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Macrophages facilitate essential homeostatic functions e.g., endocytosis, phagocytosis, and signaling during inflammation, and express a variety of scavenger receptors including CD163 and CD206, which are upregulated in response to inflammation. In healthy individuals, soluble forms of CD163 and CD206 are constitutively shed from macrophages, however, during inflammation pathogen- and damage-associated stimuli induce this shedding. Activation of resident liver macrophages viz. Kupffer cells is part of the inflammatory cascade occurring in acute and chronic liver diseases. We here review the existing literature on sCD163 and sCD206 function and shedding, and potential as biomarkers in acute and chronic liver diseases with a particular focus on Acute-on-Chronic Liver Failure (ACLF). In multiple studies sCD163 and sCD206 are elevated in relation to liver disease severity and established as reliable predictors of morbidity and mortality. However, differences in expression- and shedding-stimuli for CD163 and CD206 may explain dissimilarities in prognostic utility in patients with acute decompensation of cirrhosis and ACLF.
Background and purpose: The aim of the study was to determine the effects of post-traumatically released High Mobility Group Box-1 protein (HMGB1) and extracellular histones on cardiomyocytes (CM). We also evaluated a therapeutic option to capture circulating histones after trauma, using a hemadsorption filter to treat CM dysfunction. Experimental Approach: We evaluated cell viability, calcium handling and mitochondrial respiration of human cardiomyocytes in the presence of HMGB-1 and extracellular histones. In a translational approach, a hemadsorption filter was applied to either directly eliminate extracellular histones or to remove them from blood samples obtained from multiple injured patients. Key results: Incubation of human CM with HMGB-1 or histones is associated with changes in calcium handling, a reduction of cell viability and a substantial reduction of the mitochondrial respiratory capacity. Filtrating plasma from injured patients with a hemadsorption filter reduces histone concentration ex vivo and in vitro, depending on dosage. Conclusion and implications: Danger associated molecular patterns such as HMGB-1 and extracellular histones impair human CM in vitro. A hemadsorption filter could be a therapeutic option to reduce high concentrations of histones.
The occupation of dental assistants (DAs) involves many health risks of the musculoskeletal system due to static and prolonged work, which can lead to musculoskeletal disorders (MSDs). The aim of the study was to investigate the prevalence of MSDs in DAs in Germany. Methods: For this purpose, an online questionnaire analyzed 406 (401 female participants and 5 male participants, 401w/5m) DAs. It was based on the Nordic Questionnaire (lifetime, 12-month, and seven-day MSDs’ prevalence separated into neck, shoulder, elbow, wrist, upper back, lower back, hip, knee, and ankle), and occupational and sociodemographic questions as well as questions about specific medical conditions. Results: 98.5% of the participants reported complaints of at least one body region in their lives, 97.5% reported at least one complaint in the last 12 months and 86.9% affirmed at least one complaint in the last seven days. For lifetime, 12-month and seven-day prevalence, the neck was the region that was most affected followed by the shoulder, the upper back and the lower back. Conclusion: The prevalence of MSDs among German (female) DAs was very high. The most affected area is the neck, followed by the shoulder, the lower back, and the upper back. It, therefore, seems necessary to devote more attention to ergonomics at the working practice of DAs as well in education and in dental work.
This study proposes a novel multi-network architecture consisting of a multi-scale convolution neural network (MSCNN) with fully connected graph convolution network (GCN), named MSCNN-GCN, for the detection of musculoskeletal abnormalities via musculoskeletal radiographs. To obtain both detailed and contextual information for a better description of the characteristics of the radiographs, the designed MSCNN contains three subnetwork sequences (three different scales). It maintains high resolution in each sub-network, while fusing features with different resolutions. A GCN structure was employed to demonstrate global structure information of the images. Furthermore, both the outputs of MSCNN and GCN were fused through the concat of the two feature vectors from them, thus making the novel framework more discriminative. The effectiveness of this model was verified by comparing the performance of radiologists and three popular CNN models (DenseNet169, CapsNet, and MSCNN) with three evaluation metrics (Accuracy, F1 score, and Kappa score) using the MURA dataset (a large dataset of bone X-rays). Experimental results showed that the proposed framework not only reached the highest accuracy, but also demonstrated top scores on both F1 metric and kappa metric. This indicates that the proposed model achieves high accuracy and strong robustness in musculoskeletal radiographs, which presents strong potential for a feasible scheme with intelligent medical cases.
Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.
Proper speech production requires auditory speech feedback control. Models of speech production associate this function with the right cerebral hemisphere while the left hemisphere is proposed to host speech motor programs. However, previous studies have investigated only spectral perturbations of the auditory speech feedback. Since auditory perception is known to be lateralized, with right-lateralized analysis of spectral features and left-lateralized processing of temporal features, it is unclear whether the observed right-lateralization of auditory speech feedback processing reflects a preference for speech feedback control or for spectral processing in general. Here we use a behavioral speech adaptation experiment with dichotically presented altered auditory feedback and an analogous fMRI experiment with binaurally presented altered feedback to confirm a right hemisphere preference for spectral feedback control and to reveal a left hemisphere preference for temporal feedback control during speaking. These results indicate that auditory feedback control involves both hemispheres with differential contributions along the spectro-temporal axis.
