Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport

Abstract Background: Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood-brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery. Methods: Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis. Results: Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy. Conclusions: Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching therapeutic implications for CNS malignancies

Search for CP Violation in the Decay Z -> b (b bar) g

About three million hadronic decays of the Z collected by ALEPH in the years 1991-1994 are used to search for anomalous CP violation beyond the Standard Model in the decay Z -> b \bar{b} g. The study is performed by analyzing angular correlations between the two quarks and the gluon in three-jet events and by measuring the differential two-jet rate. No signal of CP violation is found. For the combinations of anomalous CP violating couplings, ${\hat{h}}_b = {\hat{h}}_{Ab}g_{Vb}-{\hat{h}}_{Vb}g_{Ab}$ and $h^{\ast}_b = \sqrt{\hat{h}_{Vