Higher Depressive Symptoms in Irregular Menstrual Cycles: Converging Evidence from Cross-Sectional and Prospective Assessments.

BACKGROUND: Menstrual cycle regularity is an important marker of reproductive health and associated with physiological and psychological illnesses, as well as experiencing stress. We hypothesized that individuals with irregular menstrual cycles report higher depressive symptom severity, after controlling for stress occurrence. METHODS: The hypothesis was examined through two measurement approaches: a cross-sectional and a prospective, longitudinal study. In the cross-sectional study, participants (n = 394) reported depressive symptoms and their overall menstrual cycle regularity. In the longitudinal study, participants (n = 77) completed questionnaires on depressive symptoms and stress during the mid-follicular and periovulatory phase of one menstrual cycle. Depressive symptoms were compared between participants with regular and irregular cycles through a Welch t test and an ANCOVA. RESULTS: Participants with irregular menstrual cycles reported more depressive symptoms in the cross-sectional analysis. Similarly, in the longitudinal analysis, the group with a current irregular menstrual cycle reported more depressive symptoms after controlling for stress occurrence. When including only complete data sets without multiple imputation (n = 52), the direction of the effects remained but did not reach statistical significance. CONCLUSIONS: The results indicate an association between depressive symptoms and menstrual cycle irregularity. Limitations were that although we investigated the menstrual cycle prospectively, it would have been more precise to include two or more cycles and daily sex hormone measurements. Further limitations were the suboptimal statistical power and the data collection during the COVID pandemic. We give recommendations on how to incorporate the association of depressive symptoms and cycle irregularity in future study designs on women's mental health.

A cardiac amino-terminal GRK2 peptide inhibits insulin resistance yet enhances maladaptive cardiovascular and brown adipose tissue remodeling in females during diet-induced obesity.

Obesity and metabolic disorders are increasing in epidemic proportions, leading to poor outcomes including heart failure. With a growing recognition of the effect of adipose tissue dysfunction on heart disease, it is less well understood how the heart can influence systemic metabolic homeostasis. Even less well understood is sex differences in cardiometabolic responses. Previously, our lab investigated the role of the amino-terminus of GRK2 in cardiometabolic remodeling using transgenic mice with cardiac restricted expression of a short peptide, ßARKnt. Male mice preserved insulin sensitivity, enhanced metabolic flexibility and adipose tissue health, elicited cardioprotection, and improved cardiac metabolic signaling. To examine the effect of cardiac ßARKnt expression on cardiac and metabolic function in females in response to diet-induced obesity, we subjected female mice to high fat diet (HFD) to trigger cardiac and metabolic adaptive changes. Despite equivalent weight gain, ßARKnt mice exhibited improved glucose tolerance and insulin sensitivity. However, ßARKnt mice displayed a progressive reduction in energy expenditure during cold challenge after acute and chronic HFD stress. They also demonstrated reduced cardiac function and increased markers of maladaptive remodeling and tissue injury, and decreased or aberrant metabolic signaling. ßARKnt mice exhibited reduced lipid deposition in the brown adipose tissue (BAT), but delayed or decreased markers of BAT activation and function suggested multiple mechanisms contributed to the decreased thermogenic capacity. These data suggest a non-canonical cardiac regulation of BAT lipolysis and function that highlights the need for studies elucidating the mechanisms of sex-specific responses to metabolic dysfunction.

HPA axis activity across the menstrual cycle - a systematic review and meta-analysis of longitudinal studies.

