Classical Whipple's disease (CWD) affects the gastrointestinal tract and rather elicits regulatory than inflammatory immune reactions. Mechanisms of malabsorption, diarrhea, and systemic immune ...activation are unknown. We here analyzed mucosal architecture, barrier function, and immune activation as potential diarrheal trigger in specimens from 52 CWD patients. Our data demonstrate villus atrophy and crypt hyperplasia associated with epithelial apoptosis and reduced alkaline phosphatase expression in the duodenum of CWD patients. Electrophysiological and flux experiments revealed increased duodenal permeability to small solutes and macromolecules. Duodenal architecture and permeability ameliorated upon antibiotic treatment. Structural correlates for these alterations were concordant changes of membranous claudin-1, claudin-2, claudin-3, and tricellulin expression. Tumor necrosis factor-α and interleukin-13 were identified as probable mediators of epithelial apoptosis, and altered tight junction expression. Increased serum markers of microbial translocation and their decline following treatment corroborated the biological significance of the mucosal barrier defect. Hence, mucosal immune responses in CWD elicit barrier dysfunction. Diarrhea is caused by loss of absorptive capacity and leak flux of ions and water. Downregulation of tricellulin causes increased permeability to macromolecules and subsequent microbial translocation contributes to systemic inflammation. Thus, therapeutic strategies to reconstitute the mucosal barrier and control inflammation could assist symptomatic control of CWD.
Pyrolysis experiments were carried out with polymeric model compounds containing defined forms of bound nitrogen. The chosen compounds, polyvinylcarbazole, polyvinylpyridine and polyvinylpyrrolidone, ...were pyrolysed in a fixed bed annular reactor at 873 and 1173 K. The functionalities of the nitrogen in the precursors as well as that in the derived chars were determined by X-ray photoelectron spectroscopy (XPS). Additional information about the structure was received from FT-IR, solid-state 13C-NMR and, in part, X-ray absorption near edge structure (XANES) spectroscopy. The application of different analytical methods should result in a more reliable classification of the N 1s electron binding energies than is possible by the sole use of XPS. It is interesting to note that the nitrogen in five-membered rings (N-5) of the N-heterocyclic compounds remains in existence in the high temperature products. In the case of the carbazole system it is still the dominant bonding form. The high-temperature char from polyvinylpyridine contains nitrogen in both five- and six-membered rings. It may be concluded that the behaviour of the nitrogen during pyrolysis does not only depend on its functionality but also on its chemical environment. A comprehensible mechanism of the transformation of N-6 into N-5 nitrogen is discussed on the basis of the FT-IR and solid-state 13C-NMR spectra of the low temperature chars.
Abstract
Background and aims
Cytotoxic CD8+ T cells mediate myocardial damage in patients with virus induced myocarditis, plaque erosion during acute coronary syndrome, and promote adverse ...post-ischemic cardiac remodeling. There is emerging evidence to support a link between inflammation and atrial fibrillation (AF). Protease-activated receptor 1 (PAR1) is the thrombin receptor expressed on platelets, but it is also expressed in endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and CD8+ T cells. The role of CD8+ T cells and PAR1 in atrial myopathy and early AF have not been studied.
Methods
In 80 non-anticoagulated patients with a first documented episode of AF, and 20 control subjects without AF but with a comparable cardiovascular risk profile (e.g. SCORE2, CHA2DS2-VASc, p>0.05), we studied PAR1-related cytotoxic T cell activity in the first hours (up to 24 h) of AF clinical manifestation. The Apolipoprotein E–knock out (ApoEko) mouse is a commonly used model of metabolic syndrome that develops atrial myopathy (structural correlate of AF). ApoEko male mice (Apoetm1Unc with a C57BL/6 genetic background) were fed for six weeks with a standard chew, western-type diet (high fat and high sucrose = WD) ± the specific PAR1 inhibitor vorapaxar.
Results
High levels of circulating, activated CD8+ T cells (CD8+CD57+ T cells with pro-inflammatory and high cytotoxic properties) were present in patients with early AF (flow cytometry). Stimulation of cytotoxic T cells, that expressed the thrombin receptor PAR1, that were isolated from patients with new onset of AF, released pro-inflammatory cytokines (e.g. IFN-γ, TNF-α). Enhanced cytotoxic activity of CD8+ T cells was suggested by elevated plasma levels of effector molecules (e.g. granulysin and granzyme).
