Accès aux soins et maintien dans la communauté des personnes difficiles à engager dans un traitement psychiatrique [Access to care and maintenance in the community of persons who are difficult to engage in psychiatric treatment]

Psychotic patients to not access easily to psychiatric care. First, psychotic disorders are difficult to identify among a great number of non psychotic depressive and anxious disorders. Second, inpatient care has shortened and now focus on acute care rather than long stay. For some psychotic patients, desinstitutionalization means exclusion and marginalization. Intensive case management can answer these needs in collaboration with relatives and professionals of patient's social network. Results and care's steps of intensive case management as practiced in Lausanne are described and illustrated with cases vignettes.

Life-history evolution and the polyphenic regulation of somatic maintenance and survival.

Here we discuss life-history evolution from the perspective of adaptive phenotypic plasticity, with a focus on polyphenisms for somatic maintenance and survival. Polyphenisms are adaptive discrete alternative phenotypes that develop in response to changes in the environment. We suggest that dauer larval diapause and its associated adult phenotypes in the nematode (Caenorhabditis elegans), reproductive dormancy in the fruit fly (Drosophila melanogaster) and other insects, and the worker castes of the honey bee (Apis mellifera) are examples of what may be viewed as the polyphenic regulation of somatic maintenance and survival. In these and other cases, the same genotype can--depending upon its environment--express either of two alternative sets of life-history phenotypes that differ markedly with respect to somatic maintenance, survival ability, and thus life span. This plastic modulation of somatic maintenance and survival has traditionally been underappreciated by researchers working on aging and life history. We review the current evidence for such adaptive life-history switches and their molecular regulation and suggest that they are caused by temporally and/or spatially varying, stressful environments that impose diversifying selection, thereby favoring the evolution of plasticity of somatic maintenance and survival under strong regulatory control. By considering somatic maintenance and survivorship from the perspective of adaptive life-history switches, we may gain novel insights into the mechanisms and evolution of aging.

Mechanisms involved in the maintenance of inbreeding depression in gynodioecious "Silene vulgaris" (Caryophyllaceae): an experimental investigation

