Neurovascular Unit Dysfunction with Blood-Brain Barrier Hyperpermeability Contributes to Major Depressive Disorder: A Review of Clinical and Experimental Evidence

About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer’s disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches

Neuroinflammation and Psychiatric Illness

Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). Investigations into the pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review the link between autoimmunity and neuropsychiatric disorders, and the human and experimental evidence supporting the pathogenic role of neuroinflammation in selected classical psychiatric disorders. Understanding how psychosocial, genetic, immunological and neurotransmitter systems interact can reveal pathogenic clues and help target new preventive and symptomatic therapies

Blood Levels of S-100 Calcium-Binding Protein B, High-Sensitivity C-Reactive Protein, and Interleukin-6 for Changes in Depressive Symptom Severity after Coronary Artery Bypass Grafting: Prospective Cohort Nested within a Randomized, Controlled Trial

Background: Cross-sectional and retrospective studies have associated major depressive disorder with glial activation and injury as well as blood–brain barrier disruption, but these associations have not been assessed prospectively. Here, we aimed to determine the relationship between changes in depressive symptom severity and in blood levels of S-100 calcium- binding protein B (S-100B), high-sensitivity C-reactive protein, and interleukin-6 following an inflammatory challenge. Methods: Fifty unselected participants were recruited from a randomized, controlled trial comparing coronary artery bypass grafting procedures performed with versus without cardiopulmonary bypass for the risk of neurocognitive decline. Depressive symptom severity was measured at baseline, discharge, and six-month follow-up using the Beck Depression Inventory II (BDI-II). The primary outcome of the present biomarker study was acute change in depressive symptom severity, defined as the intra-subject difference between baseline and discharge BDI-II scores. Blood biomarker levels were determined at baseline and 2 days postoperative. Results: Changes in S-100B levels correlated positively with acute changes in depressive symptom severity (Spearman r, 0.62; P=0.0004) and accounted for about one-fourth of their observed variance (R2, 0.23; P=0.0105). This association remained statistically significant after adjusting for baseline S-100B levels, age, weight, body-mass index, or b-blocker use, but not baseline BDI-II scores (P = 0.064). There was no statistically significant association between the primary outcome and baseline S-100B levels, baseline high-sensitivity C-reactive protein or interleukin-6 levels, or changes in high-sensitivity C- reactive protein or interleukin-6 levels. Among most participants, levels of all three biomarkers were normal at baseline and markedly elevated at 2 days postoperative. Conclusions: Acute changes in depressive symptom severity were specifically associated with incremental changes in S- 100B blood levels, largely independent of covariates associated with either. These findings support the hypothesis that glial activation and injury and blood–brain barrier disruption can be mechanistically linked to acute exacerbation of depressive symptoms in some individuals

Antidepressant Effects of High and Low Frequency Repetitive Transcranial Magnetic Stimulation to the Dorsolateral Prefrontal Cortex

Repetitive transcranial magnetic stimulation(rTMS) has antidepressant effects in patients withmajor depressive disorder. The mechanisms of ac-tion and optimal stimulation parameters remainunclear. To test the hypothesis that rTMS exertsantidepressant effects either by enhancing left dor-solateral prefrontal cortex (DLPFC) excitability orby decreasing right DLPFC excitability, the au-thors studied 45 patients with unipolar recurrentmajor depressive disorder in a double-blind, ran-domized, parallel group, sham-controlled trial. Pa-tients were randomized to receive 1 Hz or 10 HzrTMS to the left DLPFC, 1 Hz to the rightDLPFC or sham TMS. Left 10 Hz and right 1 HzrTMS showed similar significant antidepressanteffects. Other parameters led to no significantantidepressant effectThis study was supported in part by grants from the Spanish Ministerio de Educacion y Cienca (DGICYT), the Milton Fund, the Stanley Vada NAMI Foundation, the National Alliance for Research in Schizophrenia and Depression, and NIMHMedicin