In ApoEko mice fed a WD, atrial myopathy as the structural correlate for AF, was paralleled by increased expression of effector molecules that were associated with CD8+ T cell activity (like perforin, granzyme A, granzyme B, IFN-γ). Cytotoxic T cell activity disrupted the release of the potective atrial natriuretic peptide, ANP, and increased signaling pathways associated with atrial fibrosis (e.g. TGF-β, cTGF, TGF-β receptor). The specific PAR1 inhibitor, vorapaxar, reduced inflammatory T cell activity, transcription of fibrotic mediators, and reconstituted ANP secretion in atria of ApoEko mice.
Conclusions
Targeting the FXa/FIIa-PAR1-CD8+ axis might be a promising approach to reduce atrial fibrosis and inflammation.
Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): BIH Charité Clinician Scientist Program
Proceeding from the knowledge of the functional forms of nitrogen in coals it should be possible to draw conclusions on the mechanisms of its release during devolatilization. Pyrolysis experiments ...were carried out with a series of lignite from the main German mining districts in a temperature range from 673 to 1173
K. Nitrogen functionalities of the coals and the obtained chars were determined by XPS. The nitrogen content of the residual pyrolysis chars was found to be dependent on a wide variety of parameters: coal type, temperature, residence time, mineral matter. An increasing N/C ratio was detected for chars obtained under conditions of oxopyrolysis. The conversion of fuel-bound nitrogen to NO
x
-precursors (HCN, NH
3) is also strongly dependent on coal type. The mineral matter of the parent coals was found to affect both the primary devolatilization process and the reaction paths to form ammonia. The balance of the nitrogen distribution during pyrolysis shows a large amount of N
2 to which the coal-N is converted.
Abstract
Background
Hemostasis is dysregulated in patients with moderate-to-severe coronavirus disease 2019 (COVID-19). However, patients with respiratory diseases other than COVID-19 can also show ...disturbed coagulation reactions during the acute inflammatory process. Parameters of coagulation and platelet function are here compared between patients with upper respiratory infections with and without COVID-19 and are related to the clinical outcome.
Methods
Hospitalized patients with acute respiratory symptoms and with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)-positive (COVpos) and SARS-CoV2-negative (COVneg) status were included. We assessed several parameters of coagulation and fibrinolysis as well as adenosine diphosphate (ADP)-, thrombin receptor activator peptide 6 (TRAP)-, and arachidonic acid (AA)-induced platelet reactivity by impedance aggregometry, as well as leukocyte subtype spectrum and platelet-leukocyte aggregates by flow cytometry and inflammatory cytokines by cytometric bead array. The SOFA score was assessed as marker of the clinical outcome.
Results
87 patients were included in the study of which 50 were COVpos and 37 were COVneg. Von Willebrand factor was significantly higher in COVID positive patients compared to the control group (4456,4 mU/ml 2701,4; 9067,0 vs. 2528,0 mU/ml 1301,2; 3693,8, p<0,001). COVID-positive patients exhibited also more tissue plasminogen activator in the circulating blood than COVID-negative patients with an respiratory infection (11,4 mU/ml 7,2; 24,6 vs. 7,3 mU/ml 4,9; 10,5, p=0,001). ADP, TRAP-, and AA-induced platelet reactivity was significantly higher in COVpos than in COVneg patients. The SOFA score was higher in COVpos than in COVneg patients and again higher in deceased COVpos patients than in surviving COVpos. The SOFA score correlated significantly with parameters of coagulation and platelet function. A larger percentage of classical and intermediate monocytes, and of CD4pos T cells (TH) aggregated with platelets in COVpos than in COVneg patients. Interleukin (IL)-1 receptor antagonist (RA) and IL-6 levels were higher in COVpos than in COVneg patients and again higher in deceased COVpos patients than in surviving COVpos. IL-1RA and IL-6 levels correlated with the SOFA score in COVpos but not in COVneg patients, indicating a COVID-19-specific mechanism.
Conclusion
In moderate-to-severe COVID-19, but not in other respiratory diseases, disease severity was associated with parameters of coagulation and platelet function. Dysregulated coagulation and platelet hyperreactivity were associated to a worse clinical outcome in patients with COVID-19, pointing to the importance of antithrombotic therapy for reducing disease severity.
