The Light-activated Effect of Natural Anthraquinone Parietin against Candida auris and Other Fungal Priority Pathogens.

Antimicrobial photodynamic therapy (aPDT) is an evolving treatment strategy against human pathogenic microbes such as the Candida species, including the emerging pathogen C. auris. Using a modified EUCAST protocol, the light-enhanced antifungal activity of the natural compound parietin was explored. The photoactivity was evaluated against three separate strains of five yeasts, and its molecular mode of action was analysed via several techniques, i.e., cellular uptake, reactive electrophilic species (RES), and singlet oxygen yield. Under experimental conditions (λ = 428 nm, H = 30 J/cm2, PI = 30 min), microbial growth was inhibited by more than 90% at parietin concentrations as low as c = 0.156 mg/L (0.55 µM) for C. tropicalis and Cryptococcus neoformans, c = 0.313 mg/L (1.10 µM) for C. auris, c = 0.625 mg/L (2.20 µM) for C. glabrata, and c = 1.250 mg/L (4.40 µM) for C. albicans. Mode-of-action analysis demonstrated fungicidal activity. Parietin targets the cell membrane and induces cell death via ROS-mediated lipid peroxidation after light irradiation. In summary, parietin exhibits light-enhanced fungicidal activity against all Candida species tested (including C. auris) and Cryptococcus neoformans, covering three of the four critical threats on the WHO's most recent fungal priority list.

The influence of explainable vs non-explainable clinical decision support systems on rapid triage decisions: a mixed methods study.

BACKGROUND: During the COVID-19 pandemic, a variety of clinical decision support systems (CDSS) were developed to aid patient triage. However, research focusing on the interaction between decision support systems and human experts is lacking. METHODS: Thirty-two physicians were recruited to rate the survival probability of 59 critically ill patients by means of chart review. Subsequently, one of two artificial intelligence systems advised the physician of a computed survival probability. However, only one of these systems explained the reasons behind its decision-making. In the third step, physicians reviewed the chart once again to determine the final survival probability rating. We hypothesized that an explaining system would exhibit a higher impact on the physicians' second rating (i.e., higher weight-on-advice). RESULTS: The survival probability rating given by the physician after receiving advice from the clinical decision support system was a median of 4 percentage points closer to the advice than the initial rating. Weight-on-advice was not significantly different (p = 0.115) between the two systems (with vs without explanation for its decision). Additionally, weight-on-advice showed no difference according to time of day or between board-qualified and not yet board-qualified physicians. Self-reported post-experiment overall trust was awarded a median of 4 out of 10 points. When asked after the conclusion of the experiment, overall trust was 5.5/10 (non-explaining median 4 (IQR 3.5-5.5), explaining median 7 (IQR 5.5-7.5), p = 0.007). CONCLUSIONS: Although overall trust in the models was low, the median (IQR) weight-on-advice was high (0.33 (0.0-0.56)) and in line with published literature on expert advice. In contrast to the hypothesis, weight-on-advice was comparable between the explaining and non-explaining systems. In 30% of cases, weight-on-advice was 0, meaning the physician did not change their rating. The median of the remaining weight-on-advice values was 50%, suggesting that physicians either dismissed the recommendation or employed a "meeting halfway" approach. Newer technologies, such as clinical reasoning systems, may be able to augment the decision process rather than simply presenting unexplained bias.

Photochemical defense as trait of fungi from Cortinarius subgenus Dermocybe.

The photobiological activity of ten colorful species belonging to subgenus Dermocybe of the basidiomycete genus Cortinarius was investigated. Extracts of all species produced singlet oxygen and are thus photoactive. Pigment analysis was performed and showed similarities of the anthraquinone pigments across the species in dependency to their respective pigmentation types. Detailed content analysis of the pigments in the whole agaricoid fruiting body compared to the three different tissue types (pileus, stipe, and lamellae) revealed that the pigments emodin, dermocybin, and dermorubin, as well as their respective glycosides, are enhanced in the gills. In an independent experiment, the gills were shown to be the most photoactive tissues of the fruiting body. Photobiological experiments with invertebrates (i.e., glassworm Chaoborus crystallinus) proved a phototoxic effect of the methanolic extract of the red blood webcap (Cortinarius sanguineus var. aurantiovaginatus). This work adds further evidence to a common photobiological trait in Cortinarius subgenus Dermocybe and underpins the possibility of a photochemical defense mechanism in fungi.

