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1.
Brain Behav Immun ; 123: 353-369, 2024 Sep 18.
Article in English | MEDLINE | ID: mdl-39303816

ABSTRACT

In a subset of patients with mental disorders, such as depression, low-grade inflammation and altered immune marker concentrations are observed. However, these immune alterations are often assessed by only one data type and small marker panels. Here, we used a transdiagnostic approach and combined data from two cohorts to define subgroups of depression symptoms across the diagnostic spectrum through a large-scale multi-omics clustering approach in 237 individuals. The method incorporated age, body mass index (BMI), 43 plasma immune markers and RNA-seq data from peripheral mononuclear blood cells (PBMCs). Our initial clustering revealed four clusters, including two immune-related depression symptom clusters characterized by elevated BMI, higher depression severity and elevated levels of immune markers such as interleukin-1 receptor antagonist (IL-1RA), C-reactive protein (CRP) and C-C motif chemokine 2 (CCL2 or MCP-1). In contrast, the RNA-seq data mostly differentiated a cluster with low depression severity, enriched in brain related gene sets. This cluster was also distinguished by electrocardiography data, while structural imaging data revealed differences in ventricle volumes across the clusters. Incorporating predicted cell type proportions into the clustering resulted in three clusters, with one showing elevated immune marker concentrations. The cell type proportion and genes related to cell types were most pronounced in an intermediate depression symptoms cluster, suggesting that RNA-seq and immune markers measure different aspects of immune dysregulation. Lastly, we found a dysregulation of the SERPINF1/VEGF-A pathway that was specific to dendritic cells by integrating immune marker and RNA-seq data. This shows the advantages of combining different data modalities and highlights possible markers for further stratification research of depression symptoms.

2.
Psychother Psychosom ; 93(1): 24-35, 2024.
Article in English | MEDLINE | ID: mdl-38176391

ABSTRACT

INTRODUCTION: Schema therapy (ST) reduces depressive symptoms, but clinical trials have not investigated its effectiveness for patients suffering from severe forms of depression and high rates of comorbidities. There is high demand for exploring and improving treatments for this patient group. The objective of the current study was to evaluate whether ST is more effective than individual supportive therapy (IST) and noninferior compared with cognitive behavioral therapy (CBT) in treating depression. METHODS: For this clinical trial, medicated patients were recruited in inpatient and day clinic settings. The major inclusion criteria were age between 18 and 75 years and primary diagnosis of depression without psychotic symptoms. A total of 292 participants were randomized to ST, CBT, or IST and received 7 weeks of psychotherapy (up to 14 individual and 14 group sessions). The primary outcome was change in depression severity after treatment measured by Beck Depression Inventory-II. Primary test for efficacy was superiority of ST over IST. Secondary test was noninferiority of ST compared with CBT. Multilevel modeling was conducted. The results at 6-month follow-up were explored. RESULTS: Across treatment, ST was not superior to IST. Secondary outcome analyses and completer analyses showed similar results. However, ST showed clinically relevant noninferiority compared with CBT. CONCLUSION: ST for depression as part of a psychiatric care program showed clinical noninferiority compared to CBT, without being superior to IST. ST represents a potentially useful addition to the therapeutic repertoire for the treatment of depression but its efficacy, including long-term efficacy, should be evaluated further.


Subject(s)
Cognitive Behavioral Therapy , Schema Therapy , Humans , Adolescent , Young Adult , Adult , Middle Aged , Aged , Depression/therapy , Inpatients , Cognitive Behavioral Therapy/methods , Psychotherapy/methods , Treatment Outcome
4.
Psychol Med ; 53(10): 4405-4414, 2023 07.
Article in English | MEDLINE | ID: mdl-35534456

