Search

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and postexertional malaise. There is little known about the metabolism of specific immune cells in patients with ME/CFS. To investigate immune metabolism in ME/CFS, we isolated [CD4.sup.+] and [CD8.sup.+] T cells from 53 patients with ME/CFS and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism and plasma cytokines. We found that ME/CFS [CD8.sup.+] T cells had reduced mitochondrial membrane potential compared with those from healthy controls. Both [CD4.sup.+] and [CD8.sup.+] T cells from patients with ME/CFS had reduced glycolysis at rest, whereas [CD8.sup.+] T cells also had reduced glycolysis following activation. Patients with ME/CFS had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from correlations seen in healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease., Introduction Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a poorly understood and debilitating disease. An estimated 836,000 to 2.5 million Americans have ME/CFS (1). Patients suffer from severe fatigue, unrefreshing sleep, [...]

Background: One of the goals of the Multi-site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM) study was to evaluate whether clinicians experienced in diagnosing and caring for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) recognized the same clinical entity. Methods: We enrolled participants from seven specialty clinics in the United States. We used baseline data (n = 465) on standardized questions measuring general clinical characteristics, functional impairment, post-exertional malaise, fatigue, sleep, neurocognitive/autonomic symptoms, pain, and other symptoms to evaluate whether patient characteristics differed by clinic. Results: We found few statistically significant and no clinically significant differences between clinics in their patients' standardized measures of ME/CFS symptoms and function. Strikingly, patients in each clinic sample and overall showed a wide distribution in all scores and measures. Conclusions: Illness heterogeneity may be an inherent feature of ME/CFS. Presenting research data in scatter plots or histograms will help clarify the challenge. Relying on case–control study designs without subgrouping or stratification of ME/CFS illness characteristics may limit the reproducibility of research findings and could obscure underlying mechanisms. [ABSTRACT FROM AUTHOR]

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction. To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation. We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation. In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells. We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data. These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness's mechanism of action. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate matrix‐assisted laser desorption ionisation time of flight mass spectrometry (MALDI‐TOF MS) combined with the Sepsityper kit (Bruker Daltoniks GmbH, Bremen) for the direct detection of bacterial species from inoculated blood cultures from dogs and cats. Materials and Methods: Canine and feline blood samples were inoculated with typical sepsis‐causing bacteria such as Staphylococcus intermedius, Staphylococcus aureus, Streptococcus canis, Enterococcus faecalis, Escherichia coli and Pseudomonas aeruginosa at two distinct concentrations (each in triplicate), resulting in 72 blood culture bottles incubated at 37°C. Samples were comparatively analysed with MALDI‐TOF MS after preparation with the Sepsityper kit and also by standard bacteriology (culturing and biochemical characterisation). Results: Bacterial species identified from agar plates and by MALDI‐TOF MS from blood culture bottles were identical for all samples. The MALDI Biotyper software (Bruker Daltoniks) correctly identified all bacterial strains from inoculated canine and feline blood with analysis indicating very good precision. Clinical Significance: MALDI‐TOF MS analysis combined with the Sepsityper kit is a reliable tool for a quick detection of veterinary‐relevant bacterial species directly from blood culture bottles. This approach could reduce the time for identification of critical species to only 24 hours. [ABSTRACT FROM AUTHOR]

In the Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM), we relied on expert clinician diagnoses to enroll patients from 7 specialty clinics in the United States in order to perform a systematic collection of data on measures of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). Healthy persons and those with other illnesses that share some features with ME/CFS were enrolled in comparison groups. The major objectives were to: 1) use standardized questionnaires to measure illness domains of ME/CFS and to evaluate patient heterogeneity overall and between clinics; 2) describe the course of illness, identify the measures that best correlate with meaningful clinical differences, and assess the performances of questionnaires as patient/person-reported outcome measures; 3) describe prescribed medications, orders for laboratory and other tests, and management tools used by expert clinicians to care for persons with ME/CFS; 4) collect biospecimens for future hypothesis testing and for evaluation of morning cortisol profiles; and 5) identify measures that best distinguish persons with ME/CFS from those in the comparison groups and detect subgroups of persons with ME/CFS who may have different underlying causes. Enrollment began in 2012 and is planned to continue in multiple stages through 2017. We present the MCAM methods in detail, along with an initial description of the 471 patients with ME/CFS who were enrolled in stage 1. [ABSTRACT FROM AUTHOR]

Deals with the comparison of results from advanced oxidation processes (AOPs). Need for non-specific figure-of-merit to avoid influences by system-inherent parameters; Comparison of AOPs in pilot plants and full-scale plants.

