[Peripartal COVID-19-Related Restrictions and Psychological Burden - A Quantitative Survey in Austria]. / Peripartale COVID-19-bedingte Restriktionen und psychische Belastungen ­ eine quantitative Erhebung in Österreich.

INTRODUCTION: The period from pregnancy to postpartum is a vulnerable time with an increased risk of mental illness. The COVID-19 pandemic led to restrictions in peripartum care, such as infection control measures, or restrictions regarding accompanying persons. MATERIAL AND METHODS: Effects of COVID-19-related restrictions on the psyche and well-being during the peripartum period in Austria were retrospectively assessed using a partially standardized online questionnaire. In addition to closed questions on restrictions and psychological stress, this also contained the Edinburgh Postnatal Depression Scale (EPDS). RESULTS: Data from 850 women who had given birth during the pandemic were included in the analysis. In 8.5% of cases, appointments were canceled during prenatal care, 10.7% had to wear a face mask during the birth. One in 10 women had to cope with the birth and one in 5 with the puerperium without a companion. Unaccompanied women were significantly less likely to feel well cared for during the birth, more likely to feel alone in the puerperium and, according to the EPDS score, were more likely (39% vs. 20%; p<0.001) to have a high probability of postpartum depression. CONCLUSIONS: The pandemic-related restrictions led to anxiety, worry, loneliness and an increased risk of depression during the peripartum period. The balance of mental health was negatively affected by measures and restrictions. Even in times of pandemic, more attention needs to be paid to the vulnerable peripartum period.

Experiences of childbirth care in Lithuania and Romania: Insights from the European Babies Born Better survey.

BACKGROUND: Data on experience and satisfaction of users are essential for improvement of health care, especially in the field of childbirth. The aim of this study was to compare childbirth care experiences in Lithuania and Romania. METHODS: Data derived from the EU Babies Born Better online survey were analyzed. Parturients from Lithuania (N = 373) and Romania (N = 359) who had given birth within the last 5 years were included. Participants were asked to (1) describe the best things in childbirth care and (2) suggest changes in the care received at their birthplace. Qualitative data were analyzed using a previously developed deductive coding framework. RESULTS: In agreement with previous findings from Austria, positive experiences mainly addressed care experienced at an individual level (in particular healthcare practitioners' competence and personality traits) and suggested changes mainly addressed services at birthplace (issues related to infrastructure, information and counseling, and empowerment). Responses not initially included in the coding framework addressed aspects such as informal payment (in both countries), desire for home birth (particularly in Lithuania), or mistreatment of parturients (particularly in Romania). CONCLUSIONS: We conclude that similar trends in childbirth care exist in Lithuania and Romania with regard to parturients' personal experiences and psychosocial needs and that addressing the needs of parturients is important for improving service provision.

End of life care during the COVID-19 pandemic: A qualitative study on the perspectives of nurses and nurse assistants.

AIM: To explore nurses' and nurse assistants' experiences of providing end-of-life care during the COVID-19 pandemic in Austria, Germany and Northern Italy. DESIGN: A qualitative explorative interview study. METHOD: Data were collected between August and December 2020 and analysed using content analysis. Healthcare professionals (nurses (n = 30), nurse coordinators (n = 6) and nurse assistants (n = 5)) from hospitals (n = 32) and long-term care facilities (n = 9) in Austria, Germany and Northern Italy were interviewed for this study. RESULTS: Five main categories were identified as follows: (i) end-of-life care involves love and duty, (ii) last wishes and dignity of the patient, (iii) communication with the family, (iv) organizational and religious aspects and (v) personal emotions. Results indicate that more training and guidelines are needed to prepare nurses and nurse assistants for end-of-life care during pandemics. PUBLIC CONTRIBUTION: This research can help prepare nurses and nurse assistants for end-of-life care in pandemics and will be of value for improving the institutional and government health policies. Furthermore, it can be of value in preparing training for healthcare professionals patient-relatives.

Facing the unknown COVID-19 pandemic: A qualitative study with nurses and nursing assistants in three European countries.

