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Objective
Acute pancreatitis (AP) is an inflammatory disorder, the severe form of which is burdened with multi-organ dysfunction and high mortality. The pathogenesis of life –threatening organ complications, such as respiratory and renal failure, is unknown.
Design
Organ dysfunction was investigated in a mouse model of AP. The influence of monocytes and neutrophils on multi organ dysfunction syndrome (MODS) was investigated in vivo by antibody depletion. Using real-time-fluorescence and deformability-cytometry (RT-DC) analysis we determined the mechanical properties of neutrophils and monocytes during AP. Furthermore, blood samples of pancreatitis patients were used to characterize severity-dependent chemokine profiles according to the revised Atlanta classification.
Results
Similar to AP in humans, severe disease in the mouse model associates with organ dysfunction mainly of lung and kidney, which is triggered by a mobilisation of Ly6g-/CD11b+/Ly6c hi monocytes, but not of Ly6g+/CD11b+ neutrophils. Monocyte depletion by anti-CCR2 antibody treatment ameliorated lung function (oxygen consumption) without interfering with the systemic immune response. RT-DC analysis of circulation monocytes showed a significant increase in cell size during SAP, but without a compensatory increase in elasticity. Patient chemokine profiles show a correlation of AP severity with monocyte attracting chemokines like MCP-1 or MIG and with leukocyte mobilisation.
Conclusion
In AP, the physical properties of mobilized monocytes, especially their large size, result in an obstruction of the fine capillary systems of the lung and of the kidney glomeruli. A selective depletion of monocytes may represent a treatment strategy for pancreatitis as well as for other inflammation-related disorders.
Objectives: To investigate the co-occurrence of 4 behavioral health risk factors (BHRFs), namely tobacco smoking, alcohol at-risk drinking, physical inactivity and unhealthy diet and their association with sick days prior to hospitalization in general hospital patients.
Methods: Over 10 weeks (11/2020-04/2021), all 18-64-year-old patients admitted to internal medicine, general and trauma surgery, and otorhinolaryngology wards of a tertiary care hospital were systematically approached. Among 355 eligible patients, 278 (78.3%) participated, and 256 (72.1%) were analyzed. Three BHRF sum scores were determined, including current tobacco smoking, alcohol use, physical inactivity and 1 of 3 indicators of unhealthy diet. Associations between BHRF sum scores and sick days in the past 6 months were analyzed using multivariate zero-inflated negative binomial regressions.
Results: Sixty-two percent reported multiple BHRFs (≥2). The BHRF sum score was related to the number of sick days if any (p = 0.009) with insufficient vegetable and fruit intake as diet indicator.
Conclusion: The majority of patients disclosed multiple BHRFs. These were associated with sick days prior to admission. The findings support the need to implement interventions targeting multiple BHRFs in general hospitals.
Abstract
Differentiation of cardiac progenitor cells (CPC) into cardiomyocytes is a fundamental step in cardiogenesis, which is marked by changes in gene expression responsible for remodeling of the cytoskeleton and in altering the mechanical properties of cells. Here we have induced the differentiation of CPC derived from human pluripotent stem cells into immature cardiomyocytes (iCM) which we compare with more differentiated cardiomyocytes (mCM). Using atomic force microscopy and real‐time deformability cytometry, we describe the mechanodynamic changes that occur during the differentiation process and link our findings to protein expression data of cytoskeletal proteins. Increased levels of cardiac‐specific markers as well as evolution of cytoskeletal morphology and contractility parameters correlated with the expected extent of cell differentiation that was accompanied by hypertrophic growth of cells. These changes were associated with switching in the balance of the different actin isoforms where β‐actin is predominantly found in CPC, smooth muscle α‐actin is dominant in iCM cells and sarcomeric α‐actin is found in significantly higher levels in mCM. We link these cytoskeletal changes to differences in mechano‐dynamic behavior of cells that translate to changes in Young's modulus that depend on the cell adherence. Our results demonstrate that the intracellular balance of actin isoform expression can be used as a sensitive ruler to determine the stage of differentiation during early phases of cardiomyocyte differentiation that correlates with an increased expression of sarcomeric proteins and is accompanied by changes in cellular elasticity.
Considering cancer not only as malignant cells on their own but as a complex disease in which tumor cells interact and communicate with their microenvironment has motivated the establishment of clinically relevant 3D models in past years. Technological advances gave rise to novel bioengineered models, improved organoid systems, and microfabrication approaches, increasing scientific importance in preclinical research. Notwithstanding, mammalian in vivo models remain closest to mimic the patient’s situation but are limited by cost, time, and ethical constraints. Herein, the in ovo model bridges the gap as an advanced model for basic and translational cancer research without the need for ethical approval. With the avian embryo being a naturally immunodeficient host, tumor cells and primary tissues can be engrafted on the vascularized chorioallantoic membrane (CAM) with high efficiencies regardless of species-specific restrictions. The extraembryonic membranes are connected to the embryo through a continuous circulatory system, readily accessible for manipulation or longitudinal monitoring of tumor growth, metastasis, angiogenesis, and matrix remodeling. However, its applicability in immunoncological research is largely underexplored. Dual engrafting of malignant and immune cells could provide a platform to study tumor-immune cell interactions in a complex, heterogenic and dynamic microenvironment with high reproducibility. With some caveats to keep in mind, versatile methods for in and ex ovo monitoring of cellular and molecular dynamics already established in ovo are applicable alike. In this view, the present review aims to emphasize and discuss opportunities and limitations of the chicken embryo model for pre-clinical research in cancer and cancer immunology.
