A systematic review of endovascular stent-electrode arrays, a minimally invasive approach to brain-machine interfaces.

OBJECTIVE: The goal of this study was to systematically review the feasibility and safety of minimally invasive neurovascular approaches to brain-machine interfaces (BMIs). METHODS: A systematic literature review was performed using the PubMed database for studies published between 1986 and 2019. All studies assessing endovascular neural interfaces were included. Additional studies were selected based on review of references of selected articles and review articles. RESULTS: Of the 53 total articles identified in the original literature search, 12 studies were ultimately selected. An additional 10 articles were included from other sources, resulting in a total of 22 studies included in this systematic review. This includes primarily preclinical studies comparing endovascular electrode recordings with subdural and epidural electrodes, as well as studies evaluating stent-electrode gauge and material type. In addition, several clinical studies are also included. CONCLUSIONS: Endovascular stent-electrode arrays provide a minimally invasive approach to BMIs. Stent-electrode placement has been shown to be both efficacious and safe, although further data are necessary to draw comparisons between subdural and epidural electrode measurements given the heterogeneity of the studies included. Greater access to deep-seated brain regions is now more feasible with stent-electrode arrays; however, further validation is needed in large clinical trials to optimize this neural interface. This includes the determination of ideal electrode material type, venous versus arterial approaches, the feasibility of deep brain stimulation, and more streamlined computational decoding techniques

The Drug Excipient Cyclodextrin Interacts With d

Cyclodextrins are well-characterized, barrel-shaped molecules that can solubilize organic small molecules in aqueous solution via host–guest interactions. As such, cyclodextrins are used as excipients for experimental therapeutics in vivo. We observed unanticipated modifications to bioluminescence imaging (BLI) signal intensity when 2-hydroxy-propyl-β-cyclodextrin (HPCD) was coinjected as an excipient. We hypothesized that HPCD binds d -luciferin and interferes with the BLI signal. Using luciferase-expressing cell lines, we showed that HPCD lowers the BLI signal in a concentration-dependent manner. Flow cytometry revealed that HPCD resulted in reduced cellular accumulation of d -luciferin, and mass spectrometry revealed d -luciferin HPCD species, confirming a direct interaction. In vivo imaging using a luciferase mouse model demonstrated that HPCD reduced luciferin-mediated BLI compared to luciferin alone. The implications of using HPCD as an excipient in BLI studies are discussed

Enteropathogenic Escherichia coli inhibits intestinal vitamin B1 (thiamin) uptake: studies with human-derived intestinal epithelial Caco-2 cells

Infection with the gram-negative enteropathogenic Escherichia coli (EPEC), a food-borne pathogen, represents a significant risk to human health. Whereas diarrhea is a major consequence of this infection, malnutrition also occurs especially in severe and prolonged cases, which may aggravate the health status of the infected hosts. Here we examined the effect of EPEC infection on the intestinal uptake of the water-soluble vitamin B1 (thiamin) using an established human intestinal epithelial Caco-2 cell model. The results showed that infecting Caco-2 cells with wild-type EPEC (but not with nonpathogenic E. coli, killed EPEC, or filtered supernatant) leads to a significant (P < 0.01) inhibition in thiamin uptake. Kinetic parameters of both the nanomolar (mediated by THTR-2) and the micromolar (mediated by THTR-1) saturable thiamin uptake processes were affected by EPEC infection. Cell surface expression of hTHTR-1 and -2 proteins, (determined by the biotinylation method) showed a significantly (P < 0.01) lower expression in EPEC-treated cells compared with controls. EPEC infection also affected the steady-state mRNA levels as well as promoter activity of the SLC19A2 and SLC19A3 genes. Infecting Caco-2 cells with EPEC mutants that harbor mutations in the escN gene (which encodes a putative ATPase for the EPEC type III secretion system, TTSS) or the espA, espB, or espD genes (which encode structural components of the TTSS) did not affect thiamin uptake. On the other hand, mutations in espF and espH genes (which encode effector proteins) exhibited partial inhibition in thiamin uptake. These results demonstrate for the first time that EPEC infection of human intestinal epithelial cells leads to inhibition in thiamin uptake via effects on physiological and molecular parameters of hTHTR-1 and -2. Furthermore, the inhibition appears to be dependent on a functional TTSS of EPEC

Inhibition of intestinal biotin absorption by chronic alcohol feeding: cellular and molecular mechanisms

The water-soluble vitamin biotin is essential for normal cellular functions and its deficiency leads to a variety of clinical abnormalities. Mammals obtain biotin from exogenous sources via intestinal absorption, a process mediated by the sodium-dependent multivitamin transporter (SMVT). Chronic alcohol use in humans is associated with a significant reduction in plasma biotin levels, and animal studies have shown inhibition in intestinal biotin absorption by chronic alcohol feeding. Little, however, is known about the cellular and molecular mechanisms involved in the inhibition in intestinal biotin transport by chronic alcohol use. These mechanisms were investigated in this study by using rats and transgenic mice carrying the human full-length SLC5A6 5′-regulatory region chronically fed alcohol liquid diets; human intestinal epithelial Caco-2 cells chronically exposed to alcohol were also used as models. The results showed chronic alcohol feeding of rats to lead to a significant inhibition in carrier-mediated biotin transport events across jejunal brush border and basolateral membrane domains. This inhibition was associated with a significant reduction in level of expression of the SMVT protein, mRNA, and heterogenous nuclear RNA. Chronic alcohol feeding also inhibited carrier-mediated biotin uptake in rat colon. Studies with transgenic mice confirmed the above findings and further showed chronic alcohol feeding significantly inhibited the activity of SLC5A6 5′-regulatory region. Finally, chronic exposure of Caco-2 cells to alcohol led to a significant decrease in the activity of both promoters P1 and P2 of the human SLC5A6 gene. These studies identify for the first time the cellular and molecular parameters of the intestinal biotin absorptive processes that are affected by chronic alcohol feeding