Background: The coronavirus disease (COVID-19) is now a worldwide public health emergency. As essential and central parts of the COVID-19 patient care team, nurses and nurse assistants are facing all kinds of challenges caused by the disease and the pandemic. Understanding these challenges and the way nurses and nurse assistants handle and cope with them provides important knowledge on how to improve management of future pandemics and endemic situations. Thus, the present study explored the challenges faced by nurses and nurse asssitants who cared for COVID-19 patients in hospitals and long term care facilities in Italy, Austria and Germany. Methods: The study employed a qualitative design. Purposive sampling was used to select the participants consisting on nurses (n = 30), nurse coordinators (n = 6) and nurse assistants (n = 5) from hospitals (n = 32) and long-term care facilities (n = 9) in Austria, Germany, and Italy. Data were collected between August and December 2020 through semi-structured interviews. The collected data were analyzed using qualitative content analysis. Results: The analysis of the data revealed three main themes with twelve sub-categories: (i) Knowledge, skills, and training (lack of knowledge; skills; organizational issues; training); (ii) resources and risk (lack of protective equipment; difficulties with protective equipment; risk and infection; feelings and isolation); (iii) coping strategies (humor; adaption; team effort; self-care; family and friends). Conclusion: Nurses and nurse assistants who participated in this study faced many personal and professional challenges, and used different coping strategies to manage the situation. Some of these strategies can be applied to reduce these challenges and create better working conditions for nurses and nurse assistants in similar events. Further research, training of staff, and adaptation of institutional policies may help develop new strategies to face future pandemics successfully.

Response of salivary biomarkers to an empathy triggering film sequence-a pilot study.

Empathy is a multifaceted phenomenon that is difficult to measure. Self-report questionnaires are the most common and well-validated measures while currently no validated protein biomarkers associated with the empathic reaction have been established. Trigger films have been previously used in psychological research to evoke emotions. Thus, in the present randomized cross-over study we investigated the responses of nine salivary biomarkers that have been related to emotions and stress following an empathy triggering and a control film sequence. Additionally, questionnaires for empathy (Saarbrucken Personality Questionnaire (SPQ)) and current mental stress were applied and participants were asked to assess the film protagonists' emotions using the Positive and Negative Affect Schedule. Data from 46 participants were included in the analysis. α-Amylase, IgA, IL-1ß and estradiol showed a significantly different response between the empathy and control intervention. Moreover, normalized levels of these biomarkers significantly correlated with single scales of the SPQ (control film sequence: α-amylase and IgA with personal distress; estradiol with empathic concern; IL-1ß with fantasy; empathy triggering film sequence: IgA with empathic concern, fantasy and the total empathy score). These findings indicated that the observed changes in salivary biomarker levels were reflective of a physiological response to the empathy triggering film sequence. Future studies using different triggers and settings will show if the identified biomarkers can be considered as surrogate markers for empathic reactions in general.

[Factors Influencing the Paternal Experience of Birth in the Labour Ward: A Qualitative Study]. / Einflussfaktoren auf das väterliche Erleben der Geburt im Kreißsaal: Eine qualitative Studie.

INTRODUCTION: Today the majority of fathers-to-be are present at the birth of their children in the labour ward. Their presence at the birth is a significant event in their lives. The aim of this study is to identify factors influencing the paternal birth experience in the labour ward. MATERIAL AND METHODS: The experiences of 12 first-time fathers during pregnancy and birth and their perception of birth in the labour ward were gathered through problem-centred interviews. The transcribed and anonymised interviews were analysed by means of content analysis according to Mayring. RESULTS: All fathers retrospectively assessed the experience of the birth of their child positively. A large number of potential factors influencing the paternal birth experience were identified, both biographical factors and factors during pregnancy and birth. In particular, the medical staff, especially the midwife, proved to be of importance. CONCLUSION: Medical professionals should pay more attention to the paternal birth experience. The focus for further research could lie on concepts to promote a positive birth experience for fathers.

