The effects of remote ischaemic preconditioning on coronary artery function in patients with stable coronary artery disease.

BACKGROUND: Remote ischaemic preconditioning (RIPC) is a cardioprotective intervention invoking intermittent periods of ischaemia in a tissue or organ remote from the heart. The mechanisms of this effect are incompletely understood. We hypothesised that RIPC might enhance coronary vasodilatation by an endothelium-dependent mechanism. METHODS: We performed a prospective, randomised, sham-controlled, blinded clinical trial. Patients with stable coronary artery disease (CAD) undergoing elective invasive management were prospectively enrolled, and randomised to RIPC or sham (1:1) prior to angiography. Endothelial-dependent vasodilator function was assessed in a non-target coronary artery with intracoronary infusion of incremental acetylcholine doses (10-6, 10-5, 10-4mol/l). Venous blood was sampled pre- and post-RIPC or sham, and analysed for circulating markers of endothelial function. Coronary luminal diameter was assessed by quantitative coronary angiography. The primary outcome was the between-group difference in the mean percentage change in coronary luminal diameter following the maximal acetylcholine dose (Clinicaltrials.gov identifier: NCT02666235). RESULTS: 75 patients were enrolled. Following angiography, 60 patients (mean±SD age 57.5±8.5years; 80% male) were eligible and completed the protocol (n=30 RIPC, n=30 sham). The mean percentage change in coronary luminal diameter was -13.3±22.3% and -2.0±17.2% in the sham and RIPC groups respectively (difference 11.32%, 95%CI: 1.2- 21.4, p=0.032). This remained significant when age and sex were included as covariates (difference 11.01%, 95%CI: 1.01- 21.0, p=0.035). There were no between-group differences in endothelial-independent vasodilation, ECG parameters or circulating markers of endothelial function. CONCLUSIONS: RIPC attenuates the extent of vasoconstriction induced by intracoronary acetylcholine infusion. This endothelium-dependent mechanism may contribute to the cardioprotective effects of RIPC.

What's new about clopidogrel.

Clopidogrel is an oral tyenopiridin with a central role in the management of acute coronary syndromes and after stent implantation. Despite the use of this drug, many patients continue to experience thrombotic events which are usually referred as "therapy failure". Actually, to date, only stent thrombosis is considered therapy failure: mainly, it could be due to patient genetic predisposition or drug interaction, in particular with proton pump inhibitors. Genetic mutations in the CYP2C19 cytochrome (involved in the metabolism of clopidogrel and many other drugs) may lead to a lower concentration of active metabolites of the drug. In the same way, proton pump inhibitors interaction with the cytochrome may reduce clopidogrel activation. To overcome the problem some authors have suggested to increase the dosage of the drug, to use other drugs, to genotype patients, and not to use proton pomp inhibitors in patients on double antiplatelet therapy. Recent studies have shown that the interaction between clopidogrel and proton pump inhibitors is far to be clinically relevant and that the variability between the different assay to determine patients response to the drug does not allow, to date, to rely on their use. Moreover, double clopidogrel dose is as effective as low one in preventing major cardiovascular events, with a significant reduction in stent thrombosis in spite of a modest increase in major bleeding. Aim of this review article was to update current knowledge on clopidogrel, particularly focusing on the problem of "resistance" and PPI interaction. Moreover, we will discuss current strategies to overcome the resistance.

[A reply to Perron regarding the Inserm report "Psychotherapy. The assessment of three approaches"]. / Réponse à Perron et al. concernant leur texte: "Quelques remarques méthodologiques à propos du rapport Inserm psychothérapie. Trois approches évaluées".