ABSTRACT

BACKGROUND: Advancements in the treatment of depression are pivotal due to high levels of non-response and relapse. This study evaluated the role of personality pathology in the treatment of depression by testing whether maladaptive personality traits (1) predict changes in depression over treatment or vice versa, (2) change themselves over treatment, (3) change differentially depending on treatment with schema therapy (ST) or cognitive behavioural therapy (CBT), and (4) moderate the effectiveness of these treatments. METHODS: We included 193 depressed inpatients (53.4% women, Mage = 42.9, SD = 13.4) participating in an assessor-blind randomized clinical trial and receiving a 7-week course of ST or CBT. The research questions were addressed using multiple indicator latent change score models as well as multigroup structural equation models implemented in EffectLiteR. RESULTS: Maladaptive traits did not predict changes in depressive symptoms at post-treatment, or vice versa. However, maladaptive trait domains decreased over treatment (standardized Δµ range: -0.38 to -0.89), irrespective of treatment with ST or CBT. Maladaptive traits at baseline did not moderate the effectiveness of these treatments. CONCLUSIONS: Self-reported maladaptive personality traits can change during treatment of depression, but may have limited prognostic or prescriptive value, at least in the context of ST or CBT. These results need to be replicated using follow-up data, larger and more diverse samples, and informant-rated measures of personality pathology.


Subject(s)
Cognitive Behavioral Therapy , Depression , Humans , Female , Adult , Male , Depression/therapy , Schema Therapy , Treatment Outcome , Cognitive Behavioral Therapy/methods , Personality
5.
Article in English | MEDLINE | ID: mdl-37741946

ABSTRACT

Emerging evidence suggests the usefulness of psychological interventions targeting metacognitive change mechanisms in patients experiencing psychosis. Although many of these patients are treated in acute psychiatric contexts, only few studies have adapted such interventions for acute inpatient settings. The present study aimed to assess the feasibility, acceptability, and preliminary clinical outcomes of a novel modularized group intervention focusing on different aspects of metacognitive change mechanisms. In particular, the intervention aims to reduce patients' acute symptoms by enhancing cognitive insight and to relieve distress via cognitive defusion (i.e. coping). A sample of 37 participants with acute psychosis received up to nine sessions of the intervention. Baseline and post-intervention assessments were conducted for general psychopathology, psychotic symptoms, global functioning, and symptom distress. Measures of change mechanisms were assessed before and after the respective treatment module. Participants' experiences were explored in feedback questionnaires and interviews. Recruitment, retention, and attendance rate met the pre-set feasibility benchmark of 80%. The intervention was well received by participants, who emphasised the group's clear structure, positive atmosphere, and helpful contents. Response rates were high and linear mixed models revealed significant medium-to-large time effects on all clinical outcomes. As expected, increase in hypothesised change mechanisms cognitive insight and decrease in cognitive fusion was found. However, the uncontrolled design limits interpreting clinical effects. The study provides evidence that an intervention based on a metacognitive model is feasible and acceptable for acute inpatients with psychosis. Positive results on clinical outcomes and change mechanisms warrant further exploration in a randomized controlled trial.

6.
BMC Psychiatry ; 23(1): 316, 2023 05 04.
Article in English | MEDLINE | ID: mdl-37143013

ABSTRACT

BACKGROUND: The physical activity counseling for in-patients with major depression (PACINPAT) randomized controlled trial was launched to tackle physical inactivity for in-patients with major depressive disorder. Evidence shows that despite potential treatment effects, physical inactivity is prevalent in this population. To contribute to the assessment of how this in-person and remote, theory-based, individually tailored intervention was designed, received and effected behavior, the aim of this study was to evaluate its implementation. METHODS: This implementation evaluation was conducted within a multi-center randomized controlled trial according to the Process Evaluation Framework by the Medical Research Council including the analysis of reach, dose, fidelity and adaptation. Data were collected from the implementers and the participants randomized to the intervention group of the trial. RESULTS: The study sample comprised 95 physically inactive in-patients (mean age: 42 years, 53% women) with diagnosed major depressive disorder. The intervention reached the intended population (N = 95 in-patients enrolled in the study). The intervention dose varied between early dropouts (counseling sessions, M = 1.67) and study completers with some participants receiving a low dose (counseling sessions, M = 10.05) and high dose (counseling sessions, M = 25.37). Differences in the attendance groups were recognizable in the first two counseling sessions (duration of counseling session about 45 min in early dropouts versus 60 min for study completers). Fidelity of the in-person counseling content was partly achieved and adapted, whereas that of the remote counseling content was well achieved. Participants (86% at follow up) reported satisfaction with the implementers of the intervention. Adaptations were made to content, delivery mode and dose. CONCLUSION: The PACINPAT trial was implemented in the intended population, in varying doses and with adaptations made to in-person counseling content and remote counseling dose. These findings are key to understanding outcome analyses within the PACINPAT trial, further developing interventions and contributing to implementation research among in-patients with depressive disorders. TRIAL REGISTRATION: ISRCTN, ISRCTN10469580 , registered on 3rd September 2018.


Subject(s)
Depressive Disorder, Major , Humans , Female , Adult , Male , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/psychology , Counseling , Exercise , Sedentary Behavior
7.
Eur J Neurosci ; 55(9-10): 2464-2473, 2022 05.
Article in English | MEDLINE | ID: mdl-33780086

ABSTRACT

The prefrontal cortex is a key player in stress response regulation. Electroencephalographic (EEG) responses, such as a decrease in frontal alpha and an increase in frontal beta power, have been proposed to reflect stress-related brain activity. However, the stress response is likely composed of different parts such as cognitive effort, time pressure, and social-evaluative threat, which have not been distinguished in previous studies. This distinction, however, is crucial if we aim to establish reliable tools for early detection of stress-related conditions and monitoring of stress responses throughout treatment. This randomized cross-over study (N = 38) aimed to disentangle EEG correlates of stress. With linear mixed models accounting for missing values in some conditions, we found a decrease in frontal alpha and increase in beta power when performing the Paced Auditory Serial Addition Test (PASAT; cognitive effort; n = 32) compared to resting state (n = 33). No change in EEG power was found when the PASAT was performed under time pressure (n = 29) or when adding social-evaluative threat (video camera; n = 29). These findings suggest that frontal EEG power can discriminate stress from resting state but not more fine-grained differences of the stress response.


Subject(s)
Cognition , Electroencephalography , Cognition/physiology , Neuropsychological Tests
8.
J Pers Assess ; 104(4): 522-531, 2022.
Article in English | MEDLINE | ID: mdl-34431747

ABSTRACT

Early adaptive schemas (EAS) are resilience-oriented counterparts to early maladaptive schemas (EMS), which are central in schema therapy. The Young Positive Schema Questionnaire (YPSQ) was developed as a measure of EAS but has been evaluated neither in relation to a clinical population nor in a German-speaking sample. Objectives of this study were therefore the psychometric validation of a German YPSQ in a community sample and the comparison of EAS to psychiatric patients. Participants were 1,418 individuals from a community sample and 182 psychiatric patients with a main diagnosis of major depressive disorder. A factor structure of 10 EAS, instead of the original 14, demonstrated satisfactory factorial validity and internal consistency in both samples. EAS exhibited divergent validity to EMS, childhood trauma, and psychopathology. Convergent validity was evident with resilience, self-efficacy, and satisfaction with life. Support for incremental validity beyond EMS was especially shown for resilience, self-efficacy, and satisfaction with life, and was also evident for several dimensions of psychopathology. Individuals in the community sample exhibited more pronounced EAS compared to psychiatric patients with the exception of empathic consideration. Especially for concepts associated with mental health, the YPSQ has the potential to be a highly valuable addition to current research and practice.


