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Background: The intrathecal humoral response is the characteristic diagnostic finding in the cerebrospinal fluid (CSF) analysis of patients with multiple sclerosis (MS). Although the average age of MS patients increases, little is known about the sensitivity of diagnostic markers in elderly MS patients. Methods: In this retrospective two-center study, intrathecal free light chains kappa fraction (FLCk IF) and oligoclonal bands (OCB) were studied in a large cohort of patients with early and late onset relapsing (RMS) and progressive (PMS) MS. Furthermore, the humoral immune profile in CSF was analyzed, including the polyspecific intrathecal immune response measured as the MRZ reaction. Results: While the frequency of CSF-specific OCB did not differ between early and late onset RMS and PMS, the sensitivity of positive FLCk IF and absolute FLCk IF values were lower in PMS. The positivity of the MRZ reaction was equally frequent in early and late onset RMS and PMS. PMS patients had higher local IgA concentrations than RMS patients (p = 0.0123). Conclusions: OCB are slightly superior to FLCk IF in progressive MS in terms of sensitivity for detecting intrathecal immunoglobulin synthesis. The MRZ reaction, as the most specific parameter for MS, is also applicable in patients with late onset and progressive MS.
In der Geschichte der Sinne führt der Tastsinn ein Schattendasein und steht immer wieder hinter dem Sehsinn zurück. In den Medien-, Bild- und Literaturwissenschaften haben der Tastsinn und das Berühren in den letzten Jahren jedoch
vermehrt Aufmerksamkeit erfahren – die soziale und politische Dimension des
Berührens in der Literatur wurde hierbei meistens nur am Rande thematisiert.1
Das vorliegende Themenheft setzt an dieser Stelle an.
Casein kinase II (CK2) and cyclin-dependent kinases (CDKs) frequently interact within multiple pathways in pancreatic ductal adenocarcinoma (PDAC). Application of CK2- and CDK-inhibitors have been considered as a therapeutic option, but are currently not part of routine chemotherapy regimens. We investigated ten PDAC cell lines exposed to increasing concentrations of silmitasertib and dinaciclib. Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated, and bioinformatic clustering was used to classify cell lines into sensitive groups based on their response to inhibitors. Furthermore, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) was conducted to assess recurrent mutations and the expression profile of inhibitor targets and genes frequently mutated in PDAC, respectively. Dinaciclib and silmitasertib demonstrated pronounced and limited cell line specific effects in cell death induction, respectively. WES revealed no genomic variants causing changes in the primary structure of the corresponding inhibitor target proteins. RNA-Seq demonstrated that the expression of all inhibitor target genes was higher in the PDAC cell lines compared to non-neoplastic pancreatic tissue. The observed differences in PDAC cell line sensitivity to silmitasertib or dinaciclib did not depend on target gene expression or the identified gene variants. For the PDAC hotspot genes kirsten rat sarcoma virus (KRAS) and tumor protein p53 (TP53), three and eight variants were identified, respectively. In conclusion, both inhibitors demonstrated in vitro efficacy on the PDAC cell lines. However, aberrations and expression of inhibitor target genes did not appear to affect the efficacy of the corresponding inhibitors. In addition, specific aberrations in TP53 and KRAS affected the efficacy of both inhibitors.
Four aerobic bacteria with bacteriolytic capabilities were isolated from the brackish water site Strait Uzynaral of Lake Balkhash in Kazakhstan. The morphology and physiology of the bacterial isolates have subsequently been analyzed. Using matrix assisted laser desorption ionization-time of flight mass spectrum and partial 16S rRNA gene sequence analyses, three of the isolates have been identified as Pseudomonas veronii and one as Paenibacillus apiarius. We determined the capability of both species to lyse pre-grown cells of the Gram-negative strains Pseudomonas putida SBUG 24 and Escherichia coli SBUG 13 as well as the Gram-positive strains Micrococcus luteus SBUG 16 and Arthrobacter citreus SBUG 321 on solid media. The bacteriolysis process was analyzed by creating growth curves and electron micrographs of co-cultures with the bacteriolytic isolates and the lysis sensitive strain Arthrobacter citreus SBUG 321 in nutrient-poor liquid media. One metabolite of Paenibacillus apiarius was isolated and structurally characterized by various chemical structure determination methods. It is a novel antibiotic substance.
Klebsiella pneumoniae is a common member of the intestinal flora of vertebrates. In addition to opportunistic representatives, hypervirulent (hvKp) and antibiotic-resistant K. pneumoniae (ABR-Kp) occur. While ABR-Kp isolates often cause difficult-to-treat diseases due to limited therapeutic options, hvKp is a pathotype that can infect healthy individuals often leading to recurrent infection. Here, we investigated the clinical K. pneumoniae isolate PBIO3459 obtained from a blood sample, which showed an unusual colony morphology. By combining whole-genome and RNA sequencing with multiple in vitro and in vivo virulence-associated assays, we aimed to define the respective Klebsiella subtype and explore the unusual phenotypic appearance. We demonstrate that PBIO3459 belongs to sequence type (ST)20 and carries no acquired resistance genes, consistent with phenotypic susceptibility tests. In addition, the isolate showed low-level virulence, both at genetic and phenotypic levels. We thus suggest that PBIO3459 is an opportunistic (commensal) K. pneumoniae isolate. Genomic comparison of PBIO3459 with closely related ABR-Kp ST20 isolates revealed that they differed only in resistance genes. Finally, the unusual colony morphology was mainly associated with carbohydrate and amino acid transport and metabolism. In conclusion, our study reveals the characteristics of a Klebsiella sepsis isolate and suggests that opportunistic representatives likely acquire and accumulate antibiotic resistances that subsequently enable their emergence as ABR-Kp pathogens.
Periodontitis is a multifactorial disease. The aim of this explorative study was to investigate the role of Interleukin-(IL)-1, IL-4, GATA-3 and Cyclooxygenase-(COX)-2 polymorphisms after non-surgical periodontal therapy with adjunctive systemic antibiotics (amoxicillin/metronidazole) and subsequent maintenance in a Caucasian population. Analyses were performed using blood samples from periodontitis patients of a multi-center trial (ClinicalTrials.gov NCT00707369=ABPARO-study). Polymorphisms were analyzed using quantitative real-time PCR. Clinical attachment levels (CAL), percentage of sites showing further attachment loss (PSAL) ≥1.3 mm, bleeding on probing (BOP) and plaque score were assessed. Exploratory statistical analysis was performed. A total of 209 samples were genotyped. Patients carrying heterozygous genotypes and single-nucleotide-polymorphisms (SNP) on the GATA-3-IVS4 +1468 gene locus showed less CAL loss than patients carrying wild type. Heterozygous genotypes and SNPs on the IL-1A-889, IL-1B +3954, IL-4-34, IL-4-590, GATA-3-IVS4 +1468 and COX-2-1195 gene loci did not influence CAL. In multivariate analysis, CAL was lower in patients carrying GATA-3 heterozygous genotypes and SNPs than those carrying wild-types. For the first time, effects of different genotypes were analyzed in periodontitis progression after periodontal therapy and during supportive treatment using systemic antibiotics demonstrating a slight association of GATA-3 gene locus with CAL. This result suggests that GATA-3 genotypes are a contributory but non-essential risk factor for periodontal disease progression.
