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Background & Aims: Deep crypt secretory (DCS) cells are a critical component of the colonic stem cell niche. However, the regulatory mechanisms controlling DCS cell numbers and function are not well understood. Sprouty2 is an inflammation-responsive regulator of intracellular signaling that influences colonic secretory cell numbers in colitis via an epithelial–stromal interleukin (IL)33/IL13 signaling loop. Here, we tested the hypothesis that IL13, induced by epithelial Sprouty2 down-regulation, promotes DCS cell differentiation and function. Methods: Distal colons from mice with an intestinal epithelial-specific Sprouty2 deletion (Spry2ΔIE) and littermate controls were analyzed by in situ hybridization for Reg4+ DCS cells. Single-cell RNA sequencing and immunostaining were used to identify DCS cell–derived host defense peptides (HDPs) and localization of IL13 and IL13 receptor; bulk RNA sequencing and quantitative polymerase chain reaction were used to quantify changes in expression of identified HDPs. Cytokine-treated colonoids were assessed for DCS cells. A requirement for an IL33/IL13 signaling loop in the regulation of DCS cells was assessed in vivo using IL13 null mice. Results: Reg4+ DCS cell numbers were increased 2-fold in distal colons of Spry2ΔIE mice with a concomitant overall increase in DCS cell marker expression (Reg4, Spink4, and Agr2). Single-cell transcriptomics showed the HDP Retnlb/Resistin Like Beta (RELMβ) is highly enriched in DCS cells. Retnlb/RELMβ expression was increased in Spry2ΔIE colons. IL13, but not IL33, induced Reg4 and Retnlb expression in colonic epithelial organoids, and IL33-mediated expansion of the DCS cell population in vivo was dependent on IL13, which was expressed predominantly by type II innate lymphoid cells in the colonic mucosa. Conclusions: Sprouty2 limits colonic DCS cell differentiation through suppression of IL13 signaling. At homeostasis, DCS cells are marked by high levels of the HDP RELMβ. Loss of epithelial Sprouty2 activates type II innate lymphoid cells to release IL13, promoting expansion of the DCS cell population and increased colonic RELMβ levels.

Background & Aims: Loss of leucine-rich repeat-containing G-protein–coupled receptor 5–positive crypt base columnar cells provides permissive conditions for different facultative stem cell populations to dedifferentiate and repopulate the stem cell compartment. In this study, we used a defensin α4-Cre recombinase (Defa4Cre) line to define the potential of Paneth cells to dedifferentiate and contribute to intestinal stem cell (ISC) maintenance during normal homeostasis and after intestinal injury. Methods: Small intestine and enteroids from Defa4Cre;Rosa26 tandem dimer Tomato (tdTomato), a red fluoresent protein, (or Rosa26 Enhanced Yellow Fluorescent Protein (EYFP)) reporter, Notch gain-of-function (Defa4Cre;Rosa26 Notch Intracellular Domain (NICD)-ires-nuclear Green Fluorescent Protein (nGFP) and Defa4Cre;Rosa26reverse tetracycline transactivator–ires Enhanced Green Fluorescent Protein (EGFP);TetONICD), A Disintegrin and Metalloproteinase domain-containing protein 10 (ADAM10) loss-of-function (Defa4Cre;ADAM10flox/flox), and Adenomatous polyposis coli (APC) inactivation (Defa4Cre;APCflox/flox) mice were analyzed. Doxorubicin treatment was used as an acute intestinal injury model. Lineage tracing, proliferation, and differentiation were assessed in vitro and in vivo. Results: Defa4Cre-expressing cells are fated to become mature Paneth cells and do not contribute to ISC maintenance during normal homeostasis in vivo. However, spontaneous lineage tracing was observed in enteroids, and fluorescent-activated cell sorter–sorted Defa4Cre-marked cells showed clonogenic enteroid growth. Notch activation in Defa4Cre-expressing cells caused dedifferentiation to multipotent ISCs in vivo and was required for adenoma formation. ADAM10 deletion had no significant effect on crypt homeostasis. However, after acute doxorubicin-induced injury, Defa4Cre-expressing cells contributed to regeneration in an ADAM10–Notch–dependent manner. Conclusions: Our studies have shown that Defa4Cre-expressing Paneth cells possess cellular plasticity, can dedifferentiate into multipotent stem cells upon Notch activation, and can contribute to intestinal regeneration in an acute injury model. Keywords: Defensin, Paneth Cell, Intestinal Stem Cells, Regeneration, Enteroid, Notch, Chemotherapy

