Hypothalamic Structural and Functional Imbalances in Anorexia Nervosa.

The hypothalamus contains integrative systems that support life, including physiological processes such as food intake, energy expenditure, and reproduction. Here, we show that anorexia nervosa (AN) patients, contrary to normal weight and constitutionally lean individuals, respond with a paradoxical reduction in hypothalamic levels of glutamate/glutamine (Glx) upon feeding. This reversal of the Glx response is associated with decreased wiring in the arcuate nucleus and increased connectivity in the lateral hypothalamic area, which are involved in the regulation on a variety of physiological and behavioral functions including the control of food intake and energy balance. The identification of distinct hypothalamic neurochemical dysfunctions and associated structural variations in AN paves the way for the development of new diagnostic and treatment strategies in conditions associated with abnormal body mass index and a maladaptive response to negative energy balance.

Characterization of functional polymorphisms and glucocorticoid-responsive elements in the promoter of TDO2, a candidate gene for ethanol-induced behavioural disorders.

AIMS: In response to acute ethanol consumption, tryptophan 2,3-dioxygenase (TDO) induces the kynurenine pathway (KP) through a glucocorticoid-mediated mechanism, which could lead to a dramatic accumulation of neurotoxic metabolites in association with serotonin depletion. As a result, interindividual variability in ethanol-induced behavioural disorders, such as black-outs and violent impulsive behaviours (BOVIBs) following binge drinking, could be partly explained by genetic polymorphisms affecting the KP. The aim of this study was to identify polymorphisms on the promoter of the TDO2 gene that could affect expression and/or activity of TDO through glucocorticoid induction. METHODS: Polymorphisms were screened using a PCR-sequencing strategy applied to 31 alcohol-dependent patients and 49 unrelated healthy volunteers, and functionally analysed with bioinformatic prediction tools and gene reporter assays in HepG2 and A549 cell lines. RESULTS: We identified 12 polymorphisms in the human TDO2 promoter region, 2 of them corresponding to previously unknown single-nucleotide polymorphisms (SNPs) and 3 of them located in putative glucocorticoid-responsive elements (GREs). Gene reporter assays using HepG2 and A549 cell lines confirmed the presence of several functional GREs in the promoter region of TDO2 and revealed that some of the identified polymorphisms affect the promoter activity under glucocorticoid receptor over-expression and dexamethasone exposure conditions. CONCLUSIONS: Correlational studies in larger samples could help to determine whether these polymorphisms are responsible for variations of expression and/or activity of TDO, in particular under conditions where release of glucocorticoids is increased, such as acute ethanol intake. If confirmed, such results would be of major interest in explaining part of the interindividual variability observed in behavioural responses to acute ethanol consumption.

[Outpatient withdrawal programme: advanced practice in addictology]. / Sevrage ambulatoire: une expérience de la coopération en addictologie.

Advanced nursing practices are procedures enabling nurses to carry out, in a structured and predefined manner, tasks usually entrusted to doctors. Introduced in France by the Berland reports of 2003 and 2006, advanced nursing practices remain under-developed in the fields of psychiatry and addictology. In this context, Lille regional and university hospital has set up an outpatient programme for alcohol withdrawal, a scheme coordinated by a nurse, authorised to modifythe treatment dosage according to the patient's clinical state and who is supported by a network of caregivers during the period of medicalised withdrawal.

Impact of tryptophan metabolism on the vulnerability to alcohol-related blackouts and violent impulsive behaviours.