IntroductionA substantial number of patients diagnosed with COVID-19 experience long-term persistent symptoms. First evidence suggests that long-term symptoms develop largely independently of disease severity and include, among others, cognitive impairment. For these symptoms, there are currently no validated therapeutic approaches available. Cognitive training interventions are a promising approach to counteract cognitive impairment. Combining training with concurrent transcranial direct current stimulation (tDCS) may further increase and sustain behavioural training effects. Here, we aim to examine the effects of cognitive training alone or in combination with tDCS on cognitive performance, quality of life and mental health in patients with post-COVID-19 subjective or objective cognitive impairments.Methods and analysisThis study protocol describes a prospective randomised open endpoint-blinded trial. Patients with post-COVID-19 cognitive impairment will either participate in a 3-week cognitive training or in a defined muscle relaxation training (open-label interventions). Irrespective of their primary intervention, half of the cognitive training group will additionally receive anodal tDCS, all other patients will receive sham tDCS (double-blinded, secondary intervention). The primary outcome will be improvement of working memory performance, operationalised by an n-back task, at the postintervention assessment. Secondary outcomes will include performance on trained and untrained tasks and measures of health-related quality of life at postassessment and follow-up assessments (1 month after the end of the trainings).Ethics and disseminationEthical approval was granted by the Ethics Committee of the University Medicine Greifswald (number: BB 066/21). Results will be available through publications in peer-reviewed journals and presentations at national and international conferences.Trial registration numberNCT04944147.
Person-centered care (PCC) requires knowledge about patient preferences. An analytic hierarchy process (AHP) is one approach to quantify, weigh and rank patient preferences suitable for People living with Dementia (PlwD), due to simple pairwise comparisons of individual criteria from a complex decision problem. The objective of the present study was to design and pretest a dementia-friendly AHP survey. Methods: Two expert panels consisting of n = 4 Dementia Care Managers and n = 4 physicians to ensure content-validity, and “thinking-aloud” interviews with n = 11 PlwD and n = 3 family caregivers to ensure the face validity of the AHP survey. Following a semi-structured interview guide, PlwD were asked to assess appropriateness and comprehensibility. Data, field notes and partial interview transcripts were analyzed with a constant comparative approach, and feedback was incorporated continuously until PlwD had no further comments or struggles with survey completion. Consistency ratios (CRs) were calculated with Microsoft® Excel and ExpertChoice Comparion®. Results: Three main categories with sub-categories emerged: (1) Content: clear task introduction, (sub)criteria description, criteria homogeneity, (sub)criteria appropriateness, retest questions and sociodemography for heterogeneity; (2) Format: survey structure, pairwise comparison sequence, survey length, graphical design (incl. AHP scale), survey procedure explanation, survey assistance and response perspective; and (3) Layout: easy wording, short sentences and visual aids. Individual CRs ranged from 0.08 to 0.859, and the consolidated CR was 0.37 (0.038). Conclusions: Our formative qualitative study provides initial data for the design of a dementia-friendly AHP survey. Consideration of our findings may contribute to face and content validity in future quantitative preference research in dementia.
Background: Retrospective research on real-world data provides the ability to gain evidence on specific topics especially when running across different sites in research networks. Those research networks have become increasingly relevant in recent years; not least due to the special situation caused by the COVID-19 pandemic. An important requirement for those networks is the data harmonization by ensuring the semantic interoperability. Aims: In this paper we demonstrate (1) how to facilitate digital infrastructures to run a retrospective study in a research network spread across university and non-university hospital sites; and (2) to answer a medical question on COVID-19 related change in diagnostic counts for diabetes-related eye diseases. Materials and methods: The study is retrospective and non-interventional and runs on medical case data documented in routine care at the participating sites. The technical infrastructure consists of the OMOP CDM and other OHDSI tools that is provided in a transferable format. An ETL process to transfer and harmonize the data to the OMOP CDM has been utilized. Cohort definitions for each year in observation have been created centrally and applied locally against medical case data of all participating sites and analyzed with descriptive statistics. Results: The analyses showed an expectable drop of the total number of diagnoses and the diagnoses for diabetes in general; whereas the number of diagnoses for diabetes-related eye diseases surprisingly decreased stronger compared to non-eye diseases. Differences in relative changes of diagnoses counts between sites show an urgent need to process multi-centric studies rather than single-site studies to reduce bias in the data. Conclusions: This study has demonstrated the ability to utilize an existing portable and standardized infrastructure and ETL process from a university hospital setting and transfer it to non-university sites. From a medical perspective further activity is needed to evaluate data quality of the utilized real-world data documented in routine care and to investigate its eligibility of this data for research.
Metabolites are intermediates or end products of biochemical processes involved in both health and disease. Here, we take advantage of the well-characterized Cooperative Health Research in South Tyrol (CHRIS) study to perform an exome-wide association study (ExWAS) on absolute concentrations of 175 metabolites in 3294 individuals. To increase power, we imputed the identified variants into an additional 2211 genotyped individuals of CHRIS. In the resulting dataset of 5505 individuals, we identified 85 single-variant genetic associations, of which 39 have not been reported previously. Fifteen associations emerged at ten variants with >5-fold enrichment in CHRIS compared to non-Finnish Europeans reported in the gnomAD database. For example, the CHRIS-enriched ETFDH stop gain variant p.Trp286Ter (rs1235904433-hexanoylcarnitine) and the MCCC2 stop lost variant p.Ter564GlnextTer3 (rs751970792-carnitine) have been found in patients with glutaric acidemia type II and 3-methylcrotonylglycinuria, respectively, but the loci have not been associated with the respective metabolites in a genome-wide association study (GWAS) previously. We further identified three gene-trait associations, where multiple rare variants contribute to the signal. These results not only provide further evidence for previously described associations, but also describe novel genes and mechanisms for diseases and disease-related traits.
Osmotic changes are common challenges for marine microorganisms. Bacteria have developed numerous ways of dealing with this stress, including reprogramming of global cellular processes. However, specific molecular adaptation mechanisms to osmotic stress have mainly been investigated in terrestrial model bacteria. In this work, we aimed to elucidate the basis of adjustment to prolonged salinity challenges at the proteome level in marine bacteria. The objects of our studies were three representatives of bacteria inhabiting various marine environments, Shewanella baltica, Vibrio harveyi and Aliivibrio fischeri. The proteomic studies were performed with bacteria cultivated in increased and decreased salinity, followed by proteolytic digestion of samples which were then subjected to liquid chromatography with tandem mass spectrometry analysis. We show that bacteria adjust at all levels of their biological processes, from DNA topology through gene expression regulation and proteasome assembly, to transport and cellular metabolism. The finding that many similar adaptation strategies were observed for both low- and high-salinity conditions is particularly striking. The results show that adaptation to salinity challenge involves the accumulation of DNA-binding proteins and increased polyamine uptake. We hypothesize that their function is to coat and protect the nucleoid to counteract adverse changes in DNA topology due to ionic shifts.
Background
Based on learned helplessness theory and conservation of resources theory, the present study explores the role of schools’ social environments (i.e., school belonging, school exclusion, and teacher–student relationships) as potential buffers and amplifiers in students’ development of learned helplessness during adolescence.
Aims
We examine whether school belonging, school exclusion, and teacher–student relationship moderate the longitudinal association of learned helplessness differently for students from low‐track schools and high‐track schools.
Sample
The study uses a sample of N = 1,088 (Mage = 13.70, SD = 0.53; 54% girls) adolescent students who participated in a two‐wave longitudinal study.
Methods
We conducted latent moderated structural equation modelling to examine whether school belonging, school exclusion, and teacher–student relationship moderate the longitudinal association of learned helplessness differently for students from low‐track schools and high‐track schools.
Results
The moderation analyses revealed that students from both school tracks are differently affected by school belonging and school exclusion in their development of learned helplessness. Teacher–student relationship did not moderate the association.
Conclusion
Our findings underline the important role of the social environment in students’ development of learned helplessness. Particularly, the differential effects found for the different educational tracks highlight the necessary awareness of educators to interindividual differences of their students.