Subject(s)
Depressive Disorder, Major , Depressive Disorder, Major/diagnosis , Humans , Psychometrics , Reproducibility of Results , Surveys and Questionnaires
9.
Sensors (Basel) ; 21(15)2021 Jul 23.
Article in English | MEDLINE | ID: mdl-34372242

ABSTRACT

The fusion of motion data is key in the fields of robotic and automated driving. Most existing approaches are filter-based or pose-graph-based. By using filter-based approaches, parameters should be set very carefully and the motion data can usually only be fused in a time forward direction. Pose-graph-based approaches can fuse data in time forward and backward directions. However, pre-integration is needed by applying measurements from inertial measurement units. Additionally, both approaches only provide discrete fusion results. In this work, we address this problem and present a uniform B-spline-based continuous fusion approach, which can fuse motion measurements from an inertial measurement unit and pose data from other localization systems robustly, accurately and efficiently. In our continuous fusion approach, an axis-angle is applied as our rotation representation method and uniform B-spline as the back-end optimization base. Evaluation results performed on the real world data show that our approach provides accurate, robust and continuous fusion results, which again supports our continuous fusion concept.

10.
Sensors (Basel) ; 21(10)2021 May 12.
Article in English | MEDLINE | ID: mdl-34066256

ABSTRACT

Accurately estimating the current state of local traffic scenes is one of the key problems in the development of software components for automated vehicles. In addition to details on free space and drivability, static and dynamic traffic participants and information on the semantics may also be included in the desired representation. Multi-layer grid maps allow the inclusion of all of this information in a common representation. However, most existing grid mapping approaches only process range sensor measurements such as Lidar and Radar and solely model occupancy without semantic states. In order to add sensor redundancy and diversity, it is desired to add vision-based sensor setups in a common grid map representation. In this work, we present a semantic evidential grid mapping pipeline, including estimates for eight semantic classes, that is designed for straightforward fusion with range sensor data. Unlike other publications, our representation explicitly models uncertainties in the evidential model. We present results of our grid mapping pipeline based on a monocular vision setup and a stereo vision setup. Our mapping results are accurate and dense mapping due to the incorporation of a disparity- or depth-based ground surface estimation in the inverse perspective mapping. We conclude this paper by providing a detailed quantitative evaluation based on real traffic scenarios in the KITTI odometry benchmark dataset and demonstrating the advantages compared to other semantic grid mapping approaches.

11.
Angew Chem Int Ed Engl ; 60(41): 22562-22569, 2021 Oct 04.
Article in English | MEDLINE | ID: mdl-34382295

ABSTRACT

Using 4-(4'-pyridyl)aniline as a simple organic building block in combination with three different aldehyde components together with metal(II) salts gave three different Fe8 Pt6 -cubes and their corresponding Zn8 Pt6 analogues by employing the subcomponent self-assembly approach. Whereas the use of zinc(II) salts gave rise to diamagnetic cages, iron(II) salts yielded metallosupramolecular cages that show spin-crossover behaviour in solution. The spin-transition temperature T1/2 depends on the incorporated aldehyde component, giving a construction kit for the deliberate synthesis of spin-crossover compounds with tailored transition properties. Incorporation of 4-thiazolecarbaldehyde or N-methyl-2-imidazole-carbaldehyde yielded cages that undergo spin-crossover around room temperature whereas the cage obtained using 1H-4-imidazolecarbaldehyde shows a spin-transition at low temperatures. Three new structures were characterized by synchrotron X-ray diffraction and all structures were characterized by mass spectrometry, NMR and UV/Vis spectroscopy.