The publication of the report by experts from Inserm (France) about the efficacy of psychotherapies (2004) has raised many criticisms, mainly from psychoanalysts. The criticisms of Perron, Brusset, Baruch and Emmanuelli, professors of psychology, published on Internet (www.techniques-psychotherapiques.org) in 2004, attack the methodology that they say introduced numerous biases in favour of cognitive behaviour therapies (CBT) compared to psychodynamic psychotherapies (PP). In order to argue against these criticisms, I have selected ten points raised by this group that seemed to represent the essence of their criticisms. Perron et al. say that the Inserm report is neither objective nor scientific; although this report cannot be fully objective due to its narrative nature, it is, nevertheless, based on empirical studies that satisfy scientific criteria for quality and that are well documented. * Perron et al. suggest that the Inserm report contains numerous biases; it is not possible to avoid all statistical biases so this criticism is an attack on accepted scientific methodology. * Perron et al. do not provide any evidence in favour of their criticism that the meta-analyses included in the report have accumulated biases due to prejudices common among psychotherapy researchers; even if researchers were all subject to therapy allegiance, this would not lead, systematically, to biases in favour of CBT. * Perron et al. state that meta-analyses automatically reinforce biases from randomised controlled trials (RCTs), whereas I argue that biases in RCTs are not systematically accumulated, and that the sensitivity of meta-analyses to doubtful RCTs can be tested by comparing results from analyses with and without these studies. * They also say that, in RCTs, the comparability between groups cannot be complete, however, the aim is not identity, and the comparability can be empirically tested after randomisation. * They also declare that the use of DSM automatically favours CBT, however, despite the fact that DSM is unsatisfactory even for biological psychiatrists and CBT therapists; no unanimously accepted alternative system has yet been identified. * Perron et al. say that the use of quantitative assessment of the psychotherapy outcome favours CBT because of an epistemological split between descriptive-nosological and functional-psychodynamic approaches. However such approaches are not clearly exclusive from each other, and a reduction of psychiatry into only two approaches does not fit with the observed variety of etiological hypotheses. * The statement that the functional-psychodynamic approach is contradictory with quantitative assessment of outcome is challenged by the fact that numerous outcome instruments for psychodynamic assessment exist. Furthermore, I have examined the size of the differences between CBT and PP, by selecting studies and meta-analyses that report the direct comparison of these therapies, but this does not provide evidence of major differences. Therefore, the existence of major bias in favour of CBT, due to either the use of DSM, symptom rating scales or other causes, is not supported by these facts. * The accusation that studies included in the Inserm report did not assess patients from control groups at endpoint has being found to be untrue. * The argument that the various effect size statistics used in the meta-analyses give rise to major bias is very unlikely. However, the authors overlooked the more important problem of pooling different outcome measures. * The allegation that a bias in favour of CBT was induced because there were more studies conducted with CBT than with PP is false, because the number of studies does not influence the effect-sizes. The Inserm report does, however, because of the presentation of results by DSM disorder and emphasis on absolute efficacy studies, find more positive results for CBT than for PP compared with no treatment. In conclusion, Perron's et al. criticisms are, in fact, against the application of scientific methodology to the assessment of the efficacy of psychotherapies as a whole. Nevertheless, the Inserm report has some weaknesses; the low number of studies of PP, the lack of direct comparisons between CBT and PP, the fact that multiple efficacy criteria were not taken into consideration, and the problem of comorbidities which was insufficiently taken into consideration.

[Neuroleptic drug utilization among schizophrenic outpatients]. / Utilisation des neuroleptiques chez les patients ambulatoires souffrant de schizophrénie.

