Possible Role of Correlation Coefficients and Network Analysis of Multiple Intracellular Proteins in Blood Cells of Patients with Bipolar Disorder in Studying the Mechanism of Lithium Responsiveness: A Proof-Concept Study.

Background: The mechanism of lithium treatment responsiveness in bipolar disorder (BD) remains unclear. The aim of this study was to explore the utility of correlation coefficients and protein-to-protein interaction (PPI) network analyses of intracellular proteins in monocytes and CD4+ lymphocytes of patients with BD in studying the potential mechanism of lithium treatment responsiveness. Methods: Patients with bipolar I or II disorder who were diagnosed with the MINI for DSM-5 and at any phase of the illness with at least mild symptom severity and received lithium (serum level ≥ 0.6 mEq/L) for 16 weeks were divided into two groups, responders (≥50% improvement in Montgomery-Asberg Depression Rating Scale and/or Young Mania Rating Scale scores from baseline) and non-responders. Twenty-eight intracellular proteins/analytes in CD4+ lymphocytes and monocytes were analyzed with a tyramine-based signal-amplified flow cytometry procedure. Correlation coefficients between analytes at baseline were estimated in both responders and non-responders and before and after lithium treatment in responders. PPI network, subnetwork, and pathway analyses were generated based on fold change/difference in studied proteins/analytes between responders and non-responders. Results: Of the 28 analytes from 12 lithium-responders and 11 lithium-non-responders, there were more significant correlations between analytes in responders than in non-responders at baseline. Of the nine lithium responders with pre- and post-lithium blood samples available, the correlations between most analytes were weakened after lithium treatment with cell-type specific patterns in CD4+ lymphocytes and monocytes. PPI network/subnetwork and pathway analyses showed that lithium response was involved in four pathways, including prolactin, leptin, neurotrophin, and brain-derived neurotrophic factor pathways. Glycogen synthase kinase 3 beta and nuclear factor NF-kappa-B p65 subunit genes were found in all four pathways. Conclusions: Using correlation coefficients, PPI network/subnetwork, and pathway analysis with multiple intracellular proteins appears to be a workable concept for studying the mechanism of lithium responsiveness in BD. Larger sample size studies are necessary to determine its utility.

Cell-type specific molecular expression levels by restricted-dimensional cytometry.

BACKGROUND: Cytometric analysis has been commonly used to delineate distinct cell subpopulations among peripheral blood mononuclear cells by the differential expression of surface receptors. This capability has reached its apogee with high-dimensional approaches such as mass cytometry and spectral cytometry that include simultaneous assessment of 20-50 analytes. Unfortunately, this approach also engenders significant complexity with analytical and interpretational pitfalls. METHODS: Here, we demonstrate a complementary approach with restricted-dimensionality to assess cell-type specific intracellular molecular expression levels at exceptional levels of precision. The expression of five analytes was individually assessed in four mononuclear cell-types from peripheral blood. RESULTS: Distinctions in expression levels were seen between cell-types and between samples from different donor groups. Mononuclear cell-type specific molecular expression levels distinguished pregnant from nonpregnant women and G-CSF-treated from untreated persons. Additionally, the precision of our analysis was sufficient to quantify a novel relationship between two molecules-Rel A and translocator protein-by correlational analysis. CONCLUSIONS: Restricted-dimensional cytometry can provide a complementary approach to define characteristics of cell-type specific intracellular protein and phosphoantigen expression in mononuclear cells.

Evidence of deviant parasympathetic response to social exclusion in women with borderline personality disorder.