Differential HPA axis function has been proposed to underlie sex-differences in mental disorders; however, the impact of fluctuating sex hormones across the menstrual cycle on HPA axis activity is still unclear. This meta-analysis investigated basal cortisol concentrations as a marker for HPA axis activity across the menstrual cycle. Through a systematic literature search of five databases, 121 longitudinal studies were included, summarizing data of 2641 healthy, cycling participants between the ages of 18 and 45. The meta-analysis showed higher cortisol concentrations in the follicular vs. luteal phase (dSMC = 0.12, p =.004, [0.04 - 0.20]). Comparisons between more precise cycle phases were mostly insignificant, aside from higher concentrations in the menstrual vs. premenstrual phase (dSMC = 0.17, [0.02 - 0.33], p =.03). In all included studies, nine samples used established cortisol parameters to indicate HPA axis function, specifically diurnal profiles (k = 4) and the cortisol awakening response (CAR) (k = 5). Therefore, the meta-analysis highlights the need for more rigorous investigation of HPA axis activity and menstrual cycle phase.

Fingernail Cortisol: A Biological Signal of Lifetime Major Depressive Disorder.

INTRODUCTION: Elevated levels of the hypothalamic-pituitary-adrenal axis hormone cortisol are a frequently replicated finding in major depressive disorder (MDD). However, the current state of research is inconclusive as to whether hypercortisolism represents a trait- or state-like biological signal of MDD. The aim of the present study was to investigate, for the first time, whether cortisol in fingernails, a highly accessible tissue, could distinguish currently remitted individuals with MDD from healthy controls. A further aim was to identify potential confounders of nail cortisol. METHODS: A total of N = 100 individuals from the general population were recruited. A structured clinical interview was administered, which resulted in two groups: n = 48 with lifetime MDD and n = 52 healthy controls. All participants answered questions on sociodemographic, lifestyle, and psychosocial characteristics. They also grew their nails for 14 days and cut them for the subsequent determination of cortisol. RESULTS: The groups differed in their nail cortisol concentrations, such that the individuals with lifetime MDD had significantly higher concentrations than the healthy controls (p = 0.041). Within the group of individuals with lifetime MDD, the number of experienced episodes was significantly correlated with cortisol (p = 0.011). Income emerged as the only significant confounder of cortisol (p = 0.008). CONCLUSION: Elevated fingernail cortisol appears to be a biological signal of MDD, even in the absence of a current major depressive episode. Its high accessibility and robustness render it a promising methodology for remote research as well as for the integration of biomarkers into clinical research and practice.

Pepducin ICL1-9-Mediated ß2-Adrenergic Receptor-Dependent Cardiomyocyte Contractility Occurs in a Gi Protein/ROCK/PKD-Sensitive Manner.

PURPOSE: ß-Adrenergic receptors (ßAR) are essential targets for the treatment of heart failure (HF); however, chronic use of ßAR agonists as positive inotropes to increase contractility in a Gs protein-dependent manner is associated with increased mortality. Alternatively, we previously reported that allosteric modulation of ß2AR with the pepducin intracellular loop (ICL)1-9 increased cardiomyocyte contractility in a ß-arrestin (ßarr)-dependent manner, and subsequently showed that ICL1-9 activates the Ras homolog family member A (RhoA). Here, we aimed to elucidate both the proximal and downstream signaling mediators involved in the promotion of cardiomyocyte contractility in response to ICL1-9. METHODS: We measured adult mouse cardiomyocyte contractility in response to ICL1-9 or isoproterenol (ISO, as a positive control) alone or in the presence of inhibitors of various potential components of ßarr- or RhoA-dependent signaling. We also assessed the contractile effects of ICL1-9 on cardiomyocytes lacking G protein-coupled receptor (GPCR) kinase 2 (GRK2) or 5 (GRK5). RESULTS: Consistent with RhoA activation by ICL1-9, both Rho-associated protein kinase (ROCK) and protein kinase D (PKD) inhibition were able to attenuate ICL1-9-mediated contractility, as was inhibition of myosin light chain kinase (MLCK). While neither GRK2 nor GRK5 deletion impacted ICL1-9-mediated contractility, pertussis toxin attenuated the response, suggesting that ICL1-9 promotes downstream RhoA-dependent signaling in a Gi protein-dependent manner. CONCLUSION: Altogether, our study highlights a novel signaling modality that may offer a new approach to the promotion, or preservation, of cardiac contractility during HF via the allosteric regulation of ß2AR to promote Gi protein/ßarr-dependent activation of RhoA/ROCK/PKD signaling.

