Mentalization-oriented psychodynamic group therapy for patients with personality disorders: a naturalistic prospective cohort study.

OBJECTIVES: Patients with personality disorders (PDs) are often treated with non-manualized psychodynamic group therapy (PDT) lasting for several years. Non-manualized PDT often combines a variety of therapeutic approaches from different PDT traditions, including mentalization-based therapy. Currently, little is known about the effect of this long-term, costly treatment. This study investigated the extent to which patients with different PDs benefit from mentalization-oriented PDT as it is implemented in clinical practice in terms of symptom severity, interpersonal problems, and general functioning. METHODS: The design was a naturalistic, prospective cohort study. Seventy-five consecutive PD patients were assessed before treatment with the Symptom Checklist-90 Revised (SCL-90-R) as the primary outcome measure and the Inventory of Interpersonal Problems (IIP) and Global Assessment of Functioning (GAF) as secondary outcome measures. The sample was repeatedly assessed every 12 months for up to 36 months. Paired t-tests were applied to examine the effectiveness of the intervention. RESULTS: Among completers (n = 42; 56%), improvement was observed on the SCL-90-R: Global Severity Index (mean change = -0.45 [95% CI = -0.72, -0.19]; Cohen's d = -0.55), Positive Symptom Distress Index (-0.40 [-0.63, -0.17]; -0.56); Positive Symptoms Total (-10.70 [-17.31, -4.09]; -0.52). Secondary outcomes also improved: IIP-total (mean change = -0.50 [95%CI = -0.74, -0.25]; Cohen's d = -0.66); GAF-Functioning (8.79 [6.32, 11.27]; 1.15); and GAF-Symptoms (10.67 [8.09, 13.25]; 1.34). CONCLUSIONS: Completers improved on symptom severity, interpersonal problems, and general functioning, with within-group effect sizes ranging from medium to large. Approximately half the sample dropped out, suggesting that mentalization-oriented PDT spanning several years may be unrealistic for many patients with PD. Significant outcomesThere are no clear guidelines for psychological interventions targeting personality disorders (PDs), and currently eclectic and non-manualized psychodynamic approaches lasting for up to 3 years are prevailing in some clinical practices.Although this treatment approach may have an effect on compliant patients, the high drop-out rate indicates that it may not be suitable for a large proportion of PD patients since it requires long-term commitment. Furthermore, it is difficult to identify the content of the non-manualized psychodynamic therapy and what helps the patients.More specific clinical guidelines emphasizing the application of evidence-based treatments or at least manualized treatments are warranted for the treatment of emotionally unstable PDs and other PDs. LimitationsThe naturalistic study design, without any control group, limits conclusions about mechanisms of action of the intervention.Since the intervention was not manualized, it is unknown exactly which treatment was actually administered, which reduces external validity.The outcomes are based on completer data of a relatively small sample size with high drop-out rate.

Relapse prevention for alcohol use disorders: combined acamprosate and cue exposure therapy as aftercare.

AIMS: Many patients with alcohol use disorders are challenged by cravings leading to repeated relapses. Both cue exposure therapy (CET) and acamprosate target alcohol cravings and are often combined (CET + acamprosate). The main aim of this study was to investigate whether aftercare treatment consisting of CET combined with acamprosate is equivalent to (A) CET as monotherapy, (B) aftercare as usual (AAU) as monotherapy or (C) AAU combined with acamprosate. METHODS: Patients were randomized to receive either CET with urge-specific coping skills (USCS) as aftercare or AAU. Acamprosate prescription data were extracted from patient case records. Alcohol consumption, cravings, and USCS were assessed at pre-aftercare, post-aftercare, and 6-month follow-up. RESULTS: Overall, patients increased their alcohol consumption during and following aftercare treatment, thereby relapsing despite any treatment. However, CET + acamprosate achieved greater abstinence compared to AAU + acamprosate at follow-up (p=.047). CET + acamprosate also reduced number of drinking days (p=.020) and number of days with excessive drinking (p=.020) at post-aftercare, when compared to AAU monotherapy. CET monotherapy increased sensible drinking at post-aftercare compared to AAU monotherapy (p=.045) and AAU + acamprosate (p=.047). Only CET monotherapy showed improvement in cravings, when compared to AAU at follow-up (mean urge level: p=.032; peak urge level: p=.014). CONCLUSION: The study showed that CET both as monotherapy and combined with acamprosate was superior to AAU monotherapy and AAU + acamprosate in reducing alcohol consumption. Only CET + acamprosate was capable of reducing alcohol consumption in the longer term, indicating that anti-craving medication may not impede CET from exerting an effect on alcohol consumption. Trial registration: ClinicalTrials.gov ID: NCT02298751 (24/11-2014).

