Globus Lucidus: A porcine study of an intracranial implant designed to deliver closed, repetitive photodynamic and photochemical therapy in glioblastoma.

Objective: Herein we describe initial results in a porcine model of a fully implantable device designed to allow closed, repetitive photodynamic treatment of glioblastoma (GBM).

Methods: This implant, Globus Lucidus, is a transparent quartz glass sphere with light-emitting diodes releasing wavelengths of 630 nm (19.5 mW/cm), 405 nm (5.

The effect of targeted hyperoxemia in a randomized controlled trial employing a long-term resuscitated, model of combined acute subdural hematoma and hemorrhagic shock in swine with coronary artery disease: An exploratory, hypothesis-generating study.

Controversial evidence is available regarding suitable targets for the arterial O tension (PO) after traumatic brain injury and/or hemorrhagic shock (HS). We previously demonstrated that hyperoxia during resuscitation from hemorrhagic shock attenuated cardiac injury and renal dysfunction in swine with coronary artery disease. Therefore, this study investigated the impact of targeted hyperoxemia in a long-term, resuscitated model of combined acute subdural hematoma (ASDH)-induced brain injury and HS.

Brain Histology and Immunohistochemistry After Resuscitation From Hemorrhagic Shock in Swine With Pre-Existing Atherosclerosis and Sodium Thiosulfate (NaSO) Treatment.

Background: The hydrogen sulfide (HS) and the oxytocin/oxytocin receptor (OT/OTR) systems interact in the central nervous and cardiovascular system. As a consequence of osmotic balance stress, HS stimulates OT release from the paraventricular nuclei (PVN) in the hypothalamic regulation of blood volume and pressure. Hemorrhagic shock (HS) represents one of the most pronounced acute changes in blood volume, which, moreover, may cause at least transient brain tissue hypoxia.

Effects of Sodium Thiosulfate During Resuscitation From Trauma-and-Hemorrhage in Cystathionine-γ-Lyase Knockout Mice With Diabetes Type 1.

Background: Sodium thiosulfate (STS) is a recognized drug with antioxidant and HS releasing properties. We recently showed that STS attenuated organ dysfunction and injury during resuscitation from trauma-and-hemorrhage in CSE-ko mice, confirming its previously described organ-protective and anti-inflammatory properties. The role of HS in diabetes mellitus type 1 (DMT1) is controversial: genetic DMT1 impairs HS biosynthesis, which has been referred to contribute to endothelial dysfunction and cardiomyopathy.

HS in Critical Illness-A New Horizon for Sodium Thiosulfate?

Ever since the discovery of endogenous HS and the identification of its cytoprotective properties, efforts have been made to develop strategies to use HS as a therapeutic agent. The ability of HS to regulate vascular tone, inflammation, oxidative stress, and apoptosis might be particularly useful in the therapeutic management of critical illness. However, neither the inhalation of gaseous HS, nor the administration of inorganic HS-releasing salts or slow-releasing HS-donors are feasible for clinical use.

Human Placental Tissue Contains A Placental Lactogen-Derived Vasoinhibin.

Hormonal factors affecting the vascular adaptions of the uteroplacental unit in noncomplicated and complicated pregnancies are of interest. Here, 4 human placentas from women with and without preeclampsia (PE) were investigated for the presence of placental lactogen (PL)-derived, antiangiogenic vasoinhibin. Western blotting and mass spectrometry of placental tissue revealed the presence of a 9-kDa PL-derived vasoinhibin, the normal 22-kDa full-length PL, and a 28-kDa immunoreactive protein of undetermined nature.

Biological Connection of Psychological Stress and Polytrauma under Intensive Care: The Role of Oxytocin and Hydrogen Sulfide.

This paper explored the potential mediating role of hydrogen sulfide (HS) and the oxytocin (OT) systems in hemorrhagic shock (HS) and/or traumatic brain injury (TBI). Morbidity and mortality after trauma mainly depend on the presence of HS and/or TBI. Rapid "repayment of the O debt" and prevention of brain tissue hypoxia are cornerstones of the management of both HS and TBI.

HS and Oxytocin Systems in Early Life Stress and Cardiovascular Disease.