AIMS: We examined (1) the association of SLC6A4 genotypes and alcohol dependence (AD) in a sample of alcoholics; (2) the validity of lifetime occurrence of blacked-out violent impulsive behaviour (BOVIB) during binge drinking bouts as a criterion for subtyping AD patients and (3) a mechanistic hypothesis for BOVIB involving tryptophan-2,3-dioxygenase (TDO) activity. METHODS: Three common polymorphisms of the SLC6A4 gene (5-HTTLPR, A/G SNP of LPR region and VNTR in intron 2) were genotyped. An oral tryptophan (Trp) load (OTL) was administered to a sample of patients seeking help for AD. BOVIB history and psychological status were screened by BOVIB-Q, depression (BDI), anxiety (BAI, STAI) and personality (TCI) questionnaires. During the 7 h following Trp load, serum kynurenine (Kyn) and Trp were monitored. RESULTS: BOVIB+ patients showed significantly higher scores on depression, anxiety and character scales but no significant association was found between SLC6A4 polymorphisms and BOVIB. Patients with a history of BOVIB (BOVIB+ subgroup) differed from those exempt from such episodes (BOVIB- subgroup) for TDO activity response to OTL assessed by the Kyn:Trp ratio (P = 0.043) and the slope of concentration increase ratio (SCIR) of serum Kyn (P = 0.043). CONCLUSIONS: Put together, these findings support the validity of the BOVIB criterion to differentiate a sub-group of vulnerable AD subjects and suggest that OTL may help to concurrently define a specific endophenotype.

Adipokines and bone status in a cohort of anorexic patients.

INTRODUCTION: Bone loss in anorexia nervosa (AN) is multifactorial; its mechanisms are not yet clearly understood and may vary depending on disease duration and severity. To determine to what extent adipokines may be involved in the bone alterations found in anorexic patients, we evaluated plasma levels for leptin, adiponectin and Pref-1 against other clinical and biological parameters in a population of anorexic patients split according to weight and bone status. METHODS: Plasma concentrations of leptin, total adiponectin, high molecular weight (HMW) adiponectin, and Pref-1 were measured. The ratio of HMW adiponectin to total adiponectin - HMW (percentage) - was calculated. We divided our population into 5 groups with different phenotypes characterizing the severity of the disease and/or the severity of bone involvement: 1 - Normal BMD and body mass index (BMI): recovery from AN; 2 - Osteopenia (-217kg/m2; 3 - Osteopenia and BMI≤17kg/m2; 4 - Osteoporosis (Z-score≤-2) and BMI>17kg/m2; 5 - Osteoporosis and BMI≤17kg/m2. RESULTS: The study involved 80 anorexia nervosa patients. Mean BMI was 16.8±2.4kg/m2. No significant difference was found in total and HMW adiponectin plasma concentrations between the 5 groups. HMW (percentage) was significantly higher in group 5 compared to group 1. Leptin was significantly lower in groups 3 and 5 compared to the other groups. For the whole group femoral neck and hip BMD correlated negatively with total adiponectin and HMW adiponectin. No correlation was found between BMD (whatever the site) and plasma leptin. Multivariate analysis revealed that 2 factors - leptin and BMI - explained 10% of the variance in spine BMD. For femoral neck BMD, the 2 explanatory factors were BMI and total adiponectin which explained 14% of the variance in BMD. For total hip BMD, 27% of the variance in BMD was explained by 3 factors: leptin, BMI, and total adiponectin. CONCLUSION: Bone status in anorexia nervosa is mainly determined by BMI, leptin and adiponectin.

Comparison of regional bone marrow adiposity characteristics at the hip of underweight and weight-recovered women with anorexia nervosa using magnetic resonance spectroscopy.