Stressful social situations like social exclusion are particularly challenging for patients with borderline personality disorder (BPD) and often lead to dysfunctional reactive behaviour of aggression and withdrawal. The autonomous signature of these core symptoms of BPD remains poorly understood. The present study investigated the parasympathetic response to social exclusion in women with BPD (n = 62) and healthy controls (HC; n = 87). In a between-subjects design, participants experienced objective social exclusion or overinclusion in the Cyberball task, a virtual ball-tossing game. Need threat scores served as individual measures of perceived exclusion and the resulting frustration of cognitive-emotional needs. Five-minute measurements of high-frequency heart rate variability (HF-HRV) at three time points (before, during, after Cyberball) indicated parasympathetic tone and regulation. We observed a trend towards lowered baseline HF-HRV in BPD vs. HC in line with previous findings. Interestingly, the parasympathetic response of patients with BPD to objective and perceived social exclusion fundamentally differed from HC: higher exclusion was associated with increased parasympathetic activation in HC, while this autonomic response was reversed and blunted in BPD. Our findings suggest that during social stress, the parasympathetic nervous system fails to display an adaptive regulation in patients with BPD, but not HC. Understanding the autonomous signature of the stress response in BPD allows the formulation of clinically relevant and biologically plausible interventions to counteract parasympathetic dysregulation in this clinical group.

Causes, clinical characteristics, and outcomes of high lithium levels and intoxications: Retrospective analysis of patient records.

BACKGROUND: The mood stabilizer lithium has a narrow therapeutic index with a relevant risk of intoxication. We used real-world hospital data to identify causes, treatment courses, and outcomes of high lithium levels and intoxications. METHODS: Retrospective chart review of patients with a lithium concentration of ⩾1.1 mmol/L, who were treated at Charité University Medical Center Berlin. RESULTS: We identified 136 patients (58% women; mean age: 54.7 years) with high lithium levels or intoxication. 66.9% were chronic (stable lithium dose but changes in other variables such as co-medication). 40.4% took at least one risk medication with a relative contraindication for concurrent lithium treatment. 11.1% of the cases with a high therapeutic level showed moderate to severe intoxications. Feverish infections were significantly associated with severe intoxications. Overall, 97.1% (132/136) of patients fully recovered, two had residual but mild symptoms and two died during hospitalization (unlikely related to the intoxication). In 37.5% of patients, no psychiatrist was involved in the management of high lithium levels or intoxication. In these patients, lithium treatment was adjusted or discontinued in 37.3% of the cases compared to 64.7% when a psychiatrist was involved (χ²(1) = 9.683, p = 0.002). CONCLUSIONS: Patients and medical doctors should be aware of the increased risk of lithium intoxication already within the high therapeutic range and should consider alternative medications without relative contraindications for concurrent lithium use. Involving psychiatrists during or after an intoxication event is associated with more frequent adjustment of the maintenance lithium dose and should be considered in most cases.

Differences in intracellular protein levels in monocytes and CD4+ lymphocytes between bipolar depressed patients and healthy controls: A pilot study with tyramine-based signal-amplified flow cytometry.

BACKGROUND: Molecular biomarkers for bipolar disorder (BD) that distinguish it from other manifestations of depressive symptoms remain unknown. The aim of this study was to determine if a very sensitive tyramine-based signal-amplification technology for flow cytometry (CellPrint™) could facilitate the identification of cell-specific analyte expression profiles of peripheral blood cells for bipolar depression (BPD) versus healthy controls (HCs). METHODS: The diagnosis of psychiatric disorders was ascertained with Mini International Neuropsychiatric Interview for DSM-5. Expression levels for eighteen protein analytes previously shown to be related to bipolar disorder were assessed with CellPrint™ in CD4+ T cells and monocytes of bipolar patients and HCs. Implementation of protein-protein interaction (PPI) network and pathway analysis was subsequently used to identify new analytes and pathways for subsequent interrogations. RESULTS: Fourteen drug-naïve or -free patients with bipolar I or II depression and 17 healthy controls (HCs) were enrolled. The most distinguishable changes in analyte expression based on t-tests included GSK3ß, HMGB1, IRS2, phospho-GSK3αß, phospho-RELA, and TSPO in CD4+ T cells and calmodulin, GSK3ß, IRS2, and phospho-HS1 in monocytes. Subsequent PPI and pathway analysis indicated that prolactin, leptin, BDNF, and interleukin-3 signal pathways were significantly different between bipolar patients and HCs. LIMITATION: The sample size of the study was small and 2 patients were on medications. CONCLUSION: In this pilot study, CellPrint™ was able to detect differences in cell-specific protein levels between BPD patients and HCs. A subsequent study including samples from patients with BPD, major depressive disorder, and HCs is warranted.

