Predictors of complex PTSD: the role of trauma characteristics, dissociation, and comorbid psychopathology.

BACKGROUND: Complex Posttraumatic Stress Disorder (CPTSD) has previously been associated with earlier trauma onset, repeated interpersonal traumatization, more dissociation, and more comorbid psychopathology. However, it is still debated if the afore-mentioned risk factors are related to CPTSD diagnosis or rather indicative of a more severe form of post-traumatic distress. The aim of this study was to compare patients with a CPTSD diagnosis to those with PTSD in trauma characteristics (onset, chronicity, interpersonal nature, familiarity with perpetrator), dissociation, and psychiatric comorbidities, while accounting for symptom severity. METHODS: In total, N = 81 patients with a trauma history (n = 43 with CPTSD; n = 37 with PTSD) underwent diagnostic interviews by trained clinicians and completed measures on CPTSD symptom severity, trauma characteristics, and dissociation (Screening for Complex PTSD; Dissociative Experience Scale Taxon). RESULTS: Patients with CPTSD reported earlier onset of trauma, more trauma perpetrated by acquaintances or family members, and more comorbidities than those with PTSD, also when accounting for symptom severity. No group differences in chronicity and dissociation were found. Severity of CPTSD was associated with earlier onset, familiarity with perpetrator, more comorbid (affective) disorders, and dissociation in both diagnostic groups. CONCLUSION: Findings largely confirm earlier research, suggesting that CPTSD is associated with traumatic events that start earlier in life and are perpetrated by acquaintances. Focusing on transdiagnostic symptoms, such as dissociation, may help to detain symptom deterioration. Due to the small sample size, findings need to be interpreted with caution and further research is needed to replicate findings in larger samples. Future research should also elucidate possible working mechanisms besides dissociation, such as emotion dysregulation or negative self-image.

[Targeted treatment of posttraumatic disorders-what can confrontation therapy achieve?] / Zielgerichtete Behandlung von Traumafolgestörungen ­ was kann eine konfrontative Therapie leisten?

Confrontation with aversive trauma symptoms is a key element in the treatment of stress-associated disorders, especially posttraumatic stress disorder. It is aimed at working through and reattributing aversive memories and situations. Various techniques enable confrontation in sensu (i.e. imagined) and in vivo (in reality). Confrontation techniques are highly effective; however, since there is a risk of temporarily enhanced, possibly previously suppressed traumatic memories, confrontation must be carefully prepared and revised.

The affinity of antipsychotic drugs to dopamine and serotonin 5-HT2 receptors determines their effects on prefrontal-striatal functional connectivity.

One of the major challenges of cross-species translation in psychiatry is the identification of quantifiable brain phenotypes linked to drug efficacy and/or side effects. A measure that has received increasing interest is the effect of antipsychotic drugs on resting-state functional connectivity (FC) in magnetic resonance imaging. However, quantitative comparisons of antipsychotic drug-induced alterations of FC patterns are missing. Consideration of receptor binding affinities provides a means for the effects of antipsychotic drugs on extended brain networks to be related directly to their molecular mechanism of action. Therefore, we examined the relationship between the affinities of three second-generation antipsychotics (amisulpride, risperidone and olanzapine) to dopamine and serotonin receptors and FC patterns related to the prefrontal cortex (PFC) and striatum in Sprague-Dawley rats. FC of the relevant regions was quantified by correlation coefficients and local network properties. Each drug group (32 animals per group) was subdivided into three dose groups and a vehicle control group. A linear relationship was discovered for the mid-dose of antipsychotic compounds, with stronger affinity to serotonin 5-HT2A, 5-HT2C and 5-HT1A receptors and decreased affinity to D3 receptors associated with increased prefrontal-striatal FC (p = 0.0004, r²â€¯= 0.46; p = 0.004, r²â€¯= 0.33; p = 0.002, r²â€¯= 0.37; p = 0.02, r²â€¯= 0.22, respectively). Interestingly, no correlation was observed for the low and high dose groups, and for D2 receptors. Our results indicate that drug-induced FC patterns may be linked to antipsychotic mechanism of action on the molecular level and suggest the technique's value for drug development, especially if our results are extended to a larger number of antipsychotics.