Acute Neurofilament Light Chain Plasma Levels Correlate With Stroke Severity and Clinical Outcome in Ischemic Stroke Patients.

Background: Ischemic stroke causes increased blood-brain barrier permeability and release of markers of axonal damage and inflammation. To investigate diagnostic and prognostic roles of neurofilament light chain (NF-L), we assessed levels of NF-L, S100B, interleukin-6 (IL-6), E-selectin, vascular endothelial growth factor-A (VEGF-A), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in patients with acute ischemic stroke or transient ischemic attack (TIA) and healthy controls. Methods: We studied neurofilament (NF) expression in 2 cases of human postmortem ischemic stroke, representing infarcts aged 3- to >7-days. In a prospective study, we measured plasma NF-L and inflammatory markers <8 h of symptom onset and at 72 h in acute ischemic stroke (n = 31), TIA (n = 9), and healthy controls (n = 29). We assessed whether NF-L, S100B, and IL-6 were associated with clinical severity on admission (Scandinavian Stroke Scale, SSS), diagnosis of ischemic stroke vs. TIA, and functional outcome at 3 months (modified Rankin Scale, mRS). Results: NF expression increased in ischemic neurons and in the infarcted brain parenchyma after stroke. Plasma NF-L levels were higher in stroke patients than in TIA patients and healthy controls, but IL-6 levels were similar. Higher acute NF-L levels were associated with lower SSS scores at admission and higher mRS scores at 3 months. No correlation was observed between NF-L and S100B, NF-L and IL-6, nor between S100B or IL-6 and SSS or mRS. Compared to controls, stroke patients had significantly higher VEGF-A and VCAM-1 at <8 h that remained elevated at 72 h, with significantly higher VEGF-A at <8 h; ICAM-1 was significantly increased at <8 h, while S100B and E-selectin were unchanged. Conclusions: Plasma NF-L levels, but not IL-6 and S100B, were significant predictors of clinical severity on admission and functional outcome at 3 months. Plasma NF-L is a promising biomarker of functional outcome after ischemic stroke.

Dicarbonyl derived post-translational modifications: chemistry bridging biology and aging-related disease.

In living systems, nucleophilic amino acid residues are prone to non-enzymatic post-translational modification by electrophiles. α-Dicarbonyl compounds are a special type of electrophiles that can react irreversibly with lysine, arginine, and cysteine residues via complex mechanisms to form post-translational modifications known as advanced glycation end-products (AGEs). Glyoxal, methylglyoxal, and 3-deoxyglucosone are the major endogenous dicarbonyls, with methylglyoxal being the most well-studied. There are several routes that lead to the formation of dicarbonyl compounds, most originating from glucose and glucose metabolism, such as the non-enzymatic decomposition of glycolytic intermediates and fructosyl amines. Although dicarbonyls are removed continuously mainly via the glyoxalase system, several conditions lead to an increase in dicarbonyl concentration and thereby AGE formation. AGEs have been implicated in diabetes and aging-related diseases, and for this reason the elucidation of their structure as well as protein targets is of great interest. Though the dicarbonyls and reactive protein side chains are of relatively simple nature, the structures of the adducts as well as their mechanism of formation are not that trivial. Furthermore, detection of sites of modification can be demanding and current best practices rely on either direct mass spectrometry or various methods of enrichment based on antibodies or click chemistry followed by mass spectrometry. Future research into the structure of these adducts and protein targets of dicarbonyl compounds may improve the understanding of how the mechanisms of diabetes and aging-related physiological damage occur.