Summary Gynodioecy, the joint occurrence of females and hermaphrodites within natural populations, is a widely studied mating system ever since Darwin (1877). It is an exceptional mating system because continuous selection is necessary to maintain it. Since females only reproduce through ovules whereas hermaphrodites transmit genes through ovules and pollen, larger female fitness, in terms of seed output, is required to allow their maintenance. Two non-exclusive mechanisms can account for the maintenance of females. First, as females do not produce pollen they can reallocate their resources towards a higher ovule production. Second, hermaphrodites can self- and cross-fertilize whereas females are obligate outcrossers. Thus hermaphrodites should partly suffer from inbreeding depression (i.e.: the fitness decline of inbred relative to outbred individuals) and thereby produce less fit progeny than females. This thesis investigated the effects of self- and cross-fertilization of heimaphrodites over two consecutive generations. Inbreeding depression increased across the successive stages of the life- cycle (i.e.: from "seed traits" to "reproductive traits") displaying large inbreeding depression estimates (up to 0.76). This investigation not only detected large inbreeding depression estimates but also detected mechanisms involved in the maintenance of inbreeding depression. For instance cryptic self-incompatibility which is here a larger in vivo pollen performance of distant pollen compared to self-pollen; the expression of inbreeding depression especially in late life-cycle stages, and the appearance of females in the progeny of selfed hermaphrodites. The female biased sex ratio in the progeny of selfed hermaphrodites was a surprising result and could either come from the sex determining mechanisms (complex nucleo-cytoplasmic interaction(s)) and/or from inbreeding depression. Indeed, we not only got females and hermaphrodites but also partial male-sterile (PMS) individuals (i.e.: individuals with differing number of viable stamens). We detected that inbred pollen bearing plants (excluding females) have less viable stamens per flower than outbred plants. A positive correlation was detected between inbreeding depression for the number of viable stamens per flower and the difference in sex ratio between inbred and outbred individuals. A positive relationship was also detected between inbreeding depression for pollen viability and inbreeding depression for number of viable stamens per flower. Each correlation can either account for pleiotropic effects (a major gene acting on the two considered traits) or linkage disequilibrium between genes controlling each of the two related traits. If we hypothesize that these correlations are due to a major gene with pleiotropic effects, the positive relationship between inbreeding depression for number of viable stamens per flower and inbreeding depression for pollen viability showed that deleterious alleles present on a major gene coding for pollen production and viability depressed male fitness within inbred plants. The positive relationship between sex ratio difference between inbred and outbred individuals and inbreeding depression for number of viable stamens per flower indicates that (1) either number of viable stamens per flower is, in addition to inbreeding, also affected by the loci coding for sex determinism or, (2) the presence of females within the progeny of selfed hermaphrodites is a consequence of large inbreeding depression inhibiting pollen production, or (3) sex is here determined by a combination of loci coding for sex expression and inbreeding depression for male reproductive traits. In conclusion, Silene vulgaris has been shown to be a good model for understanding the evolution of mating systems that promote outbreeding. Résumé La gynodïoécie est définie comme étant la présence simultanée d'hermaphrodites et de femelles au sein de populations naturelles d'une même espèce. Ce système de reproduction a toujours fasciné le monde scientifique depuis Darwin, comme en témoigne ses écrits (1876, 1877) sur les systèmes de reproduction chez les plantes. Les femelles ne transmettent leurs gènes qu'à travers leurs ovules alors que les hermaphrodites transmettent leurs gènes à la fois par la voie mâle (le pollen) et la voie femelle (les ovules). La condition pour que la gynodïoécie se maintienne nécessite donc une fitness de la fonction femelle plus élevée chez les femelles que chez les hermaphrodites. Deux mécanismes mutuellement non exclusifs peuvent expliquer le maintien des femelles au sein de ces populations gynodioïques. D'une part, les femelles peuvent réallouer les ressources non utilisées pour la production de pollen et peuvent par conséquent produire plus d'ovules. D'autre part, la reproduction des femelles ne peut se faire que par allo-fécondation alors que les hermaphrodites, peuvent se reproduire à la fois par auto- et allo-fécondation. L'autofécondation s'accompagne en général d'une diminution de fitness de la descendance relativement à la progéniture issue d'allo-fécondation ; ce phénomène est connu sous le nom de dépression de consanguinité. Cette thèse avait pour but de mettre en évidence une éventuelle dépression de consanguinité chez Silene vulgaris, une espèce gynodioïque. Des hermaphrodites, issus de trois vallées alpines, ont été auto- et allo¬fécondés sur deux générations successives. La dépression de consanguinité pouvant s'exprimer à tous les stades de vie d'un individu, plusieurs traits de fitness, allant du nombre de graines par fruit à la production de gamètes ont été mesurés sur différents stades de vie successifs. L'estimation de la dépression de consanguinité totale atteignait des valeurs allant de 0.52 à 0.76 selon la vallée considérée, ce qui indiquerait que les hermaphrodites ont tout intérêt à limiter l'autofécondation et que les femelles ne devraient pas avoir de peine à subsister dans les vallées étudiées. Par la même occasion des mécanismes diminuant la purge potentielle du fardeau génétique, et permettant ainsi le maintien du « niveau » de dépression de consanguinité et par conséquence le maintien de la gynodïoécie ont été mis en évidence. En effet, nos résultats montrent que la dépression de consanguinité s'exprimait tard dans le cycle de vie permettant ainsi à un certain nombre individus consanguins de transmettre leurs allèles délétères à la génération suivante. D'autre part, la croissance in vivo des tubes polliniques d'auto-pollen était plus lente que celle de l'allo-pollen et donc en situation de compétition directe, les ovules devraient plutôt être issus d'allo-fécondation, diminuant ainsi les chances de purges d'allèles délétères. Enfin, l'apparition de femelles dans la progéniture d'hermaphrodites autofécondés diminue aussi les chances de purge d'allèles délétères. Il nous a été impossible de déterminer si l'apparition de femelles dans la descendance d'hermaphrodites autofécondés était due au déterminisme génétique du sexe ou si la différence de sexe ratio entre la descendance auto- et allo-fécondée était due à une éventuelle dépression de consanguinité inhibant la production de pollen. Nous avons observé que S. vulgaris ne présentaient pas uniquement des hermaphrodites et des femelles mais aussi toute sorte d'individus intermédiaires avec un nombre variable d'étamines viables. Nous avons pu mettre' en évidence des corrélations positives entre (1) la différence de sexe ratio (la proportion d'individus produisant du pollen) entre individus consanguins et non consanguins et une estimation de la dépression de consanguinité pour le nombre d'étamines viables d'individus produisant du pollen, ainsi qu'entre (2) la dépression de consanguinité pour le nombre d'étamines viables et celle estimée pour la viabilité du pollen. Chaque corrélation indique soit l'effet d'un (ou plusieurs) gène(s) pléiotropique(s), soit un déséquilibre de liaison entre les gènes. En considérant que ces corrélations sont le résultat d'effet pléiotropiques, la relation entre le nombre d'étamines viables par fleur et la viabilité du pollen, indiquerait un effet négatif de la consanguinité sur la production et la viabilité du pollen due partiellement à un gène majeur. La seconde corrélation indiquerait soit que les gènes responsables de la détermination du sexe agissent aussi sur l'expression de la fonction mâle soit que l'expression du sexe est sujette à la dépression de consanguinité, ou encore un mélange des deux. Aux regards de ces résultats, Silene vulgaris s'est avéré être un bon modèle de compréhension de l'évolution des systèmes de reproduction vers la séparation des sexes.