Growth, morphology, and formation of cinnabarin in Pycnoporus cinnabarinus in relation to different irradiation spectra.

BACKGROUND: The demand for natural pigments in general, and for fungi-derived pigments in particular, is constantly rising. Wood-decomposing fungi represent a promising source for natural pigments and they are usually easy to cultivate in pure culture. One of them, i.e., Pycnoporus cinnabarinus, offers a highly interesting spectrum of bioactivity, partly due to the formation of the orange-red pigment cinnabarin. However, apart from a few studies addressing its diverse potential biotechnological applications, there is still a large gap of knowledge concerning the influence of light on the formation of cinnabarin. The aim of this work was to investigate the effect of different irradiations on the cinnabarin content, the growth, and the morphology of three different P. cinnabarinus strains. We used highly standardized irradiation conditions and cultivation techniques in combination with newly developed methods for the extraction and direct quantification of cinnabarin. RESULTS: Red, green, blue, and UV-A irradiation (mean irradiance Ee = 1.5 ± 0.18 W m-2) had considerable effects on the growth and colony appearance of all three P. cinnabarinus strains tested. The cinnabarin content determined was, thus, dependent on the irradiation wavelength applied, allowing strain-specific thresholds to be defined. Irradiation with wavelengths below this strain-specific threshold corresponded to a lower cinnabarin content, at least at the intensity applied. The orange-red pigment appeared by light microscopy as incrusted extracellular plaques present on the hyphal walls. Highly efficient vegetative propagation occurred by arthroconidia, and we observed the tendency that this asexual reproduction was (i) most frequent in the dark but (ii) never occurred under UV-A exposure. CONCLUSION:  This study highlights a differential photo-dependence of growth, morphology, and cinnabarin formation in P. cinnabarinus. This confirms that it is advisable to consider the wavelength of the light used in future biotechnological productions of natural pigments.

Highlighting the Phototherapeutical Potential of Fungal Pigments in Various Fruiting Body Extracts with Informed Feature-Based Molecular Networking.

Fungal pigments are characterized by a diverse set of chemical backbones, some of which present photosensitizer-like structures. From the genus Cortinarius, for example, several biologically active photosensitizers have been identified leading to the hypothesis that photoactivity might be a more general phenomenon in the kingdom Fungi. This paper aims at testing the hypothesis. Forty-eight fruiting body-forming species producing pigments from all four major biosynthetic pathways (i.e., shikimate-chorismate, acetate-malonate, mevalonate, and nitrogen heterocycles) were selected and submitted to a workflow combining in vitro chemical and biological experiments with state-of-the-art metabolomics. Fungal extracts were profiled by high-resolution mass spectrometry and subsequently explored by spectral organization through feature-based molecular networking (FBMN), including advanced metabolite dereplication techniques. Additionally, the photochemical properties (i.e., light-dependent production of singlet oxygen), the phenolic content, and the (photo)cytotoxic activity of the extracts were studied. Different levels of photoactivity were found in species from all four metabolic groups, indicating that light-dependent effects are common among fungal pigments. In particular, extracts containing pigments from the acetate-malonate pathway, e.g., extracts from Bulgaria inquinans, Daldinia concentrica, and Cortinarius spp., were not only efficient producers of singlet oxygen but also exhibited photocytotoxicity against three different cancer cell lines. This study explores the distribution of photobiological traits in fruiting body forming fungi and highlights new sources for phototherapeutics.

Fungal Anthraquinone Photoantimicrobials Challenge the Dogma of Cationic Photosensitizers.