Body dissatisfaction is pervasive among young women in Western countries. Among the many forces that contribute to body dissatisfaction, the overrepresentation of thin bodies in visual media has received notable attention. In this study, we proposed that prevalence-induced concept change may be one of the cognitive mechanisms that explain how beauty standards shift. We conducted a preregistered online experiment with young women (N = 419) and found that when the prevalence of thin bodies in the environment increased, the concept of being overweight expanded to include bodies that would otherwise be judged as “normal.” Exploratory analyses revealed significant individual differences in sensitivity to this effect, in terms of women’s judgments about other bodies as well as their own. These results suggest that women’s judgments about other women’s bodies are biased by an overrepresentation of thinness and lend initial support to policies designed to increase size-inclusive representation in the media.
A massive shift in agricultural practices over the past decades, to support exceptionally high yields and productivities involving intensive agriculture, have led to unsustainable agriculture practices across the globe. Sustenance of such high yields and productivities demand high use of organic and industrial fertilizers. This acts as a negative pressure on the environment. Excessive use of fertilizers leads to nutrient surplus in the fields, which, as a part of catchment runoff, flows into the water bodies as diffuse pollution. These nutrients through rivers are eventually passed into seas. High nutrients ending up into water bodies cause eutrophication. The situation is worsened when such unsustainable agricultural activities are carried out on drained peatlands. As a result, the nutrients that were not part of the nutrient cycle in the landscape for years begin to leach out due to mineralization of peatlands, thereby putting an additional load of nutrients on the environment, that was already under the negative impact of nutrient surplus. In view of the above, a small lowland catchment of the Ryck river in northeast Germany was assessed for its nitrogen losses from agricultural lands through empirical modelling. Initial empirical modelling resulted in an average annual total nitrogen loss of 14.7 kg ha−1 year−1. After a comparative analysis of these results with procured data, the empirical equation was modified to suit the catchment, yielding more accurate results. The study showed that 75.6% of peatlands in the catchment are under agricultural use. Subsequently, a proposal was made for potential wetland buffer zones in the Ryck catchment. Altogether, 13 peatland sites across 8 sub-catchments were recommended for mitigation of high nutrient runoff. In the end, nutrient efficiency of proposed WBZs in one of the sub-catchments of Ryck has been discussed. The results show that (i) the modified empirical equation can act as a key tool in application-based future strategies for nitrogen reduction in the Ryck catchment, (ii) restoration of peatlands and introduction of WBZs can help in mitigating the nutrient runoff for improved water quality of Ryck, and subsequently (ii) contribute to efficient reduction of riverine loads of nutrients into the Baltic Sea.
Structured examination and treatment are essential in medicine. For dental students, a structured approach to the assessment of oral mucosal lesions is missing thus far. To validate an approach, a structured questionnaire was compared with the habitually used free description of oral lesions (white lesions, ulcers, hyperplasia). Thirty-three dental students were divided into two groups (Group 1 (n = 17) used the free description; Group 2 (n = 16) used a guided questionnaire) to characterize mucosal lesions in patients and make a tentative diagnosis. Although no difference was found between the groups regarding the suspected diagnosis or the histopathological findings, there was a significant advantage of the structured questionnaire in all aspects of the description compared to the free description (p = 0.000018). Thus, a structured description is an important aspect in the evaluation of oral mucosal changes, and a guided questionnaire should be implemented in the study of dentistry.
We present the first systematic literature review on stress and burnout in K−12 teachers during the COVID-19 pandemic. Based on a systematic literature search, we identified 17 studies that included 9,874 K−12 teachers from around the world. These studies showed some indication that burnout did increase during the COVID-19 pandemic. There were, however, almost no differences in the levels of stress and burnout experienced by K−12 teachers compared to individuals employed in other occupational fields. School principals' leadership styles emerged as an organizational characteristic that is highly relevant for K−12 teachers' levels of stress and burnout. Individual teacher characteristics associated with burnout were K−12 teachers' personality, self-efficacy in online teaching, and perceived vulnerability to COVID-19. In order to reduce stress, there was an indication that stress-management training in combination with training in technology use for teaching may be superior to stress-management training alone. Future research needs to adopt more longitudinal designs and examine the interplay between individual and organizational characteristics in the development of teacher stress and burnout during the COVID-19 pandemic and beyond.
Abstract
Purpose
Depressive disorders in children and adolescents have an enormous impact on their general quality of life. There is a clear need to effectively treat depression in this age group. Effects of psychotherapy can be enhanced by involving caregivers. In our systematic review and meta‐analysis, we examine for the first time the effects of caregiver involvement in depression‐specific interventions for children and adolescents.
Methods
We included randomized controlled trials examining the effects of interventions for children and adolescents with depression involving their caregivers or families compared to interventions without including caregivers. Primary outcome was the severity of childhood and adolescent depression.
Results
Overall, 19 randomized controlled trials could be included (N = 1553) that were highly heterogeneous regarding outcome measures or the extent of caregiver integration. We were able to include k = 17 studies in our meta‐analysis and find a small but significant effect for family‐involved interventions against active control conditions without family‐involvement at post intervention (α = 0.05, d = 0.34; [0.07; 0.60]; p = .01).
Conclusions
We detected an overall significant but small effect of family/caregivers’ involvement compared to control groups without it. Structured, guideline‐based research is urgently needed to identify for which children/adolescents with depression, under what circumstances, and in what form the family should be effectively involved in their psychotherapy.
Abstract
Pikeperch (Sander lucioperca) has become a species of interest in aquaculture. It is a popular and economically valuable food fish and can produce high numbers of offspring. However, during early development, there are transition phases when high mortality rates concur with growth changes, vital organ transformations and a limited energy budget. Up to now, no study focused on the developmental adaption of muscle tissue in pikeperch, regardless of muscle tissue influencing essential traits such as locomotion and thus the competence to hunt prey and avoid predators. In the present study, therefore, the developmental myogenesis of pikeperch was analysed using specimens from early embryonic to larval development. Myogenic and developmental genes were utilized to gain insights into transcriptomic regulation during these stages by applying a nanofluidic qPCR approach. Result, three phases of myogenic gene expression, during somitogenesis, during the late embryonic development and during the larval development were detected. Increased myostatin expression showed an interim arrest of muscle formation between embryonic and larval myogenesis. Expression patterns of satellite cell gene markers indicated an accumulation of stem cells before myogenesis interruption. The here gained data will help to broaden the knowledge on percid myogenesis and can support pikeperch rearing in aquaculture.
ObjectivesComprehensive protocols are key for the planning and conduct of randomised clinical trials (RCTs). Evidence of low reporting quality of RCT protocols led to the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist in 2013. We aimed to examine the quality of reporting of RCT protocols from three countries before and after the publication of the SPIRIT checklist.DesignRepeated cross sectional study.SettingSwiss, German and Canadian research ethics committees (RECs).ParticipantsRCT protocols approved by RECs in 2012 (n=257) and 2016 (n=292).Primary and secondary outcome measuresThe primary outcomes were the proportion of reported SPIRIT items per protocol and the proportion of trial protocols reporting individual SPIRIT items. We compared these outcomes in protocols approved in 2012 and 2016, and built regression models to explore factors associated with adherence to SPIRIT. For each protocol, we also extracted information on general trial characteristics and assessed whether individual SPIRIT items were reportedResultsThe median proportion of reported SPIRIT items among RCT protocols showed a non-significant increase from 72% (IQR, 63%–79%) in 2012 to 77% (IQR, 68%–82%) in 2016. However, in a preplanned subgroup analysis, we detected a significant improvement in investigator-sponsored protocols: the median proportion increased from 64% (IQR, 55%–72%) in 2012 to 76% (IQR, 64%–83%) in 2016, while for industry-sponsored protocols median adherence was 77% (IQR 72%–80%) for both years. The following trial characteristics were independently associated with lower adherence to SPIRIT: single-centre trial, no support from a clinical trials unit or contract research organisation, and investigator-sponsorship.ConclusionsIn 2012, industry-sponsored RCT protocols were reported more comprehensively than investigator-sponsored protocols. After publication of the SPIRIT checklist, investigator-sponsored protocols improved to the level of industry-sponsored protocols, which did not improve.
