[Idiosyncratic drug-induced agranulocytosis: 7 year-analysis in a French university hospital]. / Agranulocytoses médicamenteuses idiosyncrasiques : analyse de 7 ans dans un hôpital universitaire français.

INTRODUCTION: Idiosyncratic drug-induced agranulocytosis is a rare but potentially serious haematological disorder. The pathophysiological mechanisms are complex and poorly understood. We aimed at investigating agranulocytosis drug related causes from the myelograms with "myeloid maturation arrest" performed in our university hospital over the last seven years. METHODS: A retrospective analysis of myelograms collected for agranulocytosis was performed from 1st January 2010 to 31th December 2016. We used the method of Bégaud et al. for drug causality assessment. RESULTS: Among the 104 myelograms analysed, 41 agranulocytosis were drug-induced, whose 28 were idiosyncratic. Among these 28 cases, 26 different drugs were involved. Agranulocytosis was a known adverse reaction in the summary of the product characteristics for 24 drugs, mainly associated with undetermined frequency (n=7). Mean onset latency was 38.1 days after starting the drug (calculated for n=23 cases) and granulocyte growth factors were used in 50% of cases without shortening the mean delay of blood count recovery. Bone marrow presented hypereosinophilia in 29% of cases. Pharmacovigilance reporting rate was 48%. CONCLUSION: A "maturation arrest" in the myelogram is not pathognomonic for idiosyncratic drug-induced agranulocytosis. This rare event require multidisciplinary care involving haematologists, biologists and pharmacovigilance experts. Agranulocytosis reporting rate was high compared with usual adverse drug reaction reporting rate (5 to 10%), probably related to the potential severity of this event.

Passive detection of biological aerosols in the atmosphere with a Fourier Transform Instrument (FTIR)--the results of the measurements in the laboratory and in the field.

Fourier Transform Infrared Radiation (FTIR) spectroscopy is one of the most powerful methods for the detection of gaseous constituents, aerosols, and dust in planetary atmospheres. Infrared spectroscopy plays an important role in searching for biomarkers, organics and biological substances in the Universe. The possibility of detection and identifications with FTIR spectrometer of bio-aerosol spores (Bacillus atrophaeus var. globigii=BG) in the atmosphere is discussed in this paper. We describe the results of initial spectral measurements performed in the laboratory and in the field. The purpose of these experiments was to detect and to identify bio-aerosol spores in two conditions: 1) In a closed chamber where the thermal contrast between the background and aerosols was large, and 2) In open air where the thermal contrast between the background and aerosols was small. The extinction spectrum of BG spores was deduced by comparing our measurements with models, and other measurements known from the literature. Our theoretical and experimental studies indicate that, during passive remote sensing measurements, it is difficult-but possible to detect and to identify bio-aerosol clouds by their spectral signatures. The simple spectral analysis described in the paper can be useful for the detection of various kinds of trace aerosols-not only in the Earth's atmosphere, but also during planetary missions in the environments of other astronomical objects such as planets, comets etc. We expect that the interpretation of data from spectrometric sounding of Venus and Mars during the current missions Mars and Venus Express, and later during the Rosetta mission will benefit from our experimental work and numerical modelling.

Influence of the electric field on a bio-mimetic film supported on a gold electrode.

A model biological membrane was formed by fusion of mixed cholesterol and DMPC (dimyristoylphosphatidylcholine) phospholipid vesicles onto a gold-coated quartz support. The gold surface was charged and the influence of the charge at the solid support on the structure and integrity of the phospholipid bilayer was investigated using the specular reflection of neutrons and electrochemical measurements. When the surface charge density is close to zero, the lipid vesicles fuse directly on the surface to form a bilayer with a small number of defects and hence low water content. When the support's surface is negatively charged the film swells and incorporates water due to the field driven poration of the membrane. When the charge density is more negative then -8 microC cm(-2) the bilayer is detached from the metal surface. However, it remains in close proximity to the metal electrode, suspended on a thin cushion of water. The film thicknesses, calculated from neutron reflectivity, have allowed us to determine the tilt angle of the lipid molecules as a function of the support's charge density. The lipid molecules are tilted 55 degrees from the surface normal at zero charge density but become significantly more perpendicular (30 degrees tilt angle) at charge densities more negative than -8 microC cm(-2). The tilt angle measurements are in very good agreement with previous IR studies. This paper describes the highlights of a more in-depth study which is fully described in [1].

Electric field-driven transformations of a supported model biological membrane--an electrochemical and neutron reflectivity study.

A mixed bilayer of cholesterol and dimyristoylphosphatidylcholine has been formed on a gold-coated block of quartz by fusion of small unilamellar vesicles. The formation of this bilayer lipid membrane on a conductive surface allowed us to study the influence of the support's surface charge on the structure and hydration of the bilayer lipid membrane. We have employed electrochemical measurements and the specular reflection of neutrons to measure the thickness and water content in the bilayer lipid membrane as a function of the charge on the support's surface. When the surface charge density is close to zero, the lipid vesicles fuse directly on the surface to form a bilayer with a small number of defects and hence small water content. When the support's surface is negatively charged the film swells and incorporates water. When the charge density is more negative than -8 micro C cm(-2), the bilayer starts to detach from the metal surface. However, it remains in a close proximity to the metal electrode, being suspended on a thin cushion of the electrolyte. The field-driven transformations of the bilayer lead to significant changes in the film thicknesses. At charge densities more negative than -20 micro C cm(-2), the bilayer is approximately 37 A thick and this number is comparable to the thickness determined for hydrated multilayers of dimyristoylphosphatidylcholine from x-ray diffraction experiments. The thickness of the bilayer decreases at smaller charge densities to become equal to approximately 26 A at zero charge. This result indicates that the tilt of the acyl chains with respect to the bilayer normal changes from approximately 35 degrees to 59 degrees by moving from high negative charges (and potentials) to zero charge on the metal.

Influence of ryanodine on the mechanical restitution and on the post-extrasystolic potentiation of the guinea-pig ventricular myocardium.

This paper records the results of an investigation into potentiation and staircase phenomena in rightventricular guinea-pig papillary muscles with particular reference to the sarcoplasmic Ca(2+)-channel. As a tool to isolate the second ('late', 'tonic') component of isoproterenol-induced biphasic contractions ryanodine was used. On the evidence at present available the monophasic ryanodine-resistant component of the twitch represents that portion of the activator calcium which reaches the troponin C directly, that is, not taking the roundabout way through the intracellular storage structures. In order to avoid functional instabilities of the isolated muscle preparation a short-time double rest stimulation programme was used which combines a number of different tests and gives information on (1) the post-rest potentiation, (2) the post-extrasystolic potentiation, (3) the mechanical post-rest recovery, (4) the interval-strength relationship, and (5) the mechanical restitution. The results of the present work show that under the influence of ryanodine (1) the Bowditch staircase, a typical feature of normodynamic mammalian ventricular preparations as well as of hypodynamic frog heart preparations, does not exist, (2) the post-extrasystolic potentiation disappears, (3) the curve reflecting the mechanical restitution, under normal in vitro conditions a monotonically increasing function, becomes biphasic within the relative refractory period, (4) the conspicuous depression of the isometric post-rest contraction for long lasting pauses interrupting the regular pacing rhythm, a typical feature of isolated guinea-pig ventricular tissue, is clearly diminished, and (5) the characteristic curve, reflecting the potentiation of the post-extrasystolic post-rest contraction as a function of the delay time preceding the extrastimulus, becomes displaced to the premature interstimulus interval. The concept of an 'extended 2-calcium-store model' is supported by this work.

Deformation of the Bowditch staircase in Ca(2+)-overloaded mammalian cardiac tissue--a calcium phenomenon?

Concentrations of 1-4 mumol l-1 isoproterenol cause both in right ventricular papillary muscles and in enzymatically isolated myocytes of the guinea-pig a Ca2+ overload-induced state which is functionally characterized by biphasic (multiphasic) twitches and biphasic (multiphasic) intracellular calcium transients, respectively, during excitation-contraction coupling. This state was stabilized in the in vitro experiments for some hours by a co-ordination of the interstimulus interval, the temperature of the superfusion fluid and the addition of calcium agonists. The functional stability is the precondition for the reproducibility of the experimental results particularly after the application of long-lasting stimulation programmes. Changes in the shape of biphasic contractions were compared with changes in the time course of biphasic intracellular calcium transients using three manipulations of a different kind: (1) the interruption of the steady pacing rhythm, (2) the variation of the interstimulus interval, (3) the addition of ryanodine. It was shown that: (1) The BOWDITCH staircase in calcium overloaded multicellular preparations is changed in that each individual component of the twitch passes through its own staircase. A homologous behaviour can be observed in the configuration of the phasic and tonic component of biphasic intracellular calcium transients. (2) At different driving frequencies the relative proportion of the two components of a biphasic twitch corresponds to the time integrals of the two components of biphasic intracellular calcium transients. (3) Ryanodine suppresses both the first component of the biphasic twitch and the phasic component of the biphasic intracellular calcium transient. The SR Ca(2+)-ATPase inhibitor thapsigargin increases the second component of the biphasic calcium transient. This supports the hypothesis that the size of the tonic component is in part determined by intracellular calcium reuptake. The results of both kinds of experiments would be compatible with the assumption that in calcium overloaded mammalian cardiac cells calcium reaches the contractile system directly as well as via two intracellular stores ('extended two-Ca-store concept').

