Cognitive flexibility and attention to detail in adolescents and adults with severe forms of anorexia nervosa.

OBJECTIVE: To determine if adolescents and adults diagnosed with anorexia nervosa differ in their levels of cognitive flexibility and attention to detail independently of potential confounds. METHOD: Sixty-two adolescents and 54 adults were assessed while receiving inpatient treatment and completed the following self-reports: Eating Disorders Examination Questionnaire, Maudsley Obsessive Compulsive Inventory and Hospital Anxiety and Depression scale. Performance-based evaluations included the Wisconsin Card Sorting Test Computerised Version, the Comprehensive Trail Making Test, the Brixton Spatial Anticipation Test, the Rey Complex Figure and the Group Embedded Figures Test. RESULTS: Comparisons of the adolescents and adults with anorexia nervosa revealed no significant differences for any of the neuropsychological test scores even after adjusting for potential confounding factors. Neither cognitive flexibility nor attention to detail were associated with level of eating disorder symptomatology, depression, anxiety or obsessive-compulsive symptomatology. Unlike age, illness duration was found weakly associated with perseverative errors Wisconsin Card Sorting Test and with the central coherence index of the Rey Complex Figure recall condition. CONCLUSIONS: Set-shifting and central coherence performance were independent of age, clinical symptoms severity and emotional status. Additional studies on the relationship between the duration of anorexia nervosa and neuropsychological difficulties are needed.

[Good professional practices of French CICs - version # 2]. / Manuel de bonnes pratiques professionnelles des CIC ­ version no2.

French clinical investigation centers (CICs) are academic platforms dedicated to clinical research. The QUALI-CIC working group helps to improve and harmonize practices within the CIC network. After some years of implementation, the manual of good professional practices of CICs (MGPP CIC) completed in 2010, needed to be revised to best fit with the large panel of CIC activities. The aim was also to make it more accurate and to reinforce requirements about participants safety and data security. In its second version published in the present article, the MGPP CIC includes 255 items divided into 15 chapters. An explanatory document, currently being drafted, will complete the manual to facilitate its implementation.

Pharmacokinetic and pharmacodynamic studies of two different rabbit antithymocyte globulin dosing regimens: results of a randomized trial.

Rabbit antithymocyte globulin (rATG; Thymoglobulin(®)) is currently used to prevent acute rejection in kidney transplantation. The dose and regimen of rATG have not been optimized. Moreover, the impact of different treatment regimens on T-cell phenotype reconstitution remains unknown. We conducted a prospective randomized study of 17 renal transplant patients to determine the pharmacokinetics of total and active (bound to human cells) rATG and T-cell phenotype reconstitution after rATG administration. Patients received rATG at a total dose of 6mg/kg, administered either as 1.5mg/kg/day on days 0-3 (Group 1, n=8) or 3mg/kg on days 0 and 3 (Group 2, n=9). All patients received tacrolimus, mycophenolate mofetil and steroids. Blood samples were assayed for total rATG by enzyme linked immunosorbent assay and active rATG by flow cytometry. Maximum concentrations and terminal half-lives were similar between the two groups but at month 3 Group 1 had significantly lower values for total rATG (concentration was 6.2±1.1µg/mL versus 10.2±2.9µg/mL in Group 2, p=0.027) and total rATG dose-normalized AUC (374±83dayg/mL versus 508±149dayg/mL in Group 2, p=0.046). Time to sub-therapeutic levels (<1µg/mL) of active rATG was significantly shorter in Group 1 (18.75±6.9days versus 20±7.5days in Group 2, p<0.001). rATG induced significant depletion followed by slow reconstitution of CD3(+), CD4(+) and CD8(+) cells, with no marked differences between groups. B-cell count was unaffected, whereas CD3(-)CD56(+) NK-cell depletion was observed in both groups. rATG induced a significant decrease in the proportion of naïve CD4(+) T-cells, which plateaued after month 1 in Group 1 and after month 6 in Group 2. The proportion of central memory CD4(+) T-cells increased to a similar extent in both groups (Group 1: 38±18% at baseline, 74±23% at one year, p=0.009; Group 2: 32±14% at baseline, 65±14% at one year, p=0.001). In conclusion, our results suggest that the dosing regimen for rATG induction influences pharmacokinetic parameters without affecting the quality of immune reconstitution.

Mortality and its predictors in severe bulimia nervosa patients.