Intranasal oxytocin reduces provoked symptoms in female patients with posttraumatic stress disorder despite exerting sympathomimetic and positive chronotropic effects in a randomized controlled trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a severe psychiatric disease accompanied by neuroendocrine changes such as adrenergic overdrive and hence an elevated cardiovascular morbidity. Current pharmacotherapeutic options for PTSD are less than suboptimal, necessitating the development of PTSD-specific drugs. Although the neuropeptide oxytocin has been repeatedly suggested to be effective in PTSD treatment, there are, to our knowledge, only three studies that have assessed its efficacy on the intensity of PTSD symptoms in PTSD patients - among them one symptom provocation study in male veterans. METHODS: To evaluate for the first time how oxytocin influences the intensity of provoked PTSD symptoms and, furthermore, cardiac control in female PTSD patients, we assessed their psychic and cardiac response to trauma-script exposure with and without oxytocin pretreatment in a double-blind randomized placebo-controlled study. We used a within-subject design to study 35 female PTSD patients who received oxytocin and placebo in a 2-week interval. Furthermore, we performed a small pilot study to get an idea of the relation of the stress-modulated endogenous oxytocin levels and heart rate - we correlated oxytocin serum levels with the heart rate of 10 healthy individuals before and after exposure to the Trier Social Stress Test (TSST). RESULTS: Intranasal oxytocin treatment was followed by a reduction of provoked total PTSD symptoms, in particular of avoidance, and by an elevation in baseline and maximum heart rate together with a drop in the pre-ejection period, a marker for sympathetic cardiac control. Furthermore, we found a positive correlation between endogenous oxytocin levels and heart rate both before and after TSST challenge in healthy control subjects. CONCLUSIONS: This study provides the first evidence that oxytocin treatment reduces the intensity of provoked PTSD symptoms in female PTSD patients. The small size of both samples and the heterogeneity of the patient sample restrict the generalizability of our findings. Future studies have to explore the gender dependency and the tolerability of the oxytocin-mediated increase in heart rate. This randomized controlled trial was retrospectively registered at the German Trials Register (DRKS00009399) on the 02 October 2015.

Signal-to-noise ratio of a mouse brain (13) C CryoProbe™ system in comparison with room temperature coils: spectroscopic phantom and in vivo results.

MRI and MRS in small rodents demand very high sensitivity. Cryogenic transmit/receive radiofrequency probes (CryoProbes) designed for (1) H MRI of mouse brain provide an attractive option for increasing the performance of small-animal MR systems. As the Larmor frequency of (13) C nuclei is four times lower than that for (1) H nuclei, an even larger sensitivity improvement is expected for (13) C applications. The aim of this work was to evaluate the performance of a prototype (13) C CryoProbe™ for mouse brain MRS. To investigate the possible gain of the (13) C CryoProbe™, we acquired localized single-voxel (13) C spectra and chemical shift images of a dimethyl sulfoxide phantom with the CryoProbe™, as well as with two room temperature resonators. The cryogenically cooled resonator achieved approximately four-fold higher signal-to-noise ratio in phantom tests when compared with the best-performing room temperature coil. In addition, we present localized (13) C spectra of mouse brain obtained with the CryoProbe™, as well as with one of the room temperature coils, demonstrating the performance in vivo. In summary, the cryogenic cooling technique significantly enhances the (13) C signal sensitivity at 9.4 T and enables the investigation of metabolism within mouse brain.

[Trauma-related disorders in patients with borderline personality disorders. Results of a multicenter study]. / Traumafolgestörungen bei Patienten mit Borderline-Persönlichkeitsstörung : Ergebnisse einer Multicenterstudie.