The photoantimicrobial potential of four mushroom species (i.e., Cortinarius cinnabarinus, C. holoxanthus, C. malicorius, and C. sanguineus) was explored by studying the minimal inhibitory concentrations (MIC) via a light-modified broth microdilution assay based on the recommended protocols of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). The extracts were tested against Candida albicans, Escherichia coli, and Staphylococcus aureus under blue (λ = 428 and 478 nm, H = 30 J/cm2) and green light (λ = 528 nm, H = 30 J/cm2) irradiation. Three extracts showed significant photoantimicrobial effects at concentrations below 25 µg/mL. Targeted isolation of the major pigments from C. sanguineus led to the identification of two new potent photoantimicrobials, one of them (i.e., dermocybin) being active against S. aureus and C. albicans under green light irradiation [PhotoMIC530 = 39.5 µM (12.5 µg/mL) and 2.4 µM (0.75 µg/mL), respectively] and the other one (i.e., emodin) being in addition active against E. coli in a low micromolar range [PhotoMIC428 = 11.1 µM (3 µg/mL)]. Intriguingly, dermocybin was not (photo)cytotoxic against the three tested cell lines, adding an additional level of selectivity. Since both photoantimicrobials are not charged, this discovery shifts the paradigm of cationic photosensitizers.

Optimized isolation of 7,7'-biphyscion starting from Cortinarius rubrophyllus, a chemically unexplored fungal species rich in photosensitizers.

Mushrooms such as the dermocyboid Cortinarius rubrophyllus are characterized by strikingly colorful fruiting bodies. The molecular dyes responsible for such colors recently experienced a comeback as photoactive compounds with remarkable photophysical and photobiological properties. One of them-7,7'-biphyscion-is a dimeric anthraquinone that showed promising anticancer effects in the low nanomolar range under blue-light irradiation. Compared to acidic anthraquinones, 7,7'-biphyscion was more efficiently taken up by cells and induced apoptosis after photoactivation. However, seasonal collection of mushrooms producing this compound, low extraction yields, and tricky fungal identification hamper further developments to the clinics. To bypass these limitations, we demonstrate here an alternative approach utilizing a precursor of 7,7'-biphyscion, i.e., the pre-anthraquinone flavomannin-6,6'-dimethyl ether, which is abundant in many species of the subgenus Dermocybe. Controlled oxidation of the crude extract significantly increased the yield of 7,7'-biphyscion by 100%, which eased the isolation process. We also present the mycochemical and photobiological characterization of the yet chemically undescribed species, i.e. C. rubrophyllus. In total, eight pigments (1-8) were isolated, including two new glycosylated anthraquinones (1 and 2). Light-dependent generation of singlet oxygen was detected for the first time for emodin-1-O-ß-D-glucopyranoside (3) [photophysical measurement: Φ∆ = 0.11 (CD3OD)]. Furthermore, emodin (7) was characterized as promising compound in the photocytotoxicity assay with EC50-values in the low micromolar range under irradiation against cells of the cancer cell lines AGS, A549, and T24.

A convenient separation strategy for fungal anthraquinones by centrifugal partition chromatography.

As recently shown, some fungal pigments exhibit significant photoactivity turning them into promising agents for the photodynamic treatment of microbial infections or malignant diseases. In the present study, a separation strategy for fungal anthraquinones was developed based on centrifugal partition chromatography. A suitable method was explored employing a methanolic extract of the fruiting bodies of Cortinarius sanguineus (Agaricales, Basidiomycota). An excellent fractionation was achieved using a biphasic solvent system comprising chloroform/ethyl acetate/methanol/water/acetic acid (3:1:3:2:1, v/v/v/v/v) operating in ascending mode. Experiments on an analytical scale with extracts of closely related Cortinarius species exhibited broad applicability of the devised system. Up to six pigments could be purified directly from the crude extract. Preparative-scale fractionation of the methanol extracts of C. malicorius and C. sanguineus demonstrated that up-scaling was possible without compromising selectivity.

Digital Technology Applications in the Management of Adverse Drug Reactions: Bibliometric Analysis.