Salivary Cortisol and Alpha-Amylase in Posttraumatic Stress Disorder and Their Potential Role in the Evaluation of Cognitive Behavioral Treatment Outcomes.

Alterations in HPA-axis and autonomic nervous system activity have been associated with posttraumatic stress disorder (PTSD) development and maintenance and are potentially associated with trauma-focused cognitive behavioral therapy (TF-CBT) outcomes. We examined the role of salivary cortisol (sCort) and alpha-amylase (sAA) in PTSD and TF-CBT outcomes in German Armed Forces service members (N = 100). Participants categorized as PTSD patients (n = 39), previously deployed healthy controls (n = 33), and nondeployed healthy controls (n = 28) provided diurnal profiles of sCort and sAA; PTSD patients provided samples before, immediately after, and 3 months after an internet-based TF-CBT intervention. No group differences emerged regarding total daily sCort and sAA output or daily slopes, ps = .224-.897, fs = 0.05-0.24. Participants with PTSD demonstrated a significantly attenuated sCort awakening response compared to deployed, p = .021, d = 0.59, but not nondeployed controls, p = .918, d = 0.08. Moreover, a significantly steeper sAA awakening response emerged in PTSD patients, p = .034, d = 0.67, and deployed controls, p = .014, d = 0.80, compared to nondeployed controls. From pretreatment to posttreatment (n = 21) and posttreatment to follow-up (n = 14), stable sCort, ps = .282-.628, fs = 0.34-0.49, and sAA concentrations, ps = .068-.758, fs = 0.24-1.13 paralleled a nonsignificant treatment effect. Both PTSD and trauma exposure were associated with alterations in awakening responses, but further investigation is needed to determine whether the observed correspondence remains when PTSD symptoms significantly decline.

A peptide of the amino-terminus of GRK2 induces hypertrophy and yet elicits cardioprotection after pressure overload.

G protein-coupled receptor (GPCR) kinase 2 (GRK2) expression and activity are elevated early on in response to several forms of cardiovascular stress and are a hallmark of heart failure. Interestingly, though, in addition to its well-characterized role in regulating GPCRs, mounting evidence suggests a GRK2 "interactome" that underlies a great diversity in its functional roles. Several such GRK2 interacting partners are important for adaptive and maladaptive myocyte growth; therefore, an understanding of domain-specific interactions with signaling and regulatory molecules could lead to novel targets for heart failure therapy. Herein, we subjected transgenic mice with cardiac restricted expression of a short, amino terminal fragment of GRK2 (ßARKnt) to pressure overload and found that unlike their littermate controls or previous GRK2 fragments, they exhibited an increased left ventricular wall thickness and mass prior to cardiac stress that underwent proportional hypertrophic growth to controls after acute pressure overload. Importantly, despite this enlarged heart, ßARKnt mice did not undergo the expected transition to heart failure observed in controls. Further, ßARKnt expression limited adverse left ventricular remodeling and increased cell survival signaling. Proteomic analysis to identify ßARKnt binding partners that may underlie the improved cardiovascular phenotype uncovered a selective functional interaction of both endogenous GRK2 and ßARKnt with AKT substrate of 160 kDa (AS160). AS160 has emerged as a key downstream regulator of insulin signaling, integrating physiological and metabolic cues to couple energy demand to membrane recruitment of Glut4. Our preliminary data indicate that in ßARKnt mice, cardiomyocyte insulin signaling is improved during stress, with a coordinate increase in spare respiratory activity and ATP production without metabolite switching. Surprisingly, these studies also revealed a significant decrease in gonadal fat weight, equivalent to human abdominal fat, in male ßARKnt mice at baseline and following cardiac stress. These data suggest that the enhanced AS160-mediated signaling in the ßARKnt mice may ameliorate pathological cardiac remodeling through direct modulation of insulin signaling within cardiomyocytes, and translate these to beneficial effects on systemic metabolism.