Background & Aims: For patients with short-bowel syndrome, intestinal adaptation is required to achieve enteral independence. Although adaptation has been studied extensively in animal models, little is known about this process in human intestine. We hypothesized that analysis of matched specimens with and without luminal flow could identify new potential therapeutic pathways. Methods: Fifteen paired human ileum samples were collected from children aged 2â20 months during ileostomy-reversal surgery after short-segment intestinal resection and diversion. The segment exposed to enteral feeding was denoted as fed, and the diverted segment was labeled as unfed. Morphometrics and cell differentiation were compared histologically. RNA Sequencing and Gene Ontology Enrichment Analysis identified over-represented and under-represented pathways. Immunofluorescence staining and Western blot evaluated proteins of interest. Paired data were compared with 1-tailed Wilcoxon rank-sum tests with a P value less than .05 considered significant. Results: Unfed ileum contained shorter villi, shallower crypts, and fewer Paneth cells. Genes up-regulated by the absence of mechanoluminal stimulation were involved in digestion, metabolism, and transport. Messenger RNA expression of LGR5 was significantly higher in unfed intestine, accompanied by increased levels of phosphorylated signal transducer and activator of transcription 3 protein, and CCND1 and C-MYC messenger RNA. However, decreased proliferation and fewer LGR5+, OLFM4+, and SOX9+ intestinal stem cells (ISCs) were observed in unfed ileum. Conclusions: Even with sufficient systemic caloric intake, human ileum responds to the chronic absence of mechanoluminal stimulation by up-regulating brush-border enzymes, transporters, structural genes, and ISC genes LGR5 and ASCL2. These data suggest that unfed intestine is primed to replenish the ISC population upon re-introduction of enteral feeding. Therefore, the elucidation of pathways involved in these processes may provide therapeutic targets for patients with intestinal failure. RNA sequencing data are available at Gene Expression Omnibus series GSE82147. Keywords: Intestinal Stem Cell, LGR5, Small Intestine, Calorie Restriction, Enteric Nutrition, Mechanoluminal Flow

Amyloid beta peptides and microtubule-associated protein Tau are misfolded and form aggregates in brains of Alzheimer's disease patients. To examine their specific roles in the pathogenesis of Alzheimer's disease and their relevance in neurodegenerative processes, we have created TauPS2APP triple transgenic mice that express human mutated Amyloid Precursor Protein, presenilin 2 and Tau. We present a cross-sectional analysis of these mice at 4, 8, 12 and 16 months of age. By comparing with single transgenic Tau mice, we demonstrate that accumulation of Aβ in TauPS2APP triple transgenic mice impacts on Tau pathology by increasing the phosphorylation of Tau at serine 422, as determined by a novel immunodetection method that is able to reliably measure phospho-Tau species in transgenic mouse brains. The TauPS2APP triple transgenic mouse model will be very useful for studying the effect of new therapeutic paradigms on amyloid deposition and downstream neurofibrillary tangle development.

There is a lack of knowledge about the genetic background of eczema due to insect bite hypersensitivity, also called summer eczema, in horses. The condition is known in several horse breeds and countries and it causes reduced welfare of the horse and economic losses to the owner. The aim of this study was to estimate genetic parameters for summer eczema in Swedish-born Icelandic horses. A questionnaire was sent to owners of horses sired by stallions with more than 50 offspring born in Sweden between 1991 and 2001. Variance components of summer eczema classified as healthy, mild, moderate or severe were estimated using the threshold methodology with sire models. In addition, summer eczema was analysed as a binary trait (healthy v. affected). The analyses included 1250 horses sired by 33 stallions. The prevalence of summer eczema was 8%, with a range of 0% to 30% in different paternal half-sib groups. Offspring of dams suffering from eczema had a higher risk of developing eczema. The heritability for severity of summer eczema was estimated at 0.3 (s.d. < 0.2) with a threshold sire model. In contrast to the age of the horse, different geographic areas and gender were significantly associated with severity of the eczema. We conclude that genetic selection could decrease the prevalence of summer eczema among Swedish-born Icelandic horses. The amount and quality of data are, however, crucial for the possibility to introduce a genetic evaluation of summer eczema. The symptoms should be classified in several classes according to severity, and this classification could be made by the horse owner.

