Carbon Monoxide as a Potential Therapeutic Agent: A Molecular Analysis of Its Safety Profiles.

Carbon monoxide (CO) is endogenously produced in mammals, with blood concentrations in the high micromolar range in the hemoglobin-bound form. Further, CO has shown therapeutic effects in various animal models. Despite its reputation as a poisonous gas at high concentrations, we show that CO should have a wide enough safety margin for therapeutic applications. The analysis considers a large number of factors including levels of endogenous CO, its safety margin in comparison to commonly encountered biomolecules or drugs, anticipated enhanced safety profiles when delivered via a noninhalation mode, and the large amount of safety data from human clinical trials. It should be emphasized that having a wide enough safety margin for therapeutic use does not mean that it is benign or safe to the general public, even at low doses. We defer the latter to public health experts. Importantly, this Perspective is written for drug discovery professionals and not the general public.

On the Question of Uncatalyzed CO Insertion into a Hydrazone Double Bond: A Comparative Study Using Different CO Sources and Substrates.

Because of endogenous signaling roles of carbon monoxide (CO) and its demonstrated pharmacological effects, there has been extensive interests in developing fluorescent CO probes. Palladium-mediated CO insertion has been successfully used for such applications. However, recent years have seen many publications of using uncatalyzed CO insertion into a hydrazone double bond as a way to sense CO. Such chemistry has no precedents otherwise. Further, the rigor of the CO-sensing work was largely based on using ruthenium-carbonyl complexes such as CORM-3 as CO surrogates, which have been reported to have extensive chemical reactivity and to release largely CO2 instead of CO unless in the presence of a strong nucleophile such as dithionite. For all of these, it is important to reassess the feasibility of such a CO-insertion reaction. By studying two of the reported "CO probes" using CO gas, this study finds no evidence of CO insertion into a hydrazone double bond. Further, the chemical reaction between CO gas and a series of eight hydrazone compounds was conducted, leading to the same conclusion. Such findings are consistent with the state-of-the-art knowledge of carbonylation chemistry and do not support uncatalyzed CO insertion as a mechanism for developing fluorescent CO probes.

Augmented reality simulation-based training for midwifery students and its impact on perceived knowledge, confidence and skills for managing critical incidents.

PROBLEM: Emergency obstetric management is essential in midwifery training to prevent fetal and maternal morbidity. Repeating this management in practice is often not possible. Sustainable confidence in these procedures is usually achieved in the first few years of practice. BACKGROUND: Simulation training complements hands-on learning and improves practical skills, benefiting both students and patients. Research on obstetric emergency simulation training have demonstrated this, but the use of digital simulation approaches, such as augmented reality (AR), is under-researched. AIM: To investigate whether AR simulation training influences midwifery students' subjective perceptions of knowledge, confidence and practical skills in emergency situations. METHODS: A descriptive exploratory study was conducted using a pre-post design. AR scenarios were developed on the topics of 'preparing emergency tocolysis', 'preparing a pregnant woman for caesarean section' and 'resuscitation of newborns'. The AR simulation was conducted in the fourth to fifth semester of the midwifery programme. A questionnaire was developed for students (N = 133) to self-assess their competence in the categories of knowledge, confidence and practical skills. RESULTS: Students rated their competence significantly better in the post-survey than in the pre-survey (p=<0.05). Simulation has an impact on self-assessment of professional knowledge, confidence and practical skills in emergency situations. It enhances students' procedural knowledge and practical skills in complex contexts, complements subject knowledge and builds confidence. CONCLUSION: The results provide initial evidence that AR simulation is an effective learning strategy for emergency management preparedness. Future studies should validate the effect with control cohorts and measure competence through practical examinations.

The role of breastfeeding and formula feeding regarding depressive symptoms and an impaired mother child bonding.

Associations between depressive symptoms and breastfeeding are well documented. However, evidence is lacking for subdivisions of feeding styles, namely exclusive breastfeeding, exclusive formula feeding and a mixed feeding style (breastfeeding and formula feeding). In addition, studies examining associations between mother-child-bonding and breastfeeding have yielded mixed results. The aim of this study is to provide a more profound understanding of the different feeding styles and their associations with maternal mental health and mother-child-bonding. Data from 307 women were collected longitudinally in person (prenatally) and by telephone (3 months postnatally) using validated self-report measures, and analyzed using correlational analyses, unpaired group comparisons and regression analyses. Our results from a multinomial regression analysis revealed that impaired mother-child-bonding was positively associated with mixed feeding style (p = .003) and depressive symptoms prenatal were positively associated with exclusive formula feeding (p = .013). Further studies could investigate whether information about the underlying reasons we found for mixed feeding, such as insufficient weight gain of the child or the feeling that the child is unsatiated, could help prevent impaired mother-child-bonding. Overall, the results of this study have promising new implications for research and practice, regarding at-risk populations and implications for preventive measures regarding postpartum depression and an impaired mother-child-bonding.