Detecting changes in plasmas is compulsory for control and the detection of novelties.
Moreover, automated novelty detection allows one to investigate large data sets to substantially
enhance the efficiency of data mining approaches. To this end we introduce permutation entropy
(PE) for the detection of changes in plasmas. PE is an information-theoretic complexity measure
based in fluctuation analysis that quantifies the degree of randomness (resp. disorder,
unpredictability) of the ordering of time series data. This method is computationally fast and
robust against noise, which allows the evaluation of large data sets in an automated procedure.
PE is applied on electron cyclotron emission and soft x-ray measurements in different
Wendelstein 7-X low-iota configuration plasmas. A spontaneous transition to high core-electron
temperature (Te) was detected, as well as a localized low-coherent intermittent oscillation which
ceased when Te increased in the transition. The results are validated with spectrogram analysis
and provide evidence that a complexity measure such as PE is a method to support in-situ
monitoring of plasma parameters and for novelty detection in plasma data. Moreover, the
acceleration in processing time offers implementations of plasma-state-detection that provides
results fast enough to induce control actions even during the experiment.
Metrological methods for word learning list tests can be developed with an information theoretical approach extending earlier simple syntax studies. A classic Brillouin entropy expression is applied to the analysis of the Rey’s Auditory Verbal Learning Test RAVLT (immediate recall), where more ordered tasks—with less entropy—are easier to perform. The findings from three case studies are described, including 225 assessments of the NeuroMET2 cohort of persons spanning a cognitive spectrum from healthy older adults to patients with dementia. In the first study, ordinality in the raw scores is compensated for, and item and person attributes are separated with the Rasch model. In the second, the RAVLT IR task difficulty, including serial position effects (SPE), particularly Primacy and Recency, is adequately explained (Pearson’s correlation R=0.80) with construct specification equations (CSE). The third study suggests multidimensionality is introduced by SPE, as revealed through goodness-of-fit statistics of the Rasch analyses. Loading factors common to two kinds of principal component analyses (PCA) for CSE formulation and goodness-of-fit logistic regressions are identified. More consistent ways of defining and analysing memory task difficulties, including SPE, can maintain the unique metrological properties of the Rasch model and improve the estimates and understanding of a person’s memory abilities on the path towards better-targeted and more fit-for-purpose diagnostics.
Simple Summary
The tumor suppressor protein P53 is a major player in preventing liver cancer development and progression. In this study we could show that P53 negatively regulates the expression of Helicase, lymphoid specific (HELLS), previously described as an important pro-tumorigenic epigenetic regulator in hepatocarcinogenesis. The regulatory mechanism included induction of the P53 target gene P21 (CDKN1A) resulting in repression of HELLS via downregulation of the transcription factor Forkhead Box Protein M1 (FOXM1). Our in vitro and in vivo findings indicate an important additional aspect of the tumor suppressive function of P53 in liver cancer linked to epigenetic regulation.
Abstract
The major tumor suppressor P53 (TP53) acts primarily as a transcription factor by activating or repressing subsets of its numerous target genes, resulting in different cellular outcomes (e.g., cell cycle arrest, apoptosis and senescence). P53-dependent gene regulation is linked to several aspects of chromatin remodeling; however, regulation of chromatin-modifying enzymes by P53 is poorly understood in hepatocarcinogenesis. Herein, we identified Helicase, lymphoid specific (HELLS), a major epigenetic regulator in liver cancer, as a strong and selective P53 repression target within the SNF2-like helicase family. The underlying regulatory mechanism involved P53-dependent induction of P21 (CDKN1A), leading to repression of Forkhead Box Protein M1 (FOXM1) that in turn resulted in downregulation of HELLS expression. Supporting our in vitro data, we found higher expression of HELLS in murine HCCs arising in a Trp53−/− background compared to Trp53+/+ HCCs as well as a strong and highly significant correlation between HELLS and FOXM1 expression in different HCC patient cohorts. Our data suggest that functional or mutational inactivation of P53 substantially contributes to overexpression of HELLS in HCC patients and indicates a previously unstudied aspect of P53′s ability to suppress liver cancer formation.
We, here, provide a personal review article on the development of a functional MRI in the radiology departments of two German university medicine units. Although the international community for human brain mapping has met since 1995, the researchers fascinated by human brain function are still young and innovative. However, the impact of functional magnetic resonance imaging (fMRI) on prognosis and treatment decisions is restricted, even though standardized methods have been developed. The tradeoff between the groundbreaking studies on brain function and the attempt to provide reliable biomarkers for clinical decisions is large. By describing some historical developments in the field of fMRI, from a personal view, the rise of this method in clinical neuroscience during the last 25 years might be understandable. We aim to provide some background for (a) the historical developments of fMRI, (b) the establishment of two research units for fMRI in the departments of radiology in Germany, and (c) a description of some contributions within the selected fields of systems neuroscience, clinical neurology, and behavioral psychology.
To assess whether the treatment of children with oral midazolam and pediatric hypnosis techniques can improve the compliance in consecutive sessions, a retrospective longitudinal practice-based observational study was designed and carried out. A total of 311 children between 3 and 12 years of age were treated under hypnosis and sedation with midazolam (0.40 mg/kg body weight). Treatments were performed in one to a maximum of three sessions. A total of 183 children received one, 103 received two and 25 children received three treatment sessions. The behavior of the children during the sessions was examined by means of the Venham score. The self-evaluation of the children was based on the Wong–Baker Scale. Child behavior using midazolam and hypnosis techniques showed little difference and good compliance between the sessions. Venham scores did not increase significantly regarding total treatment from the first (0.99 ± 1.41) to the second (1.17 ± 1.39) and to the third session (1.27 ± 1.20) (p > 0.05). However, considering the highest Venham scores that occurred in each case, the behavior of the children worsened significantly (p < 0.01) during the three treatment sessions, from 1.37 ± 1.31 (first) to 1.87 ± 1.74 (second) to 2.32 ± 1.33 (third). In 6.11% of the children, treatment was discontinued in the first session (n = 19), 0.96% in the second (n = 3) and 0% in the third. Treatment with low-dose midazolam, combined with hypnosis techniques, showed to be an effective option for dental treatment in children. Within the limitations of the current study, and with consideration of highest possible compliance, no more than two treatment sessions for pediatric dental treatment should be performed.
A series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h, 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b, and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c were obtained by reacting of appropriate 2-iminocoumarin ligands L1a-h, L3a-b, and L5a-c with 3-fold molar excess of copper(II) chloride. The structure of these compounds was confirmed by IR spectroscopy, elemental analysis, and single-crystal X-ray diffraction data (2f, 2g, 2h, and 6c). All the synthesized complexes were screened for their activity against five human cancer cell lines: DAN-G, A-427, LCLC-103H, SISO, and RT-4 by using a crystal violet microtiter plate assay and relationships between structure and in vitro cytotoxic activity are discussed. The coordination of 2-iminocoumarins with copper(II) ions resulted in complexes 2a-h, 4a-b, and 6a-c with significant inhibitory properties toward tested tumor cell lines with IC50 values ranging from 0.04 μM to 15.66 μM. In comparison to the free ligands L1a-h, L3a-b, and L5a-c, the newly prepared Cu(II) complexes often displayed increased activity. In the series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h the most potent compound 2g contained a 4-phenylpiperazine moiety at position 6 of the 1,3,5-triazine ring and an electron-donating diethylamino group at position 7′ of the 2-iminocoumarin scaffold. Among the Cu(II) complexes of 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c the most active was benzoxazole-2-iminocoumarin 4b that also possessed a diethylamino group at position 7′ of the 2-iminocoumarin moiety. Moreover, compound 4b was found to be the most prominent agent and displayed the higher potency than cisplatin against tested cell lines.