In the face of the COVID-19 pandemic it is important to identify factors that make people particularly vulnerable of developing mental-health issues in order to provide case-specific treatments. In this article, we examine the roles of two psychological constructs - originally put forth in the behavioral decision sciences - in predicting interindividual differences in fear responses: general risk aversion (GRA) and intolerance of uncertainty (IU). We first provide a review of these constructs and illustrate why they may play important roles in shaping anxiety-related disorders. Thereafter we present an empirical study that collected survey data from 550 U.S. residents, comprising self-assessments of dispositions towards risk and uncertainty, anxiety- and depression levels, as well as demographic variables - to thus test the extent to which these psychological constructs are predictive of strong fear responses related to COVID-19 (i.e., mortal fear, racing heart). The results from Bayesian multi-model inference analyses showed that GRA and IU were more powerful predictors of fear responses than demographic variables. Moreover, the predictive power of these constructs was independent of general anxiety- and depression levels. Subsequent mediation analyses showed that the effects of GRA and IU were both direct and indirect via anxiety. We conclude by discussing possible treatment options, but also highlight that future research needs to further examine causal pathways and conceptual overlaps., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Increases in the volume of the amygdala and hippocampus after electroconvulsive therapy (ECT) are among the most robust effects known to the brain-imaging field. Recent advances in the segmentation of substructures of these regions allow for novel insights on the relationship between brain structure and clinical outcomes of ECT., Objective: We aimed to provide a comprehensive synthesis of evidence available on changes in brain structure after ECT, including recently published data on hippocampal subfields., Methods: A meta-analysis of published studies was carried out using random-effects models of standardized mean change of regional brain volumes measured with longitudinal magnetic resonance imaging of depressive patients before and after a series of ECT., Results: Data from 21 studies (543 depressed patients) were analysed, including 6 studies (118 patients) on hippocampal subfields. Meta-analyses could be carried out for seven brain regions for which data from at least three published studies was available. We observed increases in left and right hippocampi, amygdalae, cornua ammonis (CA) 1, CA 2/3, dentate gyri (DG) and subicula with standardized mean change scores ranging between 0.34 and 1.15. The model did not reveal significant volume increases in the caudate. Meta-regression indicated a negative relationship between the reported increases in the DG and relative symptom improvement (-0.27 (SE: 0.09) per 10%)., Conclusions: ECT is accompanied by significant volume increases in the bilateral hippocampus and amygdala that are not associated with treatment outcome. Among hippocampal subfields, the most robust volume increases after ECT were measured in the dentate gyrus. The indicated negative correlation of this effect with antidepressant efficacy warrants replication in data of individual patients., Competing Interests: Declaration of competing interest Without any relevance to this work, P. Baldinger-Melich declares that she has received an Erasmus+ Staff Mobility Grant as well as speaker honoria from Dr. Willmar Schwabe GmbH. R. Lanzenberger received travel grants and/or conference speaker honoraria within the last three years from Bruker BioSpin MR, Heel, and support from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. Siegfried Kasper received grants/research support, consulting fees and/or honoraria within the last three years from Angelini, AOP Orphan Pharmaceuticals AG, Celgene GmbH, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sage, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd., Sun Pharmaceutical Industries Ltd. and Takeda. L.R. Silberbauer is recipient of a DOC fellowship of the Austrian Academy of Sciences at the Department of Psychiatry and Psychotherapy, Medical University of Vienna. G. Gryglewski, R. Frey, D. Pacher and R. Rupprecht have no conflict of interest to declare. Preliminary findings of this study were presented at the 31st CINP congress in Vienna, Austria, and the CINP 2021 Virtual World Congress.., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Since many patients with major depressive disorder (MDD) do not satisfactorily respond to initial antidepressant monotherapy, add-on treatment strategies with other psychiatric compounds are often established. The present European multicenter cross-sectional study comprising 1410 MDD in- and outpatients investigated the prescription pattern of benzodiazepines as add-on treatment in the psychopharmacotherapy of MDD. Analyses of variance, chi-squared tests, and logistic regression analyses were conducted to examine differences in socio-demographic, clinical, and treatment characteristics between benzodiazepine users and non-users. The prescription rate for adjunctive benzodiazepine treatment amounted to 31.35%. The most often administered benzodiazepines were lorazepam (11.13%), clonazepam (6.74%), and alprazolam (6.60%). Benzodiazepine users exhibited more severe depressive symptoms expressed by a higher mean Montgomery and Åsberg Depression Rating Scale total score at study entry (26.92 ± 11.07 vs 23.55 ± 11.23, p<.0001) and at the beginning of the current major depressive episode (35.74 ± 8.08 vs 33.31 ± 7.40, p<.0001). Furthermore, they were characterized by a higher proportion of patients receiving additional augmentation/combination medications with antidepressants (40.95% vs 24.28%, p<.0001), antipsychotics (41.63% vs 18.39%, p<.0001), and low-potency antipsychotics (10.18% vs 4.75%, p<.0001). Moreover, benzodiazepine prescription was associated with older age, unemployment, inpatient treatment, suicide risk, psychotic and melancholic features, comorbid panic disorder, agoraphobia, social phobia, and obsessive-compulsive disorder. Taken together, our findings indicate that benzodiazepine augmentation in MDD is first of all established in severe/difficult-to-treat conditions and serves as predictor for the use of additional augmentation/combination treatment strategies., Competing Interests: Conflict of Interest All other authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Background: The study sought to learn about incidence and reasons for distal stent graft-induced new entry (dSINE) after thoracic endovascular aortic repair (TEVAR) or after frozen elephant trunk (FET) implantation, and develop prevention algorithms., Methods: In an analysis of an international multicenter registry (EuREC [European Registry of Endovascular Aortic Repair Complications] registry), we found 69 dSINE patients of 1430 (4.8%) TEVAR patients with type B aortic dissection and 6 dSINE patients of 100 (6%) patients after the FET procedure for aortic dissection with secondary morphological comparison., Results: The underlying aortic pathology was acute type B aortic dissection in 33 (44%) patients, subacute or chronic type B aortic dissection in 34 (45%) patients, acute type A aortic dissection in 3 patients and remaining dissection after type A repair in 3 (8%) patients, and acute type B intramural hematoma in 2 (3%) patients. dSINE occurred in 4.4% of patients in the acute setting and in 4.9% of patients in the subacute or chronic setting after TEVAR. After the FET procedure, dSINE occurred in 5.3% of patients in the acute setting and in 6.5% of patients in the chronic setting. The interval between TEVAR or FET and the diagnosis of dSINE was 489 ± 681 days. Follow-up after dSINE was 1340 ± 1151 days, and 4 (5%) patients developed recurrence of dSINE. Morphological analysis between patients after TEVAR with and without dSINE showed a smaller true lumen diameter, a more accentuated oval true lumen morphology, and a higher degree of stent graft oversizing in patients who developed dSINE., Conclusions: dSINE after TEVAR or FET is not rare and occurs with similar incidence after acute and chronic aortic dissection (early and late). Avoiding oversizing in the acute and chronic settings as well as carefully selecting patients for TEVAR in postdissection aneurysmal formation will aid in reducing the incidence of dSINE to a minimum., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

