Dissociative experiences differentiate bipolar-II from unipolar depressed patients: the mediating role of cyclothymia and the Type A behaviour speed and impatience subscale

BACKGROUND: Dissociative symptoms are often seen in patients with mood disorders, but there is little information on possible association with subgroups and temperamental features of these disorders. METHODS: The Dissociative Experience Scale was administered to 85 patients with a DSM-IV Major Depressive Disorder (MDD) or Bipolar-II Disorder (BP-II). Both broad-spectrum dissociation (DES total score) and clearly pathological forms of dissociation (DES-Taxon) were assessed. Temperament was assessed using Akiskal and Mallya;s criteria of Affective Temperaments and the Jenkins Activity Survey (JAS) for Type A Behaviour. RESULTS: Sixty-five patients gave valid answers to DES. The mean DES and DES-T scores were higher in BP-II (16.8 and 12.7 respectively) compared to MDD (9.0 and 5.7); DES odds ratio (OR)=1.58 (95% CI 1.15-2.18) and DES-T OR=1.60 (95% CI 1.14-2.25) using univariate logistic regression analyses. There was no significant difference in DES score in patients with (n=30) and without an affective temperament (n=35): mean (95% CI), 13.5 vs. 10.5 (-7.8 to 1.9), p=0.224. However the subgroup with a cyclothymic temperament (n=18) had higher DES scores (mean (95% CI): 17.8 vs. 9.7 (2.9-13.3), p=0.003), compared to patients without such a temperament. There was no significant difference in DES scores for patients with (n=35) or without (n=28) a Type A behaviour pattern (JAS>0): mean (95% CI) 12. 7 vs. 10.9 (-6.8 to 3.3), p=0.491), but a positive JAS factor S score (speed and impatience subscale) was associated with significantly higher DES scores than a negative S-score: mean (95% CI) 14.9 vs. 9.0 (1.1-10.7), p=0.017), and this was still significant (p=0.005) using multiple linear regression of DES scores vs. the JAS subscale scores. DES-T scores were significantly higher in patients with OCD (n=9) (mean (95% CI) 18.4 vs. 6.6 (6.0-17.7), p<0.001); eating disorder (n=13) (14.0 vs. 6.8 (1.8-12.6), p=0.009), psychotic symptoms during depressions (n=9) (16.6 vs. 6.9 (3.7-15.8), p=0.002), and in those with a history of suicide attempt (n=28) (11.9 vs. 5.4 (2.2-10.8), p=0.003), but only OCD was an independent predictor after multiple linear regression of DES-T scores vs. all co-morbid disorders (p=0.043). LIMITATIONS: The major limitation of the present study is a non-blind evaluation of affective diagnosis and temperaments, and assessment in a non-remission clinical status. CONCLUSIONS: Dissociative symptoms measured with the Dissociative Experience Scale are associated with bipolar features, using formal DSM-IV criteria, cyclothymic temperament and the speed and impatience subscale of the JAS.     

Peptide-MHC class I stability is a better predictor than peptide affinity of CTL immunogenicity

Efficient presentation of peptide-MHC class I (pMHC-I) complexes to immune T cells should benefit from a stable peptide-MHC-I interaction. However, it has been difficult to distinguish stability from other requirements for MHC-I binding, for example, affinity. We have recently established a high-throughput assay for pMHC-I stability. Here, we have generated a large database containing stability measurements of pMHC-I complexes, and re-examined a previously reported unbiased analysis of the relative contributions of antigen processing and presentation in defining cytotoxic T lymphocyte (CTL) immunogenicity [Assarsson et al., J. Immunol. 2007. 178: 7890-7901]. Using an affinity-balanced approach, we demonstrated that immunogenic peptides tend to be more stably bound to MHC-I molecules compared with nonimmunogenic peptides. We also developed a bioinformatics method to predict pMHC-I stability, which suggested that 30% of the nonimmunogenic binders hitherto classified as "holes in the T-cell repertoire" can be explained as being unstably bound to MHC-I. Finally, we suggest that nonoptimal anchor residues in position 2 of the peptide are particularly prone to cause unstable interactions with MHC-I. We conclude that the availability of accurate predictors of pMHC-I stability might be helpful in the elucidation of MHC-I restricted antigen presentation, and might be instrumental in future search strategies for MHC-I epitopes.     