Cesarean delivery after non-medically indicated induction of labor: A population-based study using different definitions of expectant management.

INTRODUCTION: Most observational studies found that non-medically indicated induction of labor (IOL) is not associated with an increased risk of cesarean delivery compared with expectant management, defined as all births at a later gestation. However, given the higher rate of cesarean delivery at late term, this definition of the expectant management group might bias the results of observational studies in favor of IOL at early or full term when estimating the risk of short-term (eg up to 1 week) expectant management. MATERIAL AND METHODS: We conducted a retrospective cohort study including 447 066 singleton term and post-term hospital births that occurred in Austria between 2008 and 2016. Multivariate logistic regression was used to test the association of IOL and cesarean delivery at each week of gestation from 37-41. Expectant management was either defined as all births at "next week or beyond" or "at next week". RESULTS: Non-medically indicated IOL was associated with increased odds for cesarean delivery at 37 and 38 weeks, and reduced odds at 40 and 41 weeks. At 39 weeks, IOL resulted in comparable cesarean rates compared with expectant management defined as "next week or beyond" (17.2% vs 16.2%; adjusted odds ratio [OR] 0.93; 95% confidence interval [CI] 0.86-1.00; P = .059). However, when defined as births "at the next week", expectant management was associated with significantly reduced odds for cesarean delivery (13.6%; adjusted OR 0.76; 95% CI 0.70-0.82; P < .001). Comparison of the cesarean delivery rates for the two definitions of expectant management showed that the "next week and beyond" model underestimates the benefit of short-term expectant management by up to 1 week, particularly for IOL at weeks 38 and 39. CONCLUSIONS: Our findings demonstrate that the definition of the expectant management group has a significant impact when analyzing the outcome of IOL in retrospective cohort studies. Non-medically indicated IOL is not an all-or-none choice between "elective" induction and indefinite expectant management. Thus, to define the control group as all births at the next week could be useful for clinical decision-making, as it allows to estimate the risks of expectant management until the next appointment compared with immediate IOL.

Distraction-focused interventions on examination stress in nursing students: Effects on psychological stress and biomarker levels. A randomized controlled trial.

BACKGROUND: Nursing students all over the world experience high levels of stress with negative impacts on their health, emotional state and performance. AIM: This study aimed to investigate the effects of distraction-focused interventions on examination stress and anxiety in nursing students. METHODS: A randomized controlled, parallel trial design was conducted from January to June 2016. After baseline measurement, 72 participants were randomized to one of the following groups (n = 18 each): (i) animal-assisted therapy; (ii) music therapy; (iii) mandala painting; (iv) control group. Outcomes of all groups in terms of stress-reduction were compared by measuring self-reported perceived stress (STAI-State and visual analogue stress scale) and salivary biomarker levels (Cortisol and Immunoglobulin A). RESULTS: Fifty-seven complete data sets (n = 12-16 for each group) were analysed. All distraction-focused interventions showed stress and anxiety reduction in everyday school situations. By contrast, on days with examinations, stress reductions did not reach statistical significance in regard to self-reported psychological stress. At the same time, interventions resulted in significantly decreased levels of stress biomarkers (P < .001). CONCLUSIONS: Our preliminary findings suggest positive but situation-dependent effects of distraction-focused interventions in academic settings. Further research should investigate the complex relationship between physiological and psychological stress parameters.

Health professionals' views on maternity care for women with physical disabilities: a qualitative study.