As industrial biocatalysis is maturing, access to enzymatic activities beyond chiral resolutions, asymmetric ketone reductions and reductive aminations is gradually becoming reality. Especially the utilization of carbon-hydrogen bond (C-H) activating enzymes is very attractive as they catalyze a variety of chemically extremely challenging transformations. Because of their intrinsic complexity, the use of these enzymes in manufacturing has been limited. However, recent advances in enzyme engineering and bioinformatics have led to activity improvements for native and non-native substrates, the introduction of new-to-nature chemistries and the identification of promising novel enzyme families. Looking forward, the use of automation and advanced computer algorithms will help to streamline the evolution process of C-H activating enzymes leading to more robust and active biocatalysts., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: The induction of brain-derived neurotrophic factor (BDNF) release and subsequent restoration of neuroplastic homeostasis may underlie the effects of electroconvulsive therapy (ECT)., Objectives: We aimed to assess serum and plasma BDNF levels during the course of acute ECT, as well as before and after subsequent continuation ECT, in patients with depression., Methods: We included 24 patients with major depressive disorder (mean age ± SD: 54.5 ± 13.7; f/m: 17/7; baseline 17-item Hamilton Depression Rating Scale score of 26.79 ± 4.01). Serum and plasma BDNF (sBDNF, pBDNF) levels were assessed at nine time-points before, during, and after acute ECT series. Data were analysed using linear regression and linear mixed models, which were adjusted for multiple comparisons via Bonferroni correction. Five patients received continuation ECT subsequent to the acute ECT series. In these patients, BDNF levels were assessed before and after each two continuation ECT sessions using Wilcoxon signed-rank tests., Results: Relative to baseline (mean ng/ml ±SD: 24.68 ± 14.40), sBDNF levels were significantly higher 1 day (33.04 ± 14.11, p = 0.013, corrected), 1 week (37.03 ± 10.29, p < 0.001, corrected), and 1 month (41.05 ± 10.67, p = 0.008, corrected) after the final ECT session, while pBDNF levels did not significantly differ (p > 0.1). Furthermore, our results indicated that sBDNF levels increased after each continuation ECT session. There was no significant association between sBDNF levels and clinical parameters or treatment response., Conclusion: The absence of an association between changes in sBDNF levels and depressive symptoms challenges the proposed concept of sBDNF/pBDNF as key markers of the effects of ECT., (Copyright © 2019. Published by Elsevier Inc.)