BACKGROUND: Our objective was to describe and compare neuroleptic drug utilization patterns among French schizophrenic outpatients in public and private care settings. METHODS: A cross sectional survey was carried out by a random sample of 61 public and 112 private psychiatrists who registered for one month all schizophrenic adult outpatients treated with a neuroleptic drug. Among registered patients, each psychiatrist was to include a maximum of 18 patients (public setting) or 9 patients (private setting). Statistical analysis was weighted to take into account for psychiatrist activity level, assessed by patient registration. RESULTS: Psychiatrists included 934 patients in the public care setting and 927 patients in the private care setting. Patients were (mean+/-sd) 40.1+/-12.1 years old, 60.9% men. The patients' social and clinical characteristics were less favorable in the public setting than in the private setting: no professional activity (78.9% vs 65.1%), living in institution (7.2% vs 3.7%), under legal protection (35.1% vs 14.5%), drug abuse (9.6% vs 5.6%). An atypical neuroleptic was prescribed for 63.0% of patients and a classic neuroleptic for 49.7%, an association of neuroleptics for 22.0%. In both settings, the most prescribed neuroleptics were olanzapine (28.0%) and risperidone (18.6%) with a higher mean daily dosage in the public care setting. At least one neuroleptic treatment change (drug and/or dosage) occurred during the previous year for 44.9% and 39.2% patients, in public and private settings, respectively. In both settings, reasons for changes were mainly lack of efficacy (55.1%) and side effects (49.8%). CONCLUSION: Public and private care populations were different but not as much as expected. In both settings, atypical neuroleptics were the predominant drugs used in the treatment of schizophrenia outpatients. The high frequency of drug change for lack of efficacy or side effects demonstrates the difficulties with the use of the present neuroleptic armamentarium.

[Homeopathic specialties as substitutes for benzodiazepines: double-blind vs. placebo study]. / Spécialités homéopathiques en substitution de benzodiazépines: étude en double-insu vs. placebo.

The objective of this study was to compare the efficacy of homeopathic drugs Homéogène 46 and Sédatif PC with a placebo as substitute for benzodiazepines in patients treated for at least 3 months with low doses (less than 10 mg/d of diazepam equivalents). A double-blind randomized trial was carried out in general practice. The treatment lasted one month. Several rating scales were used. The main outcome was success/failure defined according to the doctor's clinical judgement and interruption of treatment. A total of 61 patients were randomized, and 19 interrupted their treatment. Comparability between the groups was good. No statistically significant difference between homeopathic drugs and placebo was observed for the main outcome or for the secondary outcomes. The lack of statistical power due to accrual difficulties limits the conclusions of this trial which did not confirm the efficacy of homeopathic drugs in this indication.

Development and validation of a specific quality of life module in post-menopausal women with osteoporosis: the QUALIOST.

Established post-menopausal osteoporosis (PMO) has serious consequences on health related quality of life (HRQL), as long-term back and joint pain can severely limit normal activities. The quality of life questionnaire in osteoporosis (QUALIOST), a self-administered module consisting of 23 questions which complements the SF-36, was specifically designed to evaluate the repercussions of PMO on patient HRQL. The QUALIOST was developed simultaneously in French and English after discussion with 45 patients. A validation study in France and the UK included 140 women with PMO, with at least one osteoporotic vertebral fracture. Patients completed the SF-36 and QUALIOST twice, 7 days apart. Factorial analysis revealed a physical and emotional component. Three scores were calculated: physical repercussions (10 items), emotional repercussions (13 items) and the global score (23 items). Internal reliability and stability over time were excellent. Concurrent validity with the SF-36 physical and mental fields was satisfactory. A deterioration in clinical state, as measured by pain severity, hospital admission and walking stick use, increased the repercussions on HRQL for all three scores, demonstrating the clinical validity of the questionnaire. The QUALIOST, combined with the SF-36, is a valid rating scale for measuring HRQL in clinical trials for established PMO, providing both general and specific data on the effects of PMO on patient HRQL.

Psychometric validation of two Italian quality of life questionnaires in menopausal women.

