Corticosteroids and cellulose purification improve, respectively, the in vivo translation and vaccination efficacy of sa-mRNAs.

Synthetic mRNAs are an appealing platform with multiple biomedical applications ranging from protein replacement therapy to vaccination. In comparison with conventional mRNA, synthetic self-amplifying mRNAs (sa-mRNAs) are gaining interest because of their higher and longer-lasting expression. However, sa-mRNAs also elicit an innate immune response, which may complicate their clinical application.

The phosphodiesterase-4 and glycine transporter-1 inhibitors enhance in vivo hippocampal theta network connectivity and synaptic plasticity, whereas D-serine does not.

Dysfunctional N-methyl-D-aspartate receptors (NMDARs) and cyclic adenosine monophosphate (cAMP) have been associated with deficits in synaptic plasticity and cognition found in neurodegenerative and neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. Therapeutic approaches that indirectly enhance NMDAR function through increases in glycine and/or D-serine levels as well as inhibition of phosphodiesterases that reduces degradation of cAMP, are expected to enhance synaptic strength, connectivity and to potentially impact cognition processes. The present in vivo study investigated effects of subcutaneous administration of D-serine, the glycine transporter 1 (GlyT1) inhibitor SSR504734 and the PDE4 inhibitor rolipram, on network oscillations, connectivity and long-term potentiation (LTP) at the hippocampi circuits in Sprague-Dawley rats.

Mononuclear but Not Polymorphonuclear Phagocyte Depletion Increases Circulation Times and Improves Mammary Tumor-Homing Efficiency of Donor Bone Marrow-Derived Monocytes.

Tumor associated macrophages are an essential part of the tumor microenvironment. Consequently, bone marrow-derived monocytes (BMDMs) are continuously recruited to tumors and are therefore seen as ideal delivery vehicles with tumor-targeting properties. By using immune cell depleting agents and macroscopic in vivo fluorescence imaging, we demonstrated that removal of endogenous monocytes and macrophages (but not neutrophils) leads to an increased tumor accumulation of exogenously administered BMDMs.

Expression Kinetics and Innate Immune Response after Electroporation and LNP-Mediated Delivery of a Self-Amplifying mRNA in the Skin.

In this work, we studied the expression kinetics and innate immune response of a self-amplifying mRNA (sa-RNA) after electroporation and lipid-nanoparticle (LNP)-mediated delivery in the skin of mice. Intradermal electroporation of the sa-RNA resulted in a plateau-shaped expression, with the plateau between day 3 and day 10. The overall protein expression of sa-RNA was significantly higher than that obtained after electroporation of plasmid DNA (pDNA) or non-replication mRNAs.

Improving the Repeatability and Efficacy of Intradermal Electroporated Self-Replicating mRNA.

Local administration of naked self-replicating mRNA (sr-mRNA) in the skin or muscle using electroporation is effective but hampered by low repeatability. In this manuscript, we demonstrated that intradermal electroporation of sr-mRNA in combination with a protein-based RNase inhibitor increased the expression efficiency, success rate, and repeatability of the data. The RNase inhibitor should be added just before administration because storage of the inhibitor together with the sr-mRNA at -80°C resulted in a partial loss of the beneficial effect.

Spike-Wave Discharges and Sleep-Wake States during Circadian Desynchronization: No Effects of Agomelatine upon Re-Entrainment.

Rapid changes in the light-dark cycle cause circadian desynchronization between rhythms of spike-wave discharges (SWDs) and motor activity in genetic epileptic rats, and this is accompanied by an increase in epileptic activity. Given the close relationship between absence seizures and sleep-wake states, the present study assessed firstly a putative relationship between vigilance rhythms and SWDs during re-synchronization, and secondly sleep-wake patterns responsible for increased epileptic activity. Lastly, in a view of existing evidence that melatonin and its agonists accelerate re-synchronization, the effects of different doses of agomelatine upon the speed of re-synchronization of different sleep-wake states and SWDs were investigated.

Comparison of the Expression Kinetics and Immunostimulatory Activity of Replicating mRNA, Nonreplicating mRNA, and pDNA after Intradermal Electroporation in Pigs.

Synthetic mRNA is becoming increasingly popular as an alternative to pDNA-based gene therapy. Currently, multiple synthetic mRNA platforms have been developed. In this study we investigated the expression kinetics and the changes in mRNA encoding cytokine and chemokine levels following intradermal electroporation in pigs of pDNA, self-replicating mRNA, and modified and unmodified mRNA.

