[Relationship between defense mechanism and therapeutic alliance]. / Relation entre mécanismes de défense et alliance thérapeutique.

INTRODUCTION: The therapeutic alliance can be defined as a collaborative relationship between the patient and the practitioner. It represents an essential component of the psychotherapeutic process (Ambresin et al., 2007; Cungi, 2006; Martin et al., 2000). Some authors suggest that a good alliance can have a favorable impact on the therapeutic success (Barber et al., 2000; Hubble, Duncan, & Miller 1999; Horvath & Luborsky, 1993; Horvath & Symonds, 1991). This alliance can be influenced by psychological and behavioral factors (Cungi, 2006) Thus, some defense mechanisms could prevent change or, on the contrary could facilitate adaptation (Ambresin et al., 2007) and have an impact on the therapeutic success (Muris & Merckelbach, 1996). However, the relationship between therapeutic alliance and defense mechanisms represents an insufficiently explored field (Ambresin et al., 2007; Cungi, 2006). The aim of the present study was to examine the relationship between therapeutic alliance and twenty defense mechanisms in a sample of French psychiatric patients, by differentiating results in men and women. We also examined the positive and the negative therapeutic alliance. METHOD: Sixty patients aged from 18 to 58 (M=41.50; SD=11.03) completed the French versions of the Defense Style Questionnaire-40 (DSQ-40) and the Helping Alliance questionnaire-II (HAq-II). RESULTS: Therapeutic alliance was significantly associated with each defense style: mature (0.62), neurotic (0.45) P<0.01and immature (0.27) p<0.05. The mature defense style was a significant predictor of therapeutic alliance (R(2) adj=36, F=12.39, ß=0.65, P<0.01) and of positive therapeutic alliance (R(2) adj=36, F=12.34, ß=0.62, P<0.001). Among women, positive therapeutic alliance was significantly associated with all mature defenses, three neurotic defenses (reaction formation, pseudo-altruism, idealization) and four immature defenses (splitting, denial, somatization, passive aggression). Among men, three mature defenses were associated (anticipation, humor, sublimation), four neurotic (reaction formation, pseudo-altruism, idealization and undoing) and two immature (somatization and denial). The negative therapeutic alliance, in our total sample, was associated with two immature defenses (denial and dissociation). Among men, displacement was the only defense associated with negative alliance, among women no defenses was significant. DISCUSSION: These results highlight the relationship between therapeutic alliance and some defense mechanisms, like some authors have suggested (Ambresin et al., 2007; Bond & Perry, 2004; Bond, 2004). Moreover, some defenses appeared to be more associated with a positive or a negative therapeutic alliance, and could depend on the patient gender. CONCLUSION: The present study confirms the importance of taking into account the gender in the study of defense mechanisms, and to increase our knowledge about the relationship between therapeutic alliance and defense mechanisms.

[Mental health service utilization among borderline personality disorder patients inpatient]. / Utilisation des services de soin par les patients hospitalisés, présentant un trouble de personnalité borderline en Midi-Pyrénées.

