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Berlin Brandenburg

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  • 1
    In: Pediatric Research, 1998, Vol.44(6), p.946
    Description: Obstruction of narrow vessels by rigid neutrophils may contribute to ischemic organ injury. In septicemia, a substantial portion of the neutrophils may become activated and the number of circulating immature neutrophils may rise sharply. Volume and deformability of mature (PMN) and immature neutrophils in healthy preterm and full-term infants and in septicemic neonates were studied by means of a micropipette system. Membrane cytoplasm tongues were aspirated into 2.5-microm (diameter) pipettes over a period of 60 s. Volume and tongue growth of mature resting PMN were similar in healthy preterm and full-term neonates and adults. Compared with mature PMN (about 360 fl), the volumes of band cells (415 fl), metamyelocytes (470 fl), and less mature cells (myeloblasts, promyelocytes, and myelocytes; 490 fl) were significantly increased (p 〈 0.005). Final tongue lengths of band cells, metamyelocytes, and less mature cells were decreased by about 50, 60, and 70%, respectively, when compared with passive mature cells. In septic neonates, the percentage of immature neutrophils was increased, but the deformability and volume of the cell subpopulations were not affected by septicemia. Active PMN were characterized by pseudopod formation. More active PMN were found in group B streptococcal (14% of total PMN), gram-negative (12%), and Staphylococcus epidermidis septicemia (8%) than in healthy neonates and adults (4%). The main bodies of active PMN were less deformable than passive PMN, and the pseudopods showed very little membrane deformation. The increased number of rigid active and immature neutrophils may contribute to impaired microcirculation and the high risk for organ injury in septic patients.
    Keywords: Hemorheology ; Infant, Newborn -- Blood ; Neutrophils -- Physiology ; Sepsis -- Blood;
    ISSN: 0031-3998
    E-ISSN: 15300447
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  • 2
    In: Circulation, 2015, Vol.132(2), pp.82-92
    Description: BACKGROUND—: Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanism-based approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K2P3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K channel–related acid-sensitive K channel-1]) 2-pore-domain K (K2P) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. METHODS AND RESULTS—: Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage- and current-clamp techniques. K2P3.1 subunits exhibited predominantly atrial expression, and atrial K2P3.1 transcript levels were highest among functional K2P channels. K2P3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD90) compared with patients in sinus rhythm. In contrast, K2P3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K2P3.1 inhibition prolonged APD90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. CONCLUSIONS—: Enhancement of atrium-selective K2P3.1 currents contributes to APD shortening in patients with chronic AF, and K2P3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K2P3.1 as a novel drug target for mechanism-based AF therapy.
    Keywords: Medicine ; Anatomy & Physiology;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 3
    In: Circulation, 2016, Vol.133(11), pp.e440-e441
    Description: We thank Dr Olschewski and colleagues for their interest in our article,1 and we appreciate their recapitulation of 2 key findings of our work: (1) the identification of increased atrial K2P3.1 (TASK-1) K+ channel expression, I K2P3.1 upregulation, and action potential shortening as substrate in patients with chronic atrial fibrillation (AF); and (2) the presentation of K2P3.1 current inhibition and resulting action potential prolongation as mechanism-based therapeutic paradigm in this subentity of the arrhythmia. Our study focused on the mechanistic contribution of K2P3.1 channels to human atrial electrophysiology and action potential regulation, with particular emphasis on pathophysiological dysregulation in AF. Based on mechanistic data presented in the study, functional correction of atrial ionic remodeling through the suppression of atrial K2P3.1 current emerged as a novel antiarrhythmic option for AF management. We agree with Olschewski et al that efficacy and safety require in-depth preclinical evaluation before transfer of novel therapeutic principles into human application. In their letter, the authors highlight their findings of K2P3.1 expression and functional …