12.
Circulation ; 139(4): 448-457, 2019 01 22.
Article in English | MEDLINE | ID: mdl-30026282

ABSTRACT

BACKGROUND: Experimental trials suggest improved outcome by mild therapeutic hypothermia for cardiogenic shock after acute myocardial infarction. The objective of this study was to investigate the hemodynamic effects of mild therapeutic hypothermia in patients with cardiogenic shock complicating acute myocardial infarction. METHODS: Patients (n=40) with cardiogenic shock undergoing primary percutaneous coronary intervention without classic indications for mild therapeutic hypothermia underwent randomization in a 1:1 fashion to mild therapeutic hypothermia for 24 hours or control. The primary end point was cardiac power index at 24 hours; secondary end points included other hemodynamic parameters and serial measurements of arterial lactate. RESULTS: No relevant differences were observed for the primary end point of cardiac power index at 24 hours (mild therapeutic hypothermia versus control: 0.41 [interquartile range, 0.31-0.52] versus 0.36 [interquartile range, 0.31-0.48] W/m2; P=0.50; median difference, -0.025 W/m2; 95% CI, -0.12 to 0.06). Similarly, all other hemodynamic measurements were not statistically different. Arterial lactate levels at 6, 8, and 10 hours were significantly higher in patients in the mild therapeutic hypothermia group with a slower decline ( P for interaction=0.03). There were no differences in 30-day mortality (60% versus 50%; hazard ratio, 1.27; 95% CI, 0.55-2.94; P=0.55). CONCLUSIONS: In this randomized trial, mild therapeutic hypothermia failed to show a substantial beneficial effect on cardiac power index at 24 hours in patients with cardiogenic shock after acute myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01890317.


Subject(s)
Hypothermia, Induced/methods , Myocardial Infarction/therapy , Percutaneous Coronary Intervention , Shock, Cardiogenic/therapy , Aged , Aged, 80 and over , Biomarkers/blood , Female , Germany , Hemodynamics , Humans , Hypothermia, Induced/adverse effects , Hypothermia, Induced/mortality , Lactic Acid/blood , Male , Myocardial Infarction/diagnosis , Myocardial Infarction/mortality , Myocardial Infarction/physiopathology , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/mortality , Prospective Studies , Recovery of Function , Shock, Cardiogenic/diagnosis , Shock, Cardiogenic/mortality , Shock, Cardiogenic/physiopathology , Time Factors , Treatment Outcome
13.
BMC Med ; 18(1): 170, 2020 06 05.
Article in English | MEDLINE | ID: mdl-32498707

ABSTRACT

BACKGROUND: Antidepressant medication (ADM) and psychotherapy are effective treatments for major depressive disorder (MDD). It is unclear, however, if treatments differ in their effectiveness at the symptom level and whether symptom information can be utilised to inform treatment allocation. The present study synthesises comparative effectiveness information from randomised controlled trials (RCTs) of ADM versus psychotherapy for MDD at the symptom level and develops and tests the Symptom-Oriented Therapy (SOrT) metric for precision treatment allocation. METHODS: First, we conducted systematic review and meta-analyses of RCTs comparing ADM and psychotherapy at the individual symptom level. We searched PubMed Medline, PsycINFO, and the Cochrane Central Register of Controlled Trials databases, a database specific for psychotherapy RCTs, and looked for unpublished RCTs. Random-effects meta-analyses were applied on sum-scores and for individual symptoms for the Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BDI) measures. Second, we computed the SOrT metric, which combines meta-analytic effect sizes with patients' symptom profiles. The SOrT metric was evaluated using data from the Munich Antidepressant Response Signature (MARS) study (n = 407) and the Emory Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study (n = 234). RESULTS: The systematic review identified 38 RCTs for qualitative inclusion, 27 and 19 for quantitative inclusion at the sum-score level, and 9 and 4 for quantitative inclusion on individual symptom level for the HAM-D and BDI, respectively. Neither meta-analytic strategy revealed significant differences in the effectiveness of ADM and psychotherapy across the two depression measures. The SOrT metric did not show meaningful associations with other clinical variables in the MARS sample, and there was no indication of utility of the metric for better treatment allocation from PReDICT data. CONCLUSIONS: This registered report showed no differences of ADM and psychotherapy for the treatment of MDD at sum-score and symptom levels. Symptom-based metrics such as the proposed SOrT metric do not inform allocation to these treatments, but predictive value of symptom information requires further testing for other treatment comparisons.