The objective of the present multicenter study was to elucidate relevant associations between major depressive disorder (MDD) and comorbid hypertension that are known for their frequent co-occurrence and interaction with regard to functional disability. Demographic and clinical information of altogether 1410 patients were retrieved cross-sectionally. Consecutively, a comparison of patient characteristics between MDD subjects with and without comorbid hypertension were conducted by descriptive statistics, analyses of covariance (ANCOVA) and binary logistic regression analyses. The point prevalence rate for comorbid hypertension was 18.9%. Patients with MDD+comorbid hypertension were significantly older, heavier, more likely to be in a relationship, inpatient and diagnosed with further comorbid chronic somatic diseases including heart disease, diabetes and thyroid dysfunction. In addition, individuals with MDD and comorbid hypertension exhibited a higher score at the Montgomery and Åsberg Depression Rating Scale (MADRS) at onset of the current depressive episode. Melancholic features of depression showed a higher probability. The first line antidepressant treatment did not differ significantly between MDD subjects with versus without comorbid hypertension. Augmentation with pregabalin and combination with one additional antidepressant, however, were more common in the MDD+hypertension group. In conclusion, high blood pressure may influence illness severity and is associated with a distinct psychopathology in MDD patients. Patients with MDD and comorbid hypertension, that seems to be underdiagnosed in MDD patients compared to the general population, are subject to additional somatic diseases in almost 100 percent of the cases and hence, need to be screened and treated accordingly., (Copyright © 2019 Elsevier B.V. and ECNP. All rights reserved.)

Background: Electroconvulsive therapy (ECT) constitutes one of the most effective antidepressant treatment strategies in major depression (MDD). Despite its common use and uncontested efficacy, its mechanism of action is still insufficiently understood. Previously, we showed that ECT is accompanied by a global decrease of serotonin-1A receptors in MDD; however, further studies to investigate the involvement of the serotonergic system in the mechanism of action of ECT are warranted. The monoamine oxidase A (MAO-A) represents an important target for antidepressant treatments and was found to be increased in MDD. Here, we investigated whether ECT impacts on MAO-A levels in treatment-resistant patients (TRD)., Methods: 16 TRD patients (12 female, age 45.94 ± 9.68 years, HAMD 25.12 ± 3.16) with unipolar depression according to DSM-IV were scanned twice before (PET1 and PET2, to assess test-retest variability under constant psychopharmacotherapy) and once after (PET3) completing a minimum of eight unilateral ECT sessions using positron emission tomography and the radioligand [ 11 C]harmine to assess cerebral MAO-A distribution volumes (V T ). Age- and sex-matched healthy subjects (HC) were measured once., Results: Response rate to ECT was 87.5%. MAO-A V T was found to be significantly reduced after ECT in TRD patients (-3.8%) when assessed in 27 a priori defined ROIs (p < 0.001). Test-retest variability between PET1 and PET2 was 3.1%. MAO-A V T did not significantly differ between TRD patients and HC at baseline., Conclusions: The small effect size of the significant reduction of MAO-A V T after ECT in the range of test-retest variability does not support the hypothesis of a clinically relevant mechanism of action of ECT based on MAO-A. Furthermore, in contrast to studies reporting elevated MAO-A V T in unmedicated depressed patients, MAO-A levels were found to be similar in TRD patients and HC which might be attributed to the continuous antidepressant pharmacotherapy in the present sample., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: In most resource-rich countries, a large and growing proportion of older adults with complex needs will die while in a residential aged care (RAC) facility., Objectives: This study describes the impact of facility size (small/large), ownership model (profit/nonprofit) and provider (independent/chain) on resident comfort, and symptom management as reported by RAC staff., Methods: This retrospective "after-death" study collected decedent resident data from a subsample of 51 hospital-level RAC facilities in New Zealand. Symptom Management at the End-of-Life in Dementia and Comfort Assessment in Dying at End of life with Dementia (SM-EOLD and CAD-EOLD, respectively) scales were used by RAC staff who were closely associated with 217 deceased residents. Data collection occurred from January 2016 to February 2017., Results: Results indicated that residents of large, nonprofit facilities experienced greater comfort at the end of life (CAD-EOLD) as indicated by a higher mean score of 37.21 (SD = 4.85, 95% CI = 34.4, 40.0) than residents of small for-profit facilities who recorded a lower mean score of 31.56 (SD = 6.20, 95% CI = 29.6, 33.4). There was also evidence of better symptom management for residents of chain facilities, with a higher mean score for symptom management (SM-EOLD total score) recorded for residents of chain facilities (mean = 28.07, SD = 7.64, 95% CI = 26.47, 29.66) than the mean score for independent facilities (mean = 23.93, SD = 8.72, 95% CI = 21.65, 26.20)., Conclusion: Findings suggest that there are differences in the quality of end-of-life care given in RAC based on size, ownership model, and chain affiliation., (Copyright © 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

