Microcirculation: Physiology, pathophysiology, and clinical application

This paper briefly reviews the physiological components of the microcirculation, focusing on its function in homeostasis and its central function in the realization of oxygen transport to tissue cells. Its pivotal role in the understanding of circulatory compromise in states of shock and renal compromise is discussed. Our introduction of hand-held vital microscopes (HVM) to clinical medicine has revealed the importance of the microcirculation as a central target organ in states of critical illness and inadequate response to therapy. Technical and methodological developments have been made in hardware and in software including our recent introduction and validation of automatic analysis software called MicroTools, which now allows point-of-care use of HVM imaging at the bedside for instant availability of functional microcirculatory parameters needed for microcirculatory targeted resuscitation procedures to be a reality

Functional evaluation of sublingual microcirculation indicates successful weaning from VA-ECMO in cardiogenic shock

Background: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly adopted for the treatment of cardiogenic shock (CS). However, a marker of successful weaning remains largely unknown. Our hypothesis was that successful weaning is associated with sustained microcirculatory function during ECMO flow reduction. Therefore, we sought to test the usefulness of microcirculatory imaging in the same sublingual spot, using incident dark field (IDF) imaging in assessing successful weaning from VA-ECMO and compare IDF imaging with echocardiographic parameters. Methods: Weaning was performed by decreasing the VA-ECMO flow to 50% (F50) from the baseline

Preoperative right heart hemodynamics predict postoperative acute kidney injury after heart transplantation

Purpose: Acute kidney injury (AKI) frequently occurs after heart transplantation (HTx), but its relation to preoperative right heart hemodynamic (RHH) parameters remains unknown. Therefore, we aimed to determine their predictive properties for postoperative AKI severity within 30 days after HTx. Methods: From 1984 to 2016, all consecutive HTx recipients (n = 595) in our tertiary referral center were included and analyzed for the occurrence of postoperative AKI staged by the kidney disease improving global outcome criteria. The effects of preoperative RHH parameters on postoperative AKI were calculated using logistic regression, and predictive accuracy was assessed using integrated discrimination improvement (IDI), net reclassification improvement (NRI), and area under the receiver operating characteristic curves (AUC). Results: Postoperative AKI occurred in 430 (72%) patients including 278 (47%) stage 1, 66 (11%) stage 2, and 86 (14%) stage 3 cases. Renal replacement therapy (RRT) was administered in 41 (7%) patients. Patients with higher AKI stages had also higher baseline right atrial pressure (RAP; median 7, 7, 8, and in RRT 11 mmHg, p trend = 0.021), RAP-to-pulmonary capillary wedge pressure ratio (median 0.37, 0.36, 0.40, 0.47, p trend = 0.009), and lower pulmonary artery pulsatility index (PAPi) values (median 2.83, 3.17, 2.54, 2.31, p trend = 0.012). Higher RAP and lower PAPi values independently predicted AKI severity [adjusted odds ratio (OR) per doubling of RAP 1.16 (1.02–1.32), p = 0.029; of PAPi 0.85 (0.75–0.96), p = 0.008]. Based on IDI, NRI, and delta AUC, inclusion of these parameters improved the models’ predictive accuracy. Conclusions: Preoperative PAPi and RAP strongly predict the development of AKI early after HTx and can be used as early AKI predictors

Cancer stem cell differentiation: TGFß1 and versican may trigger molecules for the organization of tumor spheroids

PubMed ID: 24927163Cancer stem cells (CSCs) have the ability to self-renew similar to normal stem cells. This process is linked with metastasis and resistance to chemotherapy and radiotherapy. In the present study, we constructed an in vitro differentiation model for CSCs. CSCs isolated and proliferated for one passage were maintained as monolayers or spheroid-forming cells with serum included media for differentiation process. Differentiation of adhesion molecules and cellular ultrastructural properties were investigated and compared in both monolayer and spheroid cultures. CD133+/CD44+ cancer-initiating cells were isolated from DU-145 human prostate cancer cell line monolayer cultures and propagated as tumor spheroids and compared with the remaining heterogeneous cancer cell bulk population. Microarray-based gene expression analysis was applied to determine genes with differential expression and protein expression levels of candidates were analyzed by immunohistochemistry. Electron microscopy showed detailed analysis of morphology. TGFß1 was found to be significantly upregulated in monolayer CSCs. High expression levels of VCAN, COL7A1, ITGß3, MMP16, RPL13A, COL4A2 and TIMP1 and low expression levels of THBS1, MMP1 and MMP14 were detected when CSCs were maintained as serum-grown prostate CSC spheroids. Immunohistochemistry supported increased immunoreactivity of TGFß1 in monolayer cultures and VCAN in spheroids. CSCs were found to possess multipotential differentiation capabilities through upregulation and/or downregulation of their markers. TGFß1 is a triggering molecule, it stimulates versican, Col7A1, ITGß3 and, most importantly, the upregulation of versican was only detected in CSCs. Our data support a model where CSCs must be engaged by one or more signaling cascades to differentiate and initiate tumor formation. This mechanism occurs with intracellular and extracellular signals and it is possible that CSCc themselves may be a source for extracellular signaling. These molecules functioning in tumor progression and differentiation may help develop targeted therapy