Fingernail cortisol - State of research and future directions.

The extraction of cortisol from fingernails represents a recent advancement in the retrospective, long-term assessment of hypothalamic-pituitaryadrenal (HPA) axis activity: Fingernail cortisol has the potential to overcome some of the major disadvantages of established HPA axis markers. However, the introduction of any novel methodology also raises certain caveats. This review provides a comprehensive summary of the current state of research on fingernail cortisol. It identifies a number of strengths of his novel methodology (e.g., its high feasibility), while also pointing out open questions which currently challenge the interpretability of fingernail findings, in particular regarding the time period of cortisol secretion reflected in fingernail samples, as well as regarding potential determinants or confounders of fingernail cortisol (e.g. sociodemographic, lifestyle, or health characteristics). Clarification of these issues in the context of further methodological studies is necessary to validate the use of fingernail cortisol as a retrospective marker of HPA axis activity.

Characterization of ßARKct engineered cellular extracellular vesicles and model specific cardioprotection.

Recent data supporting any benefit of stem cell therapy for ischemic heart disease have suggested paracrine-based mechanisms via extracellular vesicles (EVs) including exosomes. We have previously engineered cardiac-derived progenitor cells (CDCs) to express a peptide inhibitor, ßARKct, of G protein-coupled receptor kinase 2, leading to improvements in cell proliferation, survival, and metabolism. In this study, we tested whether ßARKct-CDC EVs would be efficacious when applied to stressed myocytes in vitro and in vivo. When isolated EVs from ßARKct-CDCs and control GFP-CDCs were added to cardiomyocytes in culture, they both protected against hypoxia-induced apoptosis. We tested whether these EVs could protect the mouse heart in vivo, following exposure either to myocardial infarction (MI) or acute catecholamine toxicity. Both types of EVs significantly protected against ischemic injury and improved cardiac function after MI compared with mice treated with EVs from mouse embryonic fibroblasts; however, ßARKct EVs treated mice did display some unique beneficial properties including significantly altered pro- and anti-inflammatory cytokines. Importantly, in a catecholamine toxicity model of heart failure (HF), myocardial injections of ßARKct-containing EVs were superior at preventing HF compared with control EVs, and this catecholamine toxicity protection was recapitulated in vitro. Therefore, introduction of the ßARKct into cellular EVs can have improved reparative properties in the heart especially against catecholamine damage, which is significant as sympathetic nervous system activity is increased in HF.NEW & NOTEWORTHY ßARKct, the peptide inhibitor of GRK2, improves survival and metabolic functions of cardiac-derived progenitor cells. As any benefit of stem cells in the ischemic and injured heart suggests paracrine mechanisms via secreted EVs, we investigated whether CDC-ßARKct engineered EVs would show any benefit over control CDC-EVs. Compared with control EVs, ßARKct-containing EVs displayed some unique beneficial properties that may be due to altered pro- and anti-inflammatory cytokines within the vesicles.

Long-term outcomes of psychological treatment for posttraumatic stress disorder: a systematic review and meta-analysis.