Bone marrow adiposity (BMA) is an underestimated tissue, with properties that may alter bone strength especially in diseases that fragilize bone such as anorexia nervosa. In the present study, we investigated the regional characteristics of BMA at the hip of 40 underweight and 36 weight-recovered anorexic women, along with 10 healthy women, using magnetic resonance spectroscopy at multiple anatomical subregions (acetabulum, femoral neck, proximal femoral diaphysis and greater trochanter) to measure bone marrow fat fraction (BMFF) and apparent lipid unsaturation levels (aLUL). Correlations between BMFF, aLUL, body fat percentage (BF), and bone mineral density (BMD) at the femoral neck and total hip, both measured using dual-energy X-ray absorptiometry, were assessed in anorexic patients. Whereas BMFF was significantly higher and aLUL significantly lower at the femoral neck of underweight and weight-recovered patients compared to controls (BMFF: 90.1 ±â€¯6.7% and 90.3 ±â€¯7.5% respectively versus 81.3 ±â€¯8.1%; aLUL: 7.6 ±â€¯1.4% and 7.3 ±â€¯1.3% versus 9.2 ±â€¯1.5%), BMFF and aLUL were not significantly different between the 2 subgroups of patients. Besides, three noteworthy features were observed between BMA and the other measured parameters in anorexic patients. First, synergic alterations of BMA were observed at all sites, with an inverse relationship between BMFF and aLUL (ρ = -0.88). Second, bone mineral compartment and BMA were associated, as a negative correlation between total hip BMD and BMFF was observed at all sites except the greater trochanter (ρ = [-0.32;-0.29]), as well as a positive correlation with aLUL at all sites except the proximal femoral diaphysis (ρ = [0.25;0.37]). Finally, we found a positive correlation between BF and BMFF at the femoral neck (ρ = 0.35), and a negative correlation between BF and aLUL at this same subregion (ρ = -0.33), which suggest a complex relationship between BMA and BF. Overall, BMA possesses regional specificities which may impair bone health, even after weight recovering.

Factors influencing changes in bone mineral density in patients with anorexia nervosa-related osteoporosis: the effect of hormone replacement therapy.

The purpose of this longitudinal study was to evaluate factors affecting changes in bone mineral density (BMD) in patients with anorexia nervosa (AN) and osteoporosis and, more particularly, to assess the benefits of hormone replacement therapy (HRT) on BMD in these patients. Our study involved 45 AN patients, 12 of whom had been treated by HRT for 2 years following a diagnosis of osteoporosis by densitometry (WHO criteria). Patients' mean age was 25.3 +/- 6.7 years. Mean duration of illness was 5.7 +/- 5.3 years. Serum calcium and phosphate were measured at baseline, as were bone remodeling markers. Osteodensitometry by dual-energy X-ray absorptiometry was performed at inclusion and after 2 years. After 2 years, no significant differences were observed between spine, femoral neck, and total hip BMDs either in the HRT group (P = 0.3, P = 0.59, P = 0.58) or in the nontreatment group (P = 0.17, P = 0.68, P = 0.98). Moreover, there were no significant differences between the two groups when changes in spine, femoral neck, and total hip BMDs at 2 years were compared (P = 0.72, P = 0.95, P = 0.58). In both groups, change in weight at 1 year correlated with change in spine BMD at 2 years (r = 0.35, P = 0.04) and change in total-hip BMD at 2 years (r = 0.35, P = 0.04) but not with change in femoral neck BMD at 2 years. Patients with a body mass index (BMI) > or = 17 kg/m(2) at 2 years showed a significant increase in total-hip BMD when compared with patients with a BMI < 17 kg/m(2) (+4.4% +/- 6.7 vs. -0.5% +/- 6.01, P = 0.03). No significant differences were observed for spine and femoral neck BMD. In patients who had recovered their menstrual cycle, significant increases were observed in spine BMD (+4% +/- 6.3 vs. -1.9% +/- 5.6, P = 0.008), femoral neck BMD (+3% +/- 6.2 vs. -2.4% +/- 8, P = 0.05), and total-hip BMD (+3% +/- 7.1 vs. -3.7% +/- 10, P = 0.04). Prevention of bone loss at 2 years in AN patients treated by HRT was not confirmed in this study. We did confirm that increase in weight at 1 year was the most predictive factor for the improvement of spine and hip BMD at 2 years.

Dynamics of emotional expression in autobiographic speech of patients with anorexia nervosa.