Radioimmunotherapy combined with maintenance anti-CD20 antibody may trigger long-term protective T cell immunity in follicular lymphoma patients.

Growing evidence suggests that the patient's immune response may play a major role in the long-term efficacy of antibody therapies of follicular lymphoma (FL). Particular long-lasting recurrence free survivals have been observed after first line, single agent rituximab or after radioimmunotherapy (RIT). Rituximab maintenance, furthermore, has a major efficacy in prolonging recurrence free survival after chemotherapy. On the other hand, RIT as a single step treatment showed a remarkable capacity to induce complete and partial remissions when applied in recurrence and as initial treatment of FL or given for consolidation. These clinical results strongly suggest that RIT combined with rituximab maintenance could stabilize the high percentages of patients with CR and PR induced by RIT. While the precise mechanisms of the long-term efficacy of these 2 treatments are not elucidated, different observations suggest that the patient's T cell immune response could be decisive. With this review, we discuss the potential role of the patient's immune system under rituximab and RIT and argue that the T cell immunity might be particularly promoted when combining the 2 antibody treatments in the early therapy of FL.

Biomarkers of oxidative stress and its association with the urinary reducing capacity in bus maintenance workers.

BACKGROUND: Exposure to particles (PM) induces adverse health effects (cancer, cardiovascular and pulmonary diseases). A key-role in these adverse effects seems to be played by oxidative stress, which is an excess of reactive oxygen species relative to the amount of reducing species (including antioxidants), the first line of defense against reactive oxygen species. The aim of this study was to document the oxidative stress caused by exposure to respirable particles in vivo, and to test whether exposed workers presented changes in their urinary levels for reducing species.METHODS: Bus depot workers (n = 32) exposed to particles and pollutants (respirable PM4, organic and elemental carbon, particulate metal content, polycyclic aromatic hydrocarbons, NOx, O3) were surveyed over two consecutive days. We collected urine samples before and after each shift, and quantified an oxidative stress biomarker (8-hydroxy-2'-deoxyguanosine), the reducing capacity and a biomarker of PAH exposure (1-hydroxypyrene). We used a linear mixed model to test for associations between the oxidative stress status of the workers and their particle exposure as well as with their urinary level of reducing species.RESULTS: Workers were exposed to low levels of respirable PM4 (range 25-71 μg/m3). However, urinary levels of 8-hydroxy-2'-deoxyguanosine increased significantly within each shift and between both days for non-smokers. The between-day increase was significantly correlated (p < 0.001) with the concentrations of organic carbon, NOx, and the particulate copper content. The within-shift increase in 8OHdG was highly correlated to an increase of the urinary reducing capacity (Spearman ρ = 0.59, p < 0.0001).CONCLUSIONS: These findings confirm that exposure to components associated to respirable particulate matter causes a systemic oxidative stress, as measured with the urinary 8OHdG. The strong association observed between urinary 8OHdG with the reducing capacity is suggestive of protective or other mechanisms, including circadian effects. Additional investigations should be performed to understand these observations.