Subject(s)
Antidepressive Agents/therapeutic use , Combined Modality Therapy/methods , Depression/drug therapy , Depression/psychology , Psychotherapy/methods , Female , Humans , Male , Treatment Outcome
14.
BMC Psychiatry ; 20(1): 506, 2020 10 14.
Article in English | MEDLINE | ID: mdl-33054737

ABSTRACT

BACKGROUND: Major depressive disorder represents (MDD) a major cause of disability and disease burden. Beside antidepressant medication, psychotherapy is a key approach of treatment. Schema therapy has been shown to be effective in the treatment of psychiatric disorders, especially personality disorders, in a variety of settings and patient groups. Nevertheless, there is no evidence on its effectiveness for MDD in an inpatient nor day clinic setting and little is known about the factors that drive treatment response in such a target group. METHODS: In the current protocol, we outline OPTIMA (OPtimized Treatment Identification at the MAx Planck Institute): a single-center randomized controlled trial of schema therapy as a treatment approach for MDD in an inpatient and day clinic setting. Over the course of 7 weeks, we compare schema therapy with cognitive behavioral therapy and individual supportive therapy, conducted in individual and group sessions and with no restrictions regarding concurrent antidepressant medication, thus approximating real-life treatment conditions. N = 300 depressed patients are included. All study therapists undergo a specific training and supervision and therapy adherence is assessed. Primary outcome is depressive symptom severity as self-assessment (Beck Depression Inventory-II) and secondary outcomes are clinical ratings of MDD (Montgomery-Asberg Depression Rating Scale), recovery rates after 7 weeks according to the Munich-Composite International Diagnostic Interview, general psychopathology (Brief Symptom Inventory), global functioning (World Health Organization Disability Assessment Schedule), and clinical parameters such as dropout rates. Further parameters on a behavioral, cognitive, psychophysiological, and biological level are measured before, during and after treatment and in 2 follow-up assessments after 6 and 24 months after end of treatment. DISCUSSION: To our knowledge, the OPTIMA-Trial is the first to investigate the effectiveness of schema therapy as a treatment approach of MDD, to investigate mechanisms of change, and explore predictors of treatment response in an inpatient and day clinic setting by using such a wide range of parameters. Insights from OPTIMA will allow more integrative approaches of psychotherapy of MDD. Especially, the identification of intervention-specific markers of treatment response can improve evidence-based clinical decision for individualizing treatment. TRIAL REGISTRATION: Identifier on clinicaltrials.gov : NCT03287362 ; September, 12, 2017.


Subject(s)
Cognitive Behavioral Therapy , Depressive Disorder, Major , Depression , Depressive Disorder, Major/therapy , Humans , Inpatients , Psychotherapy , Randomized Controlled Trials as Topic , Schema Therapy , Treatment Outcome
15.
Angew Chem Int Ed Engl ; 59(8): 3195-3200, 2020 Feb 17.
Article in English | MEDLINE | ID: mdl-31788925

ABSTRACT

Two new heterobimetallic cages, a trigonal-bipyramidal and a cubic one, were assembled from the same mononuclear metalloligand by adopting the molecular library approach, using iron(II) and palladium(II) building blocks. The ligand system was designed to readily assemble through subcomponent self-assembly. It allowed the introduction of steric strain at the iron(II) centres, which stabilizes its paramagnetic high-spin state. This steric strain was utilized to drive dynamic complex-to-complex transformations with both the metalloligand and heterobimetallic cages. Addition of sterically less crowded subcomponents as a chemical stimulus transformed all complexes to their previously reported low-spin analogues. The metalloligand and bipyramid incorporated the new building block more readily than the cubic cage, probably because the geometric structure of the sterically crowded metalloligand favours the cube formation. Furthermore it was possible to provoke structural transformations upon addition of more favourable chelating ligands, converting the cubic structures into bipyramidal ones.