Today it is well established that early life stress leads to cardiovascular programming that manifests in cardiovascular disease, but the mechanisms by which this occurs, are not fully understood. This perspective review examines the relevant literature that implicates the dysregulation of the gasomediator hydrogen sulfide and the neuroendocrine oxytocin systems in heart disease and their putative mechanistic role in the early life stress developmental origins of cardiovascular disease. Furthermore, interesting hints towards the mutual interaction of the hydrogen sulfide and OT systems are identified, especially with regards to the connection between the central nervous and the cardiovascular system, which support the role of the vagus nerve as a communication link between the brain and the heart in stress-mediated cardiovascular disease.

Effects of Sodium Thiosulfate During Resuscitation From Trauma-and-Hemorrhage in Cystathionine Gamma Lyase (CSE) Knockout Mice.

Background: Sodium thiosulfate (Na2S2O3) is a clinically established drug with antioxidant and sulphide-releasing properties. Na2S2O3 mediated neuro- and cardioprotective effects in ischemia/reperfusion models and anti-inflammatory effects in LPS-induced acute lung injury. Moreover, Na2S2O3 improved lung function during resuscitation from hemorrhagic shock in swine with pre-existing atherosclerosis, characterized by decreased expression of cystathionine γ-lyase (CSE), a major source of hydrogen sulfide (H2S) synthesis in the vasculature.

Mouse Intensive Care Unit (MICU).

The translation of preclinical results into successful clinical therapies remains a challenge in sepsis research. One reason for this lack of translation might be the discrepancy between preclinical models and the clinical reality: nonresuscitated young healthy rodents in contrast to elderly comorbid patients in an intensive care unit. We introduce the mouse intensive care unit (MICU) as a concept to address the lack of resuscitation in preclinical studies as one of the limiting issues in translational research.

Localization of the hydrogen sulfide and oxytocin systems at the depth of the sulci in a porcine model of acute subdural hematoma.

In the porcine model discussed in this review, the acute subdural hematoma was induced by subdural injection of autologous blood over the left parietal cortex, which led to a transient elevation of the intracerebral pressure, measured by bilateral neuromonitoring. The hematoma-induced brain injury was associated with albumin extravasation, oxidative stress, reactive astrogliosis and microglial activation in the ipsilateral hemisphere. Further proteins and injury markers were validated to be used for immunohistochemistry of porcine brain tissue.

ΔMST and the Regulation of Cardiac CSE and OTR Expression in Trauma and Hemorrhage.

Genetic deletion of 3-mercaptopyruvate sulfurtransferase (MST) is known to result in hypertension and cardiac hypertrophy in older mice, and is associated with increased anxiety-like behaviors. Endogenous hydrogen sulfide (HS) produced by MST in the mitochondria is also known to be involved in physiological and cellular bioenergetics, and its dysfunction associated with depressive behavior and increased cardiovascular morbidity. Interestingly, early life stress has been shown to lead to a significant loss of cystathionine-γ-lyase (CSE) and oxytocin receptor (OTR) expression in the heart.

HS in acute lung injury: a therapeutic dead end(?).

This review addresses the plausibility of hydrogen sulfide (HS) therapy for acute lung injury (ALI) and circulatory shock, by contrasting the promising preclinical results to the present clinical reality. The review discusses how the narrow therapeutic window and width, and potentially toxic effects, the route, dosing, and timing of administration all have to be balanced out very carefully. The development of standardized methods to determine in vitro and in vivo HS concentrations, and the pharmacokinetics and pharmacodynamics of HS-releasing compounds is a necessity to facilitate the safety of HS-based therapies.

Impact of downstream effects of glucocorticoid receptor dysfunction on organ function in critical illness-associated systemic inflammation.

Glucocorticoids (GCs) are stress hormones that regulate developmental and physiological processes and are among the most potent anti-inflammatory drugs to suppress chronic and acute inflammation. GCs act through the glucocorticoid receptor (GR), a ubiquitously expressed ligand-activated transcription factor, which translocates into the nucleus and can act via two different modes, as a GR monomer or as a GR dimer. These two modes of action are not clearly differentiated in practice and may lead to completely different therapeutic outcomes.

Microcirculation vs. Mitochondria-What to Target?