BACKGROUND: During pregnancy, childbirth and puerperium, women receive care from a range of health professionals, particularly midwives. To assess the current situation of maternity care for women with physical disabilities in Austria, this study investigated the perceptions and experiences of health professionals who have provided care for women with disabilities during pregnancy, childbirth and postpartum. METHODS: The viewpoints of the participating health professionals were evaluated by means of semistructured interviews followed by an inductive qualitative content analysis of the interview transcripts, as proposed by Mayring. RESULTS: Four main categories emerged from the inductive content analysis: (i) structural conditions and accessibility, (ii) interprofessional teamwork and cooperation, (iii) action competence, and (iv) diversity-sensitive attitudes. According to the participating health professionals, the structural conditions were frequently not suitable for providing targeted group-oriented care services. Additionally, a shortage of time and staff resources also limited the necessary flexibility of treatment measures in the care of mothers with physical disabilities. The importance of interprofessional teamwork for providing adequate care was highlighted. The health professionals regarded interprofessionalism as an instrument of quality assurance and team meetings as an elementary component of high-quality care. On the other hand, the interviewees perceived a lack of action competence that was attributed to a low number of cases and a corresponding lack of experience and routine. Regarding diversity-sensitive attitudes, it became apparent that the topic of mothers with physical disabilities in care posed challenges to health professionals that influenced their natural handling of the interactions. CONCLUSION: The awareness of one's own attitudes towards diversity, in the perinatal context in particular, influences professional security and sovereignty as well as the quality of care of women with disabilities. There is a need for optimization in the support and care of women with physical disabilities during pregnancy, childbirth and puerperium.

Midwives' perception of patient safety culture-A qualitative study.

OBJECTIVE: To explore midwives' experiences with and perceptions of patient safety culture in the German-speaking countries. DESIGN AND SETTING: Semi-structured interviews with midwives were conducted between December 2013 and March 2014, whereby the narrative nature of the questions on patient safety culture provided the space for the interviewed midwives to express their own wishes and thoughts freely. The interviews were recorded and transcribed, and the transcripts were anonymized with respect to personal and institutional names. The analysis of the transcripts was based on the methods of qualitative content analysis with the goal to consider all of the remarks with open coding, following a strictly inductive approach. Data analysis and categorization was performed using the software MAXQDA Release 12.2.1. PARTICIPANTS: 14 midwives from Austria, Germany and Switzerland. FINDINGS: The interviewed midwives provided insights into their thoughts and experiences on factors that promote and inhibit patient safety culture as well as superordinate topics related to patient safety culture in general. Their statements were assigned to seven main categories; (i) institutional circumstances, (ii) role of the management, (iii) interprofessional factors, (iv) meetings, (v) education and training, and (vi) psychosocial aspects. Moreover, the majority of statements assigned to these categories additionally related to two overarching core categories, communication and knowledge / skills. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: It appears that patient safety culture is a personal matter for the majority of the participating midwives. However, it seems that at least at some institutions a discrepancy between the perceived importance of patient safety culture and an incomplete implementation into everyday work exists. A natural way of dealing with patient safety culture and an open blame-free discussion of critical incidences rely on the implementation of institutional circumstances that promote education, training as well as intra- and interprofessional exchange and transparent clear responsibilities.

In vitro coagulation triggers anti-Aspergillus fumigatus neutrophil response.

AIM: To explore Aspergillus interactions with platelets in the blood, especially during clot formation. MATERIALS & METHODS: Aspergillus fumigatus resting or swollen conidia, germlings or hyphae were inoculated into blood sampled into tubes with or without anticoagulant. Interactions were explored using microscopy, and chemokine levels were determined. RESULTS: Anatomopathological examination of the clot revealed conidia and germlings colocalization with platelet aggregates, and neutrophil recruitment around aggregates. Transmission electron microscopy showed conidia and hyphae surrounded by neutrophils. Increased CCL5 and CXCL4 when conidia or germlings but not hyphae were added suggested they could be involved in neutrophil recruitment around aggregates. CONCLUSION: These data suggest platelets could trigger coagulopathy and activate neutrophils during aspergillosis. They open up new perspectives for aspergillosis management.

Women's satisfaction with care at the birthplace in Austria: Evaluation of the Babies Born Better survey national dataset.