BACKGROUND: There is current controversy about the diagnostic overlap between personality disorders and trauma-related disorders. PATIENTS AND METHODS: Applying a multicenter study design, trauma-related disorders were investigated via interview assessment in 136 patients with borderline personality disorder (BPD) in 5 specialized treatment centers. Additionally a spectrum of psychological symptoms and prevalence of lifetime traumatic experiences were assessed by questionnaire measures. RESULTS: Diagnostic overlap between BPD and PTSD was found to be high (79%) as well as the overlap of BPD with complex PTSD (55%) and severe dissociative disorders (41%). Including neglect and emotional violence as trauma categories, an extremely high prevalence of lifetime traumatic experiences was reported (96%). Experiences of sexual violence were reported by 48% of all female and 28% of all male patients. Severe forms of physical violence were reported by 65% of all patients. CONCLUSIONS: BPD patients with severe psychopathology show a high comorbidity with trauma-related disorders including dissociative disorders. This association has to be taken into account when planning psychological treatment.

Absence of changes in GABA concentrations with age and gender in the human anterior cingulate cortex: a MEGA-PRESS study with symmetric editing pulse frequencies for macromolecule suppression.

Despite MEGA-PRESS being a robust method for editing the GABA resonance, there are macromolecule resonances at the same chemical shift that are coedited with this sequence. Although this is a known problem, it is still often overlooked. We aimed to evaluate the amount of macromolecule signal coedited, as well as the gender and age dependencies for the GABA resonance at 3.01 ppm using MEGA-PRESS with two different editing pulse frequencies. Forty-five healthy subjects (21-52 years) were included in an in vivo single voxel MEGA-PRESS study at 3.0 T. Phantom measurements were conducted to measure the signal loss when switching the editing pulse between 1.5 and 1.9 ppm instead of the mostly used switching between 1.9 and 7.5 ppm. The in vivo GABA signal detected by switching the editing pulse frequencies between 1.5 and 1.9 ppm was only 50% of the mean GABA detected by switching the editing pulse frequencies between 1.9 and 7.5 ppm. No gender differences were detected. A small age dependency was observed for GABA plus macromolecules, but not for GABA, suggesting an age-dependent macromolecule increase.

[Development and validation of an inventory of ego functions and self regulation (Hannover Self-Regulation Inventory, HSRI)]. / Entwicklung und Validierung eines Fragebogens zu Ich-Funktionen und zur Selbstregulationsfähigkeit (Hannover-Selbstregulations-Inventar, HSRI).

OBJECTIVE: The aim of this study was to construct and validate a short self-rating questionnaire for the assessment of ego functions and ability of self regulation. MATERIAL AND METHODS: An item pool of 120 items covering 6 postulated dimensions was reduced by two steps in independent samples (n = 136 + 470) via factor and item analyses to the final version consisting of 35 items. RESULTS: The 5 resulting questionnaire scales "interpersonal disturbances", "frustration tolerance and impulse control", "identity disturbances", "affect differentiation and affect tolerance" and "self-esteem" were well interpretable and showed in confirmatory factor analysis the best fit to the data (CHI²/df = 3.48; RMSEA = 0.73). Total scores were found to differentiate well between diagnostic groups of patients with more or less ego pathology (FANOVA = 9.8; df = 11; p < 0.001), thus proving good concurrent validity. Reliability was shown by testing internal consistency and test-retest correlations. CONCLUSION: The "Hannover self-regulation questionnaire" (HSRQ) evidently is an appropriate and reliable screening instrument in order to assess ego functions and capacities of self regulation in an economic and user-friendly means. The scale structure allows differentiated diagnostics of weak vs. stable ego functions and may be used for detailed therapy planning.

Brief psychodynamic interpersonal psychotherapy for patients with multisomatoform disorder: randomised controlled trial.