Circulatory shock is associated with marked disturbances of the macro- and microcirculation and flow heterogeneities. Furthermore, a lack of tissue adenosine trisphosphate (ATP) and mitochondrial dysfunction are directly associated with organ failure and poor patient outcome. While it remains unclear if microcirculation-targeted resuscitation strategies can even abolish shock-induced flow heterogeneity, mitochondrial dysfunction and subsequently diminished ATP production could still lead to organ dysfunction and failure even if microcirculatory function is restored or maintained.

The Interaction of the Endogenous Hydrogen Sulfide and Oxytocin Systems in Fluid Regulation and the Cardiovascular System.

The purpose of this review is to explore the parallel roles and interaction of hydrogen sulfide (HS) and oxytocin (OT) in cardiovascular regulation and fluid homeostasis. Their interaction has been recently reported to be relevant during physical and psychological trauma. However, literature reports on HS in physical trauma and OT in psychological trauma are abundant, whereas available information regarding HS in psychological trauma and OT in physical trauma is much more limited.

Cerebral Immunohistochemical Characterization of the HS and the Oxytocin Systems in a Porcine Model of Acute Subdural Hematoma.

The hydrogen sulfide (HS) and the oxytocin/oxytocin receptor (OT/OTR) systems interact in trauma and are implicated in vascular protection and regulation of fluid homeostasis. Acute brain injury is associated with pressure-induced edema formation, blood brain barrier disruption, and neuro-inflammation. The similarities in brain anatomy: size, gyrencephalic organization, skull structure, may render the pig a highly relevant model for translational medicine.

The Role of Glucocorticoid Receptor and Oxytocin Receptor in the Septic Heart in a Clinically Relevant, Resuscitated Porcine Model With Underlying Atherosclerosis.

The pathophysiology of sepsis-induced myocardial dysfunction is not resolved to date and comprises inflammation, barrier dysfunction and oxidative stress. Disease-associated reduction of tissue cystathionine-γ-lyase (CSE) expression, an endogenous HS-producing enzyme, is associated with oxidative stress, barrier dysfunction and organ injury. CSE-mediated cardio-protection has been suggested to be related the upregulation of oxytocin receptor (OTR).

Maternal Separation Induces Long-Term Alterations in the Cardiac Oxytocin Receptor and Cystathionine -Lyase Expression in Mice.

We recently showed that blunt chest trauma reduced the expression of the myocardial oxytocin receptor (Oxtr), which was further aggravated by genetic deletion of the HS-producing enzyme cystathionine -lyase (CSE). Exogenous HS supplementation restored myocardial Oxtr expression under these conditions. Early life stress (ELS) is a risk factor for cardiovascular disease by affecting vascular and heart structures.

Impaired Glucocorticoid Receptor Dimerization Aggravates LPS-Induced Circulatory and Pulmonary Dysfunction.

Sepsis, that can be modeled by LPS injections, as an acute systemic inflammation syndrome is the most common cause for acute lung injury (ALI). ALI induces acute respiratory failure leading to hypoxemia, which is often associated with multiple organ failure (MOF). During systemic inflammation, the hypothalamus-pituitary-adrenal axis (HPA) is activated and anti-inflammatory acting glucocorticoids (GCs) are released to overcome the inflammation.

In-depth characterization of a long-term, resuscitated model of acute subdural hematoma-induced brain injury.

Objective: Acute subdural hematoma (ASDH) is a leading entity in brain injury. Rodent models mostly lack standard intensive care, while large animal models frequently are only short term. Therefore, the authors developed a long-term, resuscitated porcine model of ASDH-induced brain injury and report their findings.

Effects of sodium thiosulfate (NaSO) during resuscitation from hemorrhagic shock in swine with preexisting atherosclerosis.

Controversial data are available on hydrogen sulfide (HS) during hemorrhage and resuscitation, depending on timing, dosing, mode of application, and the HS donor used. Sodium thiosulfate (NaSO) is a recognized drug devoid of major side effects, which attenuated murine acute lung injury and cerebral ischemia/reperfusion injury. Therefore, we tested the hypothesis whether NaSO would mitigate organ dysfunction in porcine hemorrhage-and-resuscitation.