Cortical high gamma network oscillations and connectivity: a translational index for antipsychotics to normalize aberrant neurophysiological activity.

Oscillatory activity in the gamma frequency range is a critical mechanism, which integrates neural networks within and across brain structures during cognitive processes. In schizophrenia, abnormalities in high gamma oscillations are ubiquitous and most likely reflect dysfunction in neuronal networks. In conscious rats, disturbed network oscillations associated with positive symptoms and cognitive deficits were modeled in different cortical areas by the dopaminergic agonist (amphetamine) and the N-methyl-D-aspartate (NMDA) receptor antagonists (PCP and MK801).

Ketamine: differential neurophysiological dynamics in functional networks in the rat brain.

Recently, the N-methyl-d-aspartate-receptor (NMDAR) antagonist ketamine has emerged as a fast-onset mechanism to achieve antidepressant activity, whereas its psychomimetic, dissociative and amnestic effects have been well documented to pharmacologically model schizophrenia features in rodents. Sleep-wake architecture, neuronal oscillations and network connectivity are key mechanisms supporting brain plasticity and cognition, which are disrupted in mood disorders such as depression and schizophrenia. In rats, we investigated the dynamic effects of acute and chronic subcutaneous administration of ketamine (2.

Evaluation of a xenogeneic vascular endothelial growth factor-2 vaccine in two preclinical metastatic tumor models in mice.

In this study, a xenogeneic DNA vaccine encoding for human vascular endothelial growth factor receptor-2 (hVEGFR-2) was evaluated in two murine tumor models, the B16-F10 melanoma and the EO771 breast carcinoma model. The vaccine was administered by intradermal injection followed by electroporation. The immunogenicity and the biological efficacy of the vaccine were tested in (1) a prophylactic setting, (2) a therapeutic setting, and (3) a therapeutic setting combined with surgical removal of the primary tumor.

[Who may place the first donor heart? Conflict surrounding the first heart transplant in the Netherlands].

On Friday 22 June 1984 a patient was waiting in Rotterdam to be moved to Brussels for a heart transplant. The Dutch heart surgery centres tried to mutually agree on the place where the first heart transplant should be performed. When this proved impossible, the decision was made by the cardiac surgeons from Rotterdam and Leiden.

Off-target potential of AMN082 on sleep EEG and related physiological variables: Evidence from mGluR7 (-/-) mice.

The metabotropic glutamate receptor type 7 (mGluR7), a most abundant presynaptic G protein-coupled receptor in the brain provides an attractive mechanism to fast fine-tune abnormal excitatory neurotransmission and synaptic plasticity associated with emotional and cognitive impairments in neuropsychiatric and neurodegenerative disorders. Preclinical studies using AMN082, the mGluR7 allosteric agonist, produced conflicting results, so that results of further in-vivo studies are needed. Here, we investigated effects of subcutaneous administration at the lights onset of AMN082 on sleep-wake architecture and spectral contents in rats.

Translational neurophysiological markers for activity of the metabotropic glutamate receptor (mGluR2) modulator JNJ-40411813: Sleep EEG correlates in rodents and healthy men.

Alterations in rapid eye movement sleep (REM) have been suggested as valid translational efficacy markers: activation of the metabotropic glutamate receptor 2 (mGluR2) was shown to increase REM latency and to decrease REM duration. The present paper addresses the effects on vigilance states of the mGluR2 positive allosteric modulator (PAM) JNJ-40411813 at different circadian times in rats and after afternoon dosing in humans. Due to its dual mGluR2 PAM/serotonin 2A (5-HT2A) receptor antagonism in rodents, mGlu2R specificity of effects was studied in wild-type (WT) and mGluR2 (-/-) mice.

Cortical EEG oscillations and network connectivity as efficacy indices for assessing drugs with cognition enhancing potential.

Synchronization of electroencephalographic (EEG) oscillations represents a core mechanism for cortical and subcortical networks, and disturbance in neural synchrony underlies cognitive processing deficits in neurological and neuropsychiatric disorders. Here, we investigated the effects of cognition enhancers (donepezil, rivastigmine, tacrine, galantamine and memantine), which are approved for symptomatic treatment of dementia, on EEG oscillations and network connectivity in conscious rats chronically instrumented with epidural electrodes in different cortical areas. Next, EEG network indices of cognitive impairments with the muscarinic receptor antagonist scopolamine were modeled.