Emotional disturbances in persons with anorexia nervosa have mainly been documented using static descriptions. This study presents the temporal organisation of emotional expression in autobiographical speech of anorexic patients and thereby provides a first attempt to quantify the dynamics of emotions in patients' speech. The temporal pattern of emotional expression for persons with anorexia nervosa was studied after transforming the autobiographical narratives of 14 patients and 13 matched controls into symbolic sequences of positive, negative, and neutral emotional expressions. These symbolic sequences of emotional states and silences were analyzed using static and dynamic indices. Static indices showed that patients with anorexia nervosa expressed more negative emotions and fewer neutral states than control participants. Dynamic indices showed in patients' speech a cycle of negative emotions and silence. These results showed specific dynamics of emotional expression in persons with anorexia nervosa characterised by the presence of negative emotional perseveration. The possible clinical implications of these findings are discussed.

Bone loss associated with anorexia nervosa.

The objective of this study was to evaluate the epidemiology, diagnosis, pathophysiology, and treatment of bone loss related to anorexia nervosa. Earlier onset and longer duration of anorexia nervosa are associated with more severe bone loss. Osteoporosis develops in 38-50% of cases. Bone mineral density measurement by dual-energy X-ray absorptiometry is useful for assessing bone mass, and bone marker assays provide information on bone turnover. Bone loss in anorexia nervosa is probably multifactorial. Estrogen deficiency was long felt to be the major factor. However, in contrast to postmenopausal osteoporosis, bone loss associated with anorexia nervosa is related mainly to inadequate bone formation, with only a slight increase in bone resorption. This suggests a role for nutritional factors, such as disturbances in the growth hormone-somatomedin C axis (GH/IGF-I) related to malnutrition. The best treatment strategy for correcting bone mass in patients with anorexia nervosa is not agreed on. Resumption of menstrual cycles and weight gain seem necessary but not always sufficient. Studies found no benefits with estrogen therapy, but this was usually given as estrogen-progestin contraceptives. No vast studies evaluating hormone replacement therapy have been reported. Bone formation enhancers such as IGF-I seem to provide the best results, most notably when used in combination with estrogens. This suggests that complex treatment strategies combining bone formation enhancers and bone resorption inhibitors may deserve evaluation.

[Acute and chronic cognitive disorders caused by cannabis use]. / Altération cognitive liée à la consommation aiguë et chronique du cannabis

Cannabis is currently the most commonly used illegal psychoactive substance amongst young people aged between 15 and 24, and it seems that 5% of this age group is addicted to it. Many research teams focused particularly on the cognitive disorders caused by cannabis use. Amongst the cognitive functions considered, memory-related, attention-related, psychomotor and motivation-related functions were proved deteriorated by acute and chronic cannabis use; a very important point, especially among teenagers, as possible alteration at the social and academic level could be the outcome. However studies on long-term and persistent cognitive effects haven't provided convergent conclusions. Methodological differences could partly affect these observations. Therefore it seems necessary to develop studies with larger samples.

Hair analysis of opiates in mothers and newborns for evaluating opiate exposure during pregnancy.

The increasing interest in toxicological hair analysis as a marker of human exposure to xenobiotics such as illicit substances or therapeutic drugs, has been made feasible by the extension of mass spectrometry, a highly sensitive method of detection. A newborn exposed to drugs in utero can suffer from a varying degree of withdrawal syndrome, a few days after birth. If of opiate origin, the withdrawal syndrome can be treated with morphine, among other therapeutics, but it is not easy to diagnose because of atypical symptoms presented by neonates and especially when maternal drug addiction has not been revealed. To assess and measure toxicological factors linked with the appearance and the severity of this syndrome, maternal and neonatal matrices such as urine, meconium and hair were collected during a protocol approved by the ethical committee. Opiates in particular were measured with GC-MS and potential combined dependences (cannabis, cocaine, amphetamine, LSD and benzodiazepines) and/or substitutive therapeutics (methadone or buprenorphine) were also assessed in 17 mother/neonate couples. Gestational opiate exposure profiles were drawn up and linked with the observed withdrawal syndromes. A withdrawal syndrome seems to appear more frequently after foetal exposure to an association of opiates/substitutive molecules (8 out of 10 withdrawal syndromes observed in this study), although the impact of cocaine and benzodiazepines must also be taken into account. The results obtained in neonatal hair make it possible to affirm foetal drug exposure and are in accordance, for the majority, with the appearance of a neonatal withdrawal syndrome (NWS). Neonatal hair analysis could contribute to assess in utero exposure to opiates, particularly when results in urine and meconium are negative or when these matrices are not available.