A new measurement of energy expenditure and physical activity in patients treated by maintenance hemodialysis

Purpose: The accurate estimation of total energy expenditure (TEE) is essential to allow the provision of nutritional requirements in patients treated by maintenance hemodialysis (MHD). The measurement of TEE and resting energy expenditure (REE) by direct or indirect calorimetry and doubly labeled water are complicated, timeconsuming and cumbersome in this population. Recently, a new system called SenseWear® armband (SWA) was developed to assess TEE, physical activity and REE. This device works by measurements of body acceleration in two axes, heat production and steps counts. REE measured by indirect calorimetry and SWA are well correlated. The aim of this study was to determine TEE, physical activity and REE on patients on MHD using this new device. Methods and materials: Daily TEE, REE, step count, activity time, intensity of activity and lying time were determined for 7 consecutive days in unselected stable patients on MHD and sex, age and weightmatched healthy controls (HC). Patients with malnutrition, cancer, use of immunosuppressive drugs, hypoalbumemia <35 g/L and those hospitalized in the last 3 months, were excluded. For MHD patients, separate analyses were conducted in dialysis and non-dialysis days. Relevant parameters known to affect REE, such as BMI, albumin, pre-albumin, hemoglobin, Kt/V, CRP, bicarbonate, PTH, TSH, were recorded. Results: Thirty patients on MHD and 30 HC were included. In MHD patients, there were 20 men and 10 women. Age was 60,13 years ± 14.97 (mean ± SD), BMI was 25.77 kg/m² ± 4.73 and body weight was 74.65 kg ± 16.16. There were no significant differences between the two groups. TEE was lower in MHD patients compared to HC (28.79 ± 5.51 SD versus 32.91 ± 5.75 SD kcal/kg/day; p <0.01). Activity time was significantly lower in patients on MHD (101.3 ± 12.6SD versus 50.7 ± 9.4 SD min; p = 0.0021). Energy expenditure during the time of activity was significantly lower in MHD patients. MHD patients walked 4543 ± 643 SD vs 8537 ± 744 SD steps per day (p <0.0001). Age was negatively correlated with TEE (r = -0.70) and intensity of activity (r = -0.61) in HC, but not in patients on MHD. TEE showed no difference between dialysis and non-dialysis days (29.92 ± 2.03 SD versus 28.44 ± 1.90 SD kcal/kg/day; p = NS), reflecting a lack of difference in activity (number of steps, time of physical activity) and REE. This finding was observed in MHD patients both older and younger than 60 years. However, age stratification appeared to have an influence on TEE, regardless of dialysis day, (29.92 ± 2.07 SD kcal/kg/day for <60 years-old versus 27.41 ± 1.04 SD kcal/kg/day for ≥60 years old), although failing to reach statistical significance. Conclusion: Using SWA, we have shown that stable patients on MHD have a lower TEE than matched HC. On average, a TEE of 28.79 kcal/kg/day, partially affected by age, was measured. This finding gives support to the clinical impression that it is difficult and probably unnecessary to provide an energy amount of 30-35 kcal/kg/day, as proposed by international guidelines for this population. In addition, we documented for the first time that MHD patients exert a reduced physical activity as compared to HC. There were surprisingly no differences in TEE, REE and physical activity parameters between dialysis and non-dialysis days. This observation might be due to the fact that patients on MHD produce a physical effort to reach the dialysis centre. Age per se did not influence physical activity in MHD patients, contrary to HC, reflecting the impact of co-morbidities on physical activity in this group of patients.

Social network architecture and the maintenance of deleterious cultural traits.

How have changes in communications technology affected the way that misinformation spreads through a population and persists? To what extent do differences in the architecture of social networks affect the spread of misinformation, relative to the rates and rules by which individuals transmit or eliminate different pieces of information (cultural traits)? Here, we use analytical models and individual-based simulations to study how a 'cultural load' of misinformation can be maintained in a population under a balance between social transmission and selective elimination of cultural traits with low intrinsic value. While considerable research has explored how network architecture affects percolation processes, we find that the relative rates at which individuals transmit or eliminate traits can have much more profound impacts on the cultural load than differences in network architecture. In particular, the cultural load is insensitive to correlations between an individual's network degree and rate of elimination when these quantities vary among individuals. Taken together, these results suggest that changes in communications technology may have influenced cultural evolution more strongly through changes in the amount of information flow, rather than the details of who is connected to whom.

Incidence, complications and risk factors for severe falls in patients on maintenance haemodialysis.