Several types of psychological treatment for posttraumatic stress disorder (PTSD) are considered well established and effective, but evidence of their long-term efficacy is limited. This systematic review and meta-analysis aimed to investigate the long-term outcomes across psychological treatments for PTSD. MEDLINE, Cochrane Library, PTSDpubs, PsycINFO, PSYNDEX, and related articles were searched for randomized controlled trials with at least 12 months of follow-up. Twenty-two studies (N = 2638) met inclusion criteria, and 43 comparisons of cognitive behavioral therapy (CBT) were available at follow-up. Active treatments for PTSD yielded large effect sizes from pretest to follow-up and a small controlled effect size compared with non-directive control groups at follow-up. Trauma-focused treatment (TFT) and non-TFT showed large improvements from pretest to follow-up, and effect sizes did not significantly differ from each other. Active treatments for comorbid depressive symptoms revealed small to medium effect sizes at follow-up, and improved PTSD and depressive symptoms remained stable from treatment end to follow-up. Military personnel, low proportion of female patients, and self-rated PTSD measures were associated with decreased effect sizes for PTSD at follow-up. The findings suggest that CBT for PTSD is efficacious in the long term. Future studies are needed to determine the lasting efficacy of other psychological treatments and to confirm benefits beyond 12-month follow-up.

Genes and hormones of the hypothalamic-pituitary-adrenal axis in post-traumatic stress disorder. What is their role in symptom expression and treatment response?

BACKGROUND: Less than half of all individuals with post-traumatic stress disorder (PTSD) remit spontaneously and a large proportion of those seeking treatment do not respond sufficiently. This suggests that there may be subgroups of individuals who are in need of augmentative or alternative treatments. One of the most frequent pathophysiological findings in PTSD is alterations in the hypothalamic-pituitary-adrenal (HPA) axis, including enhanced negative feedback sensitivity and attenuated peripheral cortisol. Given the role of the HPA axis in cognition, this pattern may contribute to PTSD symptoms and interfere with key processes of standard first-line treatments, such as trauma-focused cognitive behavioural therapy (TF-CBT). METHODS: This review provides a comprehensive summary of the current state of research regarding the role of HPA axis functioning in PTSD symptoms and treatment. RESULTS: Overall, there is preliminary evidence that hypocortisolaemia contributes to symptom manifestation in PTSD; that it predicts non-responses to TF-CBT; and that it is subject to change in parallel with positive treatment trajectories. Moreover, there is evidence that genetic and epigenetic alterations within the genes NR3C1 and FKBP5 are associated with this hypocortisolaemic pattern and that some of these alterations change as symptoms improve over the course of treatment. CONCLUSIONS: Future research priorities include investigations into the role of the HPA axis in day-to-day symptom variation, the time scale in which biological changes in response to treatment occur, and the effects of sex. Furthermore, before conceiving augmentative or alternative treatments that target the described mechanisms, multilevel studies are warranted.

Demographic, sampling- and assay-related confounders of endogenous oxytocin concentrations: A systematic review and meta-analysis.

Studies on endogenous oxytocin concentrations are often criticized for the debatable comparability between specimens and the variation in reported values. We performed meta-regressions on k = 229 studies (n = 12 741 participants), testing whether specimen, extraction, sex, age, time of day, or fasting instructions influenced oxytocin measurements. Predicted oxytocin concentrations differed depending on specimen and extraction: Measurements were extremely high in unextracted blood, compared to extracted blood and other specimens. Measurements were higher in samples with more female participants and higher age. Instructions not to smoke before sampling were correlated with higher oxytocin in unextracted samples. There was no impact of instructions to refrain from eating, drinking, consume caffeine, alcohol or exercising. Oxytocin concentrations increased from morning to afternoon. Our results showed that oxytocin is differentially reflected in blood, saliva, urine and cerebrospinal fluid. Extraction impacts oxytocin measurements, particularly in blood. Considering relevant confounders might increase comparability between studies.

Menstrual cycle-related fluctuations in oxytocin concentrations: A systematic review and meta-analysis.