Critically ill patients at the intensive care unit (ICU) often develop a generalized weakness, called ICU-acquired weakness (ICUAW). A major contributor to ICUAW is muscle atrophy, a loss of skeletal muscle mass and function. Skeletal muscle assures almost all of the vital functions of our body. It adapts rapidly in response to physiological as well as pathological stress, such as inactivity, immobilization, and inflammation. In response to a reduced workload or inflammation muscle atrophy develops. Recent work suggests that adaptive or maladaptive processes in the endoplasmic reticulum (ER), also known as sarcoplasmic reticulum, contributes to this process. In muscle cells, the ER is a highly specialized cellular organelle that assures calcium homeostasis and therefore muscle contraction. The ER also assures correct folding of proteins that are secreted or localized to the cell membrane. Protein folding is a highly error prone process and accumulation of misfolded or unfolded proteins can cause ER stress, which is counteracted by the activation of a signaling network known as the unfolded protein response (UPR). Three ER membrane residing molecules, protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring protein 1a (IRE1a), and activating transcription factor 6 (ATF6) initiate the UPR. The UPR aims to restore ER homeostasis by reducing overall protein synthesis and increasing gene expression of various ER chaperone proteins. If ER stress persists or cannot be resolved cell death pathways are activated. Although, ER stress-induced UPR pathways are known to be important for regulation of skeletal muscle mass and function as well as for inflammation and immune response its function in ICUAW is still elusive. Given recent advances in the development of ER stress modifying molecules for neurodegenerative diseases and cancer, it is important to know whether or not therapeutic interventions in ER stress pathways have favorable effects and these compounds can be used to prevent or treat ICUAW. In this review, we focus on the role of ER stress-induced UPR in skeletal muscle during critical illness and in response to predisposing risk factors such as immobilization, starvation and inflammation as well as ICUAW treatment to foster research for this devastating clinical problem.
Background: Men and women with valvular heart disease have different risk profiles for clinical endpoints. Non-esterified fatty acids (NEFA) are possibly involved in cardio-metabolic disease. However, it is unclear whether NEFA concentrations are associated with physical performance in patients undergoing transcatheter aortic valve implantation (TAVI) and whether there are sex-specific effects. Methods: To test the hypothesis that NEFA concentration is associated with sex-specific physical performance, we prospectively analysed data from one hundred adult patients undergoing TAVI. NEFA concentrations, physical performance and anthropometric parameters were measured before and 6 and 12 months after TAVI. Physical performance was determined by a six-minute walking test (6-MWT) and self-reported weekly bicycle riding time. Results: Before TAVI, NEFA concentrations were higher in patients (44 women, 56 men) compared to the normal population. Median NEFA concentrations at 6 and 12 months after TAVI were within the reference range reported in the normal population in men but not women. Men but not women presented with an increased performance in the 6-MWT over time (p = 0.026, p = 0.142, respectively). Additionally, men showed an increased ability to ride a bicycle after TAVI compared to before TAVI (p = 0.034). NEFA concentrations before TAVI correlated with the 6-MWT before TAVI in women (Spearman’s rho −0.552; p = 0.001) but not in men (Spearman’s rho −0.007; p = 0.964). No association was found between NEFA concentrations and physical performance 6 and 12 months after TAVI. Conclusions: NEFA concentrations improved into the reference range in men but not women after TAVI. Men but not women have an increased physical performance after TAVI. No association between NEFA and physical performance was observed in men and women after TAVI.
With more than 25 million people affected, heart failure (HF) is a global threat. As energy
production pathways are known to play a pivotal role in HF, we sought here to identify key metabolic
changes in ischemic- and non-ischemic HF by using a multi-OMICS approach. Serum metabolites and
mRNAseq and epigenetic DNA methylation profiles were analyzed from blood and left ventricular
heart biopsy specimens of the same individuals. In total we collected serum from n = 82 patients
with Dilated Cardiomyopathy (DCM) and n = 51 controls in the screening stage. We identified
several metabolites involved in glycolysis and citric acid cycle to be elevated up to 5.7-fold in DCM
(p = 1.7 × 10−6
). Interestingly, cardiac mRNA and epigenetic changes of genes encoding rate-limiting
enzymes of these pathways could also be found and validated in our second stage of metabolite
assessment in n = 52 DCM, n = 39 ischemic HF and n = 57 controls. In conclusion, we identified a
new set of metabolomic biomarkers for HF. We were able to identify underlying biological cascades
that potentially represent suitable intervention targets.