This multicenter study of the European Group for the Study of Resistant Depression (GSRD) aimed to explore the association between major depressive disorder (MDD) and comorbid thyroid disease. A total number of 1410 patients` characteristics in terms of demographic and clinical information were compared between MDD subjects with and without concurrent thyroid disease using descriptive statistics, analyses of covariance (ANCOVA) and binary logistic regression analyses. We determined a point prevalence rate for comorbid hypothyroidism of 13.2% and 1.6% for comorbid hyperthyroidism respectively. Patients with MDD+comorbid hypothyroidism were significantly older, more likely to be female, inpatient and suffering from other comorbid chronic somatic conditions. Furthermore, MADRS score at onset of the current depressive episode was significantly higher, psychotic features of depression were more likely pronounced. Overall, patients in the MDD+comorbid hypothyroidism group were rather treated with a combination of drugs, for example, pregabalin, antipsychotic drugs and mood stabilizers. In the MDD+comorbid hyperthyroidism group patients were significantly older, of Caucasian origin and diagnosed with other somatic comorbidities. In conclusion, our analyses suggest that abnormal thyroid function, especially hypothyroidism, is linked to depression severity and associated with distinct psychopathologic features of depression. However, comorbid thyroid disease has no influence on treatment response. A combination or augmentation of psychopharmacological drugs, especially with antipsychotics, mood stabilizers and pregabalin is more likely in patients with hypothyroid conditions. Thyroid disorder is frequently found in combination with other chronic somatic diseases including hypertension and heart disease., (Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.)

Riociguat is a soluble guanylate cyclase stimulator that has been approved for the treatment of pulmonary arterial hypertension and inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension following pulmonary endarterectomy. Riociguat is administered using an 8-week individual dose-adjustment scheme whereby a patient initially receives riociguat 1.0 mg three times daily (tid), and the dose is then increased every 2 weeks in the absence of hypotension, indicated by systolic blood pressure measurements and symptoms, up to a maximum dose of 2.5 mg tid. The established riociguat dose-adjustment scheme allows the dose of riociguat to be individually optimized in terms of tolerability and efficacy. The majority of patients in the phase III clinical trials and their long-term extension phases achieved the maximum riociguat dose, whereas some patients remained on lower doses. There is evidence that these patients may experience benefits at riociguat doses lower than 2.5 mg tid, with improvement in exercise capacity being observed after only 2-4 weeks of treatment in the phase III studies and in the exploratory 1.5 mg-maximum patient group of PATENT-1. This review aims to provide an overview of the rationale behind the riociguat dose-adjustment scheme and examine its application to both clinical trials and real-life clinical practice., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