Adverse drug reactions continue to be not only one of the most urgent problems in clinical medicine, but also a social problem. The aim of this study was a bibliometric analysis of the use of digital technologies to prevent adverse drug reactions and an overview of their main applications to improve the safety of pharmacotherapy. The search was conducted using the Web of Science database for the period 1991-2023. A positive trend in publications in the field of using digital technologies in the management of adverse drug reactions was revealed. A total of 72% of all relevant publications come from the following countries: the USA, China, England, India, and Germany. Among the organizations most active in the field of drug side effect management using digital technologies, American and Chinese universities dominate. Visualization of publication keywords using VOSviewer software 1.6.18 revealed four clusters: "preclinical studies", "clinical trials", "pharmacovigilance", and "reduction of adverse drug reactions in order to improve the patient's quality of life". Molecular design technologies, virtual models for toxicity modeling, data integration, and drug repurposing are among the key digital tools used in the preclinical research phase. Integrating the application of machine learning algorithms for data analysis, monitoring of electronic databases of spontaneous messages, electronic medical records, scientific databases, social networks, and analysis of digital device data into clinical trials and pharmacovigilance systems, can significantly improve the efficiency and safety of drug development, implementation, and monitoring processes. The result of combining all these technologies is a huge synergistic provision of up-to-date and valuable information to healthcare professionals, patients, and health authorities.

Patent and Bibliometric Analysis of the Scientific Landscape of the Use of Pulse Oximeters and Their Prospects in the Field of Digital Medicine.

This study conducted a comprehensive patent and bibliometric analysis to elucidate the evolving scientific landscape surrounding the development and application of pulse oximeters, including in the field of digital medicine. Utilizing data from the Lens database for the period of 2000-2023, we identified the United States, China, the Republic of Korea, Japan, Canada, Australia, Taiwan, and the United Kingdom as the predominant countries in patent issuance for pulse oximeter technology. Our bibliometric analysis revealed a consistent temporal trend in both the volume of publications and citations, underscoring the growing importance of pulse oximeters in digitally-enabled medical practice. Using the VOSviewer software(version 1.6.18), we discerned six primary research clusters: (1) measurement accuracy; (2) integration with the Internet of Things; (3) applicability across diverse pathologies; (4) telemedicine and mobile applications; (5) artificial intelligence and deep learning; and (6) utilization in anesthesiology, resuscitation, and intensive care departments. The findings of this study indicate the prospects for leveraging digital technologies in the use of pulse oximetry in various fields of medicine, with implications for advancing the understanding, diagnosis, prevention, and treatment of cardio-respiratory pathologies. The conducted patent and bibliometric analysis allowed the identification of technical solutions to reduce the risks associated with pulse oximetry: improving precision and validity, technically improved clinical diagnostic use, and the use of machine learning.

Accuracy of a Dual-Sensor Heat-Flux (DHF) Non-Invasive Core Temperature Sensor in Pediatric Patients Undergoing Surgery.

Accurate temperature measurement is crucial for the perioperative management of pediatric patients, and non-invasive thermometry is necessary when invasive methods are infeasible. A prospective observational study was conducted on 57 patients undergoing elective surgery. Temperatures were measured using a dual-sensor heat-flux (DHF) thermometer (Tcore™) and a rectal temperature probe (TRec), and the agreement between the two measurements was assessed. The DHF measurements showed a bias of +0.413 °C compared with those of the TRec. The limits of agreement were broader than the pre-defined ±0.5 °C range (-0.741 °C and +1.567 °C). Although the DHF sensors tended to overestimate the core temperature compared to the rectal measurements, an error grid analysis demonstrated that 95.81% of the DHF measurements would not have led to a wrong clinical decision, e.g., warming or cooling when not necessary. In conclusion, the low number of measurements that would have led to incorrect decisions suggests that the DHF sensor can be considered an option for continuous temperature measurement when more invasive methods are infeasible.

The photosensitizer emodin is concentrated in the gills of the fungus Cortinarius rubrophyllus.