Oxytocin affects physiological and psychological functions that are often expressed sex-specifically, suggesting interactions between oxytocin and sex hormones. As female sex hormone concentrations change during the menstrual cycle, oxytocin might fluctuate, too. This systematic review and meta-analysis investigated endogenous oxytocin concentrations across menstrual cycle phases in healthy women. Data from 13 studies (120 women) showed a significant increase of oxytocin concentrations from the early follicular phase to ovulation (g = 0.39 [0.25; 0.53], p < .001) and a significant decrease from ovulation to the mid-luteal phase (g = -0.50 [-0.81; -0.18], p < .001). There were no significant differences between the early follicular and mid-luteal phase (g = -0.19 [-0.70; -0.32], p = .471). These findings contribute to a deeper understanding of differences in normal and abnormal psychobiological processes in women. They highlight the necessity to consider the menstrual cycle phase in studies on oxytocin in women.

Evaluation of an internet-based intervention for service members of the German armed forces with deployment-related posttraumatic stress symptoms.

BACKGROUND: The present study was designed to evaluate the efficacy of a therapist-guided internet-based cognitive-behavioral therapy (iCBT) intervention for service members of the German Armed Forces with posttraumatic stress disorder (PTSD). The iCBT was adapted from Interapy, a trauma-focused evidence-based treatment based on prolonged exposure and cognitive restructuring. It lasted for 5 weeks and included 10 writing assignments (twice a week). The program included a reminder function if assignments were overdue, but no multimedia elements. Therapeutic written feedback was provided asynchronously within one working day. METHODS: Male active and former military service members were recruited from the German Armed Forces. Diagnoses were assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Mini-International Neuropsychiatric Interview. Psychopathology was assessed at pre-treatment, post-treatment, and 3-month follow-up. Severity of PTSD was the primary outcome and anxiety was the secondary outcome. Participants were randomly allocated to a treatment group that received iCBT immediately or to a waitlist group that received iCBT after 6 weeks. Due to the overall small sample size (n = 37), the two groups were collapsed for the statistical analyses. Change during the intervention period was investigated using latent-change score models. RESULTS: Improvements in the CAPS-5 were small and not statistically significant. For anxiety, small significant improvements were observed from pre- to follow-up assessment. The dropout rate was 32.3%. CONCLUSIONS: The low treatment utilization and the high dropout rate are in line with previous findings on treatment of service members. The interpretation of the current null results for the efficacy of iCBT is limited due to the small sample size, however for military samples effect estimates were also smaller in other recent studies. Our results demonstrate the need to identify factors influencing treatment engagement and efficacy in veterans. TRIAL REGISTRATION: Australian Clinical Trials Registry ACTRN12616000956404.

Cross-modal object recognition and dynamic weighting of sensory inputs in a fish.

Most animals use multiple sensory modalities to obtain information about objects in their environment. There is a clear adaptive advantage to being able to recognize objects cross-modally and spontaneously (without prior training with the sense being tested) as this increases the flexibility of a multisensory system, allowing an animal to perceive its world more accurately and react to environmental changes more rapidly. So far, spontaneous cross-modal object recognition has only been shown in a few mammalian species, raising the question as to whether such a high-level function may be associated with complex mammalian brain structures, and therefore absent in animals lacking a cerebral cortex. Here we use an object-discrimination paradigm based on operant conditioning to show, for the first time to our knowledge, that a nonmammalian vertebrate, the weakly electric fish Gnathonemus petersii, is capable of performing spontaneous cross-modal object recognition and that the sensory inputs are weighted dynamically during this task. We found that fish trained to discriminate between two objects with either vision or the active electric sense, were subsequently able to accomplish the task using only the untrained sense. Furthermore we show that cross-modal object recognition is influenced by a dynamic weighting of the sensory inputs. The fish weight object-related sensory inputs according to their reliability, to minimize uncertainty and to enable an optimal integration of the senses. Our results show that spontaneous cross-modal object recognition and dynamic weighting of sensory inputs are present in a nonmammalian vertebrate.

The German Adaptation of the Therapist Beliefs about Exposure Scale: a Validation Study among Licensed Cognitive Behavioural Therapists in Germany.