OBJECTIVE: to evaluate women's satisfaction with care at the birthplace in Austria and to provide reference data for cross-country comparisons within the international Babies Born Better project. DESIGN: a cross-sectional design was applied. The data were extracted from the Babies Born Better survey as a national sub-dataset that included all participants with Austria as the indicated country of residence. SETTING: an online survey targeting women who had given birth within the last five years and distributed primarily via social media. In addition to sociodemographic and closed-ended questions regarding pregnancy and the childbirth environment, the women's childbirth experiences and satisfaction with the birthplace were obtained with three open-ended questions regarding (i) best experience of care, (ii) required changes in care and (iii) honest description of the experienced care. PARTICIPANTS: five hundred thirty-nine women who had given birth in Austria within the last five years. MEASUREMENTS AND FINDINGS: based on the concepts of public health, salutogenesis and self-efficacy, a deductive coding framework was developed and applied to analyse the qualitative data of the Babies Born Better survey. Regarding honest descriptions of the experienced care at the birthplace, 82% were positive, indicating that most of the respondents were mostly satisfied with the care experienced. More than 95% of the survey participants' positive experiences and more than 87% of their negative experiences with care could be assigned to the categories of the deductive coding framework. Whereas positive experiences mainly addressed care experienced at the individual level, negative experiences more frequently related to issues of the existing infrastructure, breastfeeding counselling or topics not covered by the coding framework. Evaluation of these unassigned responses revealed an emphasis on antenatal and puerperal care as well as insufficient reimbursements of expenses by health insurance funds and the desire for more midwifery-led care. KEY CONCLUSIONS: although the participating women were mostly satisfied with perinatal care in Austria, it appears that shortcomings particularly exist in antenatal and puerperal care and counselling. IMPLICATIONS FOR RESEARCH: the established coding framework that covered the vast majority of the women's responses to the open-ended questions might serve as a basis for cross-country comparisons within the international Babies Born Better project.

Experiences of Austrian mothers with mobility or sensory impairments during pregnancy, childbirth and the puerperium: a qualitative study.

BACKGROUND: Approximately 8% of all women of childbearing age in Austria live with permanent impairments. In everyday life, women with disabilities face various challenges and discrimination, among which the issue of pregnancy and motherhood, in particular, is often considered taboo, and their parenting abilities are doubted. Knowledge in the medical field about the experiences of women with disabilities during pregnancy, childbirth and the puerperium is limited. METHODS: To investigate the personal meanings and experiences of women with disabilities in regard to pregnancy, childbirth and the puerperium, in-depth individual, semi-structured interviews were conducted with ten mothers with various mobility or sensory impairments who reside in Austria. The qualitative interview data were analyzed using the qualitative content analysis proposed by Mayring. RESULTS: Three main themes or categories emerged from the inductive content analysis, namely, (i) the social network, (ii) self-efficacy and self-awareness and (iii) communication, transparency and information. Participants reported limited acceptance of their life decisions and experienced an environment of discriminatory attitudes. They experienced a lack of support and lack of confidence in their parenting abilities, which negatively influenced their self-efficacy and self-awareness. Violations of personal borders and a feeling of being watched and controlled were reported. Communication with health care professionals was often characterized by mutual aspects of fear, uncertainty and awkwardness, as perceived by women with disabilities. Adequate information about pregnancy, childbirth and the puerperium, particularly about measures taken and interventions applied, was frequently missing. CONCLUSION: Heath care facilities need to be structured to ensure ease of access for women with disabilities. Education should be offered to health care professionals to improve knowledge about care for women with disabilities and to strengthen communication skills. All necessary information needs to be prepared and provided in an adequate manner. The establishment of a health-promoting environment for mothers, their children and their families requires a sensitive, respectful and non-judgmental attitude of society toward women with disabilities during pregnancy, childbirth and the puerperium.

Maternal and neonatal outcomes after induction of labor: a population-based study.

