Clusterin overexpression in mice exacerbates diabetic phenotypes but suppresses tumor progression in a mouse melanoma model

Clusterin (CLU) is an ATP-independent small heat shock protein-like chaperone, which functions both intra- and extra-cellularly. Consequently, it has been functionally involved in several physiological (including aging), as well as in pathological conditions and most age-related diseases, e.g., cancer, neurodegeneration, and metabolic syndrome. To address CLU function at an in vivo model we established CLU transgenic (Tg) mice bearing ubiquitous or pancreas-targeted CLU overexpression (OE). Our downstream analyses in established Tg lines showed that ubiquitous or pancreas-targeted CLU OE in mice affected antioxidant, proteostatic and metabolic pathways. Targeted OE of CLU in the pancreas, which also resulted in CLU upregulation in the liver likely via systemic effects, increased basal glucose levels in the circulation and exacerbated diabetic phenotypes. Furthermore, by establishing a syngeneic melanoma mouse tumor model we found that ubiquitous CLU OE suppressed melanoma cells growth, indicating a likely tumor suppressor function in early phases of tumorigenesis. Our observations provide in vivo evidence corroborating the notion that CLU is a potential modulator of metabolic and/or proteostatic pathways playing an important role in diabetes and tumorigenesis

IFN-β differentially regulates the function of T cell subsets in MS and EAE

Multiple sclerosis (MS) is considered as a T cell mediated autoimmune disease of the CNS, although a pathogenic role has also been attributed to other immune cell types as well as to environmental and genetic factors. Considering that T cells are interesting from an immunopathogenic point of view and consequently from a therapeutic perspective, various T cell targeted therapies have been approved for MS. Interferon beta (IFN-β) is widely used as first-line intervention for modulating T cell responses, although its pleiotropic and multifaceted activities influence its effectiveness on the disease development, with mechanisms that are not yet fully understood. Since different T cell populations, including pro-inflammatory and regulatory T cells, might affect the course of MS, the effects of IFN-β become even more complex. This review will summarize recent findings regarding the T cell targeted effect of IFN-β in MS and its animal model EAE, with emphasis on the direct actions of endogenous and exogenous IFN-β on each T cell subpopulation involved in CNS autoimmunity. Delineating how IFN-β exerts its action on different T cell types may eventually contribute to the designing of therapeutic strategies aiming to improve the effectiveness of this drug for MS treatment. © 2016 Elsevier Lt

Circadian disruption of ICU patients: A review of pathways, expression, and interventions

Muurlink, OT ORCiD: 0000-0002-8251-9521Intensive care unit patients typically exhibit pathologic wakefulness, poor quality of daytime sleep, nocturnal sleep fragmentation, and sleep patterns that feature the absence of slow wave sleep and rapid eye movement. This article offers a review of the existing literature examining circadian desynchronization in critically ill patients, highlighting contributing factors identified by scholars, and circadian abnormalities observed in these patients. It discusses potential implications for clinical practice and suggests avenues of future research. Elucidating the role of circadian rhythms in the management of critical illness can guide future chronotherapeutic approaches and optimize patient outcomes

Circadian disruption of ICU patients: A review of pathways, expression, and interventions

Intensive care unit patients typically exhibit pathologic wakefulness, poor quality of daytime sleep, nocturnal sleep fragmentation, and sleep patterns that feature the absence of slow wave sleep and rapid eye movement. This article offers a review of the existing literature examining circadian desynchronization in critically ill patients, highlighting contributing factors identified by scholars, and circadian abnormalities observed in these patients. It discusses potential implications for clinical practice and suggests avenues of future research. Elucidating the role of circadian rhythms in the management of critical illness can guide future chronotherapeutic approaches and optimize patient outcomes. © 2016 Elsevier Inc

Light affects heart rate's 24-h rhythmicity in intensive care unit patients: an observational study