BACKGROUND: The risk of mortality remains unclear for bulimia nervosa (BN) patients, especially the most severe. The aims of this study were to improve knowledge on BN and mortality. METHODS: With initial evaluation at admission, 258 BN (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) consecutive inpatients were included (1988-2004). Vital status was established from the French national register. Standardized Mortality Ratio (SMR) calculation and bivariate Cox analysis were performed for the hypothesised predictors of mortality. RESULTS: Mean follow-up duration was 10.5 years. Ten deaths were recorded, and the crude mortality ratio was 3.9%; SMR = 5.52 [CI95 (2.64-10.15)]. The majority of deaths were from suicide [6/10, SMR = 30.9 (5.7-68.7)]. The mean age at time of death was 29.6 years. Predictive factors were previous suicide attempt and low minimum BMI. CONCLUSIONS: Severe BN patients are at higher risk of death (mainly suicide) especially if previous suicide attempt or previous low BMI. More studies are needed to confirm these results.

Severe anorexia nervosa in men: comparison with severe AN in women and analysis of mortality.

OBJECTIVE: To compare clinical characteristics of men and women with severe AN and to analyze mortality in men. METHOD: One thousand and nine patients including 23 anorectic males were hospitalized in St. Anne Hospital in Paris between 1988 and 2004. Data were collected during hospitalization. Fatal outcome was assessed in 2008. RESULTS: Men presented significantly later age of onset, were more likely to have a history of premorbid overweight than women and less likely to have attempted suicide. Mortality in men was high (standardized mortality ratio: 8.08; 95% CI: 1.62-23.62). Several predictive factors for mortality in men were identified: lower admission body mass index (BMI), later age at admission, and AN-R subtype. All the three deceased patients had dropped out from the inpatient unit. The 10-year survival did not differ between men and women, but men died sooner after hospitalization. DISCUSSION: Male inpatients should receive close follow-up after their discharge, especially if they have a restrictive form of AN, present low BMI, or are older at admission.

Predictors of dropout from inpatient treatment for anorexia nervosa: data from a large French sample.

Dropout from anorexia nervosa inpatient treatment programs is frequent and is linked to a poorer outcome. This study aimed to identify predictive factors for dropout among anorexia nervosa inpatients. Between 1988 and 2004, 601 consecutive female inpatients with anorexia, restrictive (AN-R) or binge/purging (AN-B/P) subtype (Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV)), were assessed at admission (clinical, socio-demographic, and psychological data). A stepwise logistic model was developed. Dropout rates were respectively 50.0% and 56.2% for AN-R and AN-B/P. Seven predictive factors were identified in multivariate analysis: having one or more children, low desired body mass index (BMI), a low minimum BMI, high scores on the SCL-90 paranoid ideation and the Morgan and Russell eating behavior subscales, and low educational status. Early dropouts had a particular profile: lower desired BMI, higher score on SCL90 paranoid subscale, and more impulsive behaviors (alcohol use, suicide attempts). Dropout appeared as a multifactorial event. In clinical practice, certain factors could serve as warning messages reflecting the severity of the illness (high EDI score and low minimum BMI); while others could be targeted before hospitalization (having at least one child and low desired BMI).

Eating disorder and metabolism in narcoleptic patients.

STUDY OBJECTIVE: To evaluate eating behavior and energy balance as a cause of increased body mass index (BMI) in narcolepsy. DESIGN: Case controlled pilot study. SETTINGS: University hospital. PARTICIPANTS: 13 patients with narcolepsy (7 "typical" patients, with HLA DQB1*0602 and clear cut cataplexy, with suspected hypocretin deficiency; and 6 "atypical" narcoleptics, i.e., HLA negative or without cataplexy), and 9 healthy controls matched for age, gender, and ethnicity. INTERVENTION: Energy balance was evaluated by measuring BMI, rest energy expenditure with calorimetry, daily food and water intake, and plasma hormone levels. Eating behavior was evaluated using psychometric tests (EAT-40, EDI2, CIDI-2, MADRS). RESULTS: Patients with narcolepsy (whether typical or not) tended to be overweight and to have a lower basal metabolism than controls. Only patients with typical narcolepsy tended to eat less than controls. Narcoleptic patients who were overweight ate half as much as others, indicating caloric restriction. Plasma glucose, cortisol, thyroid, and sex hormones levels did not differ between groups, while prolactin levels were twice as high in patients with narcolepsy as in controls. Narcoleptic patients had higher EAT-40 scores and more frequent features of bulimia nervosa (independent of depressive mood) than controls, suggesting a mild eating disorder, classified as "Eating Disorder Not Other Specified." DISCUSSION: Both lower basal metabolism and subtle changes in eating behavior (rather than in calorie intake) could explain the positive energy balance leading to overweight in narcolepsy. Eating behavior changes may be a strategy to control weight or to avoid daytime sleepiness.

Factors associated with suicidal behaviors in a large French sample of inpatients with eating disorders.