BACKGROUND: Multisomatoform disorder is characterised by severe and disabling bodily symptoms, and pain is one of the most common and impairing of these. Furthermore, these bodily symptoms cannot be explained by an underlying organic disorder. Patients with multisomatoform disorder are commonly found at all levels of healthcare and are typically difficult to treat for physicians as well as for mental health specialists. AIMS: To test whether brief psychodynamic interpersonal therapy (PIT) effectively improves the physical quality of life in patients who have had multisomatoform disorder for at least 2 years. METHOD: We recruited 211 patients (from six German academic outpatient centres) who met the criteria for multisomatoform disorder for a randomised, controlled, 12-week, parallelgroup trial from 1 July 2006 to 1 January 2009 (International Standard Randomised Controlled Trial Number ISRCTN23215121). We randomly assigned the patients to receive either 12 weekly sessions of PIT (n = 107) or three sessions of enhanced medical care (EMC, n = 104). The physical component summary of the Short Form Health Survey (SF-36) was the pre-specified primary outcome at a 9-month follow-up. RESULTS: Psychodynamic interpersonal therapy improved patients' physical quality of life at follow-up better than EMC (mean improvement in SF-36 score: PIT 5.3, EMC 2.2), with a small to medium between-group effect size (d = 0.42, 95% CI 0.15-0.69, P = 0.001). We also observed a significant improvement in somatisation but not in depression, health anxiety or healthcare utilisation. CONCLUSIONS: This trial documents the long-term efficacy of brief PIT for improving the physical quality of life in patients with multiple, difficult-to-treat, medically unexplained symptoms.

Platelet mitochondrial dysfunction is evident in type 2 diabetes in association with modifications of mitochondrial anti-oxidant stress proteins.

OBJECTIVE: Mitochondrial dysfunction and oxidative stress in insulin responsive tissues is implicated in the pathogenesis of type 2 diabetes. Whether these perturbations extend to other tissues and contribute to their pathophysiology is less well established. The objective of this study was to investigate platelet mitochondria to evaluate whether type 2 diabetes associated mitochondrial dysfunction is evident in circulating cells. METHOD: A pilot study of mitochondrial respiratory function and proteomic changes comparing platelets extracted from insulin sensitive (n=8) and type 2 diabetic subjects (n=7). RESULTS: In-situ platelet mitochondria show diminished oxygen consumption and lower oxygen-dependent ATP synthesis in diabetic vs. control subjects. Mass spectrometric identification and confirmatory immunoblot analysis identifies induction of the mitochondrial anti-oxidant enzymes superoxide dismutase 2 and thioredoxin-dependent peroxide reductase 3 in platelets of diabetic subjects. As oxidative stress upregulates anti-oxidant enzymes we assessed mitochondrial protein carbonylation as an index of oxidative-stress. Platelets of diabetic subjects exhibit significantly increased protein carbonylation compared to controls. CONCLUSIONS: As platelets are anuclear fragments of megakaryocytes, our data suggest that the bone marrow compartment in type 2 diabetic subjects is exposed to increased mitochondrial oxidative stress with upregulation of nuclear-encoded antioxidant mitochondrial enzymes. This 'stress-signature' in platelets of diabetic subjects is associated with a diminution of their mitochondrial contribution to energy production and support that mitochondrial perturbations in type 2 diabetes extends beyond the classical insulin responsive tissues. Platelets, as "accessible human tissue", may be useful to measure the mitochondrial modulatory effects of emerging anti-diabetic therapeutics.

Affinity purification of a framework 1 engineered mouse/human chimeric IgA2 antibody from tobacco.

