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961.
Jacob A. Martin Alexander S. Maris Moneeb Ehtesham Robert J. Singer 《Journal of visualized experiments : JoVE》2012,(69)
Endothelial cells with tight junctions along with the basement membrane and astrocyte end feet surround cerebral blood vessels to form the blood-brain barrier1. The barrier selectively excludes molecules from crossing between the blood and the brain based upon their size and charge. This function can impede the delivery of therapeutics for neurological disorders. A number of chemotherapeutic drugs, for example, will not effectively cross the blood-brain barrier to reach tumor cells2. Thus, improving the delivery of drugs across the blood-brain barrier is an area of interest.The most prevalent methods for enhancing the delivery of drugs to the brain are direct cerebral infusion and blood-brain barrier disruption3. Direct intracerebral infusion guarantees that therapies reach the brain; however, this method has a limited ability to disperse the drug4. Blood-brain barrier disruption (BBBD) allows drugs to flow directly from the circulatory systeminto the brain and thus more effectively reach dispersed tumor cells. Three methods of barrier disruption include osmotic barrier disruption, pharmacological barrier disruption, and focused ultrasound with microbubbles. Osmotic disruption, pioneered by Neuwelt, uses a hypertonic solution of 25% mannitol that dehydrates the cells of the blood-brain barrier causing them to shrink and disrupt their tight junctions. Barrier disruption can also be accomplished pharmacologically with vasoactive compounds such as histamine5 and bradykinin6. This method, however, is selective primarily for the brain-tumor barrier7. Additionally, RMP-7, an analog of the peptide bradykinin, was found to be inferior when compared head-to-head with osmotic BBBD with 25% mannitol8. Another method, focused ultrasound (FUS) in conjunction with microbubble ultrasound contrast agents, has also been shown to reversibly open the blood-brain barrier9. In comparison to FUS, though, 25% mannitol has a longer history of safety in human patients that makes it a proven tool for translational research10-12.In order to accomplish BBBD, mannitol must be delivered at a high rate directly into the brain''s arterial circulation. In humans, an endovascular catheter is guided to the brain where rapid, direct flow can be accomplished. This protocol models human BBBD as closely as possible. Following a cut-down to the bifurcation of the common carotid artery, a catheter is inserted retrograde into the ECA and used to deliver mannitol directly into the internal carotid artery (ICA) circulation. Propofol and N2O anesthesia are used for their ability to maximize the effectiveness of barrier disruption13. If executed properly, this procedure has the ability to safely, effectively, and reversibly open the blood-brain barrier and improve the delivery of drugs that do not ordinarily reach the brain 8,13,14. 相似文献
962.
Morgan A. Clond Bong-Seop Lee Jeffrey J. Yu Matthew B. Singer Takayuki Amano Alexander W. Lamb Doniel Drazin Babak Kateb Eric J. Ley John S. Yu 《PloS one》2013,8(4)
Traumatic brain injury (TBI) is an enormous public health problem, with 1.7 million new cases of TBI recorded annually by the Centers for Disease Control. However, TBI has proven to be an extremely challenging condition to treat. Here, we apply a nanoprodrug strategy in a mouse model of TBI. The novel nanoprodrug contains a derivative of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen in an emulsion with the antioxidant α-tocopherol. The ibuprofen derivative, Ibu2TEG, contains a tetra ethylene glycol (TEG) spacer consisting of biodegradable ester bonds. The biodegradable ester bonds ensure that the prodrug molecules break down hydrolytically or enzymatically. The drug is labeled with the fluorescent reporter Cy5.5 using nonbiodegradable bonds to 1-octadecanethiol, allowing us to reliably track its accumulation in the brain after TBI. We delivered a moderate injury using a highly reproducible mouse model of closed-skull controlled cortical impact to the parietal region of the cortex, followed by an injection of the nanoprodrug at a dose of 0.2 mg per mouse. The blood brain barrier is known to exhibit increased permeability at the site of injury. We tested for accumulation of the fluorescent drug particles at the site of injury using confocal and bioluminescence imaging of whole brains and brain slices 36 hours after administration. We demonstrated that the drug does accumulate preferentially in the region of injured tissue, likely due to an enhanced permeability and retention (EPR) phenomenon. The use of a nanoprodrug approach to deliver therapeutics in TBI represents a promising potential therapeutic modality. 相似文献
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964.
965.
966.
Mireille Leduc Rouha Kasra Howard Singer Jean van Heijenoort 《FEMS microbiology letters》1984,23(2-3):137-142
Abstract Autolysis of Escherichia coli induced by a shock treatment with 10−3 M EDTA, pH 6.5 was investigated. Mutants presenting reduced rates of EDTA-induced autolysis were isolated. A remarkable feature of these mutants was their tolerance to penicillin G, cephaloridine and moenomycin. Furthermore, a reduced level of peptidoglycan endopeptidase or N -acetylmuramidase activity was observed. Penicillin-binding protein patterns were unaltered. 相似文献
967.
J A Bash A M Singer B H Waksman 《Journal of immunology (Baltimore, Md. : 1950)》1976,116(5):1350-1353
Rats given large i.v. doses of ovalbumin or sheep erythrocytes manifest suppressed spleen cell responses (3H-thymidine incorporation) to PHA within hours. Removal of glass wool-adherent cells totally restores responsiveness to that of normal nonadherent spleen cell cultures. Carrageenan, selectively toxic for macrophages, partially restores responses of antigen-suppressed spleen cells in culture, suggesting a supportive role for macrophages in the suppression phenomenon. Treatment of donors with low doses of cyclophosphamide (20 to 50 mg/kg) at the time of antigen injection abrogates the ability of their spleen cells to suppress the responses of normal cells to PHA. The low dose of cyclophosphamide required indicates a target other than the B cell or macrophage and suggests the possibility that cyclophosphamide eliminates the suppressor T cell component of the macrophage-T cell complex. 相似文献
968.
Linkage of severity of experimental allergic encephalomyelitis to the rat major histocompatibility locus 总被引:5,自引:0,他引:5
M J Moore D E Singer R M Williams 《Journal of immunology (Baltimore, Md. : 1950)》1980,124(4):1815-1820
The incidence of EAE is determined by Ir-EAE, a gene linked to the rat MHC. EAE severity can be assessed by quantitative clinical and pathologic measures. Using these measures, one can say that disease severity in LBNF1 is approximately one-tenth that in Lewis. Analysis of LBNF2, LBC, BNBC, and parental Lewis strain reveals that severity is primarily a function of dose of Lewis MHC alleles. Non-MHC genes have a small but discernable effect. 相似文献
969.
For S. pombe cells mutations in the wee1 regulatory gene have been shown previously to allow cells to be smaller than normal at cell division, to endow the cell with a significantly long G1 cell cycle interval, and to alter the timing in the cell cycle of certain mutationally-defined cell cycle steps in G2. We show here that situations which lengthen S phase in proliferating wee1 mutant cells 'suppress' to varying degrees these wee1-mediated cell cycle alterations. Conditions chosen to protract S phase were use of cdc22.M45 mutant cells at semipermissive temperatures, and the presence of sub-arresting concentrations of the S phase inhibitors hydroxyurea or deoxyadenosine. Proliferation in the presence of each of these inhibitors was shown directly to result in protracted S phase. Residual cell division measurements were used to measure the cell cycle timing of G1 and G2 cell-cycle steps. The indirect suppression of the wee1 phenotype shown here can be understood in terms of the proposed role of the wee1+ gene product in coordinating cell division with cellular growth. 相似文献
970.