Simple Summary
Small molecule inhibitors and targeted therapy are considered to have significant potential for pancreatic ductal adenocarcinoma therapies. Preclinical studies of novel inhibitors and inhibitor combinations can elucidate their acting mechanisms and provide valuable data for in vivo research and clinical trials. We explored the antitumor efficacy of KRAS inhibitors BI-3406 and sotorasib alone or in combination with the downstream inhibitors trametinib and buparlisib in PDAC cell lines, characterized by different KRAS mutational statuses. The two KRAS inhibitors demonstrated different anti-tumor efficacy and displayed synergistic or additive effects, when combined with downstream pathway inhibitors. These data emphasized the importance of KRAS as a therapeutic target for PDAC and indicate two distinct mechanisms of KRAS inhibition and their interactions with downstream pathway inhibitors.
Abstract
Kirsten rat sarcoma virus (KRAS) mutations are widespread in pancreatic ductal adenocarcinoma (PDAC) and contribute significantly to tumor initiation, progression, tumor relapse/resistance, and prognosis of patients. Although inhibitors against KRAS mutations have been developed, this therapeutic approach is not routinely used in PDAC patients. We investigated the anti-tumor efficacy of two KRAS inhibitors BI-3406 (KRAS::SOS1 inhibitor) and sotorasib (KRAS G12C inhibitor) alone or in combination with MEK1/2 inhibitor trametinib and/or PI3K inhibitor buparlisib in seven PDAC cell lines. Whole transcriptomic analysis of combined inhibition and control groups were comparatively analyzed to explore the corresponding mechanisms of inhibitor combination. Both KRAS inhibitors and corresponding combinations exhibited cytotoxicity against specific PDAC cell lines. BI-3406 enhance the efficacy of trametinib and buparlisib in BXPC-3, ASPC-1 and MIA PACA-2, but not in CAPAN-1, while sotorasib enhances the efficacy of trametinib and buparlisib only in MIA PACA-2. The whole transcriptomic analysis demonstrates that the two triple-inhibitor combinations exert antitumor effects by affecting related cell functions, such as affecting the immune system, cell adhesion, cell migration, and cytokine binding. As well as directly involved in RAF/MEK/ERK pathway and PI3K/AKT pathway affect cell survival. Our current study confirmed inhibition of KRAS and its downstream pathways as a potential novel therapy for PDAC and provides fundamental data for in vivo evaluations.
Little is known about the (co-)occurrence of smoking, alcohol at-risk drinking, physical inactivity and overweight, and the motivation to change these behavioral health risk factors (HRFs) in older general hospital patients with cardiovascular disease. Between October and December 2016, all consecutively admitted patients aged 50 to 79 years were proactively recruited on 3 cardiology wards and asked to participate in a survey on HRFs and behavior change motivation. Of the eligible patients, 80.4% participated in the survey (n = 328). The mean age was 66.5 years (standard deviation 9.0), and 65.5% were male. At least 1 HRF was present in 91.8% (n = 280), at least 2 HRFs in 54.4% (n = 166), and 3 or 4 HRFs in 12.1% (n = 37) of participants. The proportion of older adults who contemplated or were changing or planning to change their behavior to meet health behavior recommendations ranged between 66.0% (smoking) and 93.2% (alcohol consumption). The results indicate a notable co-occurrence of behavioral HRFs in older patients with cardiovascular disease. The majority of older adults were at least considering changing the respective behavior. To prevent and treat diseases efficiently, hospitalization may be a suitable moment for systematic multiple HRF screening and intervention.
Proteasomes comprise a family of proteasomal complexes essential for maintaining protein homeostasis. Accordingly, proteasomes represent promising therapeutic targets in multiple human diseases. Several proteasome inhibitors are approved for treating hematological cancers. However, their side effects impede their efficacy and broader therapeutic applications. Therefore, understanding the biology of the different proteasome complexes present in the cell is crucial for developing tailor-made inhibitors against specific proteasome complexes. Here, we will discuss the structure, biology, and function of the alternative Proteasome Activator 200 (PA200), also known as PSME4, and summarize the current evidence for its dysregulation in different human diseases. We hereby aim to stimulate research on this enigmatic proteasome regulator that has the potential to serve as a therapeutic target in cancer.
Abstract
(1) Background: Surgery is the most important element of multimodal treatment concepts in oncological patients, especially in the early stages of pancreatic tumours. While the influence of primary tumour resection on the immune status was analysed in several studies, the impact of tumour-unrelated visceral surgery on the tumour-bearing organism and on the primary tumour itself is not yet fully understood. (2) Methods: We combined a murine model of orthotopically implanted adenocarcinoma of the pancreas with the model of surgically-induced immune dysfunction (SID). Mortality and general condition including body weight were observed over a period of 28 days. Tumour growth was analysed by MRI scans on days 8 and 27 following tumour implantation. On day 28, the immune cell populations in the blood and spleen as well as the serum cytokines were quantified. (3) Results: SID results in a significant deterioration of the general condition and a reduced increase in the body weight of tumour-bearing mice compared to the control groups, while mortality and tumour growth rate were not influenced. The numbers of spleen macrophages and neutrophils were increased in tumour-bearing animals following SID. Furthermore, both macrophage and neutrophil levels were increased in the peripheral blood. (4) Conclusions: The presented results might contribute to the basic understanding of the interaction of tumour and immune system and could contribute to new approaches to immunotherapeutic strategies.
Given the increasing prevalence of chronic kidney disease (CKD) and its impact on health care, it is important to better understand the multiple factors influencing health-related quality of life (HRQOL), particularly since they have been shown to affect CKD outcomes. Determinants of HRQOL as measured by the validated Kidney Disease Quality of Life questionnaire (KDQOL) and the Patient Health Questionnaire depression screener (PHQ-9) were assessed in a routine CKD patient sample, the Greifswald Approach to Individualized Medicine (GANI_MED) renal cohort (N = 160), including a wide range of self-reported data, sociodemographic and laboratory measures. Compared to the general population, CKD patients had lower HRQOL indices. Dialysis was associated with (1) low levels of physical functioning, (2) increased impairments by symptoms and problems, and (3) more effects and burden of kidney disease. HRQOL is seriously affected in CKD patients. However, impairments were found irrespective of eGFR decline and albuminuria. Rather, the comorbid conditions of depression and diabetes predicted a lower HRQOL (physical component score). Further studies should address whether recognizing and treating depression may not only improve HRQOL but also promote survival and lower hospitalization rates of CKD patients.
Medical gas plasmas are of emerging interest in pre-clinical oncological research. Similar to an array of first-line chemotherapeutics and physics-based therapies already approved for clinical application, plasmas target the tumor redox state by generating a variety of highly reactive species eligible for local tumor treatments. Considering internal tumors with limited accessibility, medical gas plasmas help to enrich liquids with stable, low-dose oxidants ideal for intratumoral injection and lavage. Pre-clinical investigation of such liquids in numerous tumor entities and models in vitro and in vivo provided evidence of their clinical relevance, broadening the range of patients that could benefit from medical gas plasma therapy in the future. Likewise, the application of such liquids might be promising for recurrent BRAF(V600E) papillary thyroid carcinomas, resistant to adjuvant administration of radioiodine. From a redox biology point of view, studying redox-based approaches in thyroid carcinomas is particularly interesting, as they evolve in a highly oxidative environment requiring the capability to cope with large amounts of ROS/RNS. Knowledge on their behavior under different redox conditions is scarce. The present study aimed to clarify resistance, proliferative activity, and the oxidative stress response of human papillary thyroid cancer cells K1 after exposure to plasma-oxidized DMEM (oxDMEM). Cellular responses were also evaluated when treated with different dosages of hydrogen peroxide and the RNS donor sodium nitroprusside (SNP). Our findings outline plasma-oxidized liquids as a promising approach targeting BRAF(V600E) papillary thyroid carcinomas and extend current knowledge on the susceptibility of cells to undergo ROS/RNS-induced cell death.