The colorful agaricoid fruiting bodies of dermocyboid Cortinarii owe their magnificent hue to a mixture of anthraquinone (AQ) pigments. Recently, it was discovered that some of these fungal anthraquinones have an impressive photopharmacological effect. The question, therefore, arises as to whether these pigments are also of ecological or functional significance. According to the optimal defense hypothesis, toxic molecules should be enriched in spore-producing structures, such as the gills of agarics. To test this hypothesis, we studied the distribution of fungal AQs in the fruiting body of Cortinarius rubrophyllus. The fungus belongs to the well-studied Cortinarius subgenus Dermocybe but has not been chemically characterized. Here, we report on the pigment profile of this beautiful fungus and focus on the distribution of anthraquinone pigments in the fruiting body for the first time. Here it is statistically confirmed that the potent photosensitizer emodin is significantly enriched in the gills. Furthermore, we show that the extract is photoactive against cancer cells and bacteria.

Targeted isolation of photoactive pigments from mushrooms yielded a highly potent new photosensitizer: 7,7'-biphyscion.

Pigments of fungi are a fertile ground of inspiration: they spread across various chemical backbones, absorption ranges, and bioactivities. However, basidiomycetes with strikingly colored fruiting bodies have never been explored as agents for photodynamic therapy (PDT), even though known photoactive compound classes (e.g., anthraquinones or alkaloids) are used as chemotaxonomic markers. In this study, we tested the hypothesis that the dyes of skin-heads (dermocyboid Cortinarii) can produce singlet oxygen under irradiation and thus are natural photosensitizers. Three photosensitizers based on anthraquinone structures were isolated and photopharmaceutical tests were conducted. For one of the three, i.e., (-)-7,7'-biphyscion (1), a promising photoyield and photocytotoxicity of EC50 = 0.064 µM against cancer cells (A549) was found under blue light irradiation (λexc = 468 nm, 9.3 J/cm2). The results of molecular biological methods, e.g., a viability assay and a cell cycle analysis, demonstrated the harmlessness of 1 in the dark and highlighted the apoptosis-inducing PDT potential under blue light irradiation. These results demonstrate for the first time that pigments of dermocyboid Cortinarii possess a so far undescribed activity, i.e., photoactivity, with significant potential for the field of PDT. The dimeric anthraquinone (-)-7,7'-biphyscion (1) was identified as a promising natural photosensitizer.

A New High-Throughput-Screening-Assay for Photoantimicrobials Based on EUCAST Revealed Unknown Photoantimicrobials in Cortinariaceae.

Antimicrobial resistance is one of the biggest health and subsequent economic threat humanity faces. Next to massive global awareness campaigns, governments and NGOs alike stress the need for new innovative strategies to treat microbial infections. One of such innovative strategies is the photodynamic antimicrobial chemotherapy (PACT) in which the synergistic effects of photons and drugs are exploited. While many promising reports are available, PACT - and especially the drug-design part behind - is still in its infancy. Common best-practice rules, such as the EUCAST or CLSI protocols for classic antibiotics as well as high-throughput screenings, are missing, and this, in turn, hampers the identification of hit structures. Hit-like structures might come from synthetic approaches or from natural sources. They are identified via activity-guided synthesis or isolation strategies. As source for new antimicrobials, fungi are highly ranked. They share the same ecological niche with many other microbes and consequently established chemical strategies to combat with the others. Recently, in members of the Cortinariaceae, especially of the subgenus Dermocybe, photoactive metabolites were detected. To study their putative photoantimicrobial effect, a photoantimicrobial high-throughput screening (HTS) based on The European Committee on Antimicrobial Susceptibility Testing (EUCAST) was established. After validation, the established HTS was used to evaluate a sample set containing six colorful representatives from the genus Cortinarius (i.e., Cortinarius callisteus, C. rufo-olivaceus, C. traganus, C. trivialis, C. venetus, and C. xanthophyllus). The assay is built on a uniform, light-emitting diode (LED)-based light irradiation across a 96-well microtiter plate, which was achieved by a pioneering arrangement of the LEDs. The validation of the assay was accomplished with well-known photoactive drugs, so-called photosensitizers, utilizing six distinct emission wavelengths (λexc = 428, 478, 523, 598, or 640 nm) and three microbial strains (Candida albicans, Staphylococcus aureus, and Escherichia coli). Evaluating the extracts of six Cortinarius species revealed two highly promising species, i.e., C. rufo-olivaceus and C. xanthophyllus. Extracts from the latter were photoactive against the Gram-positive S. aureus (c = 7.5 µg/ml, H = 30 J/cm2, λ = 478 nm) and the fungus C. albicans (c = 75 µg/ml, H = 30 J/cm2, λ = 478 nm).