PURPOSE: To evaluate maternal and neonatal outcomes at and beyond term associated with induction of labor compared to spontaneous onset of labor stratified by week of gestational age. METHODS: In this retrospective cohort study, data form 402,960 singleton pregnancies from the Austria Perinatal Registry were used to estimate odds ratios of secondary cesarean delivery, operative vaginal delivery, epidural analgesia, fetal scalp blood testing, episiotomy, 3rd/4th-degree lacerations, retained placenta, 5-min APGAR <7, umbilical artery pH <7.1, and admission to neonatal intensive care unit. Multivariate logistic regression models based on deliveries with gestational age ≥37 + 0 were applied for adjustment for possible confounders. RESULTS: Induction of labor was associated with increased odds for cesarean delivery (adjusted OR; 99% confidence interval: 1.53; 1.45-1.60), operative vaginal delivery (1.21; 1.15-1.27), epidural analgesia (2.12; 2.03-2.22), fetal scalp blood testing (1.40; 1.28-1.52), retained placenta (1.32; 1.22-1.41), 5-min APGAR <7 (1.55; 1.27-1.89), umbilical artery pH <7.1 (1.26; 1.15-1.38), and admission to neonatal intensive care unit (1.41; 1.31-1.51). In a subgroup of induction of labor with the indication, "post-term pregnancy" induction was similarly associated with adverse outcomes. CONCLUSIONS: In Austria, induction of labor is associated with increased odds of adverse maternal and neonatal outcomes. However, due to residual confounding, currently, no recommendations for treatment can be derived.

The Potential of sGC Modulators for the Treatment of Age-Related Fibrosis: A Mini-Review.

Fibrotic diseases cause high rates of morbidity and mortality, and their incidence increases with age. Despite intense research and development efforts, effective and well-tolerated antifibrotic treatments are scarce. Transforming growth factor-ß signaling, which is widely considered the most important profibrotic factor, causes a pro-oxidant shift in redox homeostasis and a concomitant decrease in nitric oxide (NO) signaling. The NO/cyclic guanosine monophosphate (cGMP) signaling cascade plays a pivotal role in the regulation of cell and organ function in whole-body hemostasis. Increases in NO/cGMP can lead to relaxation of smooth muscle cells triggering vasorelaxation. In addition, there is consistent evidence from preclinical in vitro and in vivo models that increased cGMP also exerts antifibrotic effects. However, most of these findings are descriptive and the molecular pathways are still being investigated. Furthermore, in a variety of fibrotic diseases and also during the natural course of aging, NO/cGMP production is low, and current treatment approaches to increase cGMP levels might not be sufficient. The introduction of compounds that specifically target and stimulate soluble guanylate cyclase (sGC), the so called sGC stimulators and sGC activators, might be able to overcome these limitations and could be ideal tools for investigating antifibrotic mechanisms in vitro and in vivo as they may provide effective treatment strategies for fibrotic diseases. These drugs increase cGMP independently from NO via direct modulation of sGC activity, and have synergistic and additive effects to endogenous NO. This review article describes the NO/cGMP signaling pathway and its involvement in fibrotic remodeling. The classes of sGC modulator drugs and their mode of action are described. Finally, the preclinical in vitro and in vivo findings and antifibrotic effects of cGMP elevation via sGC modulation are reviewed. sGC stimulators and activators significantly attenuate tissue fibrosis in a variety of internal organs and in the skin. Moreover, these compounds seem to have multiple intervention sites and may reduce extracellular matrix formation, fibroblast proliferation, and myofibroblast activation. Thus, sGC stimulators and sGC activators may offer an efficacious and tolerable therapy for fibrotic diseases, and clinical trials are currently underway to assess the potential benefit for patients with systemic sclerosis.

Expression of a recombinant full-length LRP1B receptor in human non-small cell lung cancer cells confirms the postulated growth-suppressing function of this large LDL receptor family member.