BACKGROUND: Falls have been insufficiently studied in patients on maintenance haemodialysis (MHD). This study assessed the incidence and complications of severe falls and the ability of risk factors, including the Performance-Oriented Mobility Assessment (POMA) test, to predict them in this population. METHODS: All patients on MHD from our centre were asked to participate in this survey. POMA test and a record of risk factors for falls were obtained at baseline. Severe falls, as defined by an admission in an emergency ward, were documented prospectively. RESULTS: Eighty-four patients (median age 69.5 years, minimum 26 years, maximum 85 years) were enrolled. Predialytic POMA scores were low (median 20, minimum 5, maximum 26). After a mean follow-up of 20.6 months (142.2 patient-years), 31 severe falls were recorded in 24 patients (28.6%; incidence 0.22 per patient-year) and complicated by fractures in 54.8% of severe falls. In univariate analysis, age, a past history of falls, malnutrition, depression, but not POMA score, were associated with severe falls. A POMA score of >21 had a negative predictive value of 82%. CONCLUSIONS: Severe falls were common in MHD patients in this study and resulted in fractures in >50% of the cases. They were associated with ageing, a past history of falls, malnutrition and depression. Although there was a trend towards a lower POMA score in fallers as compared to non-fallers, the POMA score was not an independent predictor of severe falls in this study. These data may help to stratify the patient's risk of falling in order to target programmes to prevent falls in this population.

Calpain 3, the "gatekeeper" of proper sarcomere assembly, turnover and maintenance.

Calpain 3 is a member of the calpain family of calcium-dependent intracellular proteases. Thirteen years ago it was discovered that mutations in calpain 3 (CAPN3) result in an autosomal recessive and progressive form of limb girdle muscular dystrophy called limb girdle muscular dystrophy type 2A. While calpain 3 mRNA is expressed at high levels in muscle and appears to have some role in developmental processes, muscles of patients and mice lacking calpain 3 still form apparently normal muscle during prenatal development; thus, a functional calpain 3 protease is not mandatory for muscle to form in vivo but it is a pre-requisite for muscle to remain healthy. Despite intensive research in this field, the physiological substrates of the calpain 3 protein (hereafter referred to as CAPN3) and its alternatively spliced isoforms remain elusive. The existence of these multiple isoforms complicates the search for the physiological functions of CAPN3 and its pathophysiological role. In this review, we summarize the genetic and biochemical evidence that point to loss of function of the full-length isoform of CAPN3, also known as p94, as the pathogenic isoform. We also argue that its natural substrates must reside in its proximity within the sarcomere where it is stored in an inactive state anchored to titin. We further propose that CAPN3 has many attributes that make it ideally suited as a sensor of sarcomeric integrity and function, involved in its repair and maintenance. Loss of these CAPN3-mediated activities can explain the "progressive" development of muscular dystrophy.

Calpain 3, the "gatekeeper" of proper sarcomere assembly, turnover and maintenance.

Calpain 3 is a member of the calpain family of calcium-dependent intracellular proteases. Thirteen years ago it was discovered that mutations in calpain 3 (CAPN3) result in an autosomal recessive and progressive form of limb girdle muscular dystrophy called limb girdle muscular dystrophy type 2A. While calpain 3 mRNA is expressed at high levels in muscle and appears to have some role in developmental processes, muscles of patients and mice lacking calpain 3 still form apparently normal muscle during prenatal development; thus, a functional calpain 3 protease is not mandatory for muscle to form in vivo but it is a pre-requisite for muscle to remain healthy. Despite intensive research in this field, the physiological substrates of the calpain 3 protein (hereafter referred to as CAPN3) and its alternatively spliced isoforms remain elusive. The existence of these multiple isoforms complicates the search for the physiological functions of CAPN3 and its pathophysiological role. In this review, we summarize the genetic and biochemical evidence that point to loss of function of the full-length isoform of CAPN3, also known as p94, as the pathogenic isoform. We also argue that its natural substrates must reside in its proximity within the sarcomere where it is stored in an inactive state anchored to titin. We further propose that CAPN3 has many attributes that make it ideally suited as a sensor of sarcomeric integrity and function, involved in its repair and maintenance. Loss of these CAPN3-mediated activities can explain the "progressive" development of muscular dystrophy.

The evolution, maintenance and adaptive function of genetic colour polymorphism in birds.