Complex multimeric proteins such as dimeric and secretory immunoglobulin A (IgA) can be difficult to produce in heterologous systems, although this has been achieved using several platforms including plants. As well as topical mucosal applications, dimeric IgA (dIgA), and secretory IgA (sIgA) can be used in tumor and anti-viral therapy, where their more potent cell-killing properties may increase their efficacy compared to current drugs based on IgG. However, the development of therapeutic IgA formats is hampered by the need to co-express four different polypeptides, and the inability to purify such molecules using conventional protein A or protein G affinity chromatography. The light chain (LC)-specific affinity ligand protein L is a potential alternative, but it only recognizes certain kappa light chain (LC(κ)) subtypes. To overcome these limitations, we have adapted a framework-grafting approach to introduce LCs that bind protein L into any IgA. As a model, we used the chimeric anti-human chorionic gonadotropin (hCG) antibody cPIPP, since this contains a murine LC((κ)) subtype that does not bind protein L. Grafting was achieved by replacing selected framework region 1 (FR1) residues in the cPIPP LC(κ) variable domain with corresponding residues from LC(κ) subtypes that can bind protein L. The grafted antibody variants were successfully purified by protein L affinity chromatography. These modifications affected neither their antigen-binding properties nor the yields achieved by transient expression in tobacco plants. Our results therefore show that LC FR1 grafting can be used as generic strategy for the purification of IgA molecules.

Optimal nitrogen supply as a key to increased and sustained production of a monoclonal full-size antibody in BY-2 suspension culture.

Plant cell cultures have been used as expression hosts for recombinant proteins for over two decades. The quality of plant cell culture-produced proteins such as full-size monoclonal antibodies has been shown to be excellent in terms of protein folding and binding activity, but the productivity and yield fell short of what was achieved using mammalian cell culture, in which the key to gram-per-liter expression levels was strain selection and medium/process optimization. We carried out an extensive media analysis and optimization for the production of the full-size human anti-HIV antibody 2G12 in N. tabacum cv. BY-2. Nitrogen source and availability was found to be one key factor for the volumetric productivity of plant cell cultures. Increased amounts of nitrate in the culture medium had a dramatic impact on protein yields, resulting in a 10-20-fold increase in product accumulation through a combination of enhanced secretion and higher stability. The results were scalable from shake flasks to stirred-tank bioreactors, where the maximum yield per cultivation volume was 8 mg L(-1) over 7 days. During the stationary phase, antibody levels were 150-fold higher in nitrogen-enriched medium compared to standard medium. The enhanced medium appeared not to affect antibody quality and activity, as determined by Western blots, surface plasmon resonance binding assays and N-glycan analysis.

Recent progress in plantibody technology.

Antibodies are an important class of proteins that can be used for the prevention, treatment and diagnosis of many diseases. Consequently, there is an intense and growing demand for recombinant antibodies, placing immense pressure on current production capacity which is based largely on microbial cultures and mammalian cells. Alternative systems for cost effective antibody production would be very welcome, and plants are now gaining widespread acceptance as green bioreactors with advantages in terms of cost, scalability and safety. Several plant-produced antibodies (plantibodies) are undergoing clinical trials and the first commercial approval could be only a few years away. The performance of the first generation of products has been very encouraging so far. In terms of product authenticity, differences in glycosylation between plantibodies and their mammalian counterparts have been defined, and the scientific evaluation of any possible consequences is underway. Ongoing studies are addressing the remaining biochemical constraints, and aim to further improve product yields, homogeneity and authenticity, particularly where the antibody is intended for injection into human patients. A remaining practical challenge is the implementation of large-scale production and processing under good manufacturing practice conditions that are yet to be endorsed by regulatory bodies. The current regulatory uncertainty and the associated costs represent an entry barrier for the pharmaceutical industry. However, the favourable properties of plants are likely to make the plant systems a useful alternative for small, medium and large scale production throughout the development of new antibody-based pharmaceuticals.

[Diagnostic and clinical aspects of complex post-traumatic stress disorder]. / Diagnostische und klinische Aspekte der komplexen posttraumatischen Belastungsstörung.

The symptomatology of patients suffering in the aftermath of severe and prolonged traumatization is not entirely covered by the diagnostic criteria of post-traumatic stress disorder (PTSD). Consequently, the concept of complex PTSD was proposed, including symptoms of affective dysregulation, dissociation and somatization, alterations in self-perception, altered relationships with others, and altered systems of meaning. Thereby, a variety of symptoms usually classified as co-morbid disorders are combined in a single etiological model. The whole symptomatology is considered as more or less effective adaptation strategies and not primarily as deficits. This understand-ing of the underlying etiology in subjects with complex traumatization opens perspectives for new psychotherapeutic treatment strategies which have already shown effectiveness in daily practice.

