Global dissociation of the amygdala from the rest of the brain during REM sleep

Rapid-eye-movement sleep (REMS) or paradoxical sleep is associated with intense neuronal activity, fluctuations in autonomic control, body paralysis and brain-wide hyperemia. The mechanisms and functions of these energy-demanding patterns remain elusive and a global picture of brain activation during REMS is currently missing. In the present work, we performed functional ultrasound (fUS) imaging at the whole-brain scale during hundreds of REMS episodes to provide the spatiotemporal dynamics of vascular activity in 259 brain regions spanning more than 2/3 of the total brain volume. We first demonstrate a dissociation between basal/midbrain and cortical structures, the first ones sustaining tonic activation during REMS while the others are activated in phasic bouts. Second, we isolated the vascular compartment in our recordings and identified arteries in the anterior part of the brain as strongly involved in the blood supply during REMS episodes. Finally, we report a peculiar activation pattern in the amygdala, which is strikingly disconnected from the rest of the brain during most but not all REMS episodes. This last finding shows that amygdala undergoes specific processing during REMS and may be linked to the regulation of emotions and the creation of dream content during this very state.

Global dissociation of the amygdala from the rest of the brain during REM sleep

Rapid-eye-movement sleep (REMS) or paradoxical sleep is associated with intense neuronal activity, fluctuations in autonomic control, body paralysis and brain-wide hyperemia. The mechanisms and functions of these energy-demanding patterns remain elusive and a global picture of brain activation during REMS is currently missing. In the present work, we performed functional ultrasound (fUS) imaging at the whole-brain scale during hundreds of REMS episodes to provide the spatiotemporal dynamics of vascular activity in 259 brain regions spanning more than 2/3 of the total brain volume. We first demonstrate a dissociation between basal/midbrain and cortical structures, the first ones sustaining tonic activation during REMS while the others are activated in phasic bouts. Second, we isolated the vascular compartment in our recordings and identified arteries in the anterior part of the brain as strongly involved in the blood supply during REMS episodes. Finally, we report a peculiar activation pattern in the amygdala, which is strikingly disconnected from the rest of the brain during most but not all REMS episodes. This last finding shows that amygdala undergoes specific processing during REMS and may be linked to the regulation of emotions and the creation of dream content during this very state.

Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach

The C-X-C chemokine receptor 4 (CXCR4) is G protein-coupled receptor that upon binding to its cognate ligand, can lead to tumor progression. Several CXCR4-targeted therapies are currently under investigation, and with it comes the need for imaging agents capable of accurate depiction of CXCR4 for therapeutic stratification and monitoring. PET agents enjoy the most success, but more cost-effective and radiation-free approaches such as ultrasound (US) imaging could represent an attractive alternative. In this work, we developed a targeted microbubble (MB) for imaging of vascular CXCR4 expression in cancer. A CXCR4-targeted MB was developed through incorporation of the T140 peptide into the MB shell. Binding properties of the T140-MB and control, non-targeted MB (NT-MB) were evaluated in MDA-MB-231 cells where CXCR4 expression was knocked-down (via shRNA) through optical imaging, and in the lymphoma tumor models U2932 and SuDHL8 (high and low CXCR4 expression, respectively) by US imaging. PET imaging of [18F]MCFB, a tumor-penetrating CXCR4-targeted small molecule, was used to provide whole-tumor CXCR4 readouts. CXCR4 expression and microvessel density were performed by immunohistochemistry analysis and western blot. T140-MB were formed with similar properties to NT-MB and accumulated sensitively and specifically in cells according to their CXCR4 expression. In NOD SCID mice, T140-MB persisted longer in tumors than NT-MB, indicative of target interaction, but showed no difference between U2932 and SuDHL8. In contrast, PET imaging with [18F]MCFB showed a marked difference in tumor uptake at 40–60 min post-injection between the two tumor models (p<0.05). Ex vivo analysis revealed that the large differences in CXCR4 expression between the two models are not reflected in the vascular compartment, where the MB are restricted; in fact, microvessel density and CXCR4 expression in the vasculature was comparable between U2932 and SuDHL8 tumors. In conclusion, we successfully developed a T140-MB that can be used for imaging CXCR4 expression in the tumor vasculature.

Ovarian Hyperstimulation: Diagnosis, Prevention, and Management

Ovarian hyperstimulation syndrome (OHSS) is a severe complication of controlled ovarian stimulation (COS). Pathogenesis of the disease is based on massive transudation of protein-rich fluid from the vascular compartment into the peritoneal, pleural and pericardial spaces, with a variable picture of clinical manifestations depending on its severity. Nowadays OHSS can easily be avoided by several prevention methods, ranging from identification of high-risk patients, choice of a correct protocol stimulation, trigger with gonadotropin-releasing hormone (GnRH) agonists or, finally, the freeze-all strategy. When OHSS occurs, it can usually be managed as outpatient care. Only if severe/critical cases are diagnosed hospitalization is necessary for appropriate rehydration, monitoring of fluid balance and eventual drainage of ascitic fluid. One of the most dangerous complications of OHSS is venous thromboembolism (VTE). Thromboprophylaxis has shown to be cost effective and widely used, while there are controversies regarding the usage of low dose aspirin (LDA) as a preventive measure.