Unraveling the Interplay of Dopamine, Carbon Monoxide, and Heme Oxygenase in Neuromodulation and Cognition.

The dopaminergic system plays important roles in neuromodulation, including prominent roles in complex neurological functions such as cognition, reward, motivation, and memory. Understandably, the highly complex nature of such physiological functions means that their regulation is intertwined with other signaling pathways, as has been demonstrated by numerous studies. Contrary to its public perception of being poisonous at all concentrations, carbon monoxide (CO) is produced endogenously from heme degradation by heme oxygenase (HO) as part of the physiological process of red blood cell turnover. Physiological concentrations of CO can reach high micromolar ranges in the hemoglobin bound form. Low-dose CO has shown therapeutic effects in numerous animal models, including traumatic brain injury via engaging various hemoprotein targets. As such, the HO-CO axis has been shown to offer beneficial effects in organ protection, anti-inflammation, and neuroprotection, among many others. Further, a large number of publications have shown the interactions among CO, HO, and the dopaminergic system. In this review, we critically examine such experimental evidence in a holistic fashion and in the context of a possible dopamine-HO-CO signaling axis. We hope that this Perspective will stimulate additional investigations into the molecular connectivity related to this possible axis and open doors to the development of novel therapeutics that impact the dopaminergic system.

Plight of CORMs: The unreliability of four commercially available CO-releasing molecules, CORM-2, CORM-3, CORM-A1, and CORM-401, in studying CO biology.

Carbon monoxide (CO) is an endogenously produced gaseous signaling molecule with demonstrated pharmacological effects. In studying CO biology, three delivery forms have been used: CO gas, CO in solution, and CO donors of various types. Among the CO donors, four carbonyl complexes with either a transition metal ion or borane (BH3) (termed CO-releasing molecules or CORMs) have played the most prominent roles appearing in over 650 publications. These are CORM-2, CORM-3, CORM-A1, and CORM-401. Intriguingly, there have been unique biology findings that were only observed with these CORMs, but not CO gas; yet these properties were often attributed to CO, raising puzzling questions as to why CO source would make such a fundamental difference in terms of CO biology. Recent years have seen a large number of reports of chemical reactivity (e.g., catalase-like activity, reaction with thiol, and reduction of NAD(P)+) and demonstrated CO-independent biological activity for these four CORMs. Further, CORM-A1 releases CO in an idiosyncratic fashion; CO release from CORM-401 is strongly influenced or even dependent on reaction with an oxidant and/or a nucleophile; CORM-2 mostly releases CO2, not CO, after a water-gas shift reaction except in the presence of a strong nucleophile; and CORM-3 does not release CO except in the presence of a strong nucleophile. All these beg the question as to what constitutes an appropriate CO donor for studying CO biology. This review critically summarizes literature findings related to these aspects, with the aim of helping result interpretation when using these CORMs and development of essential criteria for an appropriate donor for studying CO biology.

Reassessing CORM-A1: redox chemistry and idiosyncratic CO-releasing characteristics of the widely used carbon monoxide donor.

Carbon monoxide (CO) is an endogenous signaling molecule with demonstrated ability to modulate immune responses and to engage key components of the circadian clock. Further, CO has been pharmacologically validated for its therapeutic benefits in animal models of various pathological conditions. For the development of CO-based therapeutics, new delivery forms are needed to address the inherent limitations of using inhaled CO for therapeutic applications. Along this line, there have been metal- and borane-carbonyl complexes reported as CO-release molecules (CORMs) for various studies. CORM-A1 is among the four most widely used CORMs in examining CO biology. Such studies are predicated on the assumptions that CORM-A1 (1) releases CO efficiently and reproducibly under commonly used experimental conditions and (2) does not have meaningful CO-independent activities. In this study, we demonstrate the important redox properties of CORM-A1 leading to the reduction of bio-relevant molecules such as NAD+ and NADP+ under near-physiological conditions; such reduction reciprocally facilitates CO release from CORM-A1. We further demonstrate that CO-release yield and rate from CORM-A1 are highly dependent on various factors such as the medium used, buffer concentrations, and redox environment; these factors seem to be so idiosyncratic that we were unable to find a uniform mechanistic explanation. Under standard experimental conditions, CO release yields were found to be low and highly variable (0.5-15%) in the initial 15 min unless in the presence of certain reagents, e.g. NAD+ or high concentrations of buffer. The significant chemical reactivity of CORM-A1 and the highly variable nature of CO release under near-physiological conditions suggest the need for much more consideration of appropriate controls, if available, and caution in using CORM-A1 as a CO surrogate in biological studies.