BACKGROUND: Borderline personality disorder (BPD) is characterized by a pervasive pattern of instability and impulsivity. Several North American prospective studies support the high level of mental health care utilization in this population. There is little data in other systems of health organization, such as France. Furthermore, little is known on the variables associated with the mental health service utilization among BPD patients. OBJECTIVE: The main objective was to compare the utilization of mental health care among BPD patients, to the general population and patients with another personality disorder (PD) and to describe the demographic and clinical factors associated with the group of patients who use the most health care. METHOD: A multi-center (5 public and private centers), epidemiological study. Data were collected prospectively (database of an insurance fund covering 80% of the population) and viewed, retrospectively. We used the data collected during the five years previously to the inclusion. Inclusion criteria were age (18-60 years) and membership in the health insurance fund targeted. Patients on legal protection, forced hospitalization, with a chronic psychotic disorder, manic, mental retardation, or not reading French were excluded. First, four groups were composed: BPD, other PD, control groups for PD and other PD. The first two groups were recruited from a screening of inpatients including a self-administered questionnaire (Personality Disorder Questionnaire 4+). Assessment by a psychologist including the Structured Interview for DSM-IV Personality Disorders (SIDP-IV) was given straight to those who had a score above 28. This questionnaire allowed us to distinguish one group of subjects with BPD and a group with other PD (without BPD). Clinical evaluation included Axis I (MINI), Axis II (SIDP-IV), psychopathological features (YSQ-I, DSQ-40), demographic variables and therapeutic alliance (Haq-II). Matched controls (age, sex) composed the 3rd and 4th group (BPD control and other PD control). They were randomly chosen in the health database insurance previously used. RESULTS: One hundred and thirty-seven (95.8%) screened patients agreed to answer the psychological assessment. In this sample, 44 (32.1%) had BPD, 39 (28.5%) other PD and another 39 (28.5%) did not have PD. The BPD group was compared to a sample of 165 matched subjects and the other group PD to a sample of 123 matched controls. There was no difference between BPD and other PD groups regarding the mental health utilization. However, there was an increased use of hospitalizations and deliverances of nervous system drugs in both clinical groups compared to their controls. The analysis of drugs supplied in pharmacies for BPD patients showed that the first two drugs were opiate substitutes (12.3% methadone, buprenorphine 6.7%). No anticonvulsants or atypical antipsychotics appear in the top 20 of treatments delivered. A composite variable (hospitalization for more than 6 months during previous five years and 500 supplied drugs) allowed the discrimination of two groups among patients with BPD: heavy users of care and low care users. No variables (demographics, Axis I, Axis II, self-aggressiveness, DSQ-40, Haq-II, YSQ-I) could discriminate the two groups except the number of previous psychotherapies (heavy users: n=0.4 (SD 0.5) vs low users: n=1.8 (SD 2.1) P=0.0054). CONCLUSION: This study confirms the important use of the service of BPD patients in France, as well as the possible moderating role of psychotherapy. We found a mismatch between these uses and recommendations.

Effect of endurance training on skeletal muscle myokine expression in obese men: identification of apelin as a novel myokine.

BACKGROUND: It has been suggested that the metabolic benefits of physical exercise could be mediated by myokines. We examined here the effect of exercise training on skeletal muscle expression of a panel of myokines in humans. Pathways regulating myokine expression were investigated in human myotubes. METHODS: Eleven obese non-diabetic male subjects were enrolled in an 8-week endurance training program. Insulin sensitivity was assessed by an oral glucose tolerance test. Subcutaneous adipose tissue and Vastus lateralis muscle biopsy samples were collected before and after training. RNAs were prepared from adipose tissue and skeletal muscle. Primary culture of myoblasts was established. RESULTS: As expected, exercise training improved aerobic capacity and decreased fat mass. No significant change in interleukin 6, fibroblast growth factor 21, myostatin (MSTN) or irisin mRNA level was found in muscle after training. A twofold increase in apelin mRNA level was found in muscle but not in adipose tissue. No change in circulating myokine and adipokine plasma levels was observed in the resting state in response to training. Interestingly, apelin was significantly expressed and secreted in primary human myotubes. Apelin gene expression was upregulated by cyclic AMP and calcium, unlike the other myokines investigated. Importantly, changes in muscle apelin mRNA levels were positively related to whole-body insulin sensitivity improvement. CONCLUSION: Collectively, our data show that exercise training upregulates muscle apelin expression in obese subjects. Apelin expression is induced by exercise signaling pathways and secreted in vitro in human primary myotubes, and may behave as a novel exercise-regulated myokine with autocrine/paracrine action.

Functional connectivity and cognitive changes after donepezil treatment in healthy participants.

RATIONALE: Donepezil is a potent, noncompetitive, reversible, clinically effective acetylcholinesterase inhibitor. The effects of this drug on healthy brains have seldom been investigated. OBJECTIVES: The primary objective of the present study was to identify possible functional connectivity markers of the effect of donepezil in healthy young adult volunteers. METHODS: The study had a double-blind, randomized, crossover design. 30 healthy adult volunteers underwent resting-state MRI scans during 15 days of donepezil or placebo treatment, in accordance with the design. RESULTS: Results showed significant differences in intrinsic functional connectivity between donepezil and placebo, mainly in the right executive control network (RECN). More specifically, we found a decrease in the connectivity of the right inferior parietal node with other RECN nodes. Analysis using the cingulate cortex and parahippocampal regions as seeds also revealed complex modulation of functional connectivity in the donepezil condition. CONCLUSIONS: In conclusion, donepezil treatment for 15 days may result in reorganization of resting-state networks, compared with placebo.

