Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor

The blood-brain barrier (BBB) is a critical structure that serves as the gatekeeper between the central nervous system and the rest of the body. It is the responsibility of the BBB to facilitate the entry of required nutrients into the brain and to exclude potentially harmful compounds; however, this complex structure has remained difficult to model faithfully in vitro. Accurate in vitro models are necessary for understanding how the BBB forms and functions, as well as for evaluating drug and toxin penetration across the barrier. Many previous models have failed to support all the cell types involved in the BBB formation and/or lacked the flow-created shear forces needed for mature tight junction formation. To address these issues and to help establish a more faithful in vitro model of the BBB, we have designed and fabricated a microfluidic device that is comprised of both a vascular chamber and a brain chamber separated by a porous membrane. This design allows for cell-to-cell communication between endothelial cells, astrocytes, and pericytes and independent perfusion of both compartments separated by the membrane. This NeuroVascular Unit (NVU) represents approximately one-millionth of the human brain, and hence, has sufficient cell mass to support a breadth of analytical measurements. The NVU has been validated with both fluorescein isothiocyanate (FITC)-dextran diffusion and transendothelial electrical resistance. The NVU has enabled in vitro modeling of the BBB using all human cell types and sampling effluent from both sides of the barrier

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

In situ oxygen isotope compositions in olivines of different types of cosmic spherules: An assessment of relationships to chondritic particles

Cosmic spherules collected from deep sea sediments of the Indian Ocean having different textures such as scoriaceous (4), relict-bearing (16), porphyritic (35) and barred olivine (2) were investigated for petrography, as well as high precision oxygen isotopic studies on olivine grains using secondary ion mass spectrometry (SIMS). The oxide FeO/MgO ratios of large olivines (>20 μm) in cosmic spherules have low values similar to those seen in the olivines of carbonaceous chondrite chondrules, rather than matching the compositions of matrix. The oxygen isotope compositions of olivines in cosmic spherules have a wide range of δ18O, δ17O and Δ17O values as follows: −9 to 40‰, −13 to 22‰ and −11 to 6‰. Our results suggest that the oxygen isotope compositions of the scoriaceous, relict-bearing, porphyritic and barred spherules show provenance related to the carbonaceous (CM, CV, CO and CR) chondrites. The different types of spherules that has experienced varied atmospheric heating during entry has not significantly altered the Δ17O values. However, one of the relict-bearing spherules with a large relict grain has Δ17O = 5.7‰, suggesting that it is derived from 16O-poor material that is not recognized in the meteorite record. A majority of the spherules have Δ17O ranging from −4 to −2‰, similar to values in chondrules from carbonaceous chondrites, signifying that chondrules of carbonaceous chondrites are the major contributors to the flux of micrometeorites, with an insignificant fraction derived from ordinary chondrites. Furthermore, barred spherule data shows that during atmospheric entry an increase in ∼10‰ of δ18O value surges Δ17O value by ∼1‰

Additional file 2: Table S1. of Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit

Cytokines measured with ELISA. (PDF 391 kb

Additional file 3: Table S2. of Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit

Tentative structural identifications. (XLSX 69 kb