[Digital midwifery care during the COVID-19 pandemic in Germany-acceptance of mothers]. / Digitale Hebammenbetreuung in der COVID-19-Pandemie in Deutschland ­ Akzeptanz bei Müttern.

BACKGROUND: To ensure outpatient midwifery care during the COVID-19 pandemic, digital midwifery services were enabled for the first time in Germany in March 2020. The aim of the survey "Digital midwifery care in the context of the Covid-19 pandemic" was to conduct an initial evaluation of the newly introduced digital services from the perspective of the midwives and the users. This publication presents the results of the mothers' survey. METHOD: In February and March 2021, a cross-sectional study with an online survey was conducted. Women insured with BARMER who gave birth to a healthy child between May and November 2020 were surveyed anonymously throughout Germany using an exploratively developed online questionnaire on the utilization, satisfaction, and potential of digital midwifery care in pregnancy and the postpartum period. RESULTS: Feedback was provided by 1821 mothers. Around one third of the responding women had used digital midwifery services during pregnancy and/or the postpartum period and rated these services positively by over 80%. From the respondents' point of view, courses and counselling are very well suited whereas postpartum care often requires the midwife's presence. Advantages were seen in infection control and in saving time and travel. CONCLUSION: The COVID-19 pandemic has become a catalyst for digitalization in midwifery care. The digital services were quickly implemented by freelance midwives and well accepted by women and can usefully complement the care provided in the presence of the midwife. The opportunity to utilize and further develop these offers should be taken.

Midwives' and women's views on digital midwifery care in Germany: Results from an online survey.

BACKGROUND: Digital midwifery services were enabled for the first time in Germany from March 2020 to ensure outpatient midwifery care in times of COVID-19. METHODS: In February and March 2021, a cross-sectional study with an online survey of midwives and mothers was conducted to find out to what extent digital services were offered by the midwives and used by the women, and to obtain information about the level of satisfaction and potential of digital midwifery care in pregnancy and post partum. RESULTS: 1821 mothers of 18,784 women, who had given birth between May and November 2020 and were asked to participate in the survey, provided feedback (response rate: 9,7%). 1551 midwives responded to the call to participate in the survey and completed the questionnaire. Around one third of the responding mothers had used digital midwifery services in pregnancy and/or the postpartum period and rated these services positively by over 80%. Half of the responding midwives offered digital services and wished to continue this care option. However, not all services were considered equally suitable for digital implementation. From the respondents' point of view, classes and counselling are very well suited whereas postpartum care often requires the midwife's presence. Mothers and midwives alike saw the advantages in COVID-19 infection control and in saving time and travel. The main challenges were seen in handling IT equipment and providing high quality care despite the lack of physical examination and direct assessment of clinical findings. The mothers wished for more interactivity and networking with each other. CONCLUSION: The COVID-19 pandemic has become a catalyst for digitalisation in midwifery care in Germany. The digital services were, mostly, well accepted and seen to usefully complement the in-person care of midwives. IT-support, guidelines and quality standards could help to optimise the digital services.

Light-Activated CO Donor as a Universal CO Surrogate for Pd-Catalyzed and Light-Mediated Carbonylation.

A low-molecular-weight, solid CO surrogate that only requires a low-power LED for activation to release 2 equiv of CO is reported. The surrogate can be universally implemented in various palladium-catalyzed carbonylative transformations. It is also compatible with protocols that employ blue-light to activate conventionally inaccessible substrates such as nonactivated alkyl halides. Furthermore, we demonstrate that the photolabile CO-releasing scaffold can be installed into polymeric materials, thereby creating new materials with CO-releasing capabilities.

Haematopoietic stem cell differentiation promotes the release of prominin-1/CD133-containing membrane vesicles--a role of the endocytic-exocytic pathway.

The differentiation of stem cells is a fundamental process in cell biology and understanding its mechanism might open a new avenue for therapeutic strategies. Using an ex vivo co-culture system consisting of human primary haematopoietic stem and progenitor cells growing on multipotent mesenchymal stromal cells as a feeder cell layer, we describe here the exosome-mediated release of small membrane vesicles containing the stem and cancer stem cell marker prominin-1 (CD133) during haematopoietic cell differentiation. Surprisingly, this contrasts with the budding mechanism underlying the release of this cholesterol-binding protein from plasma membrane protrusions of neural progenitors. Nevertheless, in both progenitor cell types, protein-lipid assemblies might be the essential structural determinant in the release process of prominin-1. Collectively, these data support the concept that prominin-1-containing lipid rafts may host key determinants necessary to maintain stem cell properties and their quantitative reduction or loss may result in cellular differentiation.

