Effects of sevoflurane and propofol on left ventricular diastolic function in patients with pre-existing diastolic dysfunction

Background. The effects of anaesthetics on left ventricular (LV) diastolic function in patients with pre-existing diastolic dysfunction are not well known. We hypothesized that propofol but not sevoflurane will worsen the pre-existing LV diastolic dysfunction. Methods. Of 24 randomized patients, 23 fulfilled the predefined echocardiographic criterion for diastolic dysfunction. They received general anaesthesia with sevoflurane 1 MAC (n=12) or propofol 4 μg ml−1 (n=11). Echocardiographic examinations were performed at baseline and in anaesthetized patients under spontaneous breathing and under positive pressure ventilation. Analysis focused on peak early diastolic velocity of the mitral annulus (Ea). Results. During spontaneous breathing, Ea was higher in the sevoflurane than in the propofol group [mean (95% CI) 7.0 (5.9-8.1) vs 5.5 (4.7-6.3) cm s−1; P<0.05], reflecting an increase of Ea from baseline only in the sevoflurane group (P<0.01). Haemodynamic findings were similar in both groups, but the end-tidal carbon dioxide content was more elevated in the propofol group (P<0.01). During positive pressure ventilation, Ea was similarly low in the sevoflurane and propofol groups [5.3 (4.2-6.3) and 4.4 (3.6-5.2) cm s−1, respectively]. Conclusions. During spontaneous breathing, early diastolic function improved in the sevoflurane but not in the propofol group. However, during positive pressure ventilation and balanced anaesthesia, there was no evidence of different effects caused by the two anaesthetic

Effects of halothane, sevoflurane and propofol on left ventricular diastolic function in humans during spontaneous and mechanical ventilation

Background. There is limited knowledge of the effects of anaesthetics on left ventricular (LV) diastolic function in humans. Our aim was to evaluate these effects in humans free from cardiovascular disease. Methods. Sixty patients (aged 18-47 yr) who had no history or signs of cardiovascular disease were randomized to receive general anaesthesia with halothane, sevoflurane or propofol. Echocardiography was performed at baseline and during spontaneous respiration at 1 minimum alveolar concentration (MAC) of the inhalational agents or propofol 4 µg ml−1 (step 1), and repeated during positive-pressure ventilation with 1 and 1.5 MAC of the inhalational agents or with propofol 4 and 6 µg ml−1 (steps 2a and 2b). Analysis of echocardiographic measurements focused on heart rate corrected isovolumic relaxation time (IVRTc) and early diastolic peak velocity of the lateral mitral annulus (Ea). Results. IVRTc decreased from baseline to step 1 in the halothane group (82 [95% CI, 76-88] ms and 74 [95% CI, 68-80] ms respectively; P=0.02), remained stable in the sevoflurane group (78 [95% CI, 72-83] ms and 73 [95% CI, 67-81] ms; n.s.) and increased in the propofol group (80 [95% CI, 74-86] ms and 92 [95% CI, 84-102] ms; P=0.02). Ea decreased in the propofol group only (18.8 [95% CI, 16.5-19.9] cm s−1 and 16.0 [95% CI, 14.9-17.9] cm s−1; P=0.003). From step 2a to step 2b, IVRTc increased further in the propofol group (109 [95% CI, 99-121] ms and 119 [95% CI, 99-135] ms; P=0.04) but remained stable in the other two groups. Ea did not change from step 2a to step 2b. Conclusions. Halothane and sevoflurane did not impair LV relaxation, whereas propofol caused a mild impairment. However, the impairment by propofol was of a magnitude that is unlikely to cause clinical diastolic dysfunctio

Sialylated N-glycans mediate monocyte uptake of extracellular vesicles secreted from Plasmodium falciparum-infected red blood cells

Glycoconjugates on extracellular vesicles (EVs) play a vital role in internalization and mediate interaction as well as regulation of the host immune system by viruses, bacteria, and parasites. During their intraerythrocytic life-cycle stages, malaria parasites, Plasmodium falciparum (Pf) mediate the secretion of EVs by infected red blood cells (RBCs) that carry a diverse range of parasitic and host-derived molecules. These molecules facilitate parasite-parasite and parasite-host interactions to ensure parasite survival. To date, the number of identified Pf genes associated with glycan synthesis and the repertoire of expressed glycoconjugates is relatively low. Moreover, the role of Pf glycans in pathogenesis is mostly unclear and poorly understood. As a result, the expression of glycoconjugates on Pf-derived EVs or their involvement in the parasite life-cycle has yet to be reported. Herein, we show that EVs secreted by Pf-infected RBCs carry significantly higher sialylated complex N-glycans than EVs derived from healthy RBCs. Furthermore, we reveal that EV uptake by host monocytes depends on N-glycoproteins and demonstrate that terminal sialic acid on the N-glycans is essential for uptake by human monocytes. Our results provide the first evidence that Pf exploits host sialylated N-glycans to mediate EV uptake by the human immune system cells

Human Mesenchymal Stem Cells Protect Human Islets from Pro-Inflammatory Cytokines