Divergent Directionality of Immune Cell-Specific Protein Expression between Bipolar Lithium Responders and Non-Responders Revealed by Enhanced Flow Cytometry.

Background and Objectives: There is no biomarker to predict lithium response. This study used CellPrint™ enhanced flow cytometry to study 28 proteins representing a spectrum of cellular pathways in monocytes and CD4+ lymphocytes before and after lithium treatment in patients with bipolar disorder (BD). Materials and Methods: Symptomatic patients with BD type I or II received lithium (serum level ≥ 0.6 mEq/L) for 16 weeks. Patients were assessed with standard rating scales and divided into two groups, responders (≥50% improvement from baseline) and non-responders. Twenty-eight intracellular proteins in CD4+ lymphocytes and monocytes were analyzed with CellPrint™, an enhanced flow cytometry procedure. Data were analyzed for differences in protein expression levels. Results: The intent-to-treat sample included 13 lithium-responders (12 blood samples before treatment and 9 after treatment) and 11 lithium-non-responders (11 blood samples before treatment and 4 after treatment). No significant differences in expression between the groups was observed prior to lithium treatment. After treatment, the majority of analytes increased expression in responders and decreased expression in non-responders. Significant increases were seen for PDEB4 and NR3C1 in responders. A significant decrease was seen for NR3C1 in non-responders. Conclusions: Lithium induced divergent directionality of protein expression depending on the whether the patient was a responder or non-responder, elucidating molecular characteristics of lithium responsiveness. A subsequent study with a larger sample size is warranted.

Impact of social exclusion on empathy in women with borderline personality disorder.

Unstable interpersonal relationships and fear of abandonment are core symptoms of borderline personality disorder (BPD) that often intensify during stress. Psychosocial stress, which includes components of social exclusion and increases cortisol secretion, enhances emotional empathy in healthy individuals. Women with BPD, on the contrary, react with reduced emotional empathy. The aim of the present study was to investigate the effects of perceived social exclusion without accompanying cortisol increase on empathy in women with BPD and healthy women. To induce social exclusion, we randomized 98 women with BPD and 98 healthy women to either an exclusion or an overinclusion (control) condition of Cyberball, a virtual ball game. Subsequently, participants underwent the Multifaceted Empathy Test (MET), which assesses cognitive and emotional empathy. There was no increase in cortisol release after Cyberball. Cognitive empathy did not differ between groups or conditions. Women with BPD reported lower emotional empathy for positive emotions (group by valence interaction), but not for negative emotions. Exploratory analyses suggested that this effect might be more pronounced after social exclusion. Our results confirm previous findings that cognitive empathy does not differ between women with BPD and healthy women and extend this evidence to social exclusion. Emotional empathy in women with BPD seems to be more sensitive to the effects of stress or ambiguous social situations. Specifically, emotional empathy seems to be reduced for positive emotions, and might further decline after social exclusion. Empathic reactions to emotional stimuli of different valences and to specific emotions should be further investigated.

Coping and well-being of school-aged children in a quarantined environment during the COVID- 19 pandemic

BACKGROUND@#School-aged children bear a lot of difficulties and discomforts brought about by the new normal during the COVID-19 pandemic.@*OBJECTIVES@#This study aimed to examine the general well-being of children during the pandemic, how the children are coping with all the challenges, and parents' strategies to help their children cope@*METHODOLOGY@#This study utilized a descriptive correlational research design with purposive sampling. Data was collected through an online survey. The standardized Kidcope-Child version was utilized to measure children's coping, while the Pediatric Quality of Life Inventory (PedsQL)™ 4.0 Short Form 15 Generic Core Scales was utilized to measure the children's well-being.@*RESULTS@#A total of 134 parents participated in the study. No significant relationship was found between the age, sex, and coping strategies of the children, as well as between the age and well-being of children. Male children experienced more difficulty in physical functioning (p-value= 0.028), social functioning (p-value= 0.017), and overall well-being (p-value= 0.031) compared to female children. The computed mean for parents' helping strategies was between 2.67 to 2.78, which lies between the categories of sometimes (2) to always (3).@*CONCLUSION@#School-aged children were found to be using more positive coping strategies than negative coping strategies during the pandemic. They have “sometimes” to “almost no” experience of difficulty in terms of the five functions of well-being. Parents used the six fundamental tasks of parenting to help their children cope.