The hypothesis that ornaments can honestly signal quality only if their expression is condition-dependent has dominated the study of the evolution and function of colour traits. Much less interest has been devoted to the adaptive function of colour traits for which the expression is not, or is to a low extent, sensitive to body condition and the environment in which individuals live. The aim of the present paper is to review the current theoretical and empirical knowledge of the evolution, maintenance and adaptive function of colour plumage traits for which the expression is mainly under genetic control. The finding that in many bird species the inheritance of colour morphs follows the laws of Mendel indicates that genetic colour polymorphism is frequent. Polymorphism may have evolved or be maintained because each colour morph facilitates the exploitation of alternative ecological niches as suggested by the observation that individuals are not randomly distributed among habitats with respect to coloration. Consistent with the hypothesis that different colour morphs are linked to alternative strategies is the finding that in a majority of species polymorphism is associated with reproductive parameters, and behavioural, life-history and physiological traits. Experimental studies showed that such covariations can have a genetic basis. These observations suggest that colour polymorphism has an adaptive function. Aviary and field experiments demonstrated that colour polymorphism is used as a criterion in mate-choice decisions and dominance interactions confirming the claim that conspecifics assess each other's colour morphs. The factors favouring the evolution and maintenance of genetic variation in coloration are reviewed, but empirical data are virtually lacking to assess their importance. Although current theory predicts that only condition-dependent traits can signal quality, the present review shows that genetically inherited morphs can reveal the same qualities. The study of genetic colour polymorphism will provide important and original insights on the adaptive function of conspicuous traits.

A pipeline approach with spatial information for segmenting multiple sclerosis lesions on brain magnetic resonance imaging

Background: Conventional magnetic resonance imaging (MRI) techniques are highly sensitive to detect multiple sclerosis (MS) plaques, enabling a quantitative assessment of inflammatory activity and lesion load. In quantitative analyses of focal lesions, manual or semi-automated segmentations have been widely used to compute the total number of lesions and the total lesion volume. These techniques, however, are both challenging and time-consuming, being also prone to intra-observer and inter-observer variability.Aim: To develop an automated approach to segment brain tissues and MS lesions from brain MRI images. The goal is to reduce the user interaction and to provide an objective tool that eliminates the inter- and intra-observer variability.Methods: Based on the recent methods developed by Souplet et al. and de Boer et al., we propose a novel pipeline which includes the following steps: bias correction, skull stripping, atlas registration, tissue classification, and lesion segmentation. After the initial pre-processing steps, a MRI scan is automatically segmented into 4 classes: white matter (WM), grey matter (GM), cerebrospinal fluid (CSF) and partial volume. An expectation maximisation method which fits a multivariate Gaussian mixture model to T1-w, T2-w and PD-w images is used for this purpose. Based on the obtained tissue masks and using the estimated GM mean and variance, we apply an intensity threshold to the FLAIR image, which provides the lesion segmentation. With the aim of improving this initial result, spatial information coming from the neighbouring tissue labels is used to refine the final lesion segmentation.Results:The experimental evaluation was performed using real data sets of 1.5T and the corresponding ground truth annotations provided by expert radiologists. The following values were obtained: 64% of true positive (TP) fraction, 80% of false positive (FP) fraction, and an average surface distance of 7.89 mm. The results of our approach were quantitatively compared to our implementations of the works of Souplet et al. and de Boer et al., obtaining higher TP and lower FP values.Conclusion: Promising MS lesion segmentation results have been obtained in terms of TP. However, the high number of FP which is still a well-known problem of all the automated MS lesion segmentation approaches has to be improved in order to use them for the standard clinical practice. Our future work will focus on tackling this issue.

Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment

Methadone is a 50:50 mixture of two enantiomers and (R)-methadone accounts for the majority of its opioid effect. The aim of this study was to determine whether a blood concentration of (R)-methadone can be associated with therapeutic response in addict patients in methadone maintenance treatment. Trough plasma concentrations of (R)-, (S)- and (R,S)-methadone were measured in 180 patients in maintenance treatment. Therapeutic response was defined by the absence of illicit opiate or cocaine in urine samples collected during a 2-month period prior to blood sampling. A large interindividual variability of (R)-methadone concentration-to-dose-to-weight ratios was found (mean, S.D., median, range: 112, 54, 100, 19-316 ng x kg/ml x mg). With regard to the consumption of illicit opiate (but not of cocaine), a therapeutic response was associated with (R)- (at 250 ng/ml) and (R,S)-methadone (at 400 ng/ml) but not with (S)-methadone concentrations. A higher specificity was calculated for (R)- than for (R,S)-methadone, as the number of non-responders above this threshold divided by the total number of non-responders was higher for (R,S)-methadone (19%) than for (R)-methadone (7%). The results support the use of therapeutic drug monitoring of (R)-methadone in cases of continued intake of illicit opiates. Due to the variability of methadone concentration-to-dose-to-weight ratios, theoretical doses of racemic methadone could be as small as 55 mg/day and as large as 921 mg/day to produce a plasma (R)-methadone concentration of 250 ng/ml in a 70-kg patient. This demonstrates the importance of individualizing methadone treatment.