Mycotoxins are toxic secondary metabolites of various fungal species that can contaminate food and feed, as well as indoor environments. Numerous studies have summarized the adverse health effects of mycotoxins and described severe intoxications of humans and animals. The major health concerns are caused via the alimentary route which unambiguously is the main source for human internal exposure; however, the relevance of other pathways under environmental and occupational conditions should also be considered. Thus firstly, this review aims in summarizing literature data on potentially inhalable mycotoxins occurring in dusts or air in residences and in working environments. Secondly, it gives an overview of the overall internal body burden of mycotoxins in humans in an attempt to characterize total human exposure. These data are also discussed in relation to the current toxicologically based values used for risk assessment. [ABSTRACT FROM AUTHOR]

Background: Melioidosis is a bacterial infection associated with high mortality. The diagnostic approach to this rare disease in Europe is challenging, especially because pulmonary manifestation of melioidosis can mimic pulmonary tuberculosis (TB). Antibiotic therapy of melioidosis consists of an initial intensive phase of 2-8 weeks followed by an eradication therapy of 3-6 months., Case Presentation: We present the case of a 46-year-old female patient with pulmonary melioidosis in Germany. The patient showed chronic cough, a pulmonary mass and a cavitary lesion, which led to the initial suspicion of pulmonary TB. Melioidosis was considered due to a long-term stay in Thailand with recurrent exposure to rice fields., Results: Microbiologic results were negative for TB. Histopathology of an endobronchial tumor showed marked chronic granulation tissue and fibrinous inflammation. Melioidosis was diagnosed via polymerase chain reaction by detection of Burkholderia pseudomallei/mallei target from mediastinal lymph-node tissue., Conclusion: This case report emphasizes that melioidosis is an important differential diagnosis in patients with suspected pulmonary tuberculosis and recent travel to South-East Asia., (© 2024. The Author(s).)

The U.S. Department of Agriculture (USDA) has performed European pear ( Pyrus communis L.) scion breeding for over a century. The breeding program started in the early 1900s by Merton B. Waite in the Washington D.C. area and the program's main goal was to develop host resistance to the devastating disease fire blight, caused by Erwinia amylovora. Most of the historic European pear cultivars being produced in the U.S. were susceptible to fire blight, prompting a need to breed for resistance. More than six generations of USDA breeders have continued this effort to breed disease-resistant European pears. Along with fire blight resistance, the pear breeding programs sought improved fruit quality, cold hardiness, and resistance to psylla ( Cacopsylla pyricola Foërster), a significant insect pest of pear. Herein, we discuss the history of the program through each generation of breeder(s). We also present breeding aims, parental selection, and releases. In total, the program has released ten named pear varieties between 1938 and 2022., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gottschalk, Bell, Volk and Dardick.)

Ragworts like tansy ragwort ( J. vulgaris Gaertn., syn. Senecio jacobaea L.) contain hepatotoxic and cancerogenic pyrrolizidine alkaloids (PA) and their corresponding pyrrolizidine alkaloid N -oxides (PANO). Due to increasing spread of ragworts ( Jacobaea spp.) PA/PANO may pose a health risk to animals and humans consuming contaminated feed and food. Therefore, the aim of the present study was to investigate the transfer of individual PA/PANO originating from a well-defined PA/PANO extract into the milk of dairy cows. For this objective, 16 German Holstein cows were assigned to four treatment groups ( n  = 4) in a 28-day dose-response study. Administration into the reticulorumen was performed daily by gavage after the morning milking. Three groups received different amounts of the J. vulgaris extract resulting in a PA/PANO exposure of 0.47, 0.95, or 1.91 mg PA/PANO/kg body weight/day, respectively. Furthermore, a control group received molasses to account for the sugar content of the used PA/PANO extract. While the composition of the PA/PANO extract was more diverse, the PA/PANO pattern in milk was dominated by the PA in their free base form. It was shown that mainly PA considered stable in the rumen environment were transferred into the milk. The main compounds in milk were jacoline (74.3 ± 2.4% of the PA/PANO sum), jaconine (11.2 ± 1.3%), and jacobine (7.2 ± 0.6%) with concentrations up to 29.7, 4.65 µg/l, or in the highest exposed group, 3.44 µg/l. There was no dose-dependent effect on the total PA/PANO transfer rate into the milk. The average transfer rate was 0.064 ± 0.005% of the administered content.