Postnatal depressive symptoms display marked similarities across continents.

BACKGROUND: Postnatal depressive symptoms measured by the Edinburgh Postnatal Depression Scale (EPDS) are reported to display measurement variance regarding factor structure and the frequency of specific depressive symptoms. However, postnatal depressive symptoms measured by EPDS have not been compared between women representing three continents. METHODS: A cross-sectional study including birth cohort samples from Denmark, Vietnam and Tanzania. Women were included during pregnancy at routine care sites. Depressive symptoms were self-reported 40-90 days postpartum using the EPDS. Exploratory and confirmatory factor analyses and generalized additive regression models were performed. RESULTS: A total of N = 4,516 participated in the study (Denmark N = 2,069, Vietnam N = 1,278, Tanzania N = 1,169). Factor analyses identified three factors (anhedonia, anxiety and depression) that were almost identical in the three study populations. The only variation between countries was that the item 'self-harm' loaded differently. Women from Tanzania and Denmark were more likely to have an EPDS total score above cut-off 12 (12.6% and 6.4%), compared to women from Vietnam (1.9%) (p<0.001). A low level of education was associated with significantly more depressive symptoms after adjusting for country (p<0.001). LIMITATIONS: EPDS data was collected at a later time point in the Danish sample. CONCLUSIONS: Postnatal depressive symptoms constitute a three-factor model across cultures including the factors anhedonia, anxiety and depression. The frequency of postnatal depressive symptoms differs between high-, medium-, and low-income countries. However, clinicians should bear in mind that low-educated women worldwide are more likely to experience postnatal depressive symptoms.

Videoconferences and Treatment of Depression: Satisfaction Score Correlated with Number of Sessions Attended but Not with Age.

Aim: To investigate whether there is a correlation between age and satisfaction with the use of videoconferences (VCs) and whether the number of video sessions had an impact on satisfaction. Methods: This study was a subanalysis of the joint European project, MasterMind, and participants were recruited from15 pilot studies in 11 different countries. The Client Satisfaction Questionnaire 8 (CSQ 8) was used as assessment tool, and scores were summed to give total scores. Results: Participants were included if they had filled out the CSQ 8 questionnaire and demographic data were available. This resulted in a total of 199 participants. We found that the total score was not significantly correlated with age (Spearman's rho = -0.0415, p = 0.563) and gender (Wilcoxon W = 5,066, p = 0.409). There was a significant positive correlation between number of sessions attended (Spearman's rho = 0.5777, p < 0.001) and total score after adjusting for age, gender, region, symptoms score, and education level in a multiple linear regression model (coefficient = 0.170, SE = 0.059, p = 0.004). Excluded responders were significantly younger than included responders, had lower symptoms score, attended fewer sessions, had a higher education, and were more likely to be employed.Conclusions: VC satisfaction scores in patients with unipolar depression do not depend on age but increase with experience in all age groups.

Disagreement in Satisfaction Between Patients and Providers in the Use of Videoconferences by Depressed Adults.

Aim: To evaluate whether there was a difference in satisfaction scores between providers and patients in the use of videoconferences (VCs) by depressed adults. Method: This study was a subanalysis of the joint European project, MasterMind, and participants were recruited from 15 pilot studies in 11 different countries. The Client Satisfaction Questionnaire (CSQ)-3 was used as assessment tool, and scores were summed to give total scores. The questionnaire consists of three items evaluating general satisfaction, fulfillment of needs in treatment, and usability. Results: A total of 362 respondents, 201 patients and 161 providers, completed the questionnaire. Providers had a mean total CSQ-3 score of 9.17 (95% confidence interval [CI] = 8.90-9.45), whereas patients had a mean of 9.70 (95% CI = 9.44-9.98). Mean scores for item 1 (the extent to which VCs had met the needs of the participants): patients 3.19, providers 2.93 (p = 0.00048); for item 2 (general satisfaction): patients 3.22, providers 3.08 (p = 0.083); and item 3 (whether participants wanted to use VCs again): patients 3.28 providers 3.16 (p = 0.045).Conclusion: The results showed that total satisfaction scores were higher in patients than in providers. The differences between patients and providers were significant for items 1 and 3 (p < 0.05), but we did not find a significant difference regarding item 2.