Low-density lipoprotein (LDL) receptor-related protein 1B (LRP1B), a member of the LDL receptor family, is frequently inactivated in multiple malignancies including lung cancer. LRP1B is therefore considered as a putative tumor suppressor. Due to its large size (4599 amino acids), until now only minireceptors or receptor fragments have been successfully cloned. To assess the effect of LRP1B on the proliferation of non-small cell lung cancer cells, we constructed and expressed a transfection vector containing the 13.800 bp full-length murine Lrp1b cDNA using a PCR-based cloning strategy. Expression of LRP1B was analyzed by quantitative RT-PCR (qRT-PCR) using primers specific for human LRP1B or mouse Lrp1b. Effective expression of the full length receptor was demonstrated by the appearance of a single 600 kDa band on Western Blots of HEK 293 cells. Overexpression of Lrp1b in non-small cell lung cancer cells with low or absent endogenous LRP1B expression significantly reduced cellular proliferation compared to empty vector-transfected control cells. Conversely, in Calu-1 cells, which express higher endogenous levels of the receptor, siRNA-mediated LRP1B knockdown significantly enhanced cellular proliferation. Taken together, these findings demonstrate that, consistent with the postulated tumor suppressor function, overexpression of full-length Lrp1b leads to impaired cellular proliferation, while LRP1B knockdown has the opposite effect. The recombinant Lrp1b construct represents a valuable tool to unravel the largely unknown physiological role of LRP1B and its potential functions in cancer pathogenesis.

Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-ß-dependent activation of matrix metalloproteases.

Dickkopf-3 (Dkk-3) is a secreted protein whose expression is downregulated in many types of cancer. Endogenous Dkk-3 is required for formation of acini in 3D cultures of prostate epithelial cells, where it inhibits transforming growth factor (TGF)-ß/Smad signaling. Here, we examined the effects of Dkk-3 on the expression and activity of matrix metalloproteases (MMPs), which mediate the effects of TGF-ß on extracellular matrix disassembly during tissue morphogenesis and promote invasion of tumor cells. Silencing of Dkk-3 in prostate epithelial cells resulted in increased expression and enzyme activity of MMP-2 and MMP-9. Inhibition of MMP-9 partially restored normal acinar morphogenesis in Dkk-3-silenced RWPE-1 prostate epithelial cells. In PC3 prostate cancer cells, Dkk-3 inhibited TGF-ß-dependent migration and invasion. Inhibition was mediated by the Dkk-3 C-terminal cysteine-rich domain (Cys2), which also inhibited TGF-ß-induced expression of MMP9 and MMP13. In contrast, Dkk-3, but not Cys2, increased formation of normal acini in Dkk-3-silenced prostate epithelial cells. These observations highlight a role for Dkk-3 in modulating TGF-ß/MMP signals in the prostate, and suggest that the Dkk-3 Cys2 domain can be used as a basis for therapies that target the tumor promoting effects of TGF-ß signaling in advanced prostate cancer.

Activators and stimulators of soluble guanylate cyclase counteract myofibroblast differentiation of prostatic and dermal stromal cells.

BACKGROUND: Fibrotic diseases encompass numerous systemic and organ-specific disorders characterized by the development and persistence of myofibroblasts. TGFß1 is considered the key inducer of fibrosis and drives myofibroblast differentiation in cells of diverse histological origin by a pro-oxidant shift in redox homeostasis associated with decreased nitric oxide (NO)/cGMP signaling. Thus, enhancement of NO/cGMP represents a potential therapeutic strategy to target myofibroblast activation and therefore fibrosis. METHODS: Myofibroblast differentiation was induced by TGFß1 in human primary prostatic (PrSCs) and normal dermal stromal cells (NDSCs) and monitored by α smooth muscle cell actin (SMA) and IGF binding protein 3 (IGFBP3) mRNA and protein levels. The potential of enhanced cGMP production by the sGC stimulator BAY 41-2272 or the sGC activator BAY 60-2770 to inhibit and revert myofibroblast differentiation in vitro was analyzed. Moreover, potential synergisms of BAY 41-2272 or BAY 60-2770 and inhibition of cGMP degradation by the PDE5 inhibitor vardenafil were investigated. RESULTS: BAY 41-2272 and BAY 60-2770 at doses of 30µM significantly inhibited induction of SMA and IGFBP3 levels in PrSCs and reduced myofibroblast marker levels in TGFß1-predifferentiated cells. At lower concentrations (3 and 10µM) only BAY 41-2272 but not BAY 60-2770 significantly inhibited and reverted myofibroblast differentiation. In NDSCs both substances significantly inhibited differentiation at all concentrations tested. Attenuation of SMA expression was more pronounced in NDSCs whereas reduction of IGFBP3 levels by BAY 41-2272 appeared more efficient in PrSCs. Moreover, administration of BAY 41-2272 or BAY 60-2770 enhanced the efficiency of the PDE5 inhibitor vardenafil to inhibit and revert myofibroblast differentiation in vitro. CONCLUSIONS: Increase of cGMP by sGC stimulation/activation significantly inhibited and reverted myofibroblast differentiation. This effect was even more pronounced when a combination treatment with a PDE5 inhibitor was applied. Thus, enhancement of NO/cGMP-signaling by sGC stimulation/activation is a promising strategy for the treatment of fibrotic diseases. Whereas, in NDSCs BAY 60-2770 and BAY 41-2272 exerted similar effects on myofibroblast differentiation, higher potency of BAY 41-2272 was observed in PrSCs, indicating phenotypical differences between fibroblasts form different organs that should be taken into account in the search for antifibrotic therapies.