Clinical characteristics and outcome of hospitalized patients with SARS-CoV-2 infection at Toulouse University hospital (France). Results from the Covid-clinic-Toul cohort.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread worldwide from epicenter of Wuhan, China since December 2019. The aim of our study was to describe the clinical characteristics and outcome of hospitalized patients with SARS-CoV-2 pneumonia at the Toulouse university hospital, France. PATIENTS AND METHODS: We selected the patients included from March 7, 2020 to April 20, 2020 in the retrolective Covid-clinic-Toul cohort that follows all hospitalized patients with SARS-CoV-2 infection at the Toulouse Hospital. Cases were confirmed by real-time reverse transcriptase polymerase chain reaction. We report demographics, clinical, biological and radiological features, as well as unfavorable outcome at Day 14 after admission (admission in an intensive care unit, mechanical ventilation, death). RESULTS: Among 263 hospitalized patients, the median age was 65 years and 155 (58.9%) were males. Two hundred and twenty-seven patients (86.3%) had at least one comorbidity. The median time from first symptom to hospital admission was 7.0 days (interquartile range: 4-10). On day 14 after admission, 111 patients (42.2%) had been transferred to intensive care unit (ICU), including 50 (19.0%) on Day 1; 61 (23.1%) needed mechanical ventilation and 19 patients (7.2%) had died. Patients admitted to ICU at Day 1 of admission (n=50) were more frequently men (66.0% vs 57.3%), smokers (25.0% vs 7.1%), with obesity (42.0% vs 24.7%) and had a higher mean level of C-reactive protein (median: 110.9mg/L vs 46.2mg/L). CONCLUSION: This cohort provides epidemiological data on SARS-CoV-2 in hospitalized patients in a University hospital in the South of France.

Levodopa raises objective pain threshold in Parkinson's disease: a RIII reflex study.

BACKGROUND: Patients suffering from Parkinson's disease (PD) describe painful sensations that could be related to neuropathic pain. Experimental data have indicated the involvement of basal ganglia and dopaminergic pathways in central nociceptive processing. AIM: The objective of this study was to assess and compare the effect of levodopa on the objective pain threshold in patients with PD and healthy subjects. METHODS: The objective pain threshold was assessed by the nociceptive flexion reflex (RIII) in 13 PD patients and 10 healthy subjects. Patients and healthy subjects were evaluated under two randomised conditions: with levodopa (ON) and without (OFF). RESULTS: Levodopa significantly increased the RIII threshold of PD patients (6.9 (1.2) mA in the OFF condition vs 8 (1.1) mA in the ON position; p = 0.02). RIII threshold was significantly lower in PD patients than in healthy subjects in the OFF condition (6.9 (1.2) mA vs 9.7 (3.4) mA; p = 0.02). RIII threshold did not change after levodopa administration in healthy subjects. CONCLUSION: These results provide evidence of a dopaminergic modulation of objective pain threshold in PD patients. In addition, the decrease in RIII threshold in PD patients, in the OFF condition, compared with controls, confirms the existence of an objective pain perception disturbance in PD.

Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans.

BACKGROUND: We conducted a double-blind, randomized, crossover study to assess the antithrombotic effects of the combination of aspirin (acetylsalicylic acid, ASA) and clopidogrel, with or without a loading dose, versus ASA alone in a model of arterial thrombosis in humans. METHODS AND RESULTS: Eighteen male volunteers received the following 3 regimens for 10 days separated by a 1-month period: (1) 325 mg ASA daily, (2) 325 mg ASA+75 mg clopidogrel daily, (3) 325 mg ASA daily+300-mg clopidogrel loading dose on day 1 and +75 mg clopidogrel per day on days 2 to 10. The antithrombotic effect was measured 1.5, 6, and 24 hours after drug intake on day 1 and 6 hours after drug intake on day 10. Arterial thrombus formation was induced ex vivo by exposing a collagen-coated coverslip in a parallel-plate perfusion chamber to native blood for 3 minutes at an arterial wall shear rate. Without a loading dose, clopidogrel+ASA developed an antithrombotic effect within 6 hours after the first intake. It was superior to that produced by ASA, but it was moderate (P

The specific thromboxane receptor antagonist S18886: pharmacokinetic and pharmacodynamic studies.