16.
Microvasc Res ; 120: 111-116, 2018 11.
Article in English | MEDLINE | ID: mdl-30048648

ABSTRACT

BACKGROUND: Psychiatric disorders are associated with a high prevalence of cardiovascular disease. Regular exercise is known to reduce depressive symptoms and improve vascular function, in turn lowering cardiovascular risk. We aimed to investigate the effects of different exercise modalities on retinal vessel diameters as a microvascular biomarker and depression severity index in patients suffering from unipolar depression. METHODS: 23 patients (female: 19, male: 4, age: 36.7, Beck-Depression-Inventory-II (BDI-II) score: 30.7) were enrolled in this two-armed randomized controlled trial. Static vessel analysis was performed to obtain central retinal arteriolar (CRAE) and venular (CRVE) diameter equivalents and the arterio-venous diameter ratio (AVR). Maximal bicycle ergometer exercise testing yielded maximal fitness parameters. Patients were assigned to either high intensity low volume (HILV) or moderate continuous aerobic training (MCT). Both intervention groups trained three times a week during a 4-week intervention period. RESULTS: Moderate interaction effects were found for AVR (ɳp2 = 0.12) whereby HILV showed a larger increase in AVR (HILV: pre: 0.89 (0.04), post: 0.91 (0.04), SMD = -0.50) compared to MCT (MCT: pre: 0.85 (0.06), post: 0.86 (0.05), SMD = -0.18). Parallel group trials revealed a 67% possibly beneficial effect of HILV over MCT. Moderate interaction effects on depression severity reduction (ɳp2 = 0.06) were found, whereby the effect size was slightly larger in MCT. CONCLUSION: Both exercise interventions improved AVR as well as BDI-II. HILV may be more effective in improving cerebrovascular health. The exercise-induced effects on retinal vessel diameter changes were relatively small and the clinical relevance remains to be investigated in larger and longer-term exercise trials.


Subject(s)
Arterioles/physiopathology , Cardiovascular Diseases/therapy , Depression/therapy , Exercise Therapy/methods , Microcirculation , Retinal Vessels/physiopathology , Venules/physiopathology , Adult , Affect , Arterioles/diagnostic imaging , Cardiovascular Diseases/diagnostic imaging , Cardiovascular Diseases/physiopathology , Depression/diagnosis , Depression/physiopathology , Depression/psychology , Female , Humans , Male , Middle Aged , Retinal Vessels/diagnostic imaging , Switzerland , Time Factors , Treatment Outcome , Venules/diagnostic imaging , Young Adult
17.
Biochemistry ; 56(32): 4201-4209, 2017 08 15.
Article in English | MEDLINE | ID: mdl-28715181

ABSTRACT

Systematic N-methylated derivatives of the melanocortin receptor ligand, SHU9119, lead to multiple binding and functional selectivity toward melanocortin receptors. However, the relationship between N-methylation-induced conformational changes in the peptide backbone and side chains and melanocortin receptor selectivity is still unknown. We conducted comprehensive conformational studies in solution of two selective antagonists of the third isoform of the melanocortin receptor (hMC3R), namely, Ac-Nle-c[Asp-NMe-His6-d-Nal(2')7-NMe-Arg8-Trp9-Lys]-NH2 (15) and Ac-Nle-c[Asp-His6-d-Nal(2')7-NMe-Arg8-NMe-Trp9-NMe-Lys]-NH2 (17). It is known that the pharmacophore (His6-DNal7-Arg8-Trp9) of the SHU-9119 peptides occupies a ß II-turn-like region with the turn centered about DNal7-Arg8. The analogues with hMC3R selectivity showed distinct differences in the spatial arrangement of the Trp9 side chains. In addition to our NMR studies, we also carried out molecular-level interaction studies of these two peptides at the homology model of hMC3R. Earlier chimeric human melanocortin 3 receptor studies revealed insights regarding the binding and functional sites of hMC3R selectivity. Upon docking of peptides 15 and 17 to the binding pocket of hMC3R, it was revealed that Arg8 and Trp9 side chains are involved in a majority of the interactions with the receptor. While Arg8 forms polar contacts with D154 and D158 of hMC3R, Trp9 utilizes π-π stacking interactions with F295 and F298, located on the transmembrane domain of hMC3R. It is hypothesized that as the frequency of Trp9-hMC3R interactions decrease, antagonistic activity increases. The absence of any interactions of the N-methyl groups with hMC3R suggests that their primary function is to modulate backbone conformations of the ligands.