Migraines are a type of headache that occur with other neurological symptoms, but the pathophysiology remains unclear. In this issue of the JCI, Nelson-Maney and authors used constitutive and inducible knockouts of the CGRP receptor components, elegantly demonstrating an essential function of CGRP in modulating meningeal lymphatic vessels (MLVs) in migraine. CGRP was shown to induce rearrangement of membrane-bound gap junction proteins in MLVs, resulting in a reduced CSF flux into cervical lymph nodes. The authors also provided evidence of a primary role for CGRP in modulating neuro-immune function. Finally, by showing that blocking CGRP signaling in MLVs attenuated pain behavior associated with acute migraine in rodents, the authors provided a target for pharmacological blockade of CGRP in relation to primary headache disorders.

The bitter rot of apple is caused by Colletotrichum spp. and is a serious pre-harvest disease that can manifest in postharvest losses on harvested fruit. In this study, we obtained genome sequences from four different species, C . chrysophilum , C. noveboracense , C. nupharicola , and C. fioriniae , that infect apple and cause diseases on other fruits, vegetables, and flowers. Our genomic data were obtained from isolates/species that have not yet been sequenced and represent geographic-specific regions. Genome sequencing allowed for the construction of phylogenetic trees, which corroborated the overall concordance observed in prior MLST studies. Bioinformatic pipelines were used to discover CAZyme, effector, and secondary metabolic (SM) gene clusters in all nine Colletotrichum isolates. We found redundancy and a high level of similarity across species regarding CAZyme classes and predicted cytoplastic and apoplastic effectors. SM gene clusters displayed the most diversity in type and the most common cluster was one that encodes genes involved in the production of alternapyrone. Our study provides a solid platform to identify targets for functional studies that underpin pathogenicity, virulence, and/or quiescence that can be targeted for the development of new control strategies. With these new genomics resources, exploration via omics-based technologies using these isolates will help ascertain the biological underpinnings of their widespread success and observed geographic dominance in specific areas throughout the country.

Penicillium spp. occupy many diverse biological niches that include plant pathogens, opportunistic human pathogens, saprophytes, indoor air contaminants, and those selected specifically for industrial applications to produce secondary metabolites and lifesaving antibiotics. Recent phylogenetic studies have established Penicillium fuscoglaucum as a synonym for Penicillium commune, which is an indoor air contaminant and toxin producer and can infect apple fruit during storage. During routine culturing on selective media in the lab, we obtained an isolate of P. fuscoglaucum Pf_T2 and sequenced its genome. The Pf_T2 genome is far superior to available genomic resources for the species. Our assembly exhibits a length of 35.1 Mb, a BUSCO score of 97.9% complete, and consists of five scaffolds/contigs representing the four expected chromosomes. It was determined that the Pf_T2 genome was colinear with a type specimen P. fuscoglaucum and contained a lineage-specific, intact cyclopiazonic acid (CPA) gene cluster. For comparison, a highly virulent postharvest apple pathogen, P. expansum strain TDL 12.1, was included and showed a similar growth pattern in culture to our Pf_T2 isolate but was far more aggressive in apple fruit than P. fuscoglaucum. The genome of Pf_T2 serves as a major improvement over existing resources, has superior annotation, and can inform forthcoming omics-based work and functional genetic studies to probe secondary metabolite production and disparities in aggressiveness during apple fruit decay.