An Introduction to the \u27Oceans and Society: Blue Planet\u27 Initiative

We live on a blue planet, and Earth’s waters benefit many sectors of society. The future of our blue planet is increasingly reliant on the services delivered by marine, coastal and inland waters and on the advancement of effective, evidence-based decisions on sustainable development. ‘Oceans and Society: Blue Planet’ is an initiative of the Group on Earth Observations (GEO) that aims to ensure the sustained development and use of ocean and coastal observations for the benefit of society. The initiative works to advance and exploit synergies among the many observational programmes devoted to ocean and coastal waters; to improve engagement with a variety of stakeholders for enhancing the timeliness, quality and range of information delivered; and to raise awareness of the societal benefits of ocean observations at the public and policy levels. This paper summarises the role of the initiative, current activities and considerations for future directions

Temperature dependence of protein dynamics simulated with three different water models

The effect of variation of the water model on the temperature dependence of protein and hydration water dynamics is examined by performing molecular dynamics simulations of myoglobin with the TIP3P, TIP4P, and TIP5P water models and the CHARMM protein force field at temperatures between 20 and 300 K. The atomic mean-square displacements, solvent reorientational relaxation times, pair angular correlations between surface water molecules, and time-averaged structures of the protein are all found to be similar, and the protein dynamical transition is described almost indistinguishably for the three water potentials. The results provide evidence that for some purposes changing the water model in protein simulations without a loss of accuracy may be possible

Evaluation of a new virtual-reality training simulator for hysteroscopy

BACKGROUND: To determine realism and training capacity of HystSim, a new virtual-reality simulator for the training of hysteroscopic interventions. METHODS: Sixty-two gynaecological surgeons with various levels of expertise were interviewed at the 13(th) Practical Course in Gynaecologic Endoscopy in Davos, Switzerland. All participants received a 20-min hands-on training on the simulator and filled out a four-page questionnaire. Twenty-three questions with respect to the realism of the simulation and the training capacity were answered on a seven-point Likert scale along with 11 agree-disagree statements concerning the HystSim training in general. RESULTS: Twenty-six participants had performed more than 50 hysteroscopies ("experts") and 36 equal to or fewer than 50 ("novices"). Four of 60 (6.6%) responding participants judged the overall impression as "7 - absolutely realistic", 40 (66.6%) as "6 - realistic", and 16 (26.6%) as "5 - somewhat realistic". Novices (6.48; 95% confidence interval [CI] 6.28-6.7) rated the overall training capacity significantly higher than experts (6.08; 95% CI 5.85-6.3), however, high-grade acceptance was found in both groups. In response to the statements, 95.2% believe that HystSim allows procedural training of diagnostic and therapeutic hysteroscopy, and 85.5% suggest that HystSim training should be offered to all novices before performing surgery on real patients. CONCLUSION: Face validity has been established for a new hysteroscopic surgery simulator. Potential trainees and trainers assess it to be a realistic and useful tool for the training of hysteroscopy. Further systematic validation studies are needed to clarify how this system can be optimally integrated into the gynaecological curriculum

Echocardiography practice, training and accreditation in the intensive care: document for the World Interactive Network Focused on Critical Ultrasound (WINFOCUS)

Echocardiography is increasingly used in the management of the critically ill patient as a non-invasive diagnostic and monitoring tool. Whilst in few countries specialized national training schemes for intensive care unit (ICU) echocardiography have been developed, specific guidelines for ICU physicians wishing to incorporate echocardiography into their clinical practice are lacking. Further, existing echocardiography accreditation does not reflect the requirements of the ICU practitioner. The WINFOCUS (World Interactive Network Focused On Critical UltraSound) ECHO-ICU Group drew up a document aimed at providing guidance to individual physicians, trainers and the relevant societies of the requirements for the development of skills in echocardiography in the ICU setting. The document is based on recommendations published by the Royal College of Radiologists, British Society of Echocardiography, European Association of Echocardiography and American Society of Echocardiography, together with international input from established practitioners of ICU echocardiography. The recommendations contained in this document are concerned with theoretical basis of ultrasonography, the practical aspects of building an ICU-based echocardiography service as well as the key components of standard adult TTE and TEE studies to be performed on the ICU. Specific issues regarding echocardiography in different ICU clinical scenarios are then described