Threephasic contractions in mammalian myocardium. Isolation and identification of a late component. Implications for rested-state contractions.

More than 100 years after Bowditch's discovery of the "Treppe" phenomenon the mechanism of the striking rate and rhythm dependence of cardiac contraction is not unequivocally established. Beside sophisticated techniques biphasic contractions seemed to be a promising approach. There was soon a general agreement that the first component of biphasic contractions is activated by Ca released from the sarcoplasmic reticulum. About the second component prevails confusion: It does not directly reflect the Ca current, but is somehow related to that. In addition, involvement of Na-Ca exchange is supposed. We produced threephasic contractions by the use of isoproterenol (0.5-.4 microM) in guinea pig papillary muscle. Either by the application of ryanodine (1 microM) or after long periods of rest a ryanodine resistant late component of contraction could be isolated. On reducing the transmembrane Na gradient either by reducing [Na]o or by experimental manoeuvres expected to increase [Na]i. (.5 mM [K]o; 2-8 microM ouabain) this component was found to be increased. The evidence suggests that this component is substantially activated by Ca entering the cell via the sarcolemmal Na-Ca exchange. The ryanodine sensitive first component of threephasic contractions was found to be sensitive to caffeine, isoproterenol and changes in stimulation as well. These findings support the view that it may be generated by Ca induced Ca release from the sarcoplasmic reticulum. The pharmacological properties of the second and third ryanodine sensitive component and its dependence on the stimulation pattern were similar to those of the aftercontraction. They were found to be sensitive to procaine, verapamil, Mg, Ni and isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)

Simulation by two calcium store models of myocardial dynamic properties: potentiation, staircase, and biphasic tension development.

Most considerations and models concerning myocardial dynamic properties e.g. potentiation and staircase, are based upon the existence of storage structures in the heart muscle cell. The phenomenon of biphasic tension development (or two-component contraction) in heart muscle preparations of several mammalian species suggests that the sarcoplasmic reticulum is one, but by no means the major, source of activator calcium for the contractile system. The simulation of dynamic properties including biphasic tension development was performed in two steps by a simple "two-Ca store-model" and by an "expanded two-Ca store-model" with following results: Increasing potentiation indicated a decrease in the degree of coupling between the Ca stores. A shift of the interval strength curve to lower intervals as well as a decrease of the steady state contraction height implies a decrease of both, the coupling and the leakage time constant. There was no standard relation between staircase phenomena and structure parameters. Analog displays showed a late (or second) component at prolongated stimulation intervals, in the transient phase after a rest period, in the case of perfectly coupled or uncoupled stores, and at great time constant tau p (which characterizes the calcium pump activity). It is concluded that the late component of biphasic tension development is due to direct activation by the transsarcolemmal Ca flux of the myofilaments, whereas the early component is caused by the release of stored calcium. In the absence of an early component neither potentiation nor marked treppe may be expected.

On the metabolic basis of pseudopotentiation and superposition in the frog myocardium.

Potentiation phenomena, tetanization and staircase of isolated surviving ventricle strips excised from hearts of 16 frogs (Rana esculenta) were studied under quasiisometric conditions. Pseudopotentiation of all kind, biphasic staircases and superposition of contractions characterizing the hypodynamic state following excision disappear in-vitro not only during normodynamic conditions but also in hypodynamia following in-vitro normodynamia.

Effects of iodoacetic acid on relaxation parameters of the rabbit papillary muscle.

Measurements have been made of isometric contractions and diastolic oscillations (after-contractions) in right ventricular rabbit papillary muscles at a temperature of 14.5 degrees C. The relaxation courses can be described as damped harmonic oscillations superposed on an exponential descending carrier function by using a model with six parameters. The influence of iodoacetic acid (10(-4) M) was investigated on contraction and relaxation parameters which result from approximation of the measured force values. The following changes were observed: 1. Decrease of the contraction height as well as of the amplitudes of diastolic oscillations. 2. Increase in the damping ratio and in the period of diastolic oscillations both calculated from relaxation parameters. 3. Diminution of the force range which is passed by the carrier function within 6 s of relaxation time accompanied by a transition to contracture. A fast and a slow Ca sequestration process are supposed to exist. The results indicate that both of them are influenced by iodoacetic acid.

[Effect of the pacing interval and extrasystole on amplitude and damping of diastolic oscillations in the rabbit papillary muscle]. / Einfluss von Treibintervall und Extrasystole auf Amplitude und Dämpfung diastolischer Oszillationen am Kaninchenpapillarmuskel.