1,2-Dehydro-pyrrolizidine alkaloids (PA), their corresponding N -oxides (PANO) and tropane alkaloids (TA), are toxic plant metabolites. If plant material, containing these toxins, is present in the feed of dairy cows these toxins can be transferred into milk. Here, milk was sampled directly from dairy farms in the German federal states of Bavaria and Schleswig-Holstein in 2020-2022 in order to investigate a possible contamination of milk at the production stage. In total, 228 milk samples were analysed for 54 PA/PANO and two TA by a sensitive LC-ESI-MS/MS method. In addition, a subset of milk samples ( n  = 85) was independently analysed for TA by a cooperating laboratory for verification. PA/PANO were found in 26 samples (11%) with a low median sum content of the contaminated samples of 0.024 µg/L. The highest level of contamination was 5.6 µg/L. Senecionine-, lycopsamine- and heliotrine-type PA/PANO were detected. In four samples (1.8%), atropine was determined up to 0.066 µg/L. The toxin levels in the milk samples hardly contributed to the total daily exposure. These data are first-time results on contamination rates and levels occurring in milk from individual dairy farms, based on a large sample number.

The increasing spread of ragworts is observed with concern. Ragworts like tansy ragwort ( Jacobaea vulgaris Gaertn.) or marsh ragwort ( J. aquatica ) contain pyrrolizidine alkaloids (PA) which may induce hepatotoxic effects. Grazing animals usually avoid ragworts if their pasture management is appropriate. Preserved feed prepared from ragworts contaminated meadows may, however, lead to a significant exposure to PA. Previous studies on toxicity of PA for dairy cows revealed inconsistent results due to feeding ragwort plant material which was associated with heterogeneous PA exposure and thus failed to conclusively deduce critical PA doses. Therefore, the aim of the present study was to expose dairy cows ( n  = 4 per group) in a short-term scenario for 28 days with increasing PA doses (PA1: 0.47 mg PA/kg body weight (BW)/day (d); PA2: 0.95 mg PA/kg BW/d; PA3: 1.91 mg PA/kg BW/d) via oral administration by gavage of a defined PA-extract. While group PA3 was dosed with the PA-extract alone, groups PA2 and PA1 received PA-extracts blended in similar volumes with molasses to provide comparable amounts of sugar. Additionally, two control groups were treated either with water (CON Water ) or with molasses (CON Molasses ) to assess the effects of sugar without PA interference. While clinical traits including dry matter intake, milking performance, rectal body temperature, ruminal activity and body condition score (BCS) were not influenced by PA exposure, activities of enzymes indicative for liver damages, such as gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH), increased significantly over time at an exposure of 1.91 mg total PA/kg BW/d.

Confocal micro X-ray fluorescence (CMXRF) spectroscopy is a non-destructive, depth-resolved, and element-specific technique that is used to analyze the elemental composition of a sample. For this, a focused beam of mono- or polychromatic X-rays is applied to excite the atoms in the sample, causing them to emit fluorescence radiation which is detected with focusing capillary optics. The confocal design of the instrument allows for depth-resolved analysis, in most cases with a resolution in the lower micrometer dimension after collecting X-rays from a predefined volume within the sample. The element-specific nature of the technique allows information to be obtained about the presence and concentration of specific elements in this volume. This makes CMXRF spectroscopy a valuable tool for a wide range of applications, especially when samples with an inhomogeneous distribution of elements and a relatively light matrix have to be analyzed, which are typical examples in materials science, geology, and biology. The technique is also commonly used in the art and archaeology fields to analyze the elemental composition of historical artifacts and works of art, helping to provide valuable insights into their provenance, composition, and making. Recent technical developments to increase sensitivity and efforts to improve quantification in three-dimensional samples will encourage wider use of this method across a multitude of fields of application in the near future. Confocal micro X-ray fluorescence (CMXRF) is based on the confocal overlap of two polycapillary lens foci, creating a depth-sensitive and non-destructive probing volume. Three-dimensional resolved element distribution images can be obtained by measuring the fluorescence intensity as function of the three-dimensional position., (© 2023. The Author(s).)

In domesticated apple ( Malus x domestica Borkh.) and other woody perennials, floral initiation can be repressed by gibberellins (GAs). The associated mechanism is a major unanswered question in plant physiology, and understanding organismal aspects of GA signaling in apple has important commercial applications. In plants, the major mechanism for elimination of GAs and resetting of GA signaling is through catabolism by GA2-oxidases (GA2ox). We found that the GA2ox gene family in apple comprises 16 genes representing eight, clearly defined homeologous pairs, which were named as MdGA2ox1A/1B to MdGA2ox8A/8B . Expression of the genes was analyzed in the various structures of the spur, where flowers are initiated, as well as in various structures of seedlings over one diurnal cycle and in response to water-deficit and salt stress. Among the results, we found that MdGA2ox2A/2B dominated expression in the shoot apex and were strongly upregulated in the apex after treatment with exogenous GA 3 , suggesting potential involvement in repression of flowering. Several MdGA2ox genes also showed preferential expression in the leaf petiole, fruit pedicel, and the seed coat of developing seeds, potentially representing mechanisms to limit diffusion of GAs across these structures. In all contexts studied, we documented both concerted and distinct expression of individual homeologs. This work introduces an accessible woody plant model for studies of GA signaling, GA2ox gene regulation, and conservation/divergence of expression of homeologous genes, and should find application in development of new cultivars of apple and other tree fruits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Gottschalk and van Nocker.)

Fruit losses due to postharvest decay caused by several fungal species is a major challenge for pear production (Sardella et al. 2016). In December 2021, a European pear (Pyrus communis L.) 'Dawn' with brown, circular, watery, and sunken lesions was observed in cold storage at the USDA Appalachian Fruit Research Station in Kearneysville, West Virginia. Only 1 of 14 'Dawn' pears examined in cold storage had the described disease symptoms. The fruit was surface sterilized, and symptomatic tissue was transferred to potato dextrose agar (PDA) and incubated at 25°C under continuous light. The isolate was hyphal tip purified and propagated on PDA plates at 25°C. The colonies grew an average of 8 mm/day and produced fluffy white aerial mycelium and pigmented rings of golden yellow which then darkened to pink with a dark pink on the reverse. The isolate was also cultured in liquid basal medium with carboxymethyl cellulose (Moura et al. 2020) for 7 days at 25°C to promote macroconidia formation. Macroconidia were slightly falcate with a tapering apical cell, usually 2 to 4 septate, and on average 16.8 µm long by 2.8 µm wide. The isolate was identified as Fusarium spp. based on morphology. Identity of the isolate was confirmed through sequencing of the ITS and TEF1 gene region (Stielow et al. 2015). The ITS and TEF1 sequences were deposited in GenBank (OP007197 and OP007198). BLAST analysis of the ITS amplicon identified multiple Fusarium spp. with 100% identity and 100% query coverage including F. avenaceum KJ562378. BLAST analysis of the TEF1 amplicon showed 99% identity and 99-100% query coverage with F. avenaceum isolates KM189442 and MK512754. Organic Bartlett pears were surface sanitized with a 1% aqueous chlorine solution, rinsed with sterile water and dried in a laminar flow hood. Fruit were then wounded with a sterile nail (4 mm diameter x 4 mm depth) and inoculated with a 4 mm mycelial plug taken from a 7- to 10-day old culture on PDA and wrapped with Parafilm. Plugs taken from sterile PDA were used as a control. Inoculated fruit were stored at 25°C in fruit trays in plastic bins for 7 days. Six fruit composed a replicate, and the experiment was repeated for a total of two replications. Lesions developed within 48 hours and expanded to an average of 28.5 mm by day 7. No lesions were observed on control fruit. Symptoms observed on inoculated pears were the same as the decay observed on the original pear obtained from cold storage. Fungal colonies isolated from the lesions and cultured on PDA morphologically resembled the original isolate from the infected pear. In 2014, F. avenaceum was first reported in the United States to cause post-harvest decay of apples in Pennsylvania (Kou et al. 2014). In the Netherlands, F. avenaceum has been reported to cause postharvest decay of 'Conference' pears but was observed at low frequencies (1-5%) in packing-house surveys (Wenneker et al. 2016). Fusarium spp. was also recently found on European pears in Southern Oregon (KC and Rasmussen 2020). F. avenaceum can produce mycotoxins which is a concern for fruit processing (Munkvold et al. 2021). Monitoring for this pathogen to prevent losses and mycotoxin contamination of processed fruit products will be import for consumer safety. To our knowledge, this is the first report of F. avenaceum causing postharvest decay of European pear in the Mid-Atlantic region of the United States.