[Sphingolipid signaling: a potential pathway for TNF-alpha induced preconditioning]. / TNF alpha mime un effet de préconditionnement ischémique: un rôle pour la voie des sphingolipides.

Although cytokine activation has long been recognized to associate with cardiac ischemia and reperfusion, the concept that these cytokines may enhance some cardioprotective mechanisms has only recently been considered. Ischemic preconditioning is a biologic phenomenon that activates innate cytoprotective programs in the heart. Ischemic preconditioning has been described where a transient non-lethal ischemic "trigger" or endogenous molecules produced/released by ischemia enables the tissue to become more resistant/tolerant to subsequent potentially lethal ischemia. The mechanisms and signalling events involved in this cytoprotective program still remain obscure. Recently, it has been suggested that cytokine activation including tumour necrosis factor (TNF alpha) may play a key role in the preconditioned phenotype. Moreover, new studies have given the evidence that the exploration of cytokine-activated sphingolipid signalling pathways may enhance our understanding of the preconditioning program.

Efficacy of plant-produced recombinant antibodies against HCG.

BACKGROUND: Antibody engineering facilitates the construction of different antibody formats [single chain variable fragment (scFv), diabody, full-size chimeric monoclonal antibody] with ease. METHODS: We constructed recombinant antibodies against HCG, which is widely used in pregnancy testing and is also produced by a number of cancers. RESULTS: The recombinant antibodies were transiently expressed in tobacco leaves to levels of up to 40 mg of pure protein per kg fresh leaf weight. Enzyme linked immunosorbent assay (ELISA) and electrophoretic mobility assay (EMSA) confirmed antibody specificity for the beta subunit of beta-HCG. The efficacy was confirmed by inhibiting HCG induced testosterone production by Leydig cells in vitro and by blocking the HCG induced increase in mouse uterine weight in vivo. CONCLUSIONS: Passive immunization with recombinant HCG-specific antibodies may have clinical utility as (i) diagnostic and therapeutic tools for HCG-expressing cancers and (ii) contraceptive measures.

Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling.

The "metabolic cocktail" comprising glucose-insulin-potassium administrated at reperfusion reduces infarct size in the in vivo rat heart. We propose that insulin is the major component mediating this protection and acts via Akt prosurvival signaling. This hypothesis was studied in isolated perfused rat hearts (measuring infarct size to area of risk [%]) subjected to 35 minutes regional myocardial ischemia and 2 hours reperfusion. Insulin administered at the onset of reperfusion attenuated infarct size by >/=45% versus control hearts (P<0.001). Insulin-mediated cardioprotection was found to be independent of the presence of glucose at reperfusion. Moreover, the cell survival benefit of insulin is temporally dependent, in that insulin administration from the onset of reperfusion and maintained for either 15 minutes or for the duration of reperfusion reduced infarct size. In contrast, protection was abrogated if insulin administration was delayed until 15 minutes into reperfusion. Pharmacological inhibition of both upstream and downstream signals in the Akt prosurvival pathway abolished the cardioprotective effects of insulin. Here coadministration of insulin with the tyrosine kinase inhibitor lavendustin A, the phosphatidylinositol3-kinase (PI3-kinase) inhibitor wortmannin, and mTOR/p70s6 kinase inhibitor rapamycin abolished cardioprotection. Steady-state levels of activated/phosphorylated Akt correlated with insulin administration. Finally, downstream prosurvival targets of Akt including p70s6 kinase and BAD were modulated by insulin. In conclusion, insulin administration at reperfusion reduces myocardial infarction, is dependent on early administration during reperfusion, and is mediated via Akt and p70s6 kinase dependent signaling pathway. Moreover, BAD is maintained in its inert phosphorylated state in response to insulin therapy.

Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients.

Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase-2 (COX-2). Methotrexate is a disease-modifying agent with a narrow therapeutic index frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheumatoid arthritis. This was a randomized, double-blind, placebo-controlled study in 25 rheumatoid arthritis patients on stable doses of methotrexate. Patients received oral methotrexate (7.5 to 20 mg) on days -1, 7, 14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days 1 to 21 only to maintain a double-blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexate and its major although inactive metabolite, 7-hydroxymethotrexate. The AUC(0-infinity) geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day -1, day 14/day -1, and day 21/day -1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93, 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 for all comparisons to day -1). All AUC(0-infinity), GMR and Cmax GMR 90% CIs fell within the predefined comparability limits of (0.80, 1.25). Similar results were observed for renal clearance of methotrexate and 7-hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofecoxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasma concentrations or renal clearance (tested at the highest dose of rofecoxib) of methotrexate in rheumatoid arthritis patients.

Ischemic and pharmacological preconditioning in Girardi cells and C2C12 myotubes induce mitochondrial uncoupling.

Pharmacological uncoupling of mitochondrial oxidation from phosphorylation promotes preconditioning-like cardioprotection in the isolated rat heart. We hypothesized that modest mitochondrial uncoupling may be a critical cellular event in orchestrating preconditioning. Human-derived Girardi cells and murine C2C12 skeletal myotubes were preconditioned using simulated ischemia, adenosine, and diazoxide. Cell viability after 6 hours of simulated ischemia was measured using lactate dehydrogenase release and propidium iodide uptake. Mitochondrial inner membrane potential (DeltaPsim) was investigated by flow cytometry, cellular ATP by recombinant firefly-luciferase bioluminescence, and cellular oxygen consumption using oximetry. Preconditioning enhanced cell viability with attenuation of lactate dehydrogenase release (>/=30%, P<0.05 versus ischemic controls) and a reduction in propidium iodide uptake by >/=26% versus ischemic controls after simulated ischemia in both cell lines. In Girardi cells, preconditioning induced the following phenotype immediately before index ischemia: (1) decreased DeltaPsim (JC-1: simulated ischemia 90+/-3%, adenosine 82+/-7%, diazoxide 87+/-4%, versus control 100%, P<0.05); (2) attenuation in cellular ATP levels (CTL 0.21+/-0.03 nmol/L ATP/microg protein, simulated ischemia 0.12+/-0.02, adenosine 0.15+/-0.02, diazoxide 0.11+/-0.02, P<0.05); and (3) enhanced cellular oxygen consumption (control 2.3+/-0.1 nmol/L oxygen/min/1x10(6) cells, simulated ischemia 3.1+/-0.1, adenosine 3.1+/-0.3, diazoxide 2.6+/-0.2, P<0.05). Cytoprotection, mitochondrial depolarization, and enhanced oxygen consumption were attenuated by the putative mitochondrial K(ATP)-channel antagonist 5-hydroxydecanoate. The uncoupled phenotype in response to preconditioning was similarly observed in C2C12 myotubes. The present study suggests that modest mitochondrial uncoupling represents a unifying cellular response which may be important in directing preconditioning-mediated cytoprotection.

[Study quality and effect-sizes - a metaanalysis of EMDR-treatment for posttraumatic stress disorder]. / Metaanalyse der Studien zur EMDR-Behandlung von Patienten mit posttraumatischen Belastungsstörungen - Der Einfluss der Studienqualität auf die Effektstärken -

Although the good efficacy of eye movement desensitization and reprocessing (EMDR) in the treatment of patients with PTSD is up to now documented by a number of studies, this new treatment technique is still the target of highly controversial critique. Our meta-analysis tries to answer the question of whether EMDR-therapy studies with higher quality standards achieve better results than others. Therefore, all published studies underwent a scoring procedure of study quality and effect sizes were computed. It can be shown that carefully planned studies, including treatment by well-trained therapists and with a sufficiently high number of treatment session achieve better results compared to studies with low methodological standards.