OBJECTIVE: The objective of the present study was to identify factors associated with suicidal behaviors among patients with eating disorders. METHOD: A large database including sociodemographic and clinical characteristics of 1,009 consecutive patients hospitalized for an eating disorder in Paris, France, was examined. Data gathered upon admission to hospital were analyzed to identify factors associated with a history of suicide attempt or current suicidal ideation, among the whole sample as well as among each subtype of eating disorder. RESULTS: Among the whole sample, the factor most strongly associated with suicide attempt or suicidal ideation was the diagnostic category, with the highest odds ratio for bulimia nervosa followed by anorexia nervosa of the binging/purging subtype. Among diagnostic subgroups, the strongest factors were drug use, alcohol use, and tobacco use. CONCLUSION: Suicide risk should be monitored carefully among patients with eating disorders, paying particular attention to combinations of risk factors.

Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: association with subtype, body-mass index, severity and age of onset.

Anorexia nervosa (AN) affects 0.3% of young girls with a mortality of 6%/decade and is strongly familial with genetic factors. Ghrelin is an upstream regulator of the orexigenic peptides NPY and AgRP and acts as a natural antagonist to leptin's effects on NPY/AgRP-expressing neurons, resulting in an increase in feeding and body weight. Obestatin which counteracts ghrelin action on feeding is derived from the same propeptide than ghrelin. BDNF has been involved in body weight regulation and its Val66Met polymorphism associated with AN. We therefore re-investigated the association between AN and the Leu72Met and Gln90Leu polymorphisms of the prepro-ghrelin/obestatin gene, the Ala67Thr polymorphism of AgRP and the Val66Met polymorphism of BDNF taking into account clinical subtypes (restrictive--ANR--and bingeing/purging--ANB--subtypes). Family trios study of these 4 single nucleotide polymorphisms were performed in 114 probands with AN and both their parents recruited in two specialized French centres. A transmission disequilibrium was observed for the Leu72Met SNP of the preproghrelin gene and for the Ala67Thr SNP of the AgRP gene. When stratified by clinical subtype, these two polymorphisms were preferentially transmitted for the trios with a bingeing/purging proband. An excess of transmission of the Gln90Leu72 preproghrelin/obestatin haplotype in patients with AN was observed. These results do not provide evidence for a preferential transmission of the 66Met allele of BDNF but support the hypothesis that ghrelin and AGRP polymorphisms confers susceptibility to AN. Further simultaneous analysis of genetic variants of the biological determinants of energy metabolism and feeding behaviour in very large populations should contribute to the understanding of the high degree of heritability of eating disorders and to the description of pathophysiological patterns leading to life-threatening conditions in a highly redundant system.

Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations.

Eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), are complex psychiatric disorders where different genetic and environmental factors are involved. Several lines of evidence support that brain-derived neurotrophic factor (BDNF) plays an essential role in eating behaviour and that alterations on this neurotrophic system participates in the susceptibility to both AN and BN. Accordingly, intraventricular administration of BDNF in rats determines food starvation and body weight loss, while BDNF or its specific receptor NTRK2 knockout mice develop obesity and hyperphagia. Case-control studies also suggest a BDNF contribution in the aetiology of ED: we have previously reported a strong association between the Met66 variant within the BDNF gene, restricting AN (ANR) and minimum body mass index (minBMI) in a Spanish sample, and a positive association between the Val66Met and -270C/T BDNF SNPs and ED in six different European populations. To replicate these results, avoiding population stratification effects, we recruited 453 ED trios from eight European centres and performed a family-based association study. Both haplotype relative risk (HRR) and haplotype-based haplotype relative risk (HHRR) methods showed a positive association between the Met66 allele and ANR. Consistently, we also observed an effect of the Met66 variant on low minBMI and a preferential transmission of the -270C/Met66 haplotype to the affected ANR offspring. These results support the involvement of BDNF in eating behaviour and further suggest its participation in the genetic susceptibility to ED, mainly ANR and low minBMI.

Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations.

Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of food intake and body weight in rodents. We previously reported a strong association of the Met66 allele of the Val66Met BDNF variant with restricting AN (ANR) and low minimum body mass index in Spanish patients. Another single nucleotide polymorphism located in the promoter region of the BDNF gene (-270C>T) showed lack of association with any ED phenotype. In order to replicate these findings in a larger sample, we performed a case-control study in 1142 Caucasian patients with ED consecutively recruited in six different centers from five European countries (France, Germany, Italy, Spain and UK) participating in the 'Factors in Healthy Eating' project. We have found that the Met66 variant is strongly associated to all ED subtypes (AN, ANR, binge-eating/purging AN and BN), and that the -270C BDNF variant has an effect on BN and late age at onset of weight loss. These are the first two variants associated with the pathophysiology of ED in different populations and support a role for BDNF in the susceptibility to aberrant eating behaviors.

The human genetics of anorexia nervosa.