Victims of rape show increased cortisol responses to trauma reminders: a study in individuals with war- and torture-related PTSD

Studies investigating cortisol responses to trauma-related stressors in patients with posttraumatic stress disorder (PTSD) have yielded inconsistent results, demonstrating that cortisol responses were enhanced or unaffected when confronted with trauma reminders. This study investigated the effect of the type of trauma experienced on both salivary and plasma cortisol responses during confrontation with trauma-related material. Participants were 30 survivors of war and torture, with and without rape among the traumatic events experienced. Participants of both groups (raped vs. non-raped) fulfilled DSM-IV criteria of PTSD. Plasma and salivary cortisol levels were measured at three time points during a standardized clinical interview: once before and twice after assessing individual traumatic experiences. Results show that groups did not differ in basal plasma and salivary cortisol levels. However, differential salivary cortisol responses were observed in PTSD patients who had been raped compared to those who had not been raped (p<.05) but had experienced an equal number of traumatic events and showed equally high PTSD symptom severity. Whereas salivary cortisol levels decreased in the course of the interview for the group with no past experience of rape (p<.05), those PTSD patients who had been raped showed a significant cortisol increase when reminded of their traumatic events (p<.001). This effect was not found in plasma cortisol. Our results indicate that the type of traumatic stress experienced contributes to cortisol responses during the confrontation with trauma-related material. We hypothesize, that the nearness of the perpetrator during the traumatic event might shape later psychophysiological responding to trauma reminders.     

Acquisition and performance effects of scopolamine and of treatment withdrawal in avoidance situations

Two experiments were carried out in order to compare the effects of scopolamine on acquisition with those of changes of state in either direction (no drug to drug and vice versa). Two avoidance tasks the acquisition of which was known to be facilitated by small doses of tertiary antimuscarinics were used. The first study on continuous discriminated lever press avoidance, with either light onset or light offset as warning signal, showed a performance enhancement after the treatment of pretrained animals, and a performance decrement in animals trained in the drug state and then shifted to placebo. The data, however, also showed a partial carry-over of the scopolamine facilitation to the no drug condition, and a partial carry-over of the no drug retardation to the drug condition. The facilitation of acquisition (reduction of shock rate, enhancement of total response rate and of discriminated responses) and all other phenomena indicated above were more marked in the light off condition, which depressed acquisition and performance in untreated animals. The second experiment on discrete-trial two-way avoidance with light onset (non directional) as CS used a 2 × 2 × 2 × 2 design, combining the features of previous studies which had shown contrasting effects of changes of state, depending on various experimental conditions. A performance decrement after treatment withdrawal was again observed in all instances. However, this experiment confirmed that the performance effects of drug administration to pretrained animals depend both on the distribution of previous practice (single 250-trial session versus 5 sessions of 50 trials each) and on the interval between the end of training and the retest (1 day versus 14 days). These results and various literature data on antimuscarinics indicate that the contrasting effects of state changes cannot be explained by simple general models. In particular, these data exclude important state dependence phenomena in the case of these agents.     

In vitro ocular metabolism and bioactivation of ketoconazole in rat,rabbit and human

Oral ketoconazole is clinically administered for treatment of severe cases for fungal keratitis. Pharmacodynamics and efficacy of oral and topical (ocular) ketoconazole have been explored in rabbit. However, metabolism of ketoconazole in the eye in any species is not well explored in any preclinical species or human. An understanding of ocular drug metabolism in the eye is crucial for ocular therapeutics to facilitate the risk assessment and development of potential drug candidates for the clinic. We aimed to investigate the metabolism of ketoconazole in rat, rabbit and human ocular S9 fractions. Metabolism in liver S9 fractions was also studied for a direct comparison. Eleven putative metabolites were identified in the in vitro incubations. Of these metabolites, six were present in rat ocular S9 whereas eight were present in rabbit and human ocular matrices. Metabolic pathways in rabbit and human ocular fractions suggested the formation of reactive intermediates in rabbit and human liver and ocular S9 incubations, which was confirmed with trapping studies. Herein, we report eight human ocular metabolites of ketoconazole for the first time. To the best of our knowledge, this is the first report of ocular metabolic pathways and ocular bioactivation of ketoconazole in preclinical species and human.     

雷公藤甲素及其氨基葡萄糖结合物的表观溶解度、表观油水分配系数和解离常数的测定

目的 测定雷公藤甲素及其氨基糖结合物的表观溶解度、表观油水分配系数和解离常数(pKTa).方法 采用平衡溶解度法、摇瓶法测定雷公藤甲素及其氨基糖结合物的表观溶解度和油水分配系数;采用分光光度指示剂法测定雷公藤甲素-氨基糖结合物的解离常数.结果 雷公藤甲素的表观溶解度随pH的增加而增加,其表观油水分配系数随pH的增加而降低,但变化并不显著.雷公藤甲素-氨基葡萄糖结合物的表观油水分布系数随pH的增加而增加,在纯水中的表观溶解度为1.9325±0.1373 g,pKT =5.938 ±0.191.结论 雷公藤甲素是一个难溶性的亲脂性化合物,而雷公藤甲素-氨基葡萄糖结合物是一个弱碱性的亲水性化合物.