Essential Oils as Multicomponent Mixtures and Their Potential for Human Health and Well-Being
(2022)
Essential oils (EOs) and their individual volatile organic constituents have been an inherent part of our civilization for thousands of years. They are widely used as fragrances in perfumes and cosmetics and contribute to a healthy diet, but also act as active ingredients of pharmaceutical products. Their antibacterial, antiviral, and anti-inflammatory properties have qualified EOs early on for both, the causal and symptomatic therapy of a number of diseases, but also for prevention. Obtained from natural, mostly plant materials, EOs constitute a typical example of a multicomponent mixture (more than one constituent substances, MOCS) with up to several hundreds of individual compounds, which in a sophisticated composition make up the property of a particular complete EO. The integrative use of EOs as MOCS will play a major role in human and veterinary medicine now and in the future and is already widely used in some cases, e.g., in aromatherapy for the treatment of psychosomatic complaints, for inhalation in the treatment of respiratory diseases, or topically administered to manage adverse skin diseases. The diversity of molecules with different functionalities exhibits a broad range of multiple physical and chemical properties, which are the base of their multi-target activity as opposed to single isolated compounds. Whether and how such a broad-spectrum effect is reflected in natural mixtures and which kind of pharmacological potential they provide will be considered in the context of ONE Health in more detail in this review.
Tafazzin—an acyltransferase—is involved in cardiolipin (CL) remodeling. CL is associated with mitochondrial function, structure and more recently with cell proliferation. Various tafazzin isoforms exist in humans. The role of these isoforms in cardiolipin remodeling is unknown. Aim of this study was to investigate if specific isoforms like Δ5 can restore the wild type phenotype with respect to CL composition, cellular proliferation and gene expression profile. In addition, we aimed to determine the molecular mechanism by which tafazzin can modulate gene expression by applying promoter analysis and (Ingenuity Pathway Analyis) IPA to genes regulated by TAZ-deficiency. Expression of Δ5 and rat full length TAZ in C6-TAZ- cells could fully restore CL composition and—as proven for Δ5—this is naturally associated with restoration of mitochondrial respiration. A similar restoration of CL-composition could not be observed after re-expression of an enzymatically dead full-length rat TAZ (H69L; TAZMut). Re-expression of only rat full length TAZ could restore proliferation rate. Surprisingly, the Δ5 variant failed to restore wild-type proliferation. Further, as expected, re-expression of the TAZMut variant completely failed to reverse the gene expression changes, whereas re-expression of the TAZ-FL variant largely did so and the Δ5 variant to somewhat less extent. Very likely TAZ-deficiency provokes substantial long-lasting changes in cellular lipid metabolism which contribute to changes in proliferation and gene expression, and are not or only very slowly reversible.
We analyzed the proteomic response of the Gram-negative fish pathogen A. salmonicida to iron limitation, an elevated incubation temperature, and the antibiotic florfenicol. Proteins from different subcellular fractions (cytosol, inner membrane, outer membrane, extracellular and outer membrane vesicles) were enriched and analyzed. We identified several iron-regulated proteins that were not reported in the literature for A. salmonicida before. We could also show that hemolysin, an oxidative-stress-resistance chaperone, a putative hemin receptor, an M36 peptidase, and an uncharacterized protein were significantly higher in abundance not only under iron limitation but also with an elevated incubation temperature. This may indicate that these proteins involved in the infection process of A. salmonicida are induced by both factors. The analysis of the outer membrane vesicles (OMVs) with and without applied stresses revealed significant differences in the proteomes. OMVs were smaller and contained more cytoplasmic proteins after antibiotic treatment. After cultivation with low iron availability, several iron-regulated proteins were found in the OMVs, indicating that A. salmonicida OMVs potentially have a function in iron acquisition, as reported for other bacteria. The presence of iron-regulated transporters further indicates that OMVs obtained from ‘stressed’ bacteria might be suitable vaccine candidates that induce a protective anti-virulence immune response.
Exogenous glucocorticoids increase the risk for osteoporosis, but the role of endogenous glucocorticoids remains elusive. Here, we describe the generation and validation of a loss- and a gain-of-function model of the cortisol producing enzyme 11β-HSD1 (HSD11B1) to modulate the endogenous glucocorticoid conversion in SCP-1 cells — a model for human mesenchymal stem cells capable of adipogenic and osteogenic differentiation. CRISPR-Cas9 was successfully used to generate a cell line carrying a single base duplication and a 5 bp deletion in exon 5, leading to missense amino acid sequences after codon 146. These inactivating genomic alterations were validated by deep sequencing and by cloning with subsequent capillary sequencing. 11β-HSD1 protein levels were reduced by 70% in the knockout cells and cortisol production was not detectable. Targeted chromosomal integration was used to stably overexpress HSD11B1. Compared to wildtype cells, HSD11B1 overexpression resulted in a 7.9-fold increase in HSD11B1 mRNA expression, a 5-fold increase in 11β-HSD1 protein expression and 3.3-fold increase in extracellular cortisol levels under adipogenic differentiation. The generated cells were used to address the effects of 11β-HSD1 expression on adipogenic and osteogenic differentiation. Compared to the wildtype, HSD11B1 overexpression led to a 3.7-fold increase in mRNA expression of lipoprotein lipase (LPL) and 2.5-fold increase in lipid production under adipogenic differentiation. Under osteogenic differentiation, HSD11B1 knockout led to enhanced alkaline phosphatase (ALP) activity and mRNA expression, and HSD11B1 overexpression resulted in a 4.6-fold and 11.7-fold increase in mRNA expression of Dickkopf-related protein 1 (DKK1) and LPL, respectively. Here we describe a HSD11B1 loss- and gain-of-function model in SCP-1 cells at genetic, molecular and functional levels. We used these models to study the effects of endogenous cortisol production on mesenchymal stem cell differentiation and demonstrate an 11β-HSD1 dependent switch from osteogenic to adipogenic differentiation. These results might help to better understand the role of endogenous cortisol production in osteoporosis on a molecular and cellular level.
Rhinoviruses (RV) account for a significant number of asthma exacerbations, and RV species C may be associated with a severe course in vulnerable patient groups. Despite important evidence on the role of RV reported by clinicians and life scientists, there are still unanswered questions regarding their influence on asthma exacerbation in young patients. Thus, we measured the RVspecies-specific IgG titers in our German pediatric exacerbation cohort using a microarray-based technology. For this approach, human sera of patients with exacerbated asthma and wheeze, as well as healthy control subjects (n = 136) were included, and correlation analyses were performed. Concordantly with previously published results, we observed significantly higher cumulative levels of RV species A-specific IgG (p = 0.011) and RV-C-specific IgG (p = 0.051) in exacerbated asthma group compared to age-matched controls. Moreover, atopic wheezers had increased RV-specific IgG levels for species A (p = 0.0011) and species C (p = 0.0009) compared to non-atopic wheezers. Hypothesizing that bacterial infection positively correlates with immune memory against RV, we included nasopharyngeal swab results in our analyses and detected limited correlations. Interestingly, the eosinophil blood titer positively correlated with RV-specific IgG levels. With these observations, we add important observations to the existing data regarding exacerbation in pediatric and adolescent medicine. We propose that scientists and clinicians should pay more attention to the relevance of RV species in susceptible pediatric patients.