No influence of mineralocorticoid and glutamatergic NMDA receptor stimulation on spatial learning and memory in individuals with major depression.

BACKGROUND: Major depressive disorder (MDD) is associated with impairments in spatial learning and memory and with altered functioning of central mineralocorticoid receptors (MR) and glutamatergic N-methyl-D-aspartate receptors (NMDA-R). Both receptors are highly expressed in the hippocampus and prefrontal cortex - brain areas that are critical for spatial learning and memory. Here, we examined the effects of separate and combined MR and NMDA-R stimulation on spatial learning and memory in individuals with MDD and healthy controls. METHODS: We used a randomized, double-blind, placebo-controlled between-group study design to examine the effects of separate and combined stimulation of the MR (with 0.4 mg fludrocortisone) and NMDA-R (with 250 mg D-cycloserine) in 116 unmedicated individuals with MDD (mean age: 34.7 ± 13.3 years; 78.4% women) and 116 age-, sex-, and education-matched healthy controls. Participants were randomly assigned to one of four conditions: 1) placebo; 2) MR stimulation; 3) NMDA-R stimulation; and 4) combined MR/NMDA-R stimulation. Three hours after drug administration, spatial learning and memory were assessed using a virtual Morris Water Maze task. RESULTS: Individuals with MDD and healthy controls did not differ in spatial learning and memory performance. Neither separate nor combined MR or NMDA-R stimulation altered measures of spatial performance. CONCLUSION: In this study of relatively young, predominantly female, and unmedicated individuals, we found no effect of MDD and no effect of separate or combined MR and NMDA-R stimulation on spatial learning and memory.

Patients' Perspectives on Artificial Intelligence in Dentistry: A Controlled Study.

Background: As artificial intelligence (AI) becomes increasingly important in modern dentistry, we aimed to assess patients' perspectives on AI in dentistry specifically for radiographic caries detection and the impact of AI-based diagnosis on patients' trust. Methods: Validated questionnaires with Likert-scale batteries (1: "strongly disagree" to 5: "strongly agree") were used to query participants' experiences with dental radiographs and their knowledge/attitudes towards AI as well as to assess how AI-based communication of a diagnosis impacted their trust, belief, and understanding. Analyses of variance and ordinal logistic regression (OLR) were used (p < 0.05). Results: Patients were convinced that "AI is useful" (mean Likert ± standard deviation 4.2 ± 0.8) and did not fear AI in general (2.2 ± 1.0) nor in dentistry (1.6 ± 0.8). Age, education, and employment status were significantly associated with patients' attitudes towards AI for dental diagnostics. When shown a radiograph with a caries lesion highlighted by an arrow, patients recognized the lesion significantly less often than when using AI-generated coloured overlays highlighting the lesion (p < 0.0005). AI-based communication did not significantly affect patients' trust in dentists' diagnosis (p = 0.44; OLR). Conclusions: Patients showed a positive attitude towards AI in dentistry. AI-supported diagnostics may assist communicating radiographic findings by increasing patients' ability to recognize caries lesions on dental radiographs.

Protein Biomarkers in Monocytes and CD4+ Lymphocytes for Predicting Lithium Treatment Response of Bipolar Disorder: a Feasibility Study with Tyramine-Based Signal-Amplified Flow Cytometry.