BACKGROUND: Exposure is an effective intervention in the treatment of pathological anxiety, but it is insufficiently disseminated. Therapists' negative attitudes towards exposure might be of relevance when considering factors contributing to the non-application of this intervention. AIMS: In order to be able to measure concerns in German-speaking therapist populations, the study aimed at validating a German version of the Therapist Beliefs about Exposure Scale. METHOD: The scale was translated into the German language and validated in a sample of 330 German licensed cognitive behavioural therapists. RESULTS: In the present sample, the mean total score was significantly lower than in the original study including US-American therapists. Confirmatory factor analysis did not confirm the proposed one-factor model, while the exploratory factor analysis indicated that more than one factor is necessary to explain the structure of negative attitudes towards exposure. The internal consistency was high. Higher scores (more negative beliefs) were significantly correlated with older age, holding a master's degree (vs PhD), not being specialized in the treatment of anxiety disorders and with less experience with performance of exposure gained during clinical training. Negative beliefs about exposure were further associated with the self-reported average number of sessions spent on exposure in current treatment of post-traumatic stress disorder and panic disorder, and with negative attitudes towards application of exposure sessions presented in case vignettes. CONCLUSIONS: The German adaptation provides the opportunity of measuring concerns regarding application of exposure in German-speaking therapist populations. However, the presented data reveal suggestions for further scale development.

Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell-Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium.

BACKGROUND: Activated fibroblasts (myofibroblasts) play a critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear, warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast progenitor cells (BM-FPCs) in pressure overload-induced cardiac fibrosis. We have previously shown that interleukin-10 (IL10) suppresses pressure overload-induced cardiac fibrosis; however, the role of IL10 in inhibition of BM-FPC-mediated cardiac fibrosis is not known. We hypothesized that IL10 inhibits pressure overload-induced homing of BM-FPCs to the heart and their transdifferentiation to myofibroblasts and thus attenuates cardiac fibrosis. METHODS: Pressure overload was induced in wild-type (WT) and IL10 knockout (IL10KO) mice by transverse aortic constriction. To determine the bone marrow origin, chimeric mice were created with enhanced green fluorescent protein WT mice marrow to the IL10KO mice. For mechanistic studies, FPCs were isolated from mouse bone marrow. RESULTS: Pressure overload enhanced BM-FPC mobilization and homing in IL10KO mice compared with WT mice. Furthermore, WT bone marrow (from enhanced green fluorescent protein mice) transplantation in bone marrow-depleted IL10KO mice (IL10KO chimeric mice) reduced transverse aortic constriction-induced BM-FPC mobilization compared with IL10KO mice. Green fluorescent protein costaining with α-smooth muscle actin or collagen 1α in left ventricular tissue sections of IL10KO chimeric mice suggests that myofibroblasts were derived from bone marrow after transverse aortic constriction. Finally, WT bone marrow transplantation in IL10KO mice inhibited transverse aortic constriction-induced cardiac fibrosis and improved heart function. At the molecular level, IL10 treatment significantly inhibited transforming growth factor-ß-induced transdifferentiation and fibrotic signaling in WT BM-FPCs in vitro. Furthermore, fibrosis-associated microRNA (miRNA) expression was highly upregulated in IL10KO-FPCs compared with WT-FPCs. Polymerase chain reaction-based selective miRNA analysis revealed that transforming growth factor-ß-induced enhanced expression of fibrosis-associated miRNAs (miRNA-21, -145, and -208) was significantly inhibited by IL10. Restoration of miRNA-21 levels suppressed the IL10 effects on transforming growth factor-ß-induced fibrotic signaling in BM-FPCs. CONCLUSIONS: Our findings suggest that IL10 inhibits BM-FPC homing and transdifferentiation to myofibroblasts in pressure-overloaded myocardium. Mechanistically, we show for the first time that IL10 suppresses Smad-miRNA-21-mediated activation of BM-FPCs and thus modulates cardiac fibrosis.