OBJECTIVE: To establish the psychometric properties of the Italian version of two quality of life (QOL) questionnaires in menopausal women: the psychological general well being index (PGWBI) and the women's health questionnaire (WHQ). METHOD: These questionnaires were translated into Italian and then self-administered to out-patient women a first time, 1 week later in stable women to assess reproducibility, and 3 months later to evaluate responsiveness over time. Baseline analyses included: factorial structure, multitrait analysis, internal consistency reliability, and clinical validity. RESULTS: Questionnaires were returned by 155 women (median age: 54 years, median duration of amenorrhoea: 56 months, median Kupperman index 26). Principal component analysis (PCA) of the PGWBI showed an important general factor and then, after rotation, three factors. The PCA of the WHQ showed ten factors. Only five reproduced the dimensions postulated à priori quite well. The item convergent validity was confirmed for all items of the major dimension of the two questionnaires, and the item divergent validity, although acceptable, was less satisfying for the PGWBI than the WHQ. The internal reliability was good (Cronbach's alpha > or = 0.70) for the PGWBI and for nine scales out of ten for the WHQ. The six dimensions of the PGWBI and most of the dimensions of the WHQ were significantly correlated to the Kupperman index, indicating the clinical validity of the instruments. The responsiveness to change in clinical status at 3 months was better in the PGWBI than in the WHQ with moderate effect size (around 0.5). CONCLUSION: The Italian versions of the PGWBI and the WHQ are reliable and useful for HRT clinical trials but the dimensional scores must be calculated bearing in mind the limitations in the structure. Other studies are needed to improve the factorial stability of certain WHQ dimensions. For the Italian version of the PGWBI, the validation process is to be completed by studies of mixed populations suffering from other types of disease.

Meta-analysis of randomised controlled trials of fluoxetine v. placebo and tricyclic antidepressants in the short-term treatment of major depression.

BACKGROUND: Previous meta-analyses of fluoxetine as an antidepressant have many methodological problems, including diagnosis of major depression, validity of outcome measures and lack of intention-to-treat analyses. AIMS: To provide an estimate of the effect of fluoxetine compared with placebo and tricyclic antidepressants (TCAs), and to investigate reasons for early discontinuation from acute treatment. METHOD: Randomised trials were analysed using both intention-to-treat, efficacy and end-point. RESULTS: Fluoxetine was superior to placebo but effect size was low. In trials comparing fluoxetine v. TCA, the results for all trials and for the USA trials showed a trend in favour of fluoxetine. Those for the non-USA trials showed a trend in favour of TCA. When combined, the results showed that significantly fewer patients on fluoxetine discontinued treatment because of adverse events. CONCLUSION: Fluoxetine is superior to placebo, irrespective of the analytical approach use, whereas the results obtained v. TCAs depend on the approach used. Hence, the results should be interpreted in this light.

[Meta-analysis of therapeutic trials: applications in psychiatry]. / La méta-analyse des essais thérapeutiques: applications en psychiatrie.

Meta-analysis is being increasingly used in therapeutic and clinical research to synthetize data from terminated clinical trials. Meta-analysis provides a powerful tool to objectively combine data in a quantitative manner, unlike the classical general review of literature, which is qualitative and subjective by definition, and thus not reproducible, and also the simple data pooling, methods which neglects the statistical heterogeneity between studies. The two most known objectives of meta-analysis are, to provide an objective decision when the trial results have produced contradictory or non-significant results, and to give a better estimation of the magnitude of the treatment effect. Precise methodological rules must be followed, but these rules are not known well enough in the scientific community. For example, particular care is necessary for the retrieval and selection of the trials: all available trials which satisfy predefined criteria of methodological validity should be taken into consideration. One of the main pitfalls in meta-analysis is the problem of unpublished trials, which represents a potential bias seen as an overestimation of treatment effect. In psychiatry, the applications of meta-analysis are numerous, especially in the domain of the treatment of depressive disorders, which will be developed in this paper. Several meta-analyses have been performed to assess the efficacy of antidepressants in major depression, especially with the "new antidepressants", which include the specific serotonine reuptake inhibitors (SSRIs). To date, these meta-analyses have shown that the main advantage of SSRIs was that they were better accepted, but without being more efficacious compared with classic antidepressants. The results of several of these meta-analyses are to be interpreted with the potential biases in mind, especially the publication bias and selection bias. Clinicians must be aware of the difficulties encountered in the choice of outcome criteria, and in deciding how to deal with patients that withdraw from treatment early (intention to treat analysis is the least biased solution for this problem.). Meta-analysis can therefore be helpful in establishing medical references in psychiatry, and to organize consensus conferences, but the limits of this method must be clearly recognized.