Differential gene expression in Aspergillus fumigatus induced by human platelets in vitro.

Invasive aspergillosis is characterized by vascular invasion and thrombosis. In order to determine the antifungal activity of human platelets, hyphal elongation and metabolic activity of a clinical A. fumigatus isolate were measured. Genome-wide identification of differentially expressed genes in A. fumigatus was performed after exposure to platelets for 15, 30, 60 and 180 min. Data were analyzed by gene ontology annotation as well as functional categories (FunCat) and KEGG enrichment analyses. Platelets attenuated hyphal elongation and viability of A. fumigatus and in total 584 differentially expressed genes were identified, many of which were associated with regulation of biological processes, stress response, transport and metabolism. FunCat and KEGG enrichment analyses showed stress response and metabolic adaptation to be increased in response to platelets. Our findings demonstrate that A. fumigatus displayed a specific transcriptional response when exposed to platelets, thus reflecting their antifungal activities.

Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFß signalling.

OBJECTIVES: We have previously described the antifibrotic role of the soluble guanylate cyclase (sGC). The mode of action, however, remained elusive. In the present study, we describe a novel link between sGC signalling and transforming growth factor ß (TGFß) signalling that mediates the antifibrotic effects of the sGC. METHODS: Human fibroblasts and murine sGC knockout fibroblasts were treated with the sGC stimulator BAY 41-2272 or the stable cyclic guanosine monophosphate (cGMP) analogue 8-Bromo-cGMP and stimulated with TGFß. sGC knockout fibroblasts were isolated from sGCI(fl/fl) mice, and recombination was induced by Cre-adenovirus. In vivo, we studied the antifibrotic effects of BAY 41-2272 in mice overexpressing a constitutively active TGF-ß1 receptor. RESULTS: sGC stimulation inhibited TGFß-dependent fibroblast activation and collagen release. sGC knockout fibroblasts confirmed that the sGC is essential for the antifibrotic effects of BAY 41-2272. Furthermore, 8-Bromo-cGMP reduced TGFß-dependent collagen release. While nuclear p-SMAD2 and 3 levels, SMAD reporter activity and transcription of classical TGFß target genes remained unchanged, sGC stimulation blocked the phosphorylation of ERK. In vivo, sGC stimulation inhibited TGFß-driven dermal fibrosis but did not change p-SMAD2 and 3 levels and TGFß target gene expression, confirming that non-canonical TGFß pathways mediate the antifibrotic sGC activity. CONCLUSIONS: We elucidated the antifibrotic mode of action of the sGC that increases cGMP levels, blocks non-canonical TGFß signalling and inhibits experimental fibrosis. Since sGC stimulators have shown excellent efficacy and tolerability in phase 3 clinical trials for pulmonary arterial hypertension, they may be further developed for the simultaneous treatment of fibrosis and vascular disease in systemic sclerosis.