Diagnostic pathology of early systemic cancer: ERBB2 gene amplification in single disseminated cancer cells determines patient survival in operable esophageal cancer.

Early metastatic dissemination and evolution of disseminated cancer cells (DCCs) outside the primary tumor is one reason for the failure of adjuvant therapies because it generates molecular genotypes and phenotypes different from primary tumors, which still underlie therapy decisions. Since ERBB2 amplification in esophageal DCCs but not in primary tumor cells predict outcome, we aimed to establish an assay with diagnostic reliability for single DCCs or circulating tumor cells. For this, we evaluated copy number alterations of more than 600 single DCCs from multiple cancer types to define reference regions suitable for quantification of target regions, such as ERBB2. We then compared ERBB2 quantitative PCR (qPCR) measurements with fluorescent in situ hybridization (FISH) data of various breast cancer cell lines and identified the aberration-calling threshold. The method was applied to two independent cohorts of esophageal cancer patients from Hamburg (n = 59) and Düsseldorf (n = 53). We found a high correlation between the single cell qPCR assay and the standard FISH assay (R = 0.98) and significant associations between amplification and survival for both patient cohorts (Hamburg (HH), p = 0.033; Düsseldorf (D), p = 0.052; pooled HH + D, p = 0.002) when applied to DCCs of esophageal cancer patients. Detection of a single ERBB2-amplified DCC was the most important risk factor for death from esophageal cancer (relative risk = 4.22; 95% CI = 1.91-9.32; p < 0.001). In our study, we detected ERBB2-amplified cells in 7% of patients. These patients could benefit from anti-ERBB2 targeting therapies.

Tumor Necrosis Factor-α in Heart Failure: an Updated Review.

PURPOSE OF THE REVIEW: Proinflammatory cytokines are consistently elevated in congestive heart failure. In the current review, we provide an overview on the current understanding of how tumor necrosis factor-α (TNFα), a key proinflammatory cytokine, potentiates heart failure by overwhelming the anti-inflammatory responses disrupting the homeostasis. RECENT FINDINGS: Studies have shown co-relationship between severity of heart failure and levels of the proinflammatory cytokine TNFα and one of its secondary mediators interleukin-6 (IL-6), suggesting their potential as biomarkers. Recent efforts have focused on understanding the mechanisms of how proinflammatory cytokines contribute towards cardiac dysfunction and failure. In addition, how unchecked proinflammatory cytokines and their cross-talk with sympathetic system overrides the anti-inflammatory response underlying failure. The review offers insights on how TNFα and IL-6 contribute to cardiac dysfunction and failure. Furthermore, this provides a forum to begin the discussion on the cross-talk between sympathetic drive and proinflammatory cytokines and its determinant role in deleterious outcomes.

Dissemination of exposure in the treatment of anxiety disorders and post-traumatic stress disorder among German cognitive behavioural therapists.

The efficacy of exposure is beyond doubt, which is reflected in guidelines recommending its application in the treatment of anxiety disorders and post-traumatic stress disorder (PTSD). Research suggests exposure to be underutilized in clinical practice in the United States and Europe. A systematic investigation of the dissemination of exposure in Germany is lacking. The present study examined the dissemination and application frequency of exposure among German cognitive behavioural therapists working in routine care. In an online-based survey, 331 psychotherapists provided information on treatment of patients with panic disorder, phobia, and PTSD. By means of multinomial logistic regression analysis, application frequency of exposure (non-users vs. users vs. frequent users) was predicted by various therapist characteristics. Younger age and less negative beliefs about exposure significantly predicted the affiliation to the frequent users group compared to the non-users in the treatment of panic disorder or phobia. Concerning treatment of PTSD, only negative beliefs about exposure was identified as significant predictor. Sex, educational level, and number of exposure sessions performed during clinical training were not of predictive value. Current findings suggest that negative beliefs about exposure and age impact the frequent provision of exposure to patients. Modification of negative attitudes might be achieved through specific training strategies.