Work addiction is associated with increased stress and reduced quality of life: Validation of the Bergen Work Addiction Scale in Danish.

Addiction to work is defined as a compulsion or an uncontrollable need to work incessantly. Only few measures exist to identify work addiction and the health consequences are sparsely explored. The Bergen Workaholic Scale (BWAS) measures seven core elements of work addiction and has been used in Norway, Hungary, Brazil, Italy, USA and Poland. The aim of this study was to validate the BWAS in a Danish sample and to investigate if high risk of work addiction was associated with stress and reduced quality of life. We conducted an online screening survey with 671 participants aged 16-68 years with the Danish translation of the BWAS. We added the perceived stress scale (PSS) and the quality of life scale EQ-5D-5L. Those with high risk of work addiction reported significantly higher mean PSS scores (20.0 points) compared to those with low risk of addiction (12.5 points) and poorer quality of life (61.9) compared to the low risk group (81.3). Furthermore, work addiction was associated with more weekly working hours (44.0 vs. 35.6 hours/week) and having more leadership responsibility. A preliminary estimate of work addiction prevalence was 6.6%. The BWAS demonstrated good reliability (α = 0.83), and factor analyses pointed at a single factor structure. Work addiction seems to be associated with health problems in terms of stress and poorer quality of life. The BWAS is recommended as a reliable and valid tool to identify work addiction in Danish.

Dimensions and subtypes of oppositionality and their relation to comorbidity and psychosocial characteristics.

The symptoms of oppositional defiant disorder (ODD), or oppositionality, seem to constitute a three-dimensional structure of angry/irritable, vindictiveness and argumentative behavior dimensions. Also, subjects with oppositionality are characterized by different comorbidity and longitudinal trajectories, suggesting that they could be divided into subtypes. This study is the first to examine the dimensions and subtypes of oppositionality in Nordic children. Study participants included 3435 children aged 7-10 years from the Danish National Birth Cohort. Information was collected using the Development and Well-Being Assessment (DAWBA) online version. A three-factor ODD model was identified. The angry/irritable dimension was associated with emotional problems and disorders, fewer social skills and fewer personal positive attributes. The argumentative behavior dimension was associated with hyperactivity/conduct problems, reduced social skills and positive attributes. The vindictiveness dimension was associated with externalizing, internalizing and prosocial problems. Four ODD subtypes were identified. The subtypes with many or mainly angry/irritable symptoms were characterized by comorbid psychopathology, increased functional impairment and psychosocial problems. Children with ODD had fewer positive attributes, more friendship/school problems and higher functional impairment than children with emotional disorders and control group children. Oppositionality consists of three dimensions differently associated with comorbidity and psychosocial characteristics, and the same pattern is seen for the four ODD subtypes identified in this study. Children with ODD experience more adversities and functional impairment than children with emotional disorders. Our results indicate that treatment of children with ODD would improve from extended knowledge on individual ODD dimensions and subtypes and the related child psychosocial characteristics.

Profiling of Methylglyoxal Blood Metabolism and Advanced Glycation End-Product Proteome Using a Chemical Probe.

Methylglyoxal (MG) is quantitatively the most important precursor to advanced glycation end-products (AGEs), and evidence is accumulating that it is also a causally linked to diabetes and aging related diseases. Living systems primarily reside on the glyoxalase system to detoxify MG into benign d-lactate. The flux to either glycation or detoxification, accordingly, is a key parameter for how well a system handles the ubiquitous glyoxal burden. Furthermore, insight into proteins and in particular their individual modification sites are central to understanding the involvement of MG and AGE in diabetes and aging related diseases. Here, we present a simple method to simultaneously monitor the flux of MG both to d-lactate and to protein AGE formation in a biological sample by employing an alkyne-labeled methylglyoxal probe. We apply the method to blood and plasma to demonstrate the impact of blood cell glyoxalase activity on plasma protein AGE formation. We move on to isolate proteins modified by the MG probe and accordingly can present the first general inventory of more than 100 proteins and 300 binding sites of the methylglyoxal probe on plasma as well as erythrocytic proteins. Some of the data could be validated against a number of in vivo and in vitro targets for advanced glycation previously known from the literature; the majority of proteins and specific sites however were previously unknown and may guide future research into MG and AGE to elucidate how these are functionally linked to diabetic disease and aging.