Purpose: To determine if enhanced flow cytometry (CellPrint™) can identify intracellular proteins of lithium responsiveness in monocytes and CD4+ lymphocytes from patients with bipolar disorder. Methods: Eligible bipolar I or II patients were openly treated with lithium for 16-weeks. Baseline levels of Bcl2, BDNF, calmodulin, Fyn, phospho-Fyn/phospho-Yes, GSK3ß, phospho-GSK3αß, HMGB1, iNOS, IRS2, mTor, NLPR3, PGM1, PKA C-α, PPAR-γ, phospho-RelA, and TPH1 in monocytes and CD4+ lymphocytes of lithium responders and non-responders were measured with CellPrint™. Their utility of discriminating responders from non-responders was explored. Protein-protein network and pathway enrichment analyses were conducted. Results: Of the 24 intent-to-treat patients, 12 patients completed the 16-week study. Eleven of 13 responders and 8 of 11 non-responders were available for this analysis. The levels of the majority of analytes in lithium responders were lower than non-responders in both cell types, but only the level of GSK3ß in monocytes was significantly different (p = 0.034). The combination of GSK3ß and phospho-GSK3αß levels in monocytes correctly classified 11/11 responders and 5/8 non-responders. Combination of GSK3ß, phospho-RelA, TPH1 and PGM1 correctly classified 10/11 responders and 6/7 non-responders, both with a likelihood of ≥ 85%. Prolactin, leptin, BDNF, neurotrophin, and epidermal growth factor/epidermal growth factor receptor signaling pathways are involved in the lithium treatment response. GSK3ß and RelA genes are involved in 4 of 5 these pathways. Conclusion: CellPrint™ flow cytometry was able to detect differences in multiple proteins in monocytes and CD4+ lymphocytes between lithium responders and non-responders. A large study is warranted to confirm or refute these findings.

Total Synthesis of (+)-Erogorgiaene and the Pseudopterosin A-F Aglycone via Enantioselective Cobalt-Catalyzed Hydrovinylation.

Due to their pronounced bioactivity and limited availability from natural resources, metabolites of the soft coral Pseudopterogorgia elisabethae, such as erogorgiaene and the pseudopterosines, represent important target molecules for chemical synthesis. We have now developed a particularly short and efficient route towards these marine diterpenes exploiting an operationally convenient enantioselective cobalt-catalyzed hydrovinylation as the chirogenic step. Other noteworthy C-C bond forming transformations include diastereoselective Lewis acid-mediated cyclizations, a Suzuki coupling and a carbonyl ene reaction. Starting from 4-methyl-styrene the anti-tubercular agent (+)-erogorgiaene (>98 % ee) was prepared in only 7 steps with 46 % overall yield. In addition, the synthesis of the pseudopterosin A aglycone was achieved in 12 steps with 30 % overall yield and, surprisingly, was found to exhibit a similar anti-inflammatory activity (inhibition of LPS-induced NF-κB activation) as a natural mixture of pseudopterosins A-D or iso-pseudopterosin A, prepared by ß-D-xylosylation of the synthetic aglycone.

Selective attention to emotional stimuli and emotion recognition in patients with major depression: The role of mineralocorticoid and glutamatergic NMDA receptors.

BACKGROUND: Mineralocorticoid receptors (MR) are highly expressed in limbic brain areas and prefrontal cortex, which are closely related to selective attention to emotional stimuli and emotion recognition. Patients with major depressive disorder (MDD) show alterations in MR functioning and both cognitive processes. MR stimulation improves cognitive processes in MDD and leads to glutamate release that binds upon N-methyl-D-aspartate receptors (NMDA-R). AIMS: We examined (1) whether MR stimulation has beneficial effects on selective attention to emotional stimuli and on emotion recognition and (2) whether these advantageous effects can be improved by simultaneous NMDA-R stimulation. METHODS: We examined 116 MDD patients and 116 healthy controls matched for age (M = 34 years), sex (78% women), and education in the following conditions: no pharmacological stimulation (placebo), MR stimulation (0.4 mg fludrocortisone + placebo), NMDA-R stimulation (placebo + 250 mg D-cycloserine (DCS)), MR + NMDA-R stimulation (fludrocortisone + DCS). An emotional dot probe task and a facial emotion recognition task were used to measure selective attention to emotional stimuli and emotion recognition. RESULTS: Patients with MDD and healthy individuals did not differ in task performance. MR stimulation had no effect on both cognitive processes in both groups. Across groups, NMDA-R stimulation had no effect on selective attention but showed a small effect on emotion recognition by increasing accuracy to recognize angry faces. CONCLUSIONS: Relatively young unmedicated MDD patients showed no depression-related cognitive deficits compared with healthy controls. Separate MR and simultaneous MR and NMDA-R stimulation revealed no advantageous effects on cognition, but NMDA-R might be involved in emotion recognition.