People seldom enjoy access to summarized information about risky options before making a decision. Instead, they may search for information and learn about environmental contingencies-thus making decisions from experience. Aging is associated with notable deficits in learning and memory-but do these translate into poorer decisions from experience? We report three studies that used a sampling paradigm to investigate younger (M=24 years) and older (M=71 years) adults' decisions from experience. In Study 1 (N=121) participants made 12 decisions between pairs of payoff distributions in the lab. Study 2 (N=70) implemented the same paradigm using portable devices, collecting 84 decisions per individual over a week. Study 3 (N=84) extended the sampling paradigm by asking participants to make 12 decisions between two, four, and eight payoff distributions (in the lab). Overall, the behavioral results suggest that younger and older adults are relatively similar in how they search and what they choose when facing two payoff distributions (Studies 1 and 2). With an increasing number of payoff distributions, however, age differences emerged (Study 3). A modeling analysis on the level of individual participants showed that a simple delta-learning rule model best described the learning processes of most participants. To the extent that ongoing updating processes unfold relatively automatically and effortlessly, older adults may be liberated from the detrimental consequences of cognitive aging in the case of decisions from experience with few decision options. We discuss implications for research on decisions from experience and choice performance over the lifespan., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling results from endothelial dysfunction and may underlie impaired cardiac relaxation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) and pulmonary hypertension (PH). The acute hemodynamic effects of riociguat, a novel soluble guanylate cyclase stimulator, were characterized in patients with PH and HFpEF., Methods: Clinically stable patients receiving standard HF therapy with a left ventricular ejection fraction > 50%, mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, and pulmonary arterial wedge pressure (PAWP) > 15 mm Hg at rest were randomized to single oral doses of placebo or riociguat (0.5, 1, or 2 mg). The primary efficacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics., Results: There was no significant change in peak decrease in mPAP with riociguat 2 mg (n = 10) vs placebo (n = 11, P = .6). However, riociguat 2 mg significantly increased stroke volume (+9 mL [95% CI, 0.4-17]; P = .04) and decreased systolic BP (-12 mm Hg [95% CI, -22 to -1]; P = .03) and right ventricular end-diastolic area (-5.6 cm2 [95% CI, -11 to -0.3]; P = .04), without significantly changing heart rate, PAWP, transpulmonary pressure gradient, or pulmonary vascular resistance. Riociguat was well tolerated., Conclusions: In patients with HFpEF and PH, riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters., Trial Registry: ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov.

Before making decisions, people often need to explore their environment to learn about initially uncertain outcomes. To date, it remains unknown to what extent a person's emotional state shapes exploration in such decisions from experience. It has been suggested that fear regulates people's informational interface with the external world through its physiological expression (e.g., a more effective sampling of the visual field from widened eyes). We investigated whether-as suggested by appraisal tendency theories of emotions-the "emotional feeling" of fear triggers analogous changes in exploration, in terms of increased information sampling in decisions from experience. In two studies, one with naturally occurring emotional states and one with induced emotional states, we found that fearful (relative to happy) people sampled substantially more information before making a final choice. These different degrees of exploration influenced the experience of rarity and, in turn, final choices. We discuss the extent to which increased information acquisition is adaptive., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Introduction: Image-derived input functions (IDIFs) represent a promising non-invasive alternative to arterial blood sampling for quantification in positron emission tomography (PET) studies. However, routine applications in patients and longitudinal designs are largely missing despite widespread attempts in healthy subjects. The aim of this study was to apply a previously validated approach to a clinical sample of patients with major depressive disorder (MDD) before and after electroconvulsive therapy (ECT)., Methods: Eleven scans from 5 patients with venous blood sampling were obtained with the radioligand [carbonyl-(11)C]WAY-100635 at baseline, before and after 11.0±1.2 ECT sessions. IDIFs were defined by two different image reconstruction algorithms 1) OSEM with subsequent partial volume correction (OSEM+PVC) and 2) reconstruction based modelling of the point spread function (TrueX). Serotonin-1A receptor (5-HT1A) binding potentials (BPP, BPND) were quantified with a two-tissue compartment (2TCM) and reference region model (MRTM2)., Results: Compared to MRTM2, good agreement in 5-HT1A BPND was found when using input functions from OSEM+PVC (R(2)=0.82) but not TrueX (R(2)=0.57, p<0.001), which is further reflected by lower IDIF peaks for TrueX (p<0.001). Following ECT, decreased 5-HT1A BPND and BPP were found with the 2TCM using OSEM+PVC (23%-35%), except for one patient showing only subtle changes. In contrast, MRTM2 and IDIFs from TrueX gave unstable results for this patient, most probably due to a 2.4-fold underestimation of non-specific binding., Conclusions: Using image-derived and venous input functions defined by OSEM with subsequent PVC we confirm previously reported decreases in 5-HT1A binding in MDD patients after ECT. In contrast to reference region modeling, quantification with image-derived input functions showed consistent results in a clinical setting due to accurate modeling of non-specific binding with OSEM+PVC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Autopsies and toxicological analyses at the Institute of Forensic Medicine revealed 85 fatal intoxications with neuroleptics in Vienna from 1991 to 1997. A total of 17 cases were linked to a single neuroleptic (NL) alone, while 68 deaths were attributed to a combination of NLs with other drugs. The most frequently detected agent was prothipendyl (n=41). During the study period the number of defined daily doses of high-potency NLs prescribed increased significantly (P< or =0.001) due to increased prescribing of new atypical antipsychotics. The quantity of intermediate- and low-potency NLs dispensed remained stable. The most frequently prescribed NL was haloperidol. The relative toxicities of different NLs were calculated by dividing the number of deaths caused by this NL into the number of defined daily doses prescribed in the observation period (f-value). Single-substance intoxications and multiple-substance intoxications were distinguished. The highest f-values were associated with low-potency NLs, especially with prothipendyl, chlorprothixene and levomepromazine. Low f-values were found for the group of high-potency NLs, including flupentixol, fluphenazine, haloperidol and pimozide, as well as olanzapine. Compared to the f-values for all NLs prescribed, f-values for low-potency NLs were shown to be significantly higher concerning single-substance intoxications (P< or = 0.05) and multiple-substance intoxications (P < or = 0.001), while f-values for high-potency NLs were significantly lower (P< or = 0.05 and P< or = 0.001). We are not aware of the psychiatric diagnoses in our post-mortem sample. However, the present results indicate that careless use of low-potent NLs should be avoided in patients with a potential risk of accidental or suicidal overdose.

