Edited by Paul E. FraserThe mammalian brain is supplied with blood by specialized vasculature that is structurally and functionally distinct from that of the periphery. A defining feature of this vasculature is a physical blood-brain barrier (BBB). The BBB separates blood components from the brain microenvironment, regulating the entry and exit of ions, nutrients, macromolecules, and energy metabolites. Over the last two decades, physiological studies of cerebral blood flow dynamics have demonstrated that substantial intercellular communication occurs between cells of the vasculature and the neurons and glia that abut the vasculature. These findings suggest that the BBB does not function independently, but as a module within the greater context of a multicellular neurovascular unit (NVU) that includes neurons, astrocytes, pericytes, and microglia as well as the blood vessels themselves. Here, we describe the roles of these NVU components as well as how they act in concert to modify cerebrovascular function and permeability in health and in select diseases.

It is known that insect kinins increase diuresis and fluid secretion in the Aedes aegypti Malpighian tubule, causing a rapid drop of the transepithelial resistance and increasing chloride conductance from the hemolymph towards the tubule lumen. The tubule is composed of both principal and stellate cells. The main route for increased chloride influx upon kinin treatment is proposed to be paracellular, with septate junctions acquiring increased chloride selectivity and conductance. Therefore, kinin treatment renders the Aedes aegypti tubule a "leaky epithelium", and under this model the kinin receptor is postulated to be expressed in principal cells. However, in another dipteran, the fruit fly Drosophila melanogaster, the main route for chloride transport is transcellular through stellate cells. In both the fruit fly and the mosquito Anopheles stephensi the kinin receptor has been immunolocalized in stellate cells, where it regulates transepithelial chloride permeability. Here we show that in Aedes aegypti, similarly, the stellate cells express the kinin receptor. This was confirmed through immunohistochemistry with two specific anti-kinin receptor antibodies and confocal analysis. The receptor is detected as a 75kDa band in western blot. These results indicate that the currently accepted model for chloride transport must be reevaluated in Aedes aegypti and suggest the kinin regulatory signals controlling intercellular junctions originate in the stellate cells.

Background and purposeThe radiologic features and patterns of primary central nervous system lymphoma (PCNSL) at initial presentation are well described. High response rates can be achieved with first-line high-dose methotrexate (HD-MTX) based regimens, yet many relapse within 2 years of diagnosis. We describe the pattern of relapse and review the potential mechanisms involved in relapse.MethodsWe identified 78 consecutive patients who attained complete radiographic response (CR) during or after first-line treatment for newly diagnosed PCNSL (CD20+, diffuse large B cell type). Patients were treated with HD-MTX based regimen in conjunction with blood–brain barrier disruption (HD-MTX/BBBD); 44 subsequently relapsed. Images and medical records of these 44 consecutive patients were retrospectively reviewed. The anatomical location of enhancing lesions at initial diagnosis and at the time of relapse were identified and compared.Results37/44 patients fulfilled inclusion criteria and had new measureable enhancing lesions at relapse; the pattern and location of relapse of these 37 patients were identified. At relapse, the new enhancement was at a spatially distinct site in 30 of 37 patients. Local relapse was found only in seven patients.DiscussionUnlike gliomas, the majority of PCNSL had radiographic relapse at spatially distinct anatomical locations within the brain behind a previously intact neurovascular unit (NVU), and in few cases outside, the central nervous system (CNS). This may suggest either (1) reactivation of occult reservoirs behind an intact NVU in the CNS (or ocular) or (2) seeding from bone marrow or other extra CNS sites.ConclusionRecognizing patterns of relapse is key for early detection and may provide insight into potential mechanisms of relapse as well as help develop strategies to extend duration of complete response.

a b s t r a c tThe evolution of the blood feeding adaptation in mosquitoes required hormonal coordination of multiple physiological processes (behavior, digestion, diuresis, oogenesis). The Aedes kinins (leucokinin-like neuropeptides) are involved in post blood feeding physiological processes, having diuretic and myotropic functions. To understand the in vivo contribution of the kinin receptor to overall female post-prandial fluid excretion, RNAi knockdown was followed by fluid secretion assays which proved its fundamental role in rapid diuresis. The Aedes kinin receptor was also localized in several tissues not previously reported in mosquitoes. Results highlight the integrative role of the Aedes kinins in the success of the blood feeding adaptation.

Intracarotid arterial hyperosmolar mannitol (ICAHM) blood–brain barrier disruption (BBBD) is effective and safe for delivery of therapeutics for central nervous system malignancies. ICAHM osmotically alters endothelial cells and tight junction integrity to achieve BBBD. However, occurrence of neuroinflammation following hemispheric BBBD by ICAHM remains unknown. Temporal proteomic changes in rat brains following ICAHM included increased damage-associated molecular patterns, cytokines, chemokines, trophic factors, and cell adhesion molecules, indicative of a sterile inflammatory response (SIR). Proteomic changes occurred within 5 min of ICAHM infusion and returned to baseline by 96 h. Transcriptomic analyses following ICAHM BBBD further supported an SIR. Immunohistochemistry revealed activated astrocytes, microglia, and macrophages. Moreover, proinflammatory proteins were elevated in serum, and proteomic and histological findings from the contralateral hemisphere demonstrated a less pronounced SIR, suggesting neuroinflammation beyond regions of ICAHM infusion. Collectively, these results demonstrate ICAHM induces a transient SIR that could potentially be harnessed for neuroimmunomodulation.