Feature-Based Molecular Networking-An Exciting Tool to Spot Species of the Genus Cortinarius with Hidden Photosensitizers.

Fungi have developed a wide array of defense strategies to overcome mechanical injuries and pathogen infections. Recently, photoactivity has been discovered by showing that pigments isolated from Cortinarius uliginosus produce singlet oxygen under irradiation. To test if this phenomenon is limited to dermocyboid Cortinarii, six colourful Cortinarius species belonging to different classical subgenera (i.e., Dermocybe, Leprocybe, Myxacium, Phlegmacium, and Telamonia) were investigated. Fungal extracts were explored by the combination of in vitro photobiological methods, UHPLC coupled to high-resolution tandem mass spectrometry (UHPLC-HRMS2), feature-based molecular networking (FBMN), and metabolite dereplication techniques. The fungi C. rubrophyllus (Dermocybe) and C. xanthophyllus (Phlegmacium) exhibited promising photobiological activity in a low concentration range (1-7 µg/mL). Using UHPLC-HRMS2-based metabolomic tools, the underlying photoactive principle was investigated. Several monomeric and dimeric anthraquinones were annotated as compounds responsible for the photoactivity. Furthermore, the results showed that light-induced activity is not restricted to a single subgenus, but rather is a trait of Cortinarius species of different phylogenetic lineages and is linked to the presence of fungal anthraquinones. This study highlights the genus Cortinarius as a promising source for novel photopharmaceuticals. Additionally, we showed that putative dereplication of natural photosensitizers can be done by FBMN.

Comparison and Reliability of Hippocampal Subfield Segmentations Within FreeSurfer Utilizing T1- and T2-Weighted Multispectral MRI Data.

The accurate segmentation of in vivo magnetic resonance imaging (MRI) data is a crucial prerequisite for the reliable assessment of disease progression, patient stratification or the establishment of putative imaging biomarkers. This is especially important for the hippocampal formation, a brain area involved in memory formation and often affected by neurodegenerative or psychiatric diseases. FreeSurfer, a widely used automated segmentation software, offers hippocampal subfield delineation with multiple input options. While a single T1-weighted (T1) sequence is regularly used by most studies, it is also possible and advised to use a high-resolution T2-weighted (T2H) sequence or multispectral information. In this investigation it was determined whether there are differences in volume estimations depending on the input images and which combination of these deliver the most reliable results in each hippocampal subfield. 41 healthy participants (age = 25.2 years ± 4.2 SD) underwent two structural MRIs at three Tesla (time between scans: 23 days ± 11 SD) using three different structural MRI sequences, to test five different input configurations (T1, T2, T2H, T1 and T2, and T1 and T2H). We compared the different processing pipelines in a cross-sectional manner and assessed reliability using test-retest variability (%TRV) and the dice coefficient. Our analyses showed pronounced significant differences and large effect sizes between the processing pipelines in several subfields, such as the molecular layer (head), CA1 (head), hippocampal fissure, CA3 (head and body), fimbria and CA4 (head). The longitudinal analysis revealed that T1 and multispectral analysis (T1 and T2H) showed overall higher reliability across all subfields than T2H alone. However, the specific subfields had a substantial influence on the performance of segmentation results, regardless of the processing pipeline. Although T1 showed good test-retest metrics, results must be interpreted with caution, as a standard T1 sequence relies heavily on prior information of the atlas and does not take the actual fine structures of the hippocampus into account. For the most accurate segmentation, we advise the use of multispectral information by using a combination of T1 and high-resolution T2-weighted sequences or a T2 high-resolution sequence alone.

