Sparing of perceptual implicit memory despite suppression of the electrophysiological word repetition effect: a study with general anesthetic isoflurane.

OBJECTIVE: Much effort has been devoted to the search for the neurophysiological correlates of implicit memory. A commonly held view is that the early portion (250-500 ms) of the event-related potential (ERP) word repetition effect reflects processes important for perceptual implicit memory whereas the latter portion reflects processes implicated in explicit memory. It is, however, difficult to disentangle with certainty the relative contributions of each form of memory on ERPs since both forms co-exist in normal subjects. To dissociate ERP effect related to implicit and explicit memory, we used isoflurane sedation in normal subjects to suppress explicit remembering while sparing implicit memory. These ERPs were compared with those of non-medicated control subjects. METHODS: Thirteen subjects performed an incidental encoding task for words presented auditorily during the inhalation of a subanesthetic dose of isoflurane. After termination of isoflurane administration, we assessed free recall and recorded ERPs during a syllable completion task (implicit memory) and during a passive listening task (ERP repetition effect). Eleven non-medicated control subjects were tested in a similar manner. RESULTS: The controls showed robust early and late ERP repetition effect. The isoflurane group had implicit memory without free recall and showed no ERP repetition effect. CONCLUSIONS: These findings failed to show an association between any part of the repetition effect and perceptual implicit memory. The results are consistent with the view that processes linked to explicit memory contribute to the ERP repetition effect since there was a marked difference in free recall between the control and isoflurane groups. SIGNIFICANCE: The present study shows that the reversible alterations of memory by general anesthetics can be used to study the neurophysiological correlates of memory processes.     

Value of Doppler ultrasound for the diagnosis of renal artery stenosis in children

To evaluate the reliability of Doppler ultrasonography (US) in identifying children with renal artery stenosis (RAS) among those with hypertension, we compared Doppler US results in 22 hypertensive children (mean age 8.9±4.3 years), with (13 cases) and without RAS at angiography, and in 33 normotensive children (mean age 8.8±4.7 years). We observed 2 false-negatives and 2 false-positives with Doppler US. Of the 2 false-negative diagnoses, 1 had RAS on an accessory renal artery located behind a normal upper polar artery and the other was observed in a patient with bilateral multiple stenosis of the very distal segments of renal arteries. The 2 false-positive diagnoses were due to sinuous left renal artery and to technical reasons, respectively. In another patient, Doppler US showed a tight RAS, while arteriography was normal. RAS was subsequently confirmed by a second arteriography. Peak systolic velocity values of Doppler US were significantly higher in patients with proven angiographic RAS (3.44±0.66 m/s) than in hypertensive patients with normal renal arteries at angiography (0.99±0.35 m/s, P <0.0001) and normotensive healthy children (1.04±0.23 m/s, P <0.0001). With the use of multiple views, and the experience acquired with practice, false-negatives or false-positives due to the geometry of the renal artery can be avoided. Nevertheless, very distal stenosis can be missed by Doppler US. Received October 30, 1995; received in revised form April 16, 1996; accepted May 14, 1996     

Positron emission tomographic investigations of central muscarinic cholinergic receptors with three isomers of [76Br]BrQNP