Approach-avoidance tendencies in depression and childhood trauma: No effect of noradrenergic stimulation.

Adverse childhood experiences (ACE) are a major risk factor for major depressive disorder (MDD) in later life. Both conditions are characterized by dysregulations in the noradrenergic system related which again could represent a mediating mechanism for deficits in affective processing and behavioral functioning. In this double-blind, placebo-controlled study we tested the hypothesis that ACE and MDD are characterized by aberrant approach-avoidance (AA) tendencies and that these are mitigated after noradrenergic stimulation with yohimbine. In a mixed-measures, fully crossed design, participants (N = 131, 73 women) with/without MDD and with/without ACE received a single-dose of yohimbine or placebo on different days, followed by an AA task. We found modulation of AA tendencies by the emotional valence of target images, yet there were no effects of group or treatment. From these results, we conclude that AA tendencies are not critically affected by MDD or ACE and that the noradrenergic system is not substantially involved in this behavior.

Yohimbine-Induced Reactivity of Heart Rate Variability in Unmedicated Depressed Patients With and Without Adverse Childhood Experience.

Stressful life events play a role in the pathogenesis of major depressive disorder (MDD) and many patients with MDD were exposed to developmental stress due to adverse childhood experiences (ACE). Furthermore, dysregulation of the autonomic nervous system and higher incidence of cardiovascular disease are found in MDD. In MDD, and independently in individuals with ACE, abnormalities in heart rate variability (HRV) have been reported. While these are often confounded, we systematically investigated them with a study which included MDD patients with/without ACE as well as healthy individuals with/without ACE. With this study, we investigated the influence of noradrenergic stimulation on HRV reactivity in unmedicated participants in a randomized, double-blind, repeated measures design. Our sample consisted of men and women with MDD and ACE (n = 25), MDD without ACE (n = 24), healthy participants with ACE (n = 27), and without ACE (n = 48). Participants received a 10 mg single dose of the alpha-2 antagonist yohimbine that increases noradrenergic activity or placebo on 2 separate days, with ECG recordings before and after drug administration at defined intervals. We found lower basal HRV in MDD and ACE: patients with MDD had reduced RMSSD whereas participants with ACE had lower LF-HRV. Contrary to our hypothesis, there was no effect of yohimbine. With this study, we were able to replicate previous findings on HRV differences in MDD and ACE. From the null effect of yohimbine, we conclude that the yohimbine-induced sympathetic activation is not a significant driver of HRV in MDD and ACE.

Dichotomic Decision Optimization for the Design of HVDC Superconducting Links.

Superconducting links are an innovative solution for bulk power transmission, distinguished by their compact dimensions, high efficiency and small environmental footprint. As with any new technology field, there is a large amount of design possibilities for such links, each of them having a profound impact on the system configuration. For instance, changing the material can imply a change in the working temperature from 20 to 70 K and has consequences on the maximum link length. This article presents the dichotomic decision possibilities for the optimized design of a high-power superconducting link, focusing on some of the key components of the cable system. The complex design optimization process is exemplified using the European project Best Paths, in which the first 3-gigawatt-class superconducting cable system was designed, optimized, manufactured, and successfully tested.

No association between major depression with and without childhood adversity and the stress hormone copeptin.

Background: Adverse childhood experiences (ACE) are associated with an increased risk of major depressive disorder (MDD) and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Within the HPA axis, corticotropin-releasing hormone and vasopressin (AVP) synergistically stimulate the release of adrenocorticotropic hormone, which promotes cortisol release. The cleavage product copeptin is produced during AVP synthesis and is a surrogate marker of AVP release. Children with ACE and young adults with depressive symptoms have higher levels of copeptin than healthy controls. Objective: To uncover the effects of MDD and ACE on copeptin levels in adult females. Methods: We recruited 94 women (mean age: 34.0 ± 3.6 years): 23 with MDD and ACE, 24 with MDD without ACE, 22 with ACE without MDD, and 25 healthy controls. ACE was defined as repeated sexual or physical abuse at least once a month over at least one year before the age of 18 years. MDD was defined by the DSM-IV criteria. Copeptin plasma levels were measured with an immunoluminometric assay. Results: The four groups did not differ in demographic variables. We found a significant negative correlation between body mass index (BMI) and copeptin plasma levels (r = -.21; p = .045). Copeptin plasma levels did not differ between the four groups after controlling for BMI. Conclusion: Neither MDD nor ACE was associated with altered plasma copeptin levels. Thus, copeptin does not seem to play a major role in MDD and ACE in adult females.