We aimed to determine the accuracy and reliability of measures characterizing anterior, lateral, and posterior acetabular coverage on intraoperative fluoroscopic images compared to postoperative radiographs when performing periacetabular osteotomies (PAOs). A study involving 100 PAOs was initiated applying a standardized intraoperative imaging protocol. Coverage was determined by the lateral center edge angle (LCEA), the Tönnis angle (TA), and the anterior and posterior wall index (AWI, PWI). An intraclass correlation coefficient (ICC) model was used to assess interrater (ICC (3,2)) and intrarater (ICC (2,1)) reliability. The ICC (2,2) between analyses obtained from intraoperative fluoroscopy and postoperative radiographs and the corresponding 95% confidence interval (CI) were determined and complemented by Bland–Altman analysis, the mean difference, and 95% limits of agreement (LOA). The ICCs were 0.849 for the LCEA (95% CI 0.783–0.896), 0.897 for the TA (95% CI 0.851–0.930), 0.864 for the AWI (95% CI 0.804–0.907), and 0.804 for the PWI (0.722–0.864). The assessed interrater reliability was excellent except for the AWI, which was graded good (ICC = 0.857, 95% CI 0.794–0.902). Interrater agreement was generally good and fair for the AWI (ICC = 0.715, 95% CI 0.603–0.780). For each postoperative radiograph, interrater reliability was good with ICCs ranging from 0.813 (TA) to 0.881 (PWI). Intrarater reliability was good for all measurements and excellent for the preoperative TA (ICC = 0.993, 95% CI 0.984–0.997) and PWI (ICC = 0.954, 95% CI 0.919–0.97). In summary, we confirm the validity and reliability of intraoperative fluoroscopy as an alternative imaging modality to radiography to evaluate acetabular fragment orientation during PAO. We affirm the LCEA and TA as precise measures for lateral head coverage, and show the suitability of the AWI and PWI to steadily assess acetabular version.
Background: Administering intraoperative analgesia in patients undergoing periacetabular osteotomy (PAO) is challenging due to both the relevant surgical approach and osteotomies, which are associated with pain. The aim of this study was to assess the effect of the transversus abdominis plane block (TAPb) on intraoperative opioid consumption and circulation parameters in PAO patients. Patients and Methods: We conducted a two-group randomized-controlled trial involving 42 consecutive patients undergoing PAO for symptomatic developmental dysplasia of the hip (DDH) in our department. Patients assigned to the study group received an ultrasound-guided TAPb with 0.75% ropivacaine before the beginning of the surgery and after general anesthesia induction. Patients assigned to the control group did not receive a TAPb. General anesthesia was conducted according to a defined study protocol. The primary endpoint of the study was the intraoperative opioid consumption, measured in morphine equivalent dose (MED). Secondary endpoints were the assessment of intraoperative heart rate, mean arterial pressure (MAP), need for hypotension treatment, and length of hospital stay (LOHS). A total of 41 patients (n = 21 TAPb group, n = 20 control group) completed the study; of these, 33 were women (88.5%) and 8 were men (19.5%). The mean age at the time of surgery was 28 years (18–43, SD ± 7.4). All operations were performed by a single high-volume surgeon and all TAPb procedures were performed by a single experienced senior anesthesiologist. Results: We observed a significantly lower intraoperative opioid consumption in the TAPb group compared to the control group (930 vs. 1186 MED per kg bodyweight; p = 0.016). No significant differences were observed in the secondary outcome parameters. We observed no perioperative complications. Conclusion: Ultrasound-guided TAPb significantly reduces intraoperative opioid consumption in patients undergoing PAO.
Long-chain fatty acids (LCFAs) serve as energy sources, components of cell membranes, and precursors for signaling molecules. Uremia alters LCFA metabolism so that the risk of cardiovascular events in chronic kidney disease (CKD) is increased. End-stage renal disease (ESRD) patients undergoing dialysis are particularly affected and their hemodialysis (HD) treatment could influence blood LCFA bioaccumulation and transformation. We investigated blood LCFA in HD patients and studied LCFA profiles in vivo by analyzing arterio–venous (A–V) LFCA differences in upper limbs. We collected arterial and venous blood samples from 12 ESRD patients, before and after HD, and analyzed total LCFA levels in red blood cells (RBCs) and plasma by LC–MS/MS tandem mass spectrometry. We observed that differences in arterial and venous LFCA contents within RBCs (RBC LCFA A–V differences) were affected by HD treatment. Numerous saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA) n-6 showed negative A–V differences, accumulated during peripheral tissue perfusion of the upper limbs, in RBCs before HD. HD reduced these differences. The omega-3 quotient in the erythrocyte membranes was not affected by HD in either arterial or venous blood. Our data demonstrate that A–V differences in fatty acids status of LCFA are present and active in mature erythrocytes and their bioaccumulation is sensitive to single HD treatment.
The present study covers the synthesis, purification and evaluation of a novel aminomethacrylate-based copolymer in terms of its suitability for improving the solubility and in vitro release of poorly water-soluble drug compounds. The new copolymer was synthesized by solvent polymerization with radical initiation and by use of a chain transfer agent. Based on its composition, it can be considered as a modified type of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate “EUDRAGIT® E PO” (ModE). ModE was specifically developed to provide a copolymer with processing and application properties that exceed those of commercially available (co-)polymers in solubility enhancement technologies where possible. By varying the concentration of the chain transfer agent in the radical polymerization process, the molecular weight of ModE was varied in a range of 173–305 kDa. To evaluate the solubility-enhancing properties of ModE, a series of drug-loaded extrudates were prepared by hot melt extrusion using the novel—as well as several commercially available—(co-)polymers. These extrudates were then subjected to comparative tests for amorphousness, solubility-enhancing properties, storage stability, and drug release. Celecoxib, efavirenz, and fenofibrate were used as model drugs in all experiments. Of all the (co-)polymers included in the study, ModE with a molecular weight of 173 kDa showed the best performance in terms of desired properties and was shown to be particularly suitable for preparing amorphous solid dispersions (ASDs) of the three model drugs, which in a first set of dissolution experiments showed better release behavior under pH conditions of the fasting stomach than higher molecular weight ModE types, as well as a variety of commercially available (co-)polymers. Therefore, the results demonstrate the successful synthesis of a new copolymer, which in future studies will be investigated in more detail for universal application in the field of solubility enhancement.
Background: Multimorbidity is a common issue in aging societies and is usually associated with dementia in older people. Physical activity (PA) may be a beneficial nonpharmacological strategy for patients with complex health needs. However, insufficient PA is predominant in this population. Thus, there is an evident need to expand the knowledge on potential determinants influencing PA engagement among elderly persons at risk of dementia and multimorbidity. Methods: We used baseline data from the multicenter, cluster-randomized controlled AgeWell.de study. The main aim was to describe PA engagement and identify potential PA determinants in a sample of community-dwelling Germans aged 60–77 years old with an increased risk of dementia and multimorbidity. Results: Of the 1030 included participants, approximately half (51.8%) engaged in PA ≥2 times/week for at least 30 min at baseline. We identified self-efficacy (beta = 0.202, (p < 0.001) and BMI (beta = −0.055, (p < 0.001) as potential PA determinants. Conclusions: The identified determinants, self-efficacy, and BMI are consistent with those reported in the literature. Specific knowledge on PA determinants and stages of change in persons with risk of dementia and multimorbidity might guide the development of effective future prevention measures and health services tailored to this population. Trial registration: German Clinical Trials Register (reference number: DRKS00013555).