We studied the potential of three radiobrominated isomers of BrQNP, (Z(-,-)-[⁷⁶Br]BrQNP,E(-,-)-[⁷⁶Br]BrQNP andE(-,+)-[⁷⁶Br]BrQNP), as suitable radioligands for imaging of central muscarinic cholinergic receptors in the human brain. These radioligands were stereospecifically prepared by electrophilic radiobromodestannylation of the respective tributylstannyl precursors using no-carrier-added [⁷⁶Br]BrNH₄ and peracetic acid. Preliminary pharmacological characterizations were determined by biodistribution, autoradiography, competition, displacement and metabolite studies in rats. The (-,-)-configuration presented important specific uptakes in brain muscarinic cholinergic receptor (mAChR)-rich structures and in heart, low metabolization rates and an apparent M₂ selectivity. The (-,+)-configuration revealed more rapid clearance, lower uptake, a higher metabolization rate and an apparent M₁ selectivity. Reversibility of the binding was confirmed for the three radiotracers. Positron emission tomography in the living baboon brain revealed high and rapid uptake in the brain and accumulation in the mAChR-rich structures studied. At 30 min p.i., theE(-,-)-radiotracer reached a plateau in cortex, pons and thalamus with concentrations of 29%, 24% and 19% ID/l, respectively.Z(-,-)-[⁷⁶Br]BrQNP also accumulated in these structures, reaching a maximal uptake (27% ID/l) in the cortex 2 h p.i. At 5 min p.i. a plateau (17% ID/l) was only observed in the cortex for theE(-,+)-[⁷⁶Br]BrQNP; by contrast, the other structures showed slow washout. After 3 weeks, the (-,-)-radiotracers were studied in the same baboon pretreated with dexetimide (1 mg/kg), a well-known muscarinic antagonist. In all the mAChR structures, the highly reduced uptake observed after this preloading step indicates that these radiotracers specifically bind to muscarinic receptors.Z(-,-)-[⁷⁶Br]BrQNP, which is displaced in higher amounts from M₂ mAChR-enriched structures, reveals an M₂ affinity. The two isomers having the (-,-)-configuration are potential probes for investigating central muscarinic receptors. The absolute configuration on the acetate chiral centre influences their muscarinic subtype selectivity and thecis-trans isomerism of the vinyl moiety affects their specific fixation.     

Avoiding drug-induced switching in patients with bipolar depression.

Antidepressant-induced switching is a major risk during the treatment of bipolar depression. Despite several clinical studies, questions remain regarding both the definition of these mood switches and the most appropriate therapeutic strategy to avoid this adverse effect.This review will first briefly consider the current guidelines for the acute treatment of bipolar depression. We will then review the mechanisms of action of antidepressant and mood stabilisers, and the switches induced by various types of antidepressant treatments, or triggered by antidepressant withdrawal, as well as by atypical antipsychotics. We then will address the risk of mood switch according to the type of mood stabiliser used. The propensity to mood switches in bipolar patients is subject to individual differences. Therefore we will describe both the clinical and biological characteristics of patients prone to mood switches under antidepressant treatment. However, the clinical characteristics of the depressive syndrome may also be a key determinant for mood switches. Various data help identify the most appropriate drug management strategies for avoiding mood switches during the treatment of bipolar depression. Selective serotonin reuptake inhibitors appear to be the drugs of first-choice because of the low associated risk of mood switching. Antidepressants must be associated with a mood stabiliser and the most effective in the prevention of switches seems to be lithium. Whatever the mood stabiliser used, effective plasma levels must be ensured. The optimal duration of antidepressant treatment for bipolar depression is still an open issue - prolonged treatments after recovery may be unnecessary and may facilitate mood elation. Moreover, some mood episodes with mixed symptoms can be worsened by antidepressants pointing to the need for a better delineation of the categories of symptoms requiring antidepressant treatment. Finally, as a result of this review, we suggest some propositions to define drug-induced switches in bipolar patients, and to try to delineate which strategies should be recommended in clinical practice to reduce as far as possible the risk of mood switch during the treatment of bipolar depression.     

Total serum IgE levels in a large cohort of patients with severe or difficult-to-treat asthma.