Funding Acknowledgement
Type of funding sources: None.
Abstract
Background
Galectin-3 is a β-galactoside-binding lectin that has been described to be overexpressed in inflammation, atherosclerosis, and in myocardial fibrosis. In COVID-19, galectin-3 has ...been proposed as an important regulator of the inflammatory response and fibrosis processes. The role of galectin-3 as a platelet activator and thrombosis enhancer has been also recently described. However, the role of galectin-3 in the thrombotic risk in COVID-19 hasn't been studied extensively.
Methods
Patients with moderate to severe COVID-19 were included in the study. Hospitalized patients with acute respiratory diseases without COVID-19 were examined as controls. We compared the levels of galectin-3, soluble ST2, tissue factor and tissue factor activity (TFa) as well as several other markers of increased thrombogenicity in both groups. The correlations between galectin-3 and coagulation as well as inflammation markers were assessed. The SOFA score was used as a marker for the clinical outcome.
Results
93 patients were included into the study of which 56 were SARS-CoV-2 positive (COV+) and 37 were SARS-CoV-2 negative controls (COV−). Galectin-3 levels were higher in the COV+ group (median 7.10 ng/ml IQR 4.61–9.81 vs. 5.47 ng/ml 3.63–6.66 p=0.016) as well as the TFa (median 334.48 pM 115.19–632.58 vs. 134.02 pM 86.92–206.66) and the ST2 levels (median 5.49 ng/ml 2.40–9.28 vs. 2.19 ng/ml 0.66–3.91 p<0.001). We also observed a positive correlation between galectin-3 and IL-6 (r=0.559, p<0.001), ST2 (r=0.332, p=0.005), SOFA score (r=0.441, p=0.003), von Willebrand factor (r=0.401, p<0.001), plasminogen (r=0.361, p=0.001), antithrombin (r=0.453, p<0.001), and D-dimer (r=0.377, p=0.001).
Conclusion
In patients with acute respiratory diseases, especially with COVID-19, galectin-3 is a marker for increased hypercoagulability and worse clinical outcome. Galactin-3 might be a useful therapeutic target for patients with COVID-19.
Funding Acknowledgement
Type of funding sources: None.
Abstract
Background
The need for cardiac intensive care unit (ICU) beds remains high in order to monitor and treat emergency patients with severe cardiovascular diseases, particularly during the ...COVID-19 pandemic. Therefore, timely discharge strategies from the cardiac ICU to peripheral wards are crucial to meet the increasing demand for cardiac ICU beds. Early patient transfer from ICU to the peripheral ward may result in worsening of the patient's clinical condition and outcome with readmission to the ICU, while late transfer may require prolonged expert care and generate unwanted costs.
Purpose
To investigate whether unplanned readmission of cardiac patients to the cardiac ICU within 72 hours after the index ICU stay is associated with increased mortality risk (primary outcome) and prolonged total hospital length of stay (LOS) (secondary outcome), as well as to identify predictors of ICU readmission in cardiac patients.
Methods
Adult patients who were admitted to the cardiac ICU due to a primary cardiac admission diagnosis at a tertiary care center between 2003 and 2021 were included. Outcomes were analysed with multivariable regression models adjusted for 26 a priori defined variables on patient demographics, underlying comorbidity levels, ICU procedures and administered ICU drugs.
Results
30,942 cardiac patients were included, out of whom 1,499 patients (4.84%) were readmitted to the cardiac ICU within 72 hours. 1,023 (68.2%) of readmitted patients were male. Compared to non-readmitted patients, readmitted patients were older, had more underlying comorbidities (Charlson Index), had more severe disease courses (SOFA score, TISS, APACHE II score and SAPS), as well as required more frequently vasopressor therapy, renal replacement therapy and coronary angiographies (Table 1). Readmission to the cardiac ICU was associated with higher in-hospital mortality risk (Odds Ratio 7.52, 95% Confidence Interval (CI) 4.15–12.27, P<0.001) and prolonged hospital LOS (Incidence Rate Ratio 1.56, 95% CI 1.15–1.58, P<0.001). Patients who were readmitted to the ICU had been discharged 18% earlier during the index ICU stay compared to non-readmitted patients (P<0.001). Of note, readmitted and non-readmitted patients had similar vital parameters at time of ICU discharge after their index ICU stay. During the index ICU stay, non-readmitted patients were prescribed more beta blockers (65.3% vs. 45.8%), ACE inhibitors (37.0% vs. 27.2%) and blood transfusions (10.7% vs. 7.7%).
