deformities. Flat foot due to posterior tibialis insufficiency. Isolated arthritis of the talonavicular joint.

[Operationalization of the "locus of control" concept: translation and first validation study of the Levenson control scale (IPC: the internal powerful others and chance scale)]. / Opérationnalisation du concept de "lieu de contrôle": traduction et première étude de validation de l'échelle de contrôle de Levenson (IPC: the internal powerful others and chance scale).

This work presents the study of validation of the French version of the Internal Powerful others and Chance Scale (IPC) of Levenson. A principal components analysis was carried out on a group of 134 healthy subjects. The Cronbach alpha coefficient and the correlation between the items and the total score of each sub-scale of the IPC were calculated. Our results were discussed in comparison with others studies.

[Nocardia farcinica infection. Cutaneous form in an immunodepressed patient]. / Infection à Nocardia farcinica. Forme cutanée pure chez une malade immunodéprimée.

Nocardiosis is a rare localized or systemic infection caused by bacteria of the Actinomycetaceae family. Nocardia farcinica, recently identified as a distinct species from Nocardia asteroides, characteristically causes severe systemic infections and is particularly resistant to antibiotics. We report a case of nocardiosis observed in a patient receiving general corticosteroid therapy for bullous pemphigoid and who developed a sub-cutaneous abscess of the breast. N. farcinica was identified on puncture specimens and found to be resistant to beta-lactams, aminosides, cyclines, chloramphenicol, fosfomycin and pefloxacin. No dissemination beyond the skin was observed. The abscess was drained and cleaned surgically and cicatrization was uneventful. Six weeks later the patient was again hospitalized for an inflammatory abscess of the left buttocks which was drained surgically. N. farcinica was again identified and a complete work-up eliminated dissemination. Cotrimoxazole was given as a long-term therapy (480 mg trimethoprim, 2.4g sulfamethoxazole) for 6 months and was well tolerated. No recurrence was observed.