Antecedentes: Las experiencias adversas de la infancia (EAI) se asocian con un mayor riesgo de trastorno depresivo mayor (TDM) y desregulación del eje hipotalámico-pituitario-adrenal (HPA). Dentro del eje HPA, la hormona liberadora de corticotropina y la vasopresina (AVP) estimulan sinérgicamente la liberación de la hormona adrenocorticotrópica, que promueve la liberación de cortisol. El producto de escisión copeptina se produce durante la síntesis de AVP y es un marcador sustituto de la liberación de AVP. Los niños con EAI y los adultos jóvenes con síntomas depresivos tienen niveles más altos de copeptina que los controles sanos.Objetivo: Descubrir los efectos del TDM y la EAI en los niveles de copeptina en mujeres adultas.Métodos: Se reclutaron 94 mujeres (edad media: 34,0 ± 3,6 años): 23 con TDM y EAI, 24 con TDM sin EAI, 22 con EAI sin TDM y 25 controles sanos. La EAI se definió como abuso sexual o físico repetido al menos una vez al mes durante al menos un año antes de los 18 años. El TDM fue definido por los criterios del DSM-IV. Los niveles plasmáticos de copeptina se midieron con un ensayo inmunoluminométrico.Resultados: Los cuatro grupos no difirieron en las variables demográficas. Encontramos una correlación negativa significativa entre el índice de masa corporal (IMC) y los niveles plasmáticos de copeptina (r = −.21; p = .045). Los niveles plasmáticos de copeptina no difirieron entre los cuatro grupos después de controlar el IMC.Conclusión: Ni el TDM ni la EAI se asociaron con niveles alterados de copeptina plasmática. Por tanto, la copeptina no parece desempeñar un papel importante en el TDM y la EAI en mujeres adultas.

Cognitive and emotional empathy after stimulation of brain mineralocorticoid and NMDA receptors in patients with major depression and healthy controls.

Mineralocorticoid receptors (MR) are predominantly expressed in the hippocampus and prefrontal cortex. Both brain areas are associated with social cognition, which includes cognitive empathy (ability to understand others' emotions) and emotional empathy (ability to empathize with another person). MR stimulation improves memory and executive functioning in patients with major depressive disorder (MDD) and healthy controls, and leads to glutamate-mediated N-methyl-D-aspartate receptor (NMDA-R) signaling. We examined whether the beneficial effects of MR stimulation can be extended to social cognition (empathy), and whether DCS would have additional beneficial effects. In this double-blind placebo-controlled single-dose study, we randomized 116 unmedicated MDD patients (mean age 34 years, 78% women) and 116 age-, sex-, and education years-matched healthy controls to four conditions: MR stimulation (fludrocortisone (0.4 mg) + placebo), NMDA-R stimulation (placebo + D-cycloserine (250 mg)), MR and NMDA-R stimulation (both drugs), or placebo. Cognitive and emotional empathy were assessed by the Multifaceted Empathy Test. The study was registered on clinicaltrials.gov (NCT03062150). MR stimulation increased cognitive empathy across groups, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients only. Independent of receptor stimulation, cognitive empathy did not differ between groups. Emotional empathy was not affected by MR or NMDA-R stimulation. However, MDD patients showed decreased emotional empathy compared with controls but, according to exploratory analyses, only for positive emotions. We conclude that MR stimulation has beneficial effects on cognitive empathy in MDD patients and healthy controls, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients. It appears that MR rather than NMDA-R are potential treatment targets to modulate cognitive empathy in MDD.

Noradrenergic system and cognitive flexibility: Disentangling the effects of depression and childhood trauma.