OBJECTIVES AND PATIENTS: We conducted a multicenter double-blind pharmacokinetic/pharmacodynamic (PK/PD) study of the new oral thromboxane receptor antagonist S18886 in 30 patients with peripheral artery disease, who were randomized to receive five different oral dosages of S18886 (1, 2.5, 5, 10 or 30 mg) for 12 weeks (83 days). Primary objective was to determine the effect of S18886 on platelet aggregation ex vivo. RESULTS: Pharmacokinetics of S18886 was linear, with peak plasma levels being reached between 30 min and 2 h and a terminal half-life of 5.8-10 h. No significant accumulation of S18886 in plasma was observed after repeated dosing. The relationship between the S18886 concentration and platelet inhibition was examined in terms of U46619-induced platelet aggregation. Over the range of doses studied, there was a predictable relation between the plasma drug concentration and the degree of platelet inhibition at each dose. Maximal inhibition of U46619-induced platelet aggregation was achieved within 1 h with all oral doses of S18886, and this effect was maintained for at least 12 h. The PK/PD relationship was direct, and U46619-induced platelet aggregation was strongly inhibited by S18886 plasma concentrations above 10 ng mL(-1). This concentration was thus the minimal effective antiplatelet level in this population, and was maintained only by the dosages of 10 and 30 mg. The safety profile of S18886 was excellent, whatever the unit dose, with no attributable adverse events. CONCLUSION: The results of this study, which included modeling and simulation, help identify the minimal effective plasma concentration of S18886 required for potent antiplatelet efficacy in patients with stable peripheral arterial disease.

Simulated microgravity increases beta-adrenergic lipolysis in human adipose tissue.

The effect of a sustained decrease in sympathetic nervous activity, achieved through 5-day head-down bed rest (HDBR), on the beta-adrenergic lipolytic activity of s.c. adipose tissue was studied in eight healthy men. The in situ beta-adrenoceptor (AR) sensitivity was studied using the microdialysis method. Local perfusion of increasing concentrations of isoprenaline showed an increased beta-AR sensitivity to lipolysis (assessed by extracellular glycerol concentration) and to vascular tone (assessed by the ethanol clearance). The adrenergic sensitivity of isolated adipocytes was studied in vitro. Basal lipolysis and the response to nonselective (isoprenaline) or selective (dobutamine, terbutaline, and CGP 12177) beta-AR agonists were increased after HDBR as was the lipolytic effect of dibutyryl cAMP. When data were expressed as a percentage of the dibutyryl cAMP effect to rule out the postreceptor events, basal and lipolytic responses to beta-AR agonists where similar before and during HDBR. The alpha 2-AR-mediated antilipolytic effects of adrenaline were not modified. Lymphocyte beta-AR number was unchanged during HDBR. Our results demonstrate that a sustained sympathoinhibition induces an increase in the lipolytic beta-adrenergic response in adipose tissue and suggest that this hypersensitization is linked to an increase in the postreceptor steps of the lipolytic cascade in the adipocyte rather than to changes in beta-adrenoceptors.

Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease.

BACKGROUND: Dyskinesias are a frequent adverse effect of long-term levodopa therapy. The relative contribution of dopamine D(1) and D(2) receptor function to the pathophysiology of levodopa-induced dyskinesias remains a matter of controversy. OBJECTIVE: To establish whether a selective D(1) dopamine agonist induces more or less dyskinesia than levodopa in primed dyskinetic patients with Parkinson disease. METHODS: We studied ABT-431, the prodrug of a fully selective D(1) agonist, in 20 subjects with advanced Parkinson disease and a fluctuating response to levodopa complicated by dyskinesias. Eight patients were studied in a double-blind, randomized design (French centers); 12, in an open, randomized design (US centers). We assessed and compared the antiparkinsonian (Unified Parkinson's Disease Rating Scale) and dyskinetic (response induced by an acute challenge of a suprathreshold dose of levodopa and by 4 different ascending doses (5, 10, 20, and 40 mg) of ABT-431 during the 6 hours after the challenge. RESULTS: The separate analysis of the double-blind and open data led to the same findings, ie, the antiparkinsonian and dyskinetic responses induced by ABT-431 were dose related. At the most effective doses (20 and 40 mg), ABT-431 exhibited similar antiparkinsonian benefit and produced similar dyskinesias as levodopa. CONCLUSION: Dopamine D(1) agonists can induce a full antiparkinsonian response but do not support previous hypotheses suggesting that D(1) agonists are more or less likely to produce dyskinesias than levodopa.