Coronary artery bypass grafting: Part 1--the evolution over the first 50 years.

Surgical treatment for angina pectoris was first proposed in 1899. Decades of experimental surgery for coronary artery disease finally led to the introduction of coronary artery bypass grafting (CABG) in 1964. Now that we are approaching 50 years of CABG experience, it is appropriate to summarize the advancement of CABG into a procedure that is safe and efficient.

Contribution of melanin-concentrating hormone (MCH1) receptor to thermoregulation and sleep stabilization: evidence from MCH1 (-/-) mice.

Recent studies have explored the implication of melanin-concentrating hormone (MCH) in the process of vigilance states. The current experiments were carried out in mice lacking the MCH(1) receptor (-/-) and wild-type (WT) littermates, to assess the role of MCH(1) receptor in the regulation of sleep architecture, body temperature (BT) and locomotor activity (LMA) under normal condition and following a 1h restraint stress at lights onset. Under baseline conditions, MCH(1) (-/-) mice exhibited consistent changes in waking and sleeping time across the 24-h recording period.

Increasing the antioxidative capacity of neonatal cardiopulmonary bypass prime solution: an in vitro study.

Inflammation and oxidative damage are believed to play an important role in the postoperative complications after cardiopulmonary bypass (CPB) in neonates. During the preparation of the prime, red blood cells (RBCs) release non-protein-bound iron (NPBI) and free haemoglobin/haem (Hb/haem). The presence of these prooxidants in the prime solution may increase oxidative stress in neonates undergoing CPB.

Structural degeneration of pulmonary homografts used as aortic valve substitute underlines early graft failure.

Objectives: The limited availability of donor valves and experimental evidence that pulmonary valves can withstand systemic pressure made us use cryopreserved pulmonary homografts as aortic valve substitutes. We observed a high incidence of early reoperation because of severe graft insufficiency due to cuspal tears. The mid-term results are evaluated in this study and histological analysis of explanted homografts is performed to investigate the cause of graft failure.

The pathology of fresh and cryopreserved homograft heart valves: an analysis of forty explanted homograft valves.

Objective: Tissue degeneration reduces the durability of aortic and pulmonary homograft heart valves. Homograft valves can evoke cellular and humoral immune responses that might be detrimental to the valve tissue. Analyzing explanted homograft valves helps in understanding the different factors that eventually lead to tissue degeneration.

Hemodynamics of the Freestyle bioprosthesis in young patients.

The objective of this study was to analyze hemodynamics of the Freestyle stentless bioprosthesis in young patients compared with the older age group. The Freestyle aortic bioprosthesis is a stentless aortic xenograft. Hemodynamics are proven to be good in older patients for a long period.

Prime solutions for cardiopulmonary bypass in neonates: antioxidant capacity of prime based on albumin or fresh frozen plasma.

Objective: Oxidative damage and inflammation are believed to play an important role in postoperative complications after cardiopulmonary bypass. During bypass, a prime solution with a high antioxidant capacity may reduce the oxidative damage and inflammation. We investigated total antioxidant capacity and individual scavengers during the preparation of 2 different prime solutions.

Outcome and follow-up of aortic valve replacement with the freestyle stentless bioprosthesis.

Background: The aim of this study was to determine the morbidity, mortality, and hemodynamics after implantation of the Freestyle stentless bioprosthesis in the aortic position.

Methods: A total of 280 patients were operated on from June 1993 to July 1999 as part of a multicenter investigation. Factors influencing hospital mortality and long-term survival were assessed by logistic regression and Cox proportional hazards analysis.

Stentless bioprostheses have ideal haemodynamics, even in the small aortic root.

Objective: To determine normal Doppler and 2D gradients and flow characteristics of the Freestyle stentless aortic bioprosthesis related to valve size.

Background: The Freestyle stentless aortic bioprosthesis is one of the newer aortic xenografts. Only limited data are available of the echocardiographic flow characteristics during a mid-term follow-up period of this valve.

Echocardiographic imaging of stentless aortic valve prostheses.

Unlabelled: Homografts and stentless xenografts are increasingly used in aortic valve surgery. Echocardiography technicians and cardiologists have to know what they will find when performing an echo-Doppler examination in patients who received a stentless valve. We therefore evaluated echocardiographic images of 74 patients who received a Freestyle stentless bioprosthesis with three techniques and a follow-up of 2 years in two high-volume hospitals.