[Substance abuse in adolescents]. / Les conduites addictives à l'adolescence.

During adolescence, addition per se is not a major issue. Drug use is either a physiological experience or a symptom related to psychopathological condition and other forms of psychic suffering. The most relevant parameters predictive of poor outcome are the precocity of the first experiences, the auto-therapeutic use, the repetition of drug intake, and the various types of individual and social vulnerability. Assimilated to addiction, some inappropriate and compulsive ways to modify body shape (dieting, and anabolic steroid abuse) are seen in teenagers although they are difficult to identify. Prevention and treatment in youths requires a pragmatic attitude from the adults, avoiding minimisation or dramatization of drug use and its consequences. Particular attention has to be paid on the detection of underlying psychiatric disorders. Treatment of problematic drug abuse in adolescents is based on both contextual interventions including systematic support of the families and a multidisciplinary approach.

Affiliative behaviour and conflictual communication during brief family therapy of patients with anorexia nervosa.

OBJECTIVE: Although patients with anorexia nervosa (AN) present positive responses to family therapy, the key features of therapeutic changes still require identification. This study explores the role of conflictual communication and affiliative nonverbal behaviour in therapeutic change in brief strategic family therapy (BSFT) for AN patients. METHODS: Ten female AN patients and their parents were included in the sample and took part in a 6-month follow-up of BSFT. The durations of conflictual communication and of affiliative nonverbal behaviour estimated by eye contact were compared between the first and the last sessions of family-based treatment using nonparametric statistical tests. RESULTS: An increase of the Body Mass Index associated with an increase in the conflictual communication expressed during BSFT sessions were observed. Moreover, affiliative nonverbal behaviour expressed by the father and the patient decrease, after a BSFT follow-up, in conflictual situations only. By contrast, no significant difference was observed in affiliative nonverbal behaviour expressed by the mother. CONCLUSION: The present study demonstrates that the impact of the BSFT differs between members of a family: the AN patient and the father have established a new form of emotional functioning with a decrease in emotional involvement. The study of the combination between verbal and nonverbal communication can represent an important step in the understanding of the mechanisms of therapeutic change.

Evaluation of bone loss and its mechanisms in anorexia nervosa.

The purpose of this cross-sectional study was to assess the extent of and mechanisms involved in bone loss in anorexia nervosa patients. We compared 113 anorexia nervosa patients (mean age 25 +/- 8 years, mean duration of disease 5.7 +/- 6.1 years) with 21 age-matched controls. Mean duration of amenorrhea was 3.2 +/- 4.7 years. We measured serum calcium and phosphate; bone remodeling markers (osteocalcin, bone-specific alkaline phosphatase [BSAP], serum crosslaps [CTX], and carboxyl-terminal telopeptide of type I collagen [ICTP]); follicle-stimulating hormone and luteinizing hormone levels; and estradiol (ultrasensitive assay), cortisol, urinary free cortisol, thyroid function, prolactin, and nutritional factors (insulin-like growth factor I [IGF-I], IGF binding protein 3 [IGFBP3]). In controls, only bone remodeling markers and nutritional factors were measured. Osteodensitometry was also performed on both patients and controls. Weight and body mass index (BMI) were significantly lower in anorexia nervosa patients than in controls (P < 0.0001). No significant differences were observed in biological indicators except for IGF-I, which was lower in anorexia nervosa patients (0.9 +/- 0.4 UI/mL) than in controls (1.5 +/- 0.4 UI/mL) (P < 0.0001). Densitometric measurements at three sites were significantly lower in anorexia nervosa patients and correlated with duration of disease and amenorrhea and with IGF-I at the hip only (P < 0.01). In the study population, osteoporosis was observed in 24 patients (21%) and osteopenia in 54 patients (48%). Patients with osteoporosis were significantly older and had longer disease and amenorrhea durations; lower weight and BMI; higher alkaline phosphatase, BSAP, and osteocalcin; and lower serum ICTP, IGF-I, and IGFBP3. All of these differences were significant and remained so even after multiple adjustments were made, except for IGF-I (P = 0.21). When multivariate analysis was performed, we found that age at onset of amenorrhea, weight, alkaline phosphatase, urinary free cortisol, and serum estradiol concentration accounted for 54% of the variance in spinal bone mineral density (BMD). Duration of amenorrhea, alkaline phosphatase, and weight explained 46.6% of the variance in femoral neck BMD. Duration of amenorrhea, IGF-I, and ICTP levels accounted for 38.6% of the variance observed in total hip BMD. The etiology of bone loss in patients with anorexia nervosa is multifactorial. Hypoestrogenia alone cannot account for this loss, and nutritional factors, IGF-I concentrations in particular, seem to play an important role.

Neonatal hair analysis contribution to establishing a gestational drug exposure profile and predicting a withdrawal syndrome.

Recently, interest in hair analysis in such fields as drug abuse, driving, or for clinical purposes (determination of drug-exposed neonates especially) has grown because of the highly sensitive method of detection (GC-MS) that can now be applied. Neonates born to drug-addicted mothers can suffer from neonatal withdrawal syndrome (NWS), which requires morphine treatment in its severe forms. To assess and measure toxicologic factors predicting the appearance and the severity of this syndrome, matrices such as urine, meconium, and hair are necessary. Cannabinoids, opiates, cocaine (and its metabolites), and methadone in particular were determined in the various matrices collected in 17 mother/neonate pairs. An immunologic screening method was used, and quantification was achieved with GC-MS. In spite of some bias (color, length, race) that might hinder an accurate interpretation, the results of hair analysis makes it possible to confirm a fetal drug exposure and to reinforce the diagnosis of the NWS observed, particularly when results obtained in other matrices are negative. Hair analysis contributes to our ability to predict a NWS.

[French nationwide survey of abstinence-oriented treatments in opiate-addicted patients. Results at 12 months]. / Observatoire national des Traitements visant à l'Abstinence d'agonistes opiacés chez les patients Dépendants (OTAD). Résultats à 12 mois.

UNLABELLED: Over the last few years, general practitioners and pharmacists in France have become more directly involved in the treatment of opiate-addicted patients with the rapid development of office-based buprenorphine and methadone maintenance programs. At the same time, demand for abstinence-oriented interventions outside established maintenance programs continues to be addressed to the primary care system. METHOD: Our prospective and multicentric survey was conducted to monitor the follow-up of such abstinence-oriented interventions during a 12 months period, by means of questionnaires investigating the psychosocial, medical and addictive status of the patients recruited. RESULTS: One hundred and sixty five general practitioners have accepted to participate in the survey. Initially, they recruited 414 patients (51% terminating a buprenorphine maintenance treatment, 5% a methadone treatment and 36% withdrawing from heroin). Naltrexone chlorhydrate was prescribed for 50% early after entry in the survey. During the 12-month follow-up period: four data collections were proposed at 1, 3, 6, and 12 months. In all, data were collected for 158 patients. No data could be collected for 63 patients who were excluded from follow-up analysis. Out of the 351 patients who attended at least one follow-up visit, 137 (one third) moved to an opiate agonist maintenance program. When naltrexone was prescribed, total duration of treatment averaged 4785 days with no significant difference in terms of heroin relapse and attendance to follow-up visits. Between the first and the last data collection, out of the 113 HCV-positive patients, 13 received/started an anti-viral treatment. No significant difference was noted according to indicators of social outcome. CONCLUSION: Our survey shows that office-base abstinence-oriented interventions in opiate-addicted patients can produce a moderate benefit. Research concerning alternative formulations for opiate antagonists (e.g., long-acting naltrexone) could be helpfully in developing new options for treatment.