BACKGROUND: Limited data are available on levels of IgE in large cohorts of patients with severe or difficult-to-treat asthma. OBJECTIVE: To examine IgE levels and disease in patients from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. METHODS: From January 2001 to October 2001, 4,923 patients were screened for inclusion in the study. Of these, 4,756 patients 6 years or older with severe or difficult-to-treat asthma were enrolled and completed a baseline study visit. Total serum IgE levels were measured at the baseline visit and are summarized by geometric means. RESULTS: The mean total IgE level of the population is 106.6 IU/mL (95% confidence interval, 101.5-112.0 IU/mL). Children (6-12 years old) and adolescents (13-17 years old) have higher mean IgE levels than adults (> or =18 years old) (P < .001). Males have a higher mean IgE level than females (P < .001). IgE levels are higher among nonwhite patients than white patients (P < .001). Current smokers have higher IgE levels than past smokers or never smokers (P < .001). Among children, patients with severe asthma have a higher mean IgE level (280.2 IU/mL) than patients with moderate (145.8 IU/mL) or mild (137.8 IU/mL) asthma (P < .001). Among adults, patients with childhood-onset asthma have higher IgE levels (124.3 IU/mL [n = 1,348]) than patients with adult-onset asthma (65.7 IU/mL [n = 1,956]) (P < .001). CONCLUSION: In patients with severe or difficult-to-treat asthma from the TENOR study, higher total IgE levels were observed in males, children, smokers, nonwhite racial/ethnic groups, and adults with childhood-onset disease. In addition, IgE levels are associated with asthma severity among younger patients.     

Polymères thiocarboxyliques, 1. Synthèse et étude de la polymérisation radicalaire de monomères dithiocarboxyliques

The syntheses and free-radical polymerizations of methyl and carboxymethyl 4-vinyldithiobenzoates are described as well as various copolymers. Copolymerisation parameters were determined for the copolymerizations of the methyl dithioester with styrene and with methyl methacrylate.     

Neuromuscular adaptations in rats trained by muscle stretch-shortening

The aim of this study was the analysis of neurophysiological, mechanical and histochemical parameters to demonstrate muscle adaptation with training. If the parameters studied were to show correlated changes, it would be possible to propose that the neural and the muscle components of motor units are both affected by the training programme used. The training consisted of repeated stretch-shortening cycles known to use extensively fast fibres. After the training period electromyographical reflex activities of the ankle plantar-flexors were recorded in awake rats and then mechanical and histochemical measurements were made on isolated soleus muscles of the control and trained rats. The reflexes studied were the H-response to electrical stimulation of the sciatic nerve and the T-response to an Achilles tendon tap. The H-response analysis indicated a decrease in reflex excitability of the trained muscles. The trained soleus muscle also presented a higher contractility as demonstrated by significantly smaller twitch contraction times and higher maximal velocities of shortening measured during tetanic contractions. The reflex and contractile muscle changes were accompanied by relative increases in the number of type II fibres. The T-response was not significantly modified by training despite the decrease in motoneuron excitability demonstrated by the decrease in H-response. This would suggest that the peripheral components of the reflex pathway such as tendon stiffness and/or spindle sensitivity might be modified by training. This would imply that both the motor and the sensory parts of a muscle are affected by training.     

Identifying candidate causal variants responsible for altered activity of the ABCB1 multidrug resistance gene

The difficulty of fine localizing the polymorphisms responsible for genotype-phenotype correlations is emerging as an important constraint in the implementation and interpretation of genetic association studies, and calls for the definition of protocols for the follow-up of associated variants. One recent example is the 3435C>T polymorphism in the multidrug transporter gene ABCB1, associated with protein expression and activity, and with several clinical conditions. Available data suggest that 3435C>T may not directly cause altered transport activity, but may be associated with one or more causal variants in the poorly characterized stretch of linkage disequilibrium (LD) surrounding it. Here we describe a strategy for the follow-up of reported associations, including a Bayesian formalization of the associated interval concept previously described by Goldstein. We focus on the region of high LD around 3435C>T to compile an exhaustive list of variants by (1) using a relatively coarse set of marker typings to assess the pattern of LD, and (2) resequencing derived and ancestral chromosomes at 3435C>T through the associated interval. We identified three intronic sites that are strongly associated with the 3435C>T polymorphism. One of them is associated with multidrug resistance in patients with epilepsy (chi2 = 3.78, P = 0.052), and sits within a stretch of significant evolutionary conservation. We argue that these variants represent additional candidates for influencing multidrug resistance due to P-glycoprotein activity, with the IVS 26+80 T>C being the best candidate among the three intronic sites. Finally, we describe a set of six haplotype tagging single-nucleotide polymorphisms that represent common ABCB1 variation surrounding 3435C>T in Europeans.     