[Study of the uni-dimensionality of the Yesavage-Brinck geriatric depression scale. Comparison between classical methods and Rasch's model]. / Etude sur l'unidimensionnalité de l'échelle de dépression gériatrique de Yesavage et Brink. Comparaison entre méthodes classiques et modèle de Rasch.

The authors present a contribution to the french validation of the self-rating questionnaire of the depression in the elderly proposed by Yesavage and Brink (1982), the Geriatric Depression Scale (30 items). This study focusses on the assessment of the homogeneity and of the unidimensionality of this scale. 99 aged women living in old-people homes or attending a geriatric somatic day-hospital, not known to be psychiatrically ill, filled the GDS and were interviewed by either a psychiatrist or by a clinical psychologist. This interview yielded 44 cases of Major Depressive Disorder or of Dysthymia (DSM III). Firstly, we have applied the classical correlational methods of assessment of scale Reliability and Construct Validity: Cronbach's coefficient alpha and item-total correlations (homogeneity) and Principal Component Analysis (PCA) without rotation. Then, we have performed a Rasch Model Analysis: this method which belongs to the general frame of Latent Trait Theory relies on a probabilistic model of subject's response to individual questions. In the Rasch model, the response probability of a given subject to a given item is a logistic function of the difference between the item location parameter and the subject location parameter along a single continuous latent dimension. Our results have shown that the Cronbach's alpha was very high (.902) and that the item-total correlations were quite satisfactory (mean .470), thus giving a strong impression of homogeneity (similar to unidimensionality for many authors).(ABSTRACT TRUNCATED AT 250 WORDS)

Citalopram in depression--meta-analysis of intended and unintended effects.

An updated qualitative meta-analysis of controlled clinical trials is presented. When compared to reference drugs, especially tricyclics, citalopram after 6 weeks of treatment showed a similar intended effect on the depression index of the Hamilton scale. However, on the sleep index of the scale citalopram was weaker than tricyclics. When compared to placebo, citalopram after 6 weeks of treatment showed to be significantly superior on the Hamilton scale and on the global assessment scales. Analysis of unintended effects showed that citalopram had fewer side-effects than tricyclics, especially of anticholinergic types. In conclusion, citalopram has been found to be a non-sedating antidepressant which is well accepted by the patients due to its lack of unintended effects.

[The questionnaire "Profile of the subjective quality of life". First data of validation]. / Le questionnaire "Profil de la qualité de la vie subjective" (PQVS). Premiers éléments de validation.

The questionnaire "Profile of the Subjective Quality of Life" (in french, PQVS) is devoted to the assessment of quality of life in therapeutic trials. On a sample of 588 subjects, factorial analysis confirm that it is not restricted to the assessment of the health, as most of the instruments actually available for that purpose. Its internal consistency is high. Correlations clearly show that its specific questions assessing the degrees of a) satisfaction and b) involvement (concerning each item) are clearly understood as having different meanings. Multiple regressions demonstrate that these specific questions strongly contribute to the explanation of the global quality of life or of the satisfaction concerning each item. Its reliability is good. It is very well accepted, and completed in no more than 15 to 30 minutes. This questionnaire is thus matching the criteria defining an effective assessment of the quality of life.

Prescription intentions in relation to therapeutic information: a study of 117 French general practitioners.