Diastolic mechanical oscillations of right ventricular rabbit papillary muscles investigated at 15 degrees C in the perfusion chamber were analysed using a relaxation model with 6 parameters. From this analysis follows that the first diastolic oscillation amplitude plotted against the driving interval ("interval amplitude curve" of the first diastolic oscillation) shows tow maxima thus differing from the shape of the interval strength curve of the preceding driven contraction. It is concluded that the amplitude of diastolic oscillations is less determined by the Ca-amount released from the sarcoplasmic reticulum during the action potential than by the frequency of processes which effect the Ca release and the Ca-sequestration. The damping ratio varies within the range of tested driving intervals (0.36 to 10 s). After an extrasystole damping ratio and period of diastolic oscillation are diminished compared with the values after regularly driven contractions.

What information contains a rest contraction curve? a theoretical study with experimental results from the rabbit papillary muscle.

On the basis of a specialized two-Ca store model the degree of coupling q between the two stores was introduced. q is defined by the time constants of the model (leakage and coupling time constant) and varies between O (uncoupled stores) and 1 (maximal coupled stores). Provided that the contraction height in first approximation is proportional to the myoplasmic Ca concentration from the rest contraction curve the degree of coupling can be calculated using the coordinates of the maximum developed tension. From 13 rabbit papillary muscles the values of q were determined at different periods of rest thus demonstrating that q cannot be considered as constant in the first period of the pause. Accordingly, the time constants change rapidly at the beginning of the rest reaching relatively constant values after the half of the maximum time of the rest contraction curve. With respect to the hypothesis of intracellular recycling Ca controlling the contraction in cardiac muscle the great values of q (about 0.9 after a longer period of rest) suggest a very little loss of Ca from intracellular stores by leakages. From our calculations it is expected that in the maximum of the rest contraction curve the Ca concentration in both stores might differ insignificantly.

[Modelling of relaxation phenomena in the myocardium]. / Modellierung von Relaxationsphänomenen am Herzmuskel.

A model describing relaxation phenomena on heart muscle preparations is proposed, permitting characterization of diastolic oscillations (aftercontractions) that are considered as being damped harmonic oscillations superposed an exponentially descending carrier function (oscillating case). If there is a high damping ratio diastolic oscillations cannot be observed except the phenomenon of hyperrelaxation. Relaxation without oscillations corresponds to the aperiodic case. Examples of relaxation time courses resulting from right ventricular rabbit papillary muscles (isometric conditions) as well as relaxation parameters and approximation curves obtained by the aid of the table computer EMG 666 are given. The model is realized by an electrical analog which is based on a hypothesis concerning the calcium sequestration in the myoplasm.

Increase of myocardial diastolic tonus at low temperatures: a Ca-phenomenon?

Myocardial diastolic tonus increases at low temperature. The chief aim of the present series of experiments was to decide whether this phenomenon should be interpreted as being caused by thermoelastic alteration or by an impairment of the Ca-pump. All experiments were performed on isolated right ventricular rabbit papillary muscles. In order to impose ramp-like and sinusoidally modulated changes of the temperature on the perfusate, a Peltier-battery was used. In Krebs-Henseleit solution with normal Ca-content (2.52 mmoles/l) changes of diastolic tonus of the driven muscle within a narrow range at low temperature amount approximately to isometric twitch tension (10(-2) up to 3.10(-2) N mm-2). Non-stimulated preparations show tension alterations of 2.10(-4) N mm-2 at best. With increasing stimulation interval the hysteresis-like loop representing changes of diastolic tonus shifts to lower temperatures. Under threefold Ca2+-concentration of the perfusate the diastolic tension varies over the total range of periodically modulated temperature in both stimulated and non-stimulated muscles. From these results it may be concluded that increasing myocardial diastolic tonus under low temperature is caused by an insufficiency of the Ca-sequestration system.

[Various critical comments on the interpretation of staircase- and potentiation phenomena in the rabbit heart muscle]. / Einige kritische Bemerkungen zur Interpretation von Treppen- und Potentiationsphänomenen am Kaninchenherzmuskel

Some critical remarks on the interpretation of staircase and potentiation phenomena (rabbit heart muscle). Isometric contractions of rabbit papillary muscles and atrial strips were investigated at temperatures from 13.2 degrees C to 35 degrees C after rests of different duration at constant stimulation frequency before rest, in a period after rest and in a transition phase following a step of stimulation frequency. Changes in potentiation as well as changes in dynamics after rest and dynamics after steps of stimulation frequency are caused by lowering the temperature. Any hypothesis on the subject of Ca-movements between intracellular stores would have to account for changes in potentiation, staircase phenomena and the development of after-contractions at low temperatures.