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  • 1
    ISSN: 1432-1238
    Keywords: Key words Lateral posture ; Hemodynamic effects ; Kinetic therapy ; Respiratory failure ; Right ventricular function ; Atrial natriuretic peptide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective: To quantify the hemodynamic effects of turning critically ill, mechanically ventilated patients to the extreme left and right lateral postures. Design: Prospective investigation. Setting: Eight-bed intensive care unit in a university hospital. Patients: Twelve consecutive patients presenting with severe respiratory failure and requiring continuous positive inotropic support. Interventions: All patients were mechanically ventilated and placed in a kinetic treatment system. They were positioned in the supine, left dependent, and right dependent postures, resting for 15 min in each position. Measurements and results: Hemodynamic measurements, assessments of right ventricular function, and determinations of intrathoracic blood volume were performed in three different positions. Concentrations of atrial natriuretic peptide in plasma were quantified. In three patients, the findings were controlled by transesophageal echocardiography. Cardiac index [median (range) 5.5 (3.2–8.1) vs 4.3 (3.2–7.5) l/min per m2, p〈0.01], intrathoracic blood volume [1125 (820–1394) vs 1037 (821–1267) ml/m2, p〈0.01], and right ventricular end-diastolic volume [130 (83–159) vs 114 (79–155) ml/m2, p〈0.05] increased significantly in the left dependent position compared to supine. Mean arterial pressure did not change. Atrial natriuretic peptide levels rose from 140 to 203 pg/ml. In the right dependent position, we found a marked decrease in the mean arterial pressure [85 mmHg (supine) to 72 mmHg (right dependent), p〈0.01]. Cardiac index and intrathoracic blood volume were unchanged, but right ventricular end-diastolic volume decreased from 114 to 102 ml/m2 (p〈0.05) Additionally, atrial natriuretic peptide levels decreased significantly (median Δ value: 37 pg/ml). In echocardiographic controls we found an increase in right ventricular end-diastolic diameters in the left dependent position and shortened diameters in the right dependent position. Conclusions: Extreme lateral posture affects the cardiovascular system in critically ill, mechanically ventilated patients: in the left dependent position a ”hyperdynamic state“ is reinforced, while the right decubitus position impairs right ventricular preload and predisposes to hypotension. Echocardiography and changes in plasma atrial natriuretic peptide values indicate that these findings are due to altered distensibility of the right ventricle caused by regional intrathoracic gravitational changes. We conclude that the duration and the angle of lateral posture should be restricted in hemodynamically unstable patients.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-1238
    Keywords: Lateral posture ; Hemodynamic effects ; Kinetic therapy ; Respiratory failure ; Kight ventricular function ; Atrial natriuretic peptide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective To quantify the hemodynamic effects of turning critically ill, mechanically ventilated patients to the extreme left and right lateral postures. Design Prospective investigation. Setting Eight-bed intensive care unit in a university hospital. Patients Twelve consecutive patients presenting with severe respiratory failure and requiring continuous positive inotropic support. Interventions All patients were mechanically ventilated and placed in a kinetic treatment system. They were positioned in the supine, left dependent, and right dependent postures, resting for 15 min in each position. Measurements and results Hemodynamic measurements, assessments of right ventricular function, and determinations of intrathoracic blood volume were performed in three different positions. Concentrations of atrial natriuretic peptide in plasma were quantified. In three patients, the findings were controlled by transesophageal echocardiography. Cardiac index [median (range) 5.5 (3.2–8.1) vs 4.3 (3.2–7.5) l/min per m2,p〈0.01], intrathoracic blood volume [1125 (820–1394) vs 1037 (821–1267) ml/m2,p〈0.01], and right ventricular end-diastolic volume [130 (83–159) vs 114 (79–155) ml/m2,p〈0.05] increased significantly in the left dependent position compared to supine. Mean arterial pressure did not change. Atrial natriuretic peptide levels rose from 140 to 203 pg/ml. In the right dependent position, we found a marked decrease in the mean arterial pressure [85 mmHg (supine) to 72 mmHg (right dependent),p〈0.01]. Cardiac index and intrathoracic blood volume were unchanged, but right ventricular enddiastolic volume decreased from 114 to 102 ml/m2 (p〈0.05) Additionally, atrial natriuretic peptide levels decreased significantly (median Δ value: 37 pg/ml). In echocardiographic controls we found an increase in right ventricular end-diastolic diameters in the left dependent position and shortened diameters in the right dependent position. Conclusions Extreme lateral posture affects the cardiovascular system in critically ill, mechanically ventilated patients: in the left dependent position a “hyperdynamic state” is reinforced, while the right decubitus position impairs right ventricular preload and predisposes to hypotension. Echocardiography and changes in plasma atrial natriuretic peptide values indicate that these findings are due to altered distensibility of the right ventricle caused by regional intrathoracic gravitational changes. We conclude that the duration and the angle of lateral posture should be restricted in hemodynamically unstable patients.
    Type of Medium: Electronic Resource
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  • 3
    Publication Date: 2017-07-21
    Description: Activated B-cell-like (ABC) and germinal center B-cell-like diffuse large B-cell lymphoma (DLBCL) represent the 2 major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these 2 subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) α/ (PI3Kα/) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor B signaling, prompting us to combine AZD8835 with the Bruton’s tyrosine kinase inhibitor ibrutinib. This combination was synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively, our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.
    Keywords: Lymphoid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 4
    Publication Date: 2013-09-27
    Description: Constitutive activation of the nuclear factor- B (NF-B) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-B regulators that cause constitutive activity of this oncogenic pathway have been identified. However, it remains unclear how specific target genes are regulated. We identified the atypical nuclear IB protein IB- to be upregulated in ABC compared with germinal center B-cell–like (GCB) DLBCL primary patient samples. Knockdown of IB- by RNA interference was toxic to ABC but not to GCB DLBCL cell lines. Gene expression profiling after IB- knockdown demonstrated a significant downregulation of a large number of known NF-B target genes, indicating an essential role of IB- in regulating a specific set of NF-B target genes. To further investigate how IB- mediates NF-B activity, we performed immunoprecipitations and detected a physical interaction of IB- with both p50 and p52 NF-B subunits, indicating that IB- interacts with components of both the canonical and the noncanonical NF-B pathway in ABC DLBCL. Collectively, our data demonstrate that IB- is essential for nuclear NF-B activity in ABC DLBCL, and thus might represent a promising molecular target for future therapies.
    Keywords: Lymphoid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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