    Keywords: Medicine ; Anatomy & Physiology;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 4
    In: Stroke, 2019, Vol.50(2), pp.349-356
    Description: BACKGROUND AND PURPOSE—: Several risk factors are known to increase mid- and long-term mortality of ischemic stroke patients. Information on predictors of early stroke mortality is scarce but often requested in clinical practice. We therefore aimed to develop a rapidly applicable tool for predicting early mortality at the stroke unit. METHODS—: We used data from the nationwide Austrian Stroke Unit Registry and multivariate regularized logistic regression analysis to identify demographic and clinical variables associated with early (≤7 days poststroke) mortality of patients admitted with ischemic stroke. These variables were then used to develop the Predicting Early Mortality of Ischemic Stroke score that was validated both by bootstrapping and temporal validation. RESULTS—: In total, 77 653 ischemic stroke patients were included in the analysis (median age: 74 years, 47% women). The mortality rate at the stroke unit was 2% and median stay of deceased patients was 3 days. Age, stroke severity measured by the National Institutes of Health Stroke Scale, prestroke functional disability (modified Rankin Scale 〉0), preexisting heart disease, diabetes mellitus, posterior circulation stroke syndrome, and nonlacunar stroke cause were associated with mortality and served to build the Predicting Early Mortality of Ischemic Stroke score ranging from 0 to 12 points. The area under the curve of the score was 0.879 (95% CI, 0.871–0.886) in the derivation cohort and 0.884 (95% CI, 0.863–0.905) in the validation sample. Patients with a score ≥10 had a 35% (95% CI, 28%–43%) risk to die within the first days at the stroke unit. CONCLUSIONS—: We developed a simple score to estimate early mortality of ischemic stroke patients treated at a stroke unit. This score could help clinicians in short-term prognostication for management decisions and counseling.
    Keywords: Stroke -- Prognosis ; Stroke -- Patient Outcomes;
    ISSN: 0039-2499
    E-ISSN: 15244628
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  • 5
    In: Circulation Research, 2009, Vol.104(5), pp.600-608
    Description: Although maternal–fetal cholesterol transfer may serve to compensate for insufficient fetal cholesterol biosynthesis under pathological conditions, it may have detrimental consequences under conditions of maternal hypercholesterolemia leading to preatherosclerotic lesion development in fetal aortas. Maternal cholesterol may enter fetal circulation by traversing syncytiotrophoblast and endothelial layers of the placenta. We hypothesized that endothelial cells (ECs) of the fetoplacental vasculature display a high and tightly regulated capacity for cholesterol release. Using ECs isolated from human term placenta (HPECs), we investigated cholesterol release capacity and examined transporters involved in cholesterol efflux pathways controlled by liver-X-receptors (LXRs). HPECs demonstrated 2.5-fold higher cholesterol release to lipid-free apolipoprotein (apo)A-I than human umbilical vein ECs (HUVECs), whereas both cell types showed similar cholesterol efflux to high-density lipoproteins (HDLs). Interestingly, treatment of HPECs with LXR activators increased cholesterol efflux to both types of acceptors, whereas no such response could be observed for HUVECs. In line with enhanced cholesterol efflux, LXR activation in HPECs increased expression of ATP-binding cassette transporters ABCA1 and ABCG1, while not altering expression of ABCG4 and scavenger receptor class B type I (SR-BI). Inhibition of ABCA1 or silencing of ABCG1 decreased cholesterol efflux to apoA-I (−70%) and HDL3 (−57%), respectively. Immunohistochemistry localized both transporters predominantly to the apical membranes of placental ECs in situ. Thus, ECs of human term placenta exhibit unique, efficient and LXR-regulated cholesterol efflux mechanisms. We propose a sequential pathway mediated by ABCA1 and ABCG1, respectively, by which HPECs participate in forming mature HDL in the fetal blood.
    Keywords: Maternal-Fetal Exchange ; ATP-Binding Cassette Transporters -- Metabolism ; Cholesterol -- Metabolism ; Endothelial Cells -- Metabolism ; Placenta -- Blood Supply;
    ISSN: 0009-7330
    E-ISSN: 15244571
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  • 6
    In: Pediatric Research, 1997, Vol.41(S4), p.9
    ISSN: 0031-3998
    E-ISSN: 15300447
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