In the area of Vienna, any person dying under questionable circumstances is examined at the Institute of Forensic Medicine, where the cause of death is determined by means of autopsy and chemical analysis. Our study on fatal intoxications was performed in the period between 1991 and 1997, when selective serotonin reuptake inhibitors (SSRIs) were establishing themselves on the market, reaching the top of prescription statistics. Tricyclic antidepressants (TCAs) were involved in 30 single- and 127 multiple-substance intoxications, with amitriptyline and doxepin being the most frequently used drugs. SSRIs were involved in five multiple-substance intoxications. The f-value, which refers to the number of deaths per million defined daily doses prescribed, was found to be significantly (P

Homograft cell viability after cryopreservation was investigated and cytoimmunologic monitoring was performed during the early postoperative course to research possible immunologic reactions after allograft aortic valve replacement. After cryopreservation, morphologic observations were made, a nonradioactive cell proliferation assay was used, and prostaglandin I2 secretion of the remaining endothelial cells was determined. Cytoimmunologic monitoring was performed daily within the first 3 weeks postoperatively. An increase of the activation index greater than 1 was rated as an immunologic reaction. Maintained metabolic activity of graft endothelial cells after cryopreservation was confirmed by prostaglandin I2 release (9.24 +/- 3.48 ng/cm2 basic release and 20.1 +/- 5.76 ng/cm2 when stimulated with 25 mumol/L Na arachidonic acid). Cell proliferation was indicated after graft incubation with the nonradioactive viability kit (0.27 +/- 0.9 at 450 nm). Cytoimmunologic examinations (n = 861) after homograft implantation showed a more intense activation in patients with ABO-incompatible grafts (activation index 2.1 +/- 1.6, n = 16) than in those with ABO-compatible grafts (activation index 1.3 +/- 0.8, n = 17). In these groups, the duration of activation by cytoimmunologic monitoring was 2.8 +/- 1.5 days and 1.3 +/- 0.6 days, respectively (p < 0.041). No activation was observed in 8 patients after xenograft valve replacement (p < 0.01). Our data indicate that cryopreservation of homograft valves represents a cell- and tissue-protective preservation method. Postoperatively, all homograft valves caused immunologic reactions, which were reversible without immunosuppression treatment.

Thirty-six male patients with a diagnosis of chronic alcoholism were detoxified and color vision tests were performed on day 4, 11, and 32 of their abstinence on an inpatient basis (Ishihara color plates, Nagel anomaloscope, three color-matching tests according to Farnsworth). Of the 36 patients, 47.2% manifested color vision deficiencies. The frequency of congenital red/green defects (11.1%) and a ratio of 3:1 deutan/protan defects showed no significant difference from the incidence in the normal population. In 36.1%, manifest acquired color vision deficiencies were diagnosed. Within the course of withdrawal, a marked improvement of these disturbances could be proved. The degree of the disturbance seems to correlate with the severity of withdrawal symptoms, but seems to be unrelated to acute toxic effects of alcohol, nicotine, or medication.

The development of interdisciplinary pain clinics is discussed; the organization and staffing is described, and an outline plan is presented. It is emphasized that interdisciplinary pain clincis are the best means of medical care for patients suffering from chronic pain.