APD-Containing Cyclolipodepsipeptides Target Mitochondrial Function in Hypoxic Cancer Cells.

The natural product family of macrocyclic lipodepsipeptides containing the 4-amido-2,4-pentadienoate functionality possesses intriguing cytotoxic selectivity toward hypoxic cancer cells. These subpopulations of cancer cells display increased metastatic potential and resistance to chemo- and radiotherapy. In this paper, we present studies on the mechanism of action of these natural products in hypoxic cancer cells and show that this involves rapid and hypoxia-selective collapse of mitochondrial integrity and function. These events drive a regulated cell death process that potentially could function as a powerful tool in the fight against chemo- and radiotherapy-resistant cancer cells. Toward that end, we demonstrate activity in two different mouse tumor models.

Ketone Body Acetoacetate Buffers Methylglyoxal via a Non-enzymatic Conversion during Diabetic and Dietary Ketosis.

The α-oxoaldehyde methylglyoxal is a ubiquitous and highly reactive metabolite known to be involved in aging- and diabetes-related diseases. If not detoxified by the endogenous glyoxalase system, it exerts its detrimental effects primarily by reacting with biopolymers such as DNA and proteins. We now demonstrate that during ketosis, another metabolic route is operative via direct non-enzymatic aldol reaction between methylglyoxal and the ketone body acetoacetate, leading to 3-hydroxyhexane-2,5-dione. This novel metabolite is present at a concentration of 10%-20% of the methylglyoxal level in the blood of insulin-starved patients. By employing a metabolite-alkyne-tagging strategy it is clarified that 3-hydroxyhexane-2,5-dione is further metabolized to non-glycating species in human blood. The discovery represents a new direction within non-enzymatic metabolism and within the use of alkyne-tagging for metabolism studies and it revitalizes acetoacetate as a competent endogenous carbon nucleophile.

Quantitative assessment of methyl-esterification and other side reactions in a standard propionylation protocol for detection of histone modifications.

Histone modifications play an important role in regulating chromatin stability and gene expression, but to date, investigating them remains challenging. In order to obtain peptides suitable for MS-based analysis, chemical derivatization of N-terminus and lysine residues by propionic anhydride is commonly performed. Several side reactions (methyl-esterification, amidation, solvolysis, overpropionylation, and missed propionylation) during propionylation protocols have been described, yet their relative abundances remain vague. Because methyl-esterification could interfere with correct interpretation of the modification pattern, it is essential to take measures to avoid it. Here we present in-depth quantitative analyses of methyl-esterification and the other side reactions in a standard propionylation protocol containing methanol, and when replacing methanol with isopropanol or acetonitrile. We show that the use of alternative solvents can eliminate methyl-esterification and that even though other side reactions are not prevented, their contribution can be kept relatively small. We also show that replacing methanol can be of importance also in other proteomics methods, such as mixed cation exchange, using methanol under acidic conditions.

A cleavable azide resin for direct click chemistry mediated enrichment of alkyne-labeled proteins.

The direct conjugation of a labeled proteome to a cleavable azide resin utilizing the copper-catalyzed azide alkyne cycloaddition is demonstrated. The procedure omits the classical streptavidin- and biotin-based affinity enrichment step and represents an operationally simpler, cheaper and less contaminated alternative for protein purification.

Development of a chemical probe for identifying protein targets of α-oxoaldehydes.

The development of a chemical probe for identifying the protein targets of reactive electrophilic α-oxoaldehydes such as methylglyoxal is presented. The probe is evaluated against methylglyoxal using human serum albumin as well as using living cells and lysates.