Anorexia nervosa is a severe eating disorder characterised by restricted eating, the relentless pursuit of thinness and obsessive fears of being fat. The involved risk factors are probably numerous, but the existence of a genetic vulnerability has been proposed for decades. The heritability in the broad sense is computed on the basis of aggregation studies, treated twin samples and twin studies from the general population. Many difficulties make this heritability estimation problematic, but the convergence of the results (from family studies and two types of twin studies) gives the most convincing evidence in favour of a major role of genetics in the vulnerability to anorexia nervosa, with a heritability around 70%. Regarding the analysis of candidate genes, the most frequently studied is the 5-HT(2A) gene, with positive and negative results. We thus propose a meta-analysis showing that a large heterogeneity between samples exists, but the main effect of the -1438A allele persists even when extracting this contaminating effect (p=0.003). Furthermore, the absence of significant correlation between odds ratio and time after first publication of each sample, and size of each sample, is in accordance with the fact that the A allele is a risk factor. In order to explain the high heterogeneity between the nine studies yet performed, an alternative explanation such as a "modifying the phenotype" effect is proposed.

Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women.

Ghrelin, a 28-amino acid octanoylated peptide, has recently been identified in rat stomach as an endogenous ligand for the GH secretagogue receptor. In addition to GH-releasing properties, exogenous ghrelin injections exert orexigenic effects in both rodents and humans. As the endogenous peptide appears directly related to feeding behavior, we assessed its plasma levels in anorexia nervosa (AN) patients before and after renutrition and in constitutionally thin subjects with body mass indexes (BMIs) equivalent to those of AN women but with no abnormal feeding behavior. The relationships between plasma ghrelin levels and other neuroendocrine and nutritional parameters, such as GH, leptin, T3, and cortisol, were also investigated. In AN patients, morning fasting plasma ghrelin levels were doubled compared with levels in controls, constitutionally thin subjects, and AN patients after renutrition. Twenty-four-hour plasma ghrelin, GH, and cortisol levels determined every 4 h were significantly increased, whereas 24-h plasma leptin levels were decreased in AN patients compared with controls and constitutionally thin subjects. Both plasma ghrelin and leptin levels returned to control values in AN patients after renutrition. Constitutionally thin subjects displayed intermediate 24-h plasma ghrelin and leptin levels, significantly different from controls and AN patients, whereas GH and cortisol were not modified. Ghrelin was negatively correlated with BMI, leptin, and T(3) in controls, constitutionally thin subjects, and AN patients, whereas no correlation was found between GH and ghrelin or between cortisol and ghrelin. Ghrelin and BMI or T3 were still correlated after renutrition, suggesting that ghrelin is also a good nutritional indicator. Basal and GHRH-stimulated GH release were significantly increased in AN patients only. In conclusion, ghrelin is increased in AN and constitutionally thin subjects who display very low BMI but different eating behaviors, suggesting that not only is ghrelin dependent on body fat mass, but it is also influenced by nutritional status. Even though endogenous ghrelin is not strictly correlated with basal GH secretion, it may be involved in the magnitude of GHRH-induced GH release in AN patients.

Hedonic response to sucrose solutions and the fear of weight gain in patients with eating disorders.

Previous research has shown that patients with bulimia nervosa (B), anorexia nervosa, restricting type, or restrictive-anorectic (RA), and anorexia nervosa, binge eating, purging type, or anorectic-bulimic (AB) exhibit a reduced hedonic response to sucrose compared with control subjects. We hypothesized that this response could be linked to an excessive fear of weight gain rather than a decreased ability to experience pleasure. We therefore compared the hedonic responses to sucrose solutions in B, RA and AB women (n=20/group) in two different conditions: sucrose solution swallowed vs. sucrose solution spit. Under double-blind conditions and according to a Latin square design, patients received sucrose in solution (0, 5, 10, 20, and 40%) and rated each concentration for pleasantness on a nine-point scale. The two test conditions were randomly administered. The threshold concentration of sweet taste perception was also assessed, and the subjects filled out Chapman's Social and Physical Anhedonia Scale. The hedonic response to sucrose adjusted for the sweet taste perception threshold was significantly lower in the 'swallow' than in the 'spit' condition. There was a significant effect of sucrose concentrations as well as a significant condition by concentration interaction. When 'fear to swallow' sucrose solution responses were included as a covariate, the significant difference between the conditions of 'swallow' or 'spit' disappeared, but there was a significant concentration by condition by fear to swallow interaction and an almost significant covariate effect. When 'Drive for Thinness' on the Eating Disorder Inventory was included as a covariate, similar results were obtained. Social Anhedonia but not Physical Anhedonia correlated positively with 'Drive for Thinness' and 'fear of swallowing sucrose solutions', and correlated inversely with maximal hedonic response to the 'swallow' condition. 'We conclude that the hedonic responses to sucrose in patients with eating disorders are decreased when solutions are swallowed. This may reflect excessive fear of gaining weight rather than decreased ability to experience pleasure'.