In 1987 we conducted a mailed questionnaire survey involving 250 GPs, randomly drawn from the 3061 GPs in the 'Rhône-Alpes' region in France, in order to study how general practitioners (GPs) react to information about drugs in terms of their prescribing practices. The aim of the questionnaire was to investigate the GPs reactions (prescription intentions) to 25 statements containing information concerning drugs. These included results from randomized clinical trials with adequate clinical criteria (pertinent information), but there were also some statements containing non-relevant information such as intermediate criteria, physiopathological or pharmacological information, and some containing general information such as advice from colleagues, the established position of the drug etc. The GPs were also asked through which channels they commonly received therapeutic information (i.e. medical journals, conferences). A total of 117 GPs returned completed questionnaires. We found the prescription intentions, for pertinent information to be between 76.9% and 95.7%, whilst the intentions, as a result of personal knowledge and/or success with a drug were around 93%. More theoretical information resulted in prescription intentions which were more widely scattered (between 23.1% and 80.3%), and for external advice the intentions were not as high but they were also widely scattered (between 3.4% and 65%). The search for latent dimensions corresponding to GPs reactions to therapeutic information, with both principal component analysis and Rasch Modelling, showed that two orthogonal latent dimensions, i.e. 'sensitivity to clinical and theoretical information', and 'sensitivity to external standards', best explained the responses to the questionnaire. These two dimensions appeared to be independent of age, sex, medical school and type of practice (urban, rural). The use of the journal 'Prescrire' by GPs was found to be significantly associated (P less than 0.005) with low scores, or good quality of perception of pertinent information in the first dimension. The use of specialists' prescriptions was associated with similar scores for the first dimension, but also with poor quality of perception of pertinent information scores (i.e. high scores) for the second dimension. These results could be used to draw up proposals for the improvement of post-graduate medical education, which should take into consideration these two dimensions of therapeutic information assessment by doctors, in order to obtain better quality of perception profiles for information assessment and prescription by doctors.

Study of the unidimensionality of the Bech-Rafaelsen Melancholia Scale using Rasch analysis in a French sample of major depressive disorders.

In a French sample of 73 major depressive disorders (according to the DSM III definition), the unidimensionality of the Bech-Rafaelsen Melancholia Scale was studied; firstly by means of traditional but not really valid methods (i.e., factor analysis and Cronbach's alpha), and second, using the Rasch logistic model. These methods would seem to show that the B.R.M.E.S. provides a unidimensional measurement of depression.

A controlled study of fluvoxamine and exposure in obsessive-compulsive disorder.

DSM-3 obsessive-compulsive out-patients were randomly assigned to fluvoxamine with antiexposure (F), fluvoxamine with exposure (Fe), or placebo with exposure (Pe) for 24 weeks. Of 65 patients offered treatment 60 entered the trial, 50 reached week 8, 44 completed treatment to week 24, and 37 reached follow up to week 48. On average the patient had depressed mood (mean Hamilton depression rating scale = 19). Drop-out numbers, clinical status and behavioural measures were comparable across groups. Most F patients did not do antiexposure, but Fe and Pe patients complied in doing exposure. All three groups improved in rituals and depression from week 0 to week 24 and 48, with a slight but non-significant superiority for combined treatment up to week 24. At week 8 there was a drug between-group effect on rituals, but not on depression. At week 24 there was a drug between-group effect on depression, but not on rituals. The drug superiority was short-lived. At week 48 there was no between-group difference in rituals or depression. Depression was related to ritual outcome at week 24 in F, and tended to be so in Fe.

An epidemiological study of infantile autism in a French department (Rhône): a research note.

In a French Department (Rhône), the prevalence of infantile autism was found to be 10.8 per 10,000 in the 5-9 age group, using broad operational criteria. The prevalence decreases to 5.1 per 10,000 when another set of criteria, similar to DSM-III, is used. The boy/girl sex ratios for these two sets of criteria were 2.1:1 and 2.3:1 respectively. The use of DSM-III turned out to be problematic for taking into account a broad spectrum of early psychotic disorders, autistic-like, yet more polymorphous. A subdivision concerning the existence of associated major neurological anomalies has appeared promising but requires finer validation.

[A problem detected by the AMDP rating of the Mar. case: the relation between phobia and obsession]. / Un problème révélé par la cotation AMDP du cas Mar.: les relations entre phobie et obsession.

The rating of the videotaped interview of the Mar. case during three meetings of the French-speaking section of the AMDP has revealed the problem of the relationships between phobia and obsession. These ratings triggered a critical reflection based on the theoretical framework from the literature, on the clinical material (the videotaped interview) and on the pragmatic difficulties which appeared during the discussions of the ratings.