Background: Intensive care unit (ICU) patients experience two affronts to normal 24-h rhythms: largely internal events such as medication and external factors such as light, noise and nursing interventions. Aims and objectives: We investigated the impact of light variance within an ICU on 24-h rhythmicity of three key physiological parameters: heart rate (HR), mean arterial blood pressure (MAP) and body temperature (BT) in this patient population. Design: Patients were assigned to beds either in the ‘light’ or ‘dark’ side within a single ICU. An actigraph continuously recorded light intensity for a 24–72-h period. Methods: Measurements of HR, MAP and BT were recorded every 30 min. Results: HR, MAP and BT did not follow 24-h rhythmicity in all patients. Higher light exposure in the Light Side of the ICU (122·3 versus 50·6 lx) was related to higher HR (89·4 versus 79·8 bpm), which may translate to clinically relevant outcomes in a larger sample. Duration of stay, the one clinical outcome measured in this study, showed no significant variation between the groups (p = 0·147). Conclusions: ICU patients are exposed to varying light intensities depending on bed positioning relative to natural sunlight, affecting the 24-h rhythm of HR. Larger, well-controlled studies also investigating the effect of relevant light intensity are indicated. Relevance to clinical practice: Light is a variable that can be manipulated in the constrained environment of an ICU, thus offering an avenue for relatively unobtrusive interventions. © 2019 British Association of Critical Care Nurse

Adrenergic Effect on Cytokine Release After Ex Vivo Healthy Volunteers’ Whole Blood LPS Stimulation

Catecholamines are molecules with immunomodulatory properties in health and disease. Several studies showed the effect of catecholamines when administered to restore hemodynamic stability in septic patients. This study investigates the effect of norepinephrine and dobutamine on whole blood cytokine release after ex vivo lipopolysaccharide (LPS) stimulation. Whole blood collected from healthy individuals was stimulated with LPS, in the presence of norepinephrine or dobutamine at different concentrations, with or without metoprolol, a β1 receptor antagonist. Cytokine measurement was performed in isolated cell culture supernatants with ELISA. Results are expressed as mean ± SEM and compared with Mann-Whitney rank-sum test. Both norepinephrine and dobutamine significantly reduced TNF-α and IL-6 production after ex vivo LPS stimulation of whole blood in a dose-dependent manner, and this effect was partially reversed by the presence of metoprolol. Norepinephrine and dobutamine reduce the LPS-induced production of pro-inflammatory cytokines, thus possibly contributing to altered balance between the inflammatory and anti-inflammatory responses, which are vital for a successful host response to severe disease, shock, and sepsis. © 2016, Springer Science+Business Media New York

Circadian disruption of ICU patients: A review of pathways, expression, and interventions

Intensive care unit patients typically exhibit pathologic wakefulness, poor quality of daytime sleep, nocturnal sleep fragmentation, and sleep patterns that feature the absence of slow wave sleep and rapid eye movement. This article offers a review of the existing literature examining circadian desynchronization in critically ill patients, highlighting contributing factors identified by scholars, and circadian abnormalities observed in these patients. It discusses potential implications for clinical practice and suggests avenues of future research. Elucidating the role of circadian rhythms in the management of critical illness can guide future chronotherapeutic approaches and optimize patient outcomes

Light affects heart rate's 24-h rhythmicity in intensive care unit patients: An observational study

Background: Intensive care unit (ICU) patients experience two affronts to normal 24-h rhythms: largely internal events such as medication and external factors such as light, noise and nursing interventions. Aims and objectives: We investigated the impact of light variance within an ICU on 24-h rhythmicity of three key physiological parameters: heart rate (HR), mean arterial blood pressure (MAP) and body temperature (BT) in this patient population. Design: Patients were assigned to beds either in the ‘light’ or ‘dark’ side within a single ICU. An actigraph continuously recorded light intensity for a 24–72-h period. Methods: Measurements of HR, MAP and BT were recorded every 30 min. Results: HR, MAP and BT did not follow 24-h rhythmicity in all patients. Higher light exposure in the Light Side of the ICU (122·3 versus 50·6 lx) was related to higher HR (89·4 versus 79·8 bpm), which may translate to clinically relevant outcomes in a larger sample. Duration of stay, the one clinical outcome measured in this study, showed no significant variation between the groups (p = 0·147). Conclusions: ICU patients are exposed to varying light intensities depending on bed positioning relative to natural sunlight, affecting the 24-h rhythm of HR. Larger, well-controlled studies also investigating the effect of relevant light intensity are indicated. Relevance to clinical practice: Light is a variable that can be manipulated in the constrained environment of an ICU, thus offering an avenue for relatively unobtrusive interventions. © 2019 British Association of Critical Care Nurse