The Role of Iron and Erythropoietin in the Association of Fibroblast Growth Factor 23 with Anemia in Chronic Kidney Disease in Humans.

Anemia in chronic kidney disease (CKD) is an almost universal complication of this condition. Fibroblast growth factor 23 (FGF23), a key-player in mineral metabolism, is reportedly associated with anemia and hemoglobin levels in non-dialysis CKD patients. Here, we sought to further characterize this association while taking into account the biologically active, intact fraction of FGF23, iron metabolism, and erythropoietin (EPO). Hemoglobin, EPO, iron, and mineral metabolism parameters, including both intact and c-terminal-FGF23 (iFGF23 and cFGF23, respectively) were measured cross-sectionally in 225 non-dialysis CKD patients (stage 1-5, median eGFR: 30 mL/min./1.73m2) not on erythropoiesis stimulating agents or intravenous iron therapy. Statistical analysis was performed by multiple linear regression. After adjustment for eGFR and other important confounders, only cFGF23 but not iFGF23 was significantly associated with hemoglobin levels and this association was largely accounted for by iron metabolism parameters. cFGF23 but not iFGF23 was also associated with mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV), again in dependence on iron metabolism parameters. Similarly, EPO concentrations were associated with cFGF23 but not iFGF23, but their contribution to the association of cFGF23 with hemoglobin levels was marginal. In pre-dialysis CKD patients, the observed association of FGF23 with hemoglobin seems to be restricted to cFGF23 and largely explained by the iron status.

A convenient workflow to spot photosensitizers revealed photo-activity in basidiomycetes.

Photodynamic therapy (PDT) is an alternative approach for the treatment of neoplastic diseases employing photosensitizers activated by light. In order to discover new natural photosensitizers, a convenient workflow was established. To validate the workflow, fungi were selected, because we hypothesized that fruiting bodies and mycelia are an overlooked source. The results proved the hypothesis, as exorbitant high photo-cytotoxicity values were detected. For example, the acetone extract of Cortinarius croceus was characterized by an EC50, 9.3 J cm-2 of 1 µg mL-1 against cells of a lung cancer cell-line (A549). In sum, a low-cost workflow for the detection and biological evaluation of photosensitizers is presented and discussed. Furthermore, this paper provides the first experimental evidence for phototoxic metabolites in basidiomycetes. This hints towards a new assignable function of fungal pigments, i.e. photochemical defense.

Influence of electrical stimulation therapy on permanent pacemaker function.

BACKGROUND: Electrical stimulation therapy (EST) and transcutaneous electrical neuromuscular stimulation (TENS), a modality of EST, have become widely applied, accepted and effective methods for the treatment of musculoskeletal and other pain conditions. According to the rising number of permanent pacemaker (PM) wearers the number of potential candidates for EST with concomitant device implantation is growing. Contradictory recommendations exist regarding the application of EST or TENS on PM wearers. AIM: The study was carried out to evaluate the impact of EST on PM function. METHODS: A full size model mimicking the electrical characteristics of the human body was used to evaluate the application of EST on permanent PM devices. Various configurations with respect to energy modality, position of the stimulation electrodes and PM device models were evaluated. Intracardiac PM electrogram tracings (iEGM) were analyzed for the interference of EST with PM function. RESULTS: Unilateral EST application did not cause interference with PM function in any of the configurations (0%; n = 700). On the contrary, bilateral stimulation (350 configurations in total) caused either ventricular inhibition or switch to V00 back-up pacing due to electrical interference in 165 cases (47.1%) depending on the applied stimulation parameters. CONCLUSION: The use of EST potentially interferes with PM therapy, especially if the electrodes are positioned bilaterally; however, unilateral EST application appeared to be safe in all tested configurations.