Antiplatelet therapy and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis

OBJECTIVE Delayed cerebral ischemia (DCI) is a potentially preventable cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). The authors performed a meta-analysis to assess the effect of antiplatelet therapy (APT) on DCI in patients with aSAH. METHODS A systematic review of the PubMed and MEDLINE databases was performed. Study inclusion criteria were 1) ≥ 5 aSAH patients; 2) direct comparison between aSAH management with APT and without APT; and 3) reporting of DCI, angiographic, or symptomatic vasospasm rates for patients treated with versus without APT. The primary efficacy outcome was DCI. The outcomes of the APT versus no-APT cohorts were compared. Bias was assessed using the Downs and Black checklist. RESULTS The overall cohort comprised 2039 patients from 15 studies. DCI occurred less commonly in the APT compared with the no-APT cohort (pooled = 15.9% vs 28.6%; OR 0.47, p < 0.01). Angiographic (pooled = 51.6% vs 68.7%; OR 0.46, p < 0.01) and symptomatic (pooled = 23.6% vs 37.7%; OR 0.51, p = 0.01) vasospasm rates were lower in the APT cohort. In-hospital mortality (pooled = 1.7% vs 4.1%; OR 0.53, p = 0.01) and functional dependence (pooled = 21.0% vs 35.7%; OR 0.53, p < 0.01) rates were also lower in the APT cohort. Bleeding event rates were comparable between the two cohorts. Subgroup analysis of cilostazol monotherapy compared with no APT demonstrated a lower DCI rate in the cilostazol cohort (pooled = 10.6% vs 28.1%; OR 0.31, p < 0.01). Subgroup analysis of surgically treated aneurysms demonstrated a lower DCI rate for the APT cohort (pooled = 18.4% vs 33.9%; OR 0.43, p = 0.02). CONCLUSIONS APT is associated with improved outcomes in aSAH without an increased risk of bleeding events, particularly in patients who underwent surgical aneurysm repair and those treated with cilostazol. Although study heterogeneity is the most significant limitation of the analysis, the findings suggest that APT is worth exploring in patients with aSAH, particularly in a randomized controlled trial setting

Tariquidar is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein Running title: Interaction of Tariquidar with P-glycoprotein Corresponding author

Abstract Since its development, tariquidar (XR9576, TQR) has been widely regarded as one of the more potent inhibitors of P-glycoprotein (P-gp), an efflux transporter of the ATP-binding cassette (ABC) transporter family. A third-generation inhibitor, TQR exhibits high affinity for Pgp, although it is also a substrate of another ABC transporter, breast cancer resistance protein (BCRP). Recently, several studies have questioned the mechanism by which TQR interfaces with P-gp, suggesting that TQR is a substrate for P-gp instead of a noncompetitive inhibitor. We investigated TQR and its interaction with human and mouse P-gp to determine if TQR is a substrate of P-gp in vitro. To address these questions, we used multiple in vitro transporter assays including cytotoxicity, flow cytometry, accumulation, ATPase, and transwell assays. A newly generated BCRP cell line was used as a positive control that demonstrates TQR-mediated transport. Based on our results, we conclude that TQR is a potent inhibitor of both human and mouse P-gp and shows no signs of being a substrate at the concentrations tested. These in vitro data further support our position that the in vivo uptake of [ 11 C]TQR into the brain can be explained by its high affinity binding to P-gp and by it being a substrate of BCRP, followed by amplification of the brain signal by ionic trapping in acidic lysosomes

Tariquidar Is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein

ABSTRACT Since its development, tariquidar (TQR; XR9576;4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]-4,5-dimethoxyphenyl]quinoline-3-carboxamide) has been widely regarded as one of the more potent inhibitors of P-glycoprotein (P-gp), an efflux transporter of the ATP-binding cassette (ABC) transporter family. A third-generation inhibitor, TQR exhibits high affinity for P-gp, although it is also a substrate of another ABC transporter, breast cancer resistance protein (BCRP). Recently, several studies have questioned the mechanism by which TQR interfaces with P-gp, suggesting that TQR is a substrate for P-gp instead of a noncompetitive inhibitor. We investigated TQR and its interaction with human and mouse P-gp to determine if TQR is a substrate of P-gp in vitro. To address these questions, we used multiple in vitro transporter assays, including cytotoxicity, flow cytometry, accumulation, ATPase, and transwell assays. A newly generated BCRP cell line was used as a positive control that demonstrates TQR-mediated transport. Based on our results, we conclude that TQR is a potent inhibitor of both human and mouse P-gp and shows no signs of being a substrate at the concentrations tested. These in vitro data further support our position that the in vivo uptake of [ 11 C]TQR into the brain can be explained by its highaffinity binding to P-gp and by it being a substrate of BCRP, followed by amplification of the brain signal by ionic trapping in acidic lysosomes