Stress plays a fundamental role in the development and maintenance of major depressive disorder (MDD). Importantly, maladaptive changes in the physiological stress regulation systems have been demonstrated. In the locus coeruleus-noradrenergic (LC-NA) system, up-regulated central alpha2-adrenergic receptors in patients with MDD affect cognitive functions. Although cognitive deficits are core symptoms of MDD, the relationship between the LC-NA system and cognitive processes has rarely been investigated in depressed patients. The aim of our study was to investigate whether noradrenergic stimulation affects cognitive flexibility in MDD. In addition, we aimed to further disentangle the effects of MDD and adverse childhood experiences (ACE), such as physical or sexual abuse on cognitive function. In a double-blind placebo-controlled study, MDD patients with ACE, MDD patients without ACE, healthy participants with ACE and healthy control participants without MDD or ACE were tested with a task switching task (total N = 125). Participants were tested twice after treatment with either 10 mg yohimbine or a placebo. Switch costs (differences between switch and repetition trials) in reaction times and accuracy served as the independent variables. We found higher switch costs in MDD patients as compared with controls, while ACE did not affect task performance. Yohimbine administration had no effect on task switching. The results of this study contribute to a better understanding of the role of the LC-NA system as a neurobiological mechanism of cognitive processes in patients with MDD.

Ultrasound Evaluation of the Cervix to Predict Failed Labor Induction.

OBJECTIVE: Labor induction does not always result in vaginal delivery, and can expose both the mother and the fetus to the risks inherent to the induction procedure or a possible cesarean section. Transvaginal sonography (TVS) of the cervix is a useful tool to predict prematurity; in the present study, this tool was used to evaluate postterm induction. METHODS: We evaluated the ultrasound characteristics of the cervix (cervical length, cervical funneling, internal os dilation, the presence or absence of the cervical gland area [CGA], and the morphological changes of the cervix as a result of applying fundal pressure) before the onset of labor induction among women with postterm pregnancy to identify the possible predictors of failed labor induction. The Bishop score (BS) was used for comparison purposes. Three groups were evaluated: successful versus unsuccessful induction; vaginal delivery versus cesarean delivery (excluding cases of acute fetal distress [AFD]); and vaginal delivery versus cesarean delivery (including cases of AFD). A fourth group including only the primiparous women from the three previous groups was also evaluated. RESULTS: Based on the studied characteristics and combinations of variables, a cervical length ≥ 3.0 cm and a BS ≤ 2 were the best predictors of induction failure. CONCLUSION: Although TVS is useful for screening for induction failure, this tool should not be used as an indication for cesarean section.

OBJETIVO: Nem sempre a indução do parto termina em parto vaginal, expondo tanto a mãe quanto o feto aos riscos inerentes ao procedimento de indução, ou a uma possível cesárea. A ultrassonografia transvaginal (UTV) se mostrou interessante instrumento na predição da prematuridade e, neste estudo, utilizamos este instrumento na situação inversa: indução do parto no pós-datismo. MéTODOS: Avaliamos variáveis ultrassonográficas do colo uterino (comprimento, presença de afunilamento, dilatação do orifício interno do colo, eco glandular endocervical [EGE] evidente ou não, e alterações morfológicas do colo uterino à compressão fúndica uterina) antes do início da indução em gestantes com pós-datismo, na tentativa de encontrar um possível preditor de falha de indução. O índice de Bishop (IB) também foi utilizado para fins de comparação. Três grupos foram avaliados: indução bem-sucedida x malsucedida; parto vaginal x cesárea (excluindo casos de sofrimento fetal agudo[SFA]); e parto vaginal x cesárea (incluindo casos de SFA). Além disso, um quarto grupo composto apenas pelas primíparas dos outros três grupos também foi avaliado. RESULTADOS: Com base em todas as características estudadas e combinações de variáveis, o comprimento do colo uterino ≥ 3,0 cm e IB ≤ 2 foram os melhores preditores em todos os grupos analisados. CONCLUSãO: Apesar de a UTV do colo uterino ser um bom exame para rastreamento de indução malsucedida, não deve ser usado para se indicar uma cesariana.