Conclusion
Early readmission to the cardiac ICU was associated with increased in-hospital mortality and prolonged hospitalisation. Readmitted patients had been discharged earlier from their index ICU stay and required more comprehensive critical care. ICU discharge strategies should optimally be based on objective patient assessments to facilitate patient safety and shorten hospital length of stay. Artificial intelligence-based algorithms may support clinicians with safe ICU discharge.
Funding Acknowledgement
Type of funding sources: None.
Abstract
Background
International organisations advocate the use of extracorporeal cardio-pulmonary resuscitation (ECPR) with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in selected ...patients with therapy-refractory cardiac arrest 1–3. Although VA-ECMO allows for full circulatory support, it is inherent to increased left ventricular (LV) pressure due to retrograde aortic perfusion, which may hamper myocardial recovery and aggravate pulmonary oedema. In order to mitigate these negative sequelae, adjunct LV unloading with an Impella microaxial flow pump may be considered. The effects of concomitant treatment with VA-ECMO and Impella (ECMELLA) in patients with therapy-refractory cardiac arrest due to acute myocardial infarction (AMI) remains unclear.
Objectives
To the best of our knowledge this is the first study to investigate whether treatment with ECMELLA is associated with improved 30-day mortality rate in patients with therapy-refractory cardiac arrest caused by AMI, compared to treatment with VA-ECMO alone.
Methods
Patients treated with ECMELLA were propensity score (PS)-matched to patients receiving VA-ECMO based on age, electrocardiogram (ECG) rhythm, cardiac arrest location (out-of-hospital or in-hospital) and Survival After Veno-Arterial ECMO (SAVE) score. Cox proportional-hazard and Poisson regression models were used to analyse 30-day mortality rate (primary outcome), hospital and intensive care unit (ICU) length of stay (LOS) (secondary outcomes). Multiple sensitivity analyses on patient demographics and cardiac arrest parameters were performed.
Results
95 adult patients from three tertiary care centers were included, out of whom 34 pairs were PS-matched. ECMELLA treatment was associated with 47% decreased 30-day mortality risk 95% Confidence Interval (CI) 0.31–0.91, P=0.021, 71% prolonged hospital 95% CI 1.50–1.95, P<0.001 and 81% prolonged ICU LOS 95% CI 1.57–2.08, P<0.001. Kaplan-Meier analyses (Figure 1) and multiple sub-group analyses (age, sex, initial ECG rhythm, Charlson comorbidity index, body mass index, SAVE score, cardiac arrest location, lactate and pH levels) confirmed survival benefits in the ECMELLA group. Especially patients with prolonged low-flow time and high initial lactate benefited from ECMELLA therapy. Moreover, LV ejection fraction strongly improved in the ECMELLA group between ICU admission and ICU discharge from 15% to 40%, compared 15% and 20% in the VA-ECMO group.
Conclusion
In this multicenter propensity score-matched cohort of patients with ECPR during therapy-refractory cardiac arrest caused by AMI, treatment with ECMELLA was associated with improved survival compared to treatment with VA-ECMO alone. These findings support current guideline recommendations on early evaluation of ECPR in well selected patients with therapy-refractory cardiac arrest. A clinical trial is urgently needed to further evaluate the role of LV unloading in patients with therapy-refractory cardiac arrest.
Funding Acknowledgement
Type of funding sources: None.
PURPOSE To describe a modified fixation technique to improve the long-term functional and cosmetic success of upper lid loading with gold weights. METHOD A retrospective single surgeon study of ...combined upper pre-tarsal and direct levator fixation of the gold weight. The minimum follow-up period was 12 months. RESULTS Gold weights were implanted with the modified technique into 29 patients. The gold weight was removed in two cases due to infection and in one case due to ptosis. There was no loss of function over the follow-up period and the cosmetic outcome was good or very good in all cases. The follow-up ranged from 12 to 84 months with a mean of 40 months. CONCLUSIONS Combined upper pre-tarsal fixation and direct levator fixation is effective in maximizing both the long-term functional and cosmetic success of upper lid loading with gold weights in paralytic lagophthalmos.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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