1,2-Unsaturated pyrrolizidine alkaloids (PA), their corresponding N-oxides (PANO), and tropane alkaloids (TA) are toxic secondary plant metabolites. Their possible transfer into the milk of dairy cows has been studied in feeding trials; however, only few data on the occurrence of these toxins in milk are available. In this study, the development of a sensitive analytical approach for the simultaneous detection and quantification of a broad range of 54 PA/PANO as well as of the TA atropine and scopolamine in milk of dairy cows is presented. The method optimisation focused on sensitivity and separation of PA/PANO isomers. Milk samples were extracted using liquid-liquid extraction with aqueous formic acid and n-hexane, followed by a cation-exchange solid-phase extraction for purification. Reversed phase liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis was performed using alkaline solvent conditions. Validation proved low limits of detection and quantification of 0.005 to 0.054 µg/L and of 0.009 to 0.123 µg/L, respectively. For 51 of the 54 tested PA/PANO and both TA, the recovery rates ranged from 64 to 127% with repeatability (RSD r ) values below 15% at concentration levels of 0.05 and 0.50 µg/L and below 8% at a concentration level of 3.00 µg/L. Only three PANO did not match the validation criteria and were therefore regarded as semiquantitative. The final method was applied to 15 milk samples obtained from milk vending stations at farms and from local marketers in Bavaria, Germany. In three of the milk samples, traces of PA were detected., (© 2022. The Author(s).)

Phytochemicals like pyrrolizidine alkaloids (PAs) can affect the health of humans and animals. PAs can occur for example in tea, honey or herbs. Some PAs are known to be cytotoxic, genotoxic, and carcinogenic. Upon intake of high amounts, hepatotoxic and pneumotoxic effects were observed in humans. This study aims to elucidate different toxicokinetic parameters like the uptake of PAs and their metabolism with in vitro models. We examined the transport rates of differently structured PAs (monoester, open-chained diester, cyclic diester) over a model of the intestinal barrier. After passing the intestinal barrier, PAs reach the liver, where they are metabolized into partially instable electrophilic metabolites interacting with nucleophilic centers. We investigated this process by the usage of human liver, intestinal, and lung microsomal preparations for incubation with different PAs. These results are completed with the detection of apoptosis as indicator for bioactivation of the PAs. Our results show a structure-dependent passage of PAs over the intestinal barrier. PAs are structure-dependently metabolized by liver microsomes and, to a smaller extent, by lung microsomes. The detection of apoptosis of A549 cells treated with lasiocarpine and monocrotaline following bioactivation by human liver or lung microsomes underlines this result. Conclusively, our results help to shape the picture of PA toxicokinetics which could further improve the knowledge of molecular processes leading to observed effects of PAs in vivo.

Defining the epidemiology of headache disorders is challenging given the prevalence of stigma and other harmful misconceptions about these diseases. Understanding the widespread impact of these disorders is essential when considering social and policy interventions to mitigate that impact. Tension-type headache is still widely considered the most common primary headache disorder, but population-based estimates of its prevalence vary widely. Migraine remains the most common headache disorder in patients who present for clinical care. Prevalence estimates have remained fairly stable over the last two decades (1-year period prevalence, United States: 18% of women and 6% of men). Recent studies indicate that people who identify as American Indian/Alaskan Native (AI/AN) have the highest migraine prevalence of any ethnic group surveyed, particularly among AI/AN men (15% vs. <10%). Studies in the United States also show an inverse relationship between income level and migraine incidence and prevalence, particularly for chronic migraine; factors mediating this relationship are difficult to define. There are many diseases comorbid with migraine, more so with migraine with aura. The burden of migraine is enormous: the Global Burden of Disease study indicates migraine is the number 1 cause of disability in women younger than 50 years and the number 2 or 3 cause of disability worldwide. Further study is needed into underdiagnosis, undertreatment, and persistent stigma associated with headache disorders, especially in underserved communities. Stakeholders including patients, providers, and governing bodies are affected by the results of epidemiologic studies and should all have a role in crafting and evaluating thoughtful and relevant questions and hypotheses in this field., Competing Interests: D.K.: no conflicts to declare.C.G.: a member of Scientific Advisory Boards for Impel NeuroPharma, Currax, Biodelivery Sciences, Amneal Pharmaceuticals, LinPharma, Upsher Smith, and Vorso (stock options) and is a paid consultant for Spherix Global Insights; Trustee, Headache Cooperative of New England (HCNE)., (Thieme. All rights reserved.)