New insights into the cell biology of hematopoietic progenitors by studying prominin-1 (CD133).

Prominin-1 (alias CD133) has received considerable interest because of its expression by several stem and progenitor cells originating from various sources, including the neural and hematopoietic systems. As a cell surface marker, prominin-1 is now used for somatic stem cell isolation. Its expression in cancer stem cells has broadened its clinical value, as it might be useful to outline new prospects for more effective cancer therapies by targeting tumor-initiating cells. Cell biological studies of this molecule have demonstrated that it is specifically concentrated in various membrane structures that protrude from the planar areas of the plasmalemma. Prominin-1 binds to the plasma membrane cholesterol and is associated with a particular membrane microdomain in a cholesterol-dependent manner. Although its physiological function is not yet determined, it is becoming clear that this cell surface protein, as a unique marker of both plasma membrane protrusions and membrane microdomains, might reveal new aspects of the cell biology of rare stem and cancer stem cells. The aim of this review is to outline the recent discoveries regarding the dynamic reorganization of the plasma membrane of rare CD133+ hematopoietic progenitor cells during cell migration and division.

Prominin-2 is a cholesterol-binding protein associated with apical and basolateral plasmalemmal protrusions in polarized epithelial cells and released into urine.

Prominin-2 is a pentaspan membrane glycoprotein structurally related to the cholesterol-binding protein prominin-1, which is expressed in epithelial and non-epithelial cells. Although prominin-1 expression is widespread throughout the organism, the loss of its function solely causes retinal degeneration. The finding that prominin-2 appears to be restricted to epithelial cells, such as those found in kidney tubules, raises the possibility that prominin-2 functionally substitutes prominin-1 in tissues other than the retina and provokes a search for a definition of its morphological and biochemical characteristics. Here, we have investigated, by using MDCK cells as an epithelial cell model, whether prominin-2 shares the biochemical and morphological properties of prominin-1. Interestingly, we have found that, whereas prominin-2 is not restricted to the apical domain like prominin-1 but is distributed in a non-polarized fashion between the apical and basolateral plasma membranes, it retains the main feature of prominin-1, i.e. its selective concentration in plasmalemmal protrusions; prominin-2 is confined to microvilli, cilia and other acetylated tubulin-positive protruding structures. Similar to prominin-1, prominin-2 is partly associated with detergent-resistant membranes in a cholesterol-dependent manner, suggesting its incorporation into membrane microdomains, and binds directly to plasma membrane cholesterol. Finally, prominin-2 is also associated with small membrane particles that are released into the culture media and found in a physiological fluid, i.e. urine. Together, these data show that all the characteristics of prominin-1 are shared by prominin-2, which is in agreement with a possible redundancy in their role as potential organizers of plasma membrane protrusions.

Polarization of human hematopoietic progenitors during contact with multipotent mesenchymal stromal cells: effects on proliferation and clonogenicity.

Establishment of a defined cell culture system that facilitates ex vivo expansion of isolated hematopoietic stem and progenitor cells (HSPCs) is a crucial issue in hematology and stem cell transplantation. Here we have evaluated the capacity of primary human multipotent mesenchymal stromal cells (MSCs) to support the ex vivo expansion of peripheral CD34(+)-enriched HSPCs. We observed that HSPCs co-cultured on MSCs showed a substantially higher total expansion rate compared to those growing without. Moreover, in addition to the expansion of CD34(+)CD133(+) and CD34(+)CD133(-) cells, a third population of CD133(+)CD34(-) stem cells became detectable after expansion. Direct contact between HSPCs and the feeder layer appears beneficial for the expansion of HSPCs harboring CD133(+) phenotype, i.e., CD34(+)CD133(+) and CD133(+)CD34(-), in contrast to CD34(+)CD133(-) cells. Interestingly, electron microscopy and immunofluorescence analyses revealed that adherent HSPCs display various morphologies; they are either round with, in some cases, the appearance of a microvillar pole or exhibit several distinct types of plasma membrane protrusions such as lamellipodium and magnupodium. CD133 is selectively concentrated therein, whereas CD34 is randomly distributed over the entire surface of HSPCs. Together, this co-culture offers a unique experimental system to further characterize the biology and role of markers of rare stem cell populations.