Transplantation of human islets is an attractive alternative to daily insulin injections for patients with type 1 diabetes. However, the majority of islet recipients lose graft function within five years. Inflammation is a primary contributor to graft loss, and inhibiting pro-inflammatory cytokine activity can reverse inflammation mediated dysfunction of islet grafts. As mesenchymal stem cells (MSCs) possess numerous immunoregulatory properties, we hypothesized that MSCs could protect human islets from pro-inflammatory cytokines. Five hundred human islets were co-cultured with 0.5 or 1.0×106 human MSCs derived from bone marrow or pancreas for 24 hours followed by 48 hour exposure to interferon-γ, tumor necrosis factor-α and interleukin 1β. Controls include islets cultured alone (± cytokines) and with human dermal fibroblasts (± cytokines). For all conditions, glucose stimulated insulin secretion (GSIS), total islet cellular insulin content, islet β cell apoptosis, and potential cytoprotective factors secreted in the culture media were determined. Cytokine exposure disrupted human islet GSIS based on stimulation index and percentage insulin secretion. Conversely, culture with 1.0×106 bMSCs preserved GSIS from cytokine treated islets. Protective effects were not observed with fibroblasts, indicating that preservation of human islet GSIS after exposure to pro-inflammatory cytokines is MSC dependent. Islet β cell apoptosis was observed in the presence of cytokines; however, culture of bMSCs with islets prevented β cell apoptosis after cytokine treatment. Hepatocyte growth factor (HGF) as well as matrix metalloproteinases 2 and 9 were also identified as putative secreted cytoprotective factors; however, other secreted factors likely play a role in protection. This study, therefore, demonstrates that MSCs may be beneficial for islet engraftment by promoting cell survival and reduced inflammation

Epithelial-Mesenchymal Transition in Cells Expanded In Vitro from Lineage-Traced Adult Human Pancreatic Beta Cells

BACKGROUND: In-vitro expansion of functional beta cells from adult human islets is an attractive approach for generating an abundant source of cells for beta-cell replacement therapy of diabetes. Using genetic cell-lineage tracing we have recently shown that beta cells cultured from adult human islets undergo rapid dedifferentiation and proliferate for up to 16 population doublings. These cells have raised interest as potential candidates for redifferentiation into functional insulin-producing cells. Previous work has associated dedifferentiation of cultured epithelial cells with epithelial-mesenchymal transition (EMT), and suggested that EMT generates cells with stem cell properties. Here we investigated the occurrence of EMT in these cultures and assessed their stem cell potential. METHODOLOGY/PRINCIPAL FINDINGS: Using cell-lineage tracing we provide direct evidence for occurrence of EMT in cells originating from beta cells in cultures of adult human islet cells. These cells express multiple mesenchymal markers, as well as markers associated with mesenchymal stem cells (MSC). However, we do not find evidence for the ability of such cells, nor of cells in these cultures derived from a non-beta-cell origin, to significantly differentiate into mesodermal cell types. CONCLUSIONS/SIGNIFICANCE: These findings constitute the first demonstration based on genetic lineage-tracing of EMT in cultured adult primary human cells, and show that EMT does not induce multipotency in cells derived from human beta cells

Imaging early endothelial inflammation following stroke by core shell silica superparamagnetic glyconanoparticles that target selectin

Activation of the endothelium is a pivotal first step for leukocyte migration into the diseased brain. Consequently, imaging this activation process is highly desirable. We synthesized carbohydrate-functionalized magnetic nanoparticles that bind specifically to the endothelial transmembrane inflammatory proteins E and P selectin. Magnetic resonance imaging revealed that the targeted nanoparticles accumulated in the brain vasculature following acute administration into a clinically relevant animal model of stroke, though increases in selectin expression were observed in both brain hemispheres. Nonfunctionalized naked particles also appear to be a plausible agent to target the ischemic vasculature. The importance of these findings is discussed regarding the potential for translation into the clinic

Consensus Recommendations for Clinical Outcome Assessments and Registry Development in Ataxias: Ataxia Global Initiative (AGI) Working Group Expert Guidance

To accelerate and facilitate clinical trials, the Ataxia Global Initiative (AGI) was established as a worldwide research platform for trial readiness in ataxias. One of AGI’s major goals is the harmonization and standardization of outcome assessments. Clinical outcome assessments (COAs) that describe or reflect how a patient feels or functions are indispensable for clinical trials, but similarly important for observational studies and in routine patient care. The AGI working group on COAs has defined a set of data including a graded catalog of COAs that are recommended as a standard for future assessment and sharing of clinical data and joint clinical studies. Two datasets were defined: a mandatory dataset (minimal dataset) that can ideally be obtained during a routine clinical consultation and a more demanding extended dataset that is useful for research purposes. In the future, the currently most widely used clinician-reported outcome measure (ClinRO) in ataxia, the scale for the assessment and rating of ataxia (SARA), should be developed into a generally accepted instrument that can be used in upcoming clinical trials. Furthermore, there is an urgent need (i) to obtain more data on ataxia-specific, patient-reported outcome measures (PROs), (ii) to demonstrate and optimize sensitivity to change of many COAs, and (iii) to establish methods and evidence of anchoring change in COAs in patient meaningfulness, e.g., by determining patient-derived minimally meaningful thresholds of change