Antimicrobial resistance is an increasing global problem and complicates successful treatments of bacterial infections in animals and humans. We conducted a longitudinal study in Mecklenburg-Western Pomerania to compare the occurrence of ESBL-producing Escherichia (E.) coli in three conventional and four organic pig farms. ESBL-positive E. coli, especially of the CTX-M type, were found in all fattening farms, confirming that antimicrobial resistance is widespread in pig fattening and affects both conventional and organic farms. The percentage of ESBL-positive pens was significantly higher on conventional (55.2%) than on organic farms (44.8%) with similar proportions of ESBL-positive pens on conventional farms (54.3–61.9%) and a wide variation (7.7–84.2%) on organic farms. Metadata suggest that the farms of origin, from which weaner pigs were purchased, had a major influence on the occurrence of ESBL-producing E. coli in the fattening farms. Resistance screening showed that the proportion of pens with multidrug-resistant E. coli was similar on conventional (28.6%) and organic (31.5%) farms. The study shows that ESBL-positive E. coli play a major role in pig production and that urgent action is needed to prevent their spread.
In the search for alternative treatment options for infections with multi-resistant germs, traditionally used medicinal plants are currently being examined more intensively. In this study, the antimicrobial and anti-biofilm activities of 14 herbal drugs were investigated. Nine of the tested drugs were traditionally used in Europe for treatment of local infections. For comparison, another five drugs monographed in the European Pharmacopoeia were used. Additionally, the total tannin and flavonoid contents of all tested drugs were analyzed. HPLC fingerprints were recorded to obtain further insights into the components of the extracts. The aim of the study was to identify herbal drugs that might be useable for treatment of infectious diseases, even with multidrug resistant E. coli, and to correlate the antimicrobial activity with the total content of tannins and flavonoids. The agar diffusion test and anti-biofilm assay were used to evaluate the antimicrobial potential of different extracts from the plants. Colorimetric methods (from European Pharmacopeia) were used for determination of total tannins and flavonoids. The direct antimicrobial activity of most of the tested extracts was low to moderate. The anti-biofilm activity was found to be down to 10 µg mL−1 for some extracts. Tannin contents between 2.2% and 10.4% of dry weight and total flavonoid contents between 0.1% and 1.6% were found. Correlation analysis indicates that the antimicrobial and the anti-biofilm activity is significantly (p < 0.05) dependent on tannin content, but not on flavonoid content. The data analysis revealed that tannin-rich herbal drugs inhibit pathogens in different ways. Thus, some of the tested herbal drugs might be useable for local infections with multi-resistant biofilm-forming pathogens. For some of the tested drugs, this is the first report about anti-biofilm activity, as well as total tannin and flavonoid content.
Inflammatory bowel diseases (IBDs) have emerged as a public health problem worldwide with a limited number of efficient therapeutic options despite advances in medical therapy. Although changes in the gut microbiota composition are recognized as key drivers of dysregulated intestinal immunity, alterations in bile acids (BAs) have been shown to influence gut homeostasis and contribute to the pathogenesis of the disease. In this review, we explore the interactions involving BAs and gut microbiota in IBDs, and discuss how the gut microbiota–BA–host axis may influence digestive inflammation.
The increasing demand for new and effective antibiotics requires intelligent strategies to obtain a wide range of potential candidates. Laccase-catalyzed reactions have been successfully applied to synthesize new β-lactam antibiotics and other antibiotics. In this work, laccases from three different origins were used to produce new aminoglycoside antibiotics. Kanamycin, tobramycin and gentamicin were coupled with the laccase substrate 2,5-dihydroxy-N-(2-hydroxyethyl)-benzamide. The products were isolated, structurally characterized and tested in vitro for antibacterial activity against various strains of Staphylococci, including multidrug-resistant strains. The cytotoxicity of these products was tested using FL cells. The coupling products showed comparable and, in some cases, better antibacterial activity than the parent antibiotics in the agar diffusion assay, and they were not cytotoxic. The products protected mice against infection with Staphylococcus aureus, which was lethal to the control animals. The results underline the great potential of laccases in obtaining new biologically active compounds, in this case new antibiotic candidates from the class of aminoglycosides.
Background
Longitudinal observational studies play on an important role for evidence-based research on health services and psychiatric rehabilitation. However, information is missing about the reasons, why patients participate in such studies, and how they evaluate their participation experience.
Methods
Subsequently to their final assessment in a 2-year follow-up study on supported housing for persons with severe mental illness, n = 182 patients answered a short questionnaire on their study participation experience (prior experiences, participation reasons, burden due to study assessments, intention to participate in studies again). Basic respondent characteristics as well as symptom severity (SCL-K9) were also included in the descriptive and analytical statistics.
Results
To help other people and curiosity were cited as the main initial reasons for study participation (>85%). Further motives were significantly associated with demographic and/or clinical variables. For instance, “relieve from boredom” was more frequently reported by men and patients with substance use disorders (compared to mood disorders), and participants ‘motive” to talk about illness” was associated with higher symptom severity at study entry. Furthermore, only a small proportion of respondents indicated significant burdens by study participation and about 87% would also participate in future studies.
Conclusions
The respondents gave an overall positive evaluation regarding their participation experience in an observational study on psychiatric rehabilitation. The results additionally suggest that health and social care professionals should be responsive to the expectations and needs of patients with mental illness regarding participation in research.
Abstract
Modeling of metabolite kinetics after oral administration of ketamine is of special interest because of the higher concentrations of active metabolites because of the hepatic first‐pass effect. This holds especially in view of the potential analgesic and antidepressant effects of 2R,6R‐ and 2S,6S‐hydroxynorketamine at low doses of ketamine. Therefore, a 9‐compartment model was developed to analyze the pharmacokinetics of ketamine enantiomers and their metabolites after racemic ketamine administered intravenously (5 mg) and as 4 doses (10, 20, 40, and 80 mg) of a prolonged‐release formulation (PR‐ketamine). Using a population approach, the serum concentration‐time data of the enantiomers of ketamine, norketamine, dehydronorketamine, and 2,6‐hydroxynorketamine obtained in 15 healthy volunteers could be adequately fitted. The estimated model parameters were used to simulate serum concentration‐time profiles; after multiple dosing of PR‐ketamine (2 daily doses of 20 mg), the steady‐state concentrations of R‐ and S‐ketamine were 1.4 and 1.3 ng/mL, respectively. The steady‐state concentration of 2R,6R‐hydroxynorketamine exceeded those of R‐norketamine (4‐fold), R‐dehydonorketamine (8‐fold), and R‐ketamine (46‐fold), whereas that of 2S,6S‐hydroxynorketamine exceeded that of S‐ketamine by 14‐fold. The model may be useful for identifying dosing regimens aiming at optimal plasma concentrations of 2,6‐hydroxynorketamines.
Abstract
Desulfarculus baarsii and Desulfurivibrio alkaliphilus are strictly anaerobic bacteria existing in marine sediments. D. baarsii gains energy through reducing sulphate and D. alkaliphilus is able to reduce elemental sulphur, thiosulphate and polysulphide in seawater. Both organisms were previously identified as key organisms in sediment derived, bidirectional electroactive biofilms. Here, we investigated the electrochemical performance of these two bacteria in bio‐electrochemical systems and their possible involvement in anodic and cathodic reactions. The results show that D. baarsii was unable to donate or accept electrons to/from an electrode, while D. alkaliphilus was able to catalyse both anodic and cathodic reactions and interact with the electrode through direct or potentially indirect electron transfer. Raman spectra of D. alkaliphilus electrode biofilms showed a high similarity to Geobacter sulfurreducens biofilms, including the specific bands of cytochromes b and c, explaining the electroactivity of D. alkaliphilus in bioelectrochemical reactions.