Effect of ropinirole on sleep onset: a randomized, placebo-controlled study in healthy volunteers.

Somnolence and "sleep attacks" have been reported as an adverse effect of several antiparkinsonian drugs. The authors document, in a placebo-controlled, randomized, double-blind, crossover study performed in 20 healthy volunteers, using the Multiple System Latency Test (MSLT) as primary outcome, that ropinirole reduces time to sleep onset in humans. Ropinirole therapy was not associated with daytime episodes of rapid eyes movement (REM) sleep.

Dual-release formulation, a novel principle in L-dopa treatment of Parkinson's disease.

A single morning dose of dual-release formulation was compared with a slow-release formulation of L-dopa plus benserazide in a randomized, double-blind, cross-over study in 16 fluctuating patients with PD. The mean time to "on" was shorter with the dual-release formulation (43 +/- 31 minutes) than with the slow-release formulation (81 +/- 39 minutes) (p < 0.001), whereas the mean time to relapse to "off" was similar for both formulations. The dual-release formulation had a significantly shorter time to reach peak concentration (t(max)) and greater maximum concentration (C(max)) and area under the plasma concentration time curve (AUC(0--5 h)) than the slow-release formulation, whereas apparent elimination half-life (t(1/2)) was similar for both formulations.

The effect of platelet PlA polymorphism on experimental thrombus formation in man depends on blood flow and thrombogenic substrate.

A number of studies have reported conflicting data on the association of the PlA1/PlA2 polymorphism of the GPIIIa gene and coronary syndromes. We have investigated the effect of this polymorphism on experimental platelet thrombus formation in man. Forty healthy male volunteers were genotyped for the PlA1/PlA2 polymorphism. Thrombus formation was induced ex vivo by exposing a tissue factor (TF) or a collagen-coated coverslip in a parallel plate perfusion chamber to native blood for 2 and 4 min. The shear rates at these surfaces were 650 and 2,600 s(-1). Platelet and fibrin deposition was quantified by immunoenzymatic methods. The frequencies of PlA1/PlA1 and PlA1/PlA2 genotypes were 52.5% and 47.5%, respectively. Ex vivo deposition of fibrin on TF was not affected by the PlA1/PlA2 polymorphism. However, the ex vivo platelet deposition at 650 s(-1) was higher in blood from PlA1/PlA1 individuals than in PlA1/PlA2 individuals (P= 0.008 at 4 min). On collagen, neither fibrin nor platelet deposition was significantly affected by the PlA1/PlA2 polymorphism. Platelet thrombus formation is significantly influenced by genetic variations in the GPIIIa platelet receptor. This effect depends on the blood flow properties and the nature of the thrombogenic stimulus.

Increase in epinephrine-induced responsiveness during microgravity simulated by head-down bed rest in humans.

The epinephrine (Epi)-induced effects on the sympathetic nervous system (SNS) and metabolic functions were studied in men before and during a decrease in SNS activity achieved through simulated microgravity. Epi was infused at 3 graded rates (0.01, 0.02, and 0. 03 microg. kg(-1). min(-1) for 40 min each) before and on the fifth day of head-down bed rest (HDBR). The effects of Epi on the SNS (assessed by plasma norepinephrine levels and spectral analysis of systolic blood pressure and heart rate variability), on plasma levels of glycerol, nonesterified fatty acids (NEFA), glucose and insulin, and on energy expenditure were evaluated. HDBR decreased urinary norepinephrine excretion (28.1 +/- 4.2 vs. 51.5 +/- 9.1 microg/24 h) and spectral variability of systolic blood pressure in the midfrequency range (16.3 +/- 1.9 vs. 24.5 +/- 0.9 normalized units). Epi increased norepinephrine plasma levels (P < 0.01) and spectral variability of systolic blood pressure (P < 0.009) during, but not before, HDBR. No modification of Epi-induced changes in heart rate and systolic and diastolic blood pressures were observed during HDBR. Epi increased plasma glucose, insulin, and NEFA levels before and during HDBR. During HDBR, the Epi-induced increase in plasma glycerol and lactate levels was more pronounced than before HDBR (P < 0.005 and P < 0.001, respectively). Epi-induced energy expenditure was higher during HDBR (P < 0.02). Our data suggest that the increased effects of Epi during simulated microgravity could be related to both the increased SNS response to Epi infusion and/or to the beta-adrenergic receptor sensitization of end organs, particularly in adipose tissue and skeletal muscle.