Detection of Antiendothelial Cell Antibodies by an Enzyme-Linked Immunosorbent Assay Using Antigens from Cell Lysate: Minimal Interference with Antinuclear Antibodies and Rheumatoid Factors

The objective of the present work was to set up a routine test adapted to screening for antiendothelial cell antibodies (AECAs) in serum samples with minimal interference from antinuclear antibodies (ANAs) or rheumatoid factors (RFs). We compared the titers of AECAs titrated following two enzyme-linked immunosorbent assays (ELISAs): (i) an ELISA with ethanol-fixed EA.hy926 monolayers as the antigenic substrate and (ii) an ELISA with nucleus-depleted lysates prepared from EA.hy926 cells and normalized for protein (1.0 to 1.7 mg/ml) and DNA (≤0.1 μg/ml) contents as a surrogate substrate (postnuclear supernatant ELISA [PNS-ELISA]). The AECA titers in 51 serum samples, including 28 samples containing ANAs, were compared. A significantly positive correlation (r = 0.77; P < 0.001) between the two series was shown only for the ANA-negative serum samples. Conversely, ANAs or RFs in samples were shown not to interfere in tests for AECAs by the PNS-ELISA. AECAs recognize their antigenic targets in postnuclear supernatants, which is representative of the endothelial antigenic content, with improvement of the reliability of the assay, a prerequisite to application of the assay for their evaluation in clinical practice.     

Binding of nucleosomes to a cell surface receptor: Redistribution and endocytosis in the presence of lupus antibodies

In the present study, we sought evidence for a surface nucleosome receptor in the fibroblastic cell line CV-1, and questioned whether anti-double-stranded (ds)DNA and/or anti-histone autoantibodies could recognized and influence the fate of cell surface-bound nucleosomes. ¹²⁵I-labeled mononucleosomes were shown to bind to the cell layer in a specific, concentration-dependent and a saturable manner. Scatchard analysis revealed the presence of two binding sites: a high-affinity site with a Kd of ～ 7nM and a low-affinity site (Kd ～ 400 nM) with a high capacity of 9 × 10⁷ sites. Visualization of bound mononucleosomes by fluorescence revealed staining on both the cell surface and the extracellular matrix (ECM). Purified mononucleosome-derived dsDNA (180–200 bp) was found to compete for binding of ¹²⁵I-mononucleosomes on the low-affinity site, to stain exclusively the ECM in immunofluorescence, and to precipitate three specific proteins of 43, 180 and 240 kDa from ¹²⁵-I-labeled cell lysates. Nucleosomes were found to precipitate not only the 180-kDa dsDNA-reactive component, but also a unique protein of 50 kDa, suggesting that this protein is a cell surface receptor for nucleosomes on these fibroblasts. Once bound on the cell surface, mononucleosomes were recognized and secondarily complexed by lupus anti-dsDNA or anti-histone antibodies (i.e. anti-nucleosome antibodies), thus forming immune complexes in situ. The presence of these complexing auto-antibodies was found dramatically to enhance the kinetics of mononucleosome internalization. Following the internalization of the nucleosome-anti-nucleosome complexes by immunofluorescence, we observed the formation of vesicles at the edge of the cells by 5–10 min which moved toward the perinuclear region by 20–30 min. By means of double-fluorescence labeling and proteolytic treatment, these fluorescent vesicles were shown to be in the cytoplasm, suggesting true endocytosis of nucleosome-anti-nucleosome immune complexes. As shown by confocal microscopy, at no stage of this endocytic process was there any indication that coated pits or coated vesicles participated. Co-distribution of the endocytic vesicles with regions rich in actin filaments and inhibition of endocytosis of nucleosome-anti-nucleosome complexes by disruption of the micro-filament network with cytochalasin D suggest a mechanism mediated by the cytoskeleton. Taken together, our data provide evidence for the presence of a surface nucleosome receptor. We also show that anti-dsDNA and anti-histone antibodies can form nucleosome-anti-nucleosome immune complexes in situ at the cell surface, and thus dramatically enhance the kinetics of nucleosome endocytosis.