Subject(s)
Melanocyte-Stimulating Hormones/chemistry , Molecular Docking Simulation , Receptor, Melanocortin, Type 3/antagonists & inhibitors , Receptor, Melanocortin, Type 3/chemistry , Binding Sites , Humans , Receptor, Melanocortin, Type 3/genetics , Receptor, Melanocortin, Type 3/metabolism , Structure-Activity Relationship
18.
Angew Chem Int Ed Engl ; 56(18): 4930-4935, 2017 04 24.
Article in English | MEDLINE | ID: mdl-28370757

ABSTRACT

By employing the subcomponent self-assembly approach utilizing 5,10,15,20-tetrakis(4-aminophenyl)porphyrin or its zinc(II) complex, 1H-4-imidazolecarbaldehyde, and either zinc(II) or iron(II) salts, we were able to prepare O-symmetric cages having a confined volume of ca. 1300 Å3 . The use of iron(II) salts yielded coordination cages in the high-spin state at room temperature, manifesting spin-crossover in solution at low temperatures, whereas corresponding zinc(II) salts led to the corresponding diamagnetic analogues. The new cages were characterized by synchrotron X-ray crystallography, high-resolution mass spectrometry, and NMR, Mössbauer, IR, and UV/Vis spectroscopy. The cage structures and UV/Vis spectra were independently confirmed by state-of-the-art DFT calculations. A remarkably high-spin-stabilizing effect through encapsulation of C70 was observed. The spin-transition temperature T1/2 is lowered by 20 K in the host-guest complex.

19.
Am J Geriatr Psychiatry ; 24(11): 1017-1027, 2016 11.
Article in English | MEDLINE | ID: mdl-27618645

ABSTRACT

OBJECTIVE: Features of behavioral variant frontotemporal dementia (bvFTD) such as executive dysfunction, apathy, and impaired empathic abilities are also observed in major depressive disorder (MDD). This may contribute to the reason why early stage bvFTD is often misdiagnosed as MDD. New assessment tools are thus needed to improve early diagnosis of bvFTD. Although emotion processing is affected in bvFTD and MDD, growing evidence indicates that the pattern of emotion processing deficits varies between the two disorders. As such, emotion processing paradigms have substantial potentials to distinguish bvFTD from MDD. DESIGN AND PARTICIPANTS: The current study compared 25 patients with bvFTD, 21 patients with MDD, 21 patients with Alzheimer disease (AD) dementia, and 31 healthy participants on a novel facial emotion intensity rating task. Stimuli comprised morphed faces from the Ekman and Friesen stimulus set containing faces of each sex with two different degrees of emotion intensity for each of the six basic emotions. MEASUREMENTS AND RESULTS: Analyses of covariance uncovered a significant dissociation between bvFTD and MDD patients in rating the intensity of negative emotions overall (i.e., bvFTD patients underrated negative emotions overall, whereas MDD patients overrated negative emotions overall compared with healthy participants). In contrast, AD dementia patients rated negative emotions similarly to healthy participants, suggesting no impact of cognitive deficits on rating facial emotions. CONCLUSIONS: By strongly differentiating bvFTD and MDDpatients through negative facial emotions, this sensitive and short rating task might help improve the early diagnosis of bvFTD.


Subject(s)
Depressive Disorder, Major/psychology , Facial Expression , Frontotemporal Dementia/psychology , Social Perception , Aged , Aged, 80 and over , Alzheimer Disease/diagnosis , Alzheimer Disease/psychology , Case-Control Studies , Depressive Disorder, Major/diagnosis , Diagnosis, Differential , Diagnostic Errors , Female , Frontotemporal Dementia/diagnosis , Humans , Male , Middle Aged
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