The teaching of professional roles in medical education is an interdisciplinary concern. However, surgeons require specific standards of professionalism for certain context-based situations. In addition to communication, studies require collaboration, leadership, error-/conflict-management, patient-safety and decision-making as essential competencies for surgeons. Standards for corresponding competencies are defined in special chapters of the German National Competency-based Learning Objectives for Undergraduate Medical Education (NKLM; chapter 8, 10). The current study asks whether these chapters are adequately taught in surgical curricula. Eight German faculties contributed to analysing mapping data considering surgical courses of undergraduate programs. All faculties used the MERlin mapping platform and agreed on procedures for data collection and processing. Sub-competency and objective coverage, as well as the achievement of the competency level were mapped. Overall counts of explicit citations were used for analysis. Collaboration within the medical team is a strongly represented topic. In contrast, interprofessional cooperation, particularly in healthcare sector issues is less represented. Patient safety and dealing with errors and complications is most emphasized for the Manager/Leader, while time management, career planning and leadership are not addressed. Overall, the involvement of surgery in teaching the competencies of the Collaborator and Manager/Leader is currently low. However, there are indications of a curricular development towards explicit teaching of these roles in surgery. Moreover, implicitly taught roles are numerous, which indicates a beginning awareness of professional roles.
Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development.
Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal.
Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants.
Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.
Background: A web-based malaria reporting information system (MRIS) has the potential to improve malaria reporting and management. The aim of this study was to evaluate the existing manual paper-based MRIS and to provide a way to overcome the obstacles by developing a web-based MRIS in Indonesia.
Methods: An exploratory study was conducted in 2012 in Lahat District, South Sumatra Province of Indonesia. We evaluated the current reporting system and identified the potential benefits of using a web-based MRIS by in-depth interviews on selected key informants. Feasibility study was then conducted to develop a prototype system. A web-based MRIS was developed, integrated and synchronized, with suitability ranging from Primary Healthcare Centres (PHCs) to the Lahat District Health Office.
Results: The paper-based reporting system was sub-optimal due to a lack of transportation, communication, and human capacity. We developed a web-based MRIS to replace the current one. Although the web-based system has the potential to improve the malaria reporting information system, there were some barriers to its implementation, including lack of skilled operators, computer availability and lack of internet access. Recommended ways to overcome the obstacles are by training operators, making the application in an offline mode and able to be operated by mobile phone text messaging for malaria reporting.
Conclusion: The web-based MRIS has the potential to be implemented as an enhanced malaria reporting information system and investment in the system to support timely management responses is essential for malaria elimination. The developed application can be cloned to other areas that have similar characteristics and MRIS with a built-in web base to aid its application in the 5G future.
NKG2D is a potent activating immunoreceptor expressed on nearly all cytotoxic lymphocytes promoting their cytotoxicity against self-cells expressing NKG2D ligands (NKG2DLs). NKG2DLs are MHC class I-like glycoproteins that usually are not expressed on “healthy” cells. Rather, their surface expression is induced by various forms of cellular stress, viral infection, or malignant transformation. Hence, cell surface NKG2DLs mark “dangerous” cells for elimination by cytotoxic lymphocytes and therefore can be considered as “kill-me” signals. In addition, NKG2DLs are up-regulated on activated leukocytes, which facilitates containment of immune responses. While the NKG2D receptor is conserved among mammals, NKG2DL genes have rapidly diversified during mammalian speciation, likely due to strong selective pressures exerted by species-specific pathogens. Consequently, NKG2DL genes are not conserved in man and mice, although their NKG2D-binding domains maintained structural homology. Human NKG2DLs comprise two members of the MIC (MICA/MICB) and six members of the ULBP family of glycoproteins (ULBP1–6) with MICA representing the best-studied human NKG2DLs by far. Many of these studies implicate a role of MICA in various malignant, infectious, or autoimmune diseases. However, conclusions from these studies often were limited in default of supporting in vivo experiments. Here, we report a MICA transgenic (MICAgen) mouse model that replicates central features of human MICA expression and function and, therefore, constitutes a novel tool to critically assess and extend conclusions from previous in vitro studies on MICA. Similarly to humans, MICA transcripts are broadly present in organs of MICAgen mice, while MICA glycoproteins are barely detectable. Upon activation, hematopoietic cells up-regulate and proteolytically shed surface MICA. Shed soluble MICA (sMICA) is also present in plasma of MICAgen mice but affects neither surface NKG2D expression of circulating NK cells nor their functional recognition of MICA-expressing tumor cells. Accordingly, MICAgen mice also show a delayed growth of MICA-expressing B16F10 tumors, not accompanied by an emergence of MICA-specific antibodies. Such immunotolerance for the xenoantigen MICA ideally suits MICAgen mice for anti-MICA-based immunotherapies. Altogether, MICAgen mice represent a valuable model to study regulation, function, disease relevance, and therapeutic targeting of MICA in vivo.