L-Dopa-induced sedation: a double-blind cross-over controlled study versus triazolam and placebo in healthy volunteers.

Incidental case reports suggest that some parkinsonian patients treated with dopaminergic drugs complain of drowsiness but few controlled data are available. We compared the sedative effects of L-Dopa (200 mg + 50 mg benserazide, PO), triazolam (0.125 mg) and placebo in a randomized double-blind cross-over design in 22 healthy volunteers pretreated with domperidone (60 mg/day). Drowsiness was assessed using a visual analog scale (VAS), a computerized choice reaction time test (CRT) and an electro-oculogram (EOG). L-Dopa and triazolam induced significant drowsiness, compared to placebo, on VAS, CRT and some EOG parameters. After this first evaluation session, all subjects were chronically treated for 11 days with 600 mg/d of L-Dopa. Drowsiness induced by L-Dopa, triazolam or placebo was then tested again on three consecutive days to assess putative dopaminergic tolerance. After chronic L-Dopa treatment, triazolam-induced sedation remained unchanged while L-Dopa sedative effects were no longer significant except on the VAS, preventing the conclusion that tolerance occurred. These data suggest that an acute dose of L-Dopa induces sedation in L-Dopa-naive subjects. This sedative effect must be considered in clinical practice and when studying the effects of L-Dopa on motor or neuropsychological performance, especially in acute tests.

[Hyperthyroidism caused by inappropriate secretion of TSH. Apropos of 2 new cases]. / Hyperthyroïdie par sécrétion inappropriée de TSH. A propos de deux nouvelles observations.

Hyperthyroidism due to inappropriate secretion of TSH is rare. It may be due to either TSH-secreting pituitary adenomas (n = 15) or selective pituitary resistance to thyroid hormone action (n = 31). The recognition of these patients is of great clinical importance since they should be treated differently than patients with more common forms of hyperthyroidism (Graves' disease, autonomous thyroid nodule).

Motor activation in multiple system atrophy and Parkinson disease: a PET study.

BACKGROUND: Multiple system atrophy (MSA) is an atypical parkinsonian syndrome including cerebellar impairment and poor response to levodopa. We assessed right hand motor activation in patients with MSA before and after an acute levodopa challenge in comparison with patients with PD and healthy volunteers (HVs). METHODS: Eighteen patients with MSA, 8 patients with PD, and 10 age-matched HVs were included. Regional cerebral blood flow measurements with H(2)(15)O PET were performed at rest and during a right hand movement. Statistical parametric mapping was used to analyze motor vs rest in OFF and ON conditions and the effect of levodopa on motor activation. RESULTS: Before levodopa, patients with MSA activated most known cerebral motor areas. Compared with HVs, patients with MSA exhibited less bilateral cerebellar activation and greater left superior parietal activation. They also had less bilateral cerebellar and greater supplementary motor and left superior parietal activation than patients with PD. Conversely, patients with PD had greater activation than HVs in the right cerebellum and less in the supplementary motor cortex. After levodopa, patients with MSA exhibited reduced activation in anterior cingulate, whereas patients with PD had greater activation in the right cerebellum. CONCLUSION: Patients with MSA and patients with PD recruited different motor networks. Patients with PD preferentially activated cerebellar pathways, possibly to compensate for basal ganglia dysfunction. This was not observed in patients with MSA, probably because of cerebellar dysfunction; other frontoparietal cortical areas were recruited.