The Glymphatic System (En)during Inflammation

The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels promote fluid exchange between the perivascular spaces and the neuropil. Cerebrospinal and interstitial fluids are together transported back to the vascular compartment by meningeal and cervical lymphatic vessels. Multiple lines of work show that neurological diseases in general impair glymphatic fluid transport. Insofar as the glymphatic system plays a pseudo-lymphatic role in the central nervous system, it is poised to play a role in neuroinflammation. In this review, we discuss how the association of the glymphatic system with the meningeal lymphatic vessel calls for a renewal of established concepts on the CNS as an immune-privileged site. We also discuss potential approaches to target the glymphatic system to combat neuroinflammation.

Interstitial Washdown and Vascular Albumin Refill During Fluid Infusion: Novel Kinetic Analysis From Three Clinical Trials

Background and Aims. Increased capillary filtration may paradoxically accelerate vascular refill of both fluid and albumin from the interstitial space, which are claimed to be edema-preventing. We characterized “interstitial washdown” by kinetic analyses of the hemodilution induced by intravenous infusion of crystalloid fluid during 3 distinctphysiological states.Methods. The dilution of blood hemoglobin and plasma albumin was compared by population volume kinetic analysis during and after intravenous infusion Ringer´s solution over 30 min in 24 conscious volunteers and 30 anesthetized patients. Data were also retrieved from 31 patients with ketoacidosis from hyperglycemia who received 1 L of0.9% saline. Greater plasma dilution of hemoglobin as compared to albumin indicated recruitment of albumin.Results. “Interstitial washdown” increased plasma albumin concentration by 0.6 g/L in volunteers, by 1.0 g/L during anesthesia, and by 0.3 g/L in ketoacidosis patients. The albumin concentration in extravascular fluid returning to the plasma was approximately 29, 29, and 22 g/L during the respective infusions, but decreased to an average of 50% to 75% lower during the subsequent 2-3 h. Pronounced washdown was associated with increased capillary filtration (high k12) and, in conscious subjects, with fluid retention due to restricted urine flow. During anesthesia, the main effect was an increase the nonexchangeable fluid volume (“third-spacing”).Conclusions. Fluid infusion induces interstitial washdown by accelerated lymphatic flow and an increase in plasma albumin. The mechanism becomes exhausted after 2-3 hours. Albumin refill helps retain infused volume within the vascular compartment.

The Dynamic Interface Between the Bone Marrow Vascular Niche and Hematopoietic Stem Cells in Myeloid Malignancy

Hematopoietic stem cells interact with bone marrow niches, including highly specialized blood vessels. Recent studies have revealed the phenotypic and functional heterogeneity of bone marrow endothelial cells. This has facilitated the analysis of the vascular microenvironment in steady state and malignant hematopoiesis. In this review, we provide an overview of the bone marrow microenvironment, focusing on refined analyses of the marrow vascular compartment performed in mouse studies. We also discuss the emerging role of the vascular niche in “inflamm-aging” and clonal hematopoiesis, and how the endothelial microenvironment influences, supports and interacts with hematopoietic cells in acute myeloid leukemia and myelodysplastic syndromes, as exemplar states of malignant myelopoiesis. Finally, we provide an overview of strategies for modulating these bidirectional interactions to therapeutic effect in myeloid malignancies.

Pretherapeutic first-in-human targeting trial of anti-hK2 antibody h11B6: A potential molecular vector for alpha-particle radioimmunotherapy.

122 Background: Radioligand therapy for metastatic castration resistant prostate cancer (mCRPC) has focused to date on targeting prostate specific membrane antigen, an approach associated with salivary gland toxicity and variable lesion expression. New targets are needed. Human kallikrein-2 (hK2) is overexpressed in most prostate cancer, with minimal normal tissue expression or serum secretion. Humanized monoclonal antibody (mAb) h11B6 exclusively targets hK2 in pre-clinical studies. This phase 0 study (NCT04116164) is a first-in-human trial of [111In]-DOTA-h11B6 to determine the hk2-targeting potential of h11B6. Objective: The purpose of this ongoing protocol is to characterize the biodistribution of [111In]-DOTA-h11B6 and determine a suitable mAb mass that targets mCRPC with minimal non-tumor targeting. Methods: Patients with progressive mCRPC were enrolled. A single slow bolus infusion of 2 mg [111In]-DOTA-h11B6 (nominally 185 MBq [111In]), was administered IV with or without 8 mg h11B6. Patients were observed for adverse events (AE) for at least 2 weeks. Serial gamma camera imaging including at least one SPECT/CT scan was performed up to 8 days post-administration. Serial blood samples were obtained over 2 weeks to determine serum radioactivity and h11B6 protein levels. Dosimetry for normal organs was estimated using OLINDA-EXM. Results: Results for the first 6 patients are summarized in Table. Treatment was tolerated in all patients with no AEs and no evidence of enhanced accumulation in any organ including salivary glands. Initial volume of distribution appeared confined to the vascular compartment. Slow clearance of radioactivity from the vascular compartment was observed with gradual targeting to skeletal and non-skeletal lesions in all patients. Conclusions: h11B6 is a novel mAb that targets hK2, localizes to bone and soft tissue metastases, has no significant normal tissue uptake, and spares salivary glands. An IND for a phase I therapeutic study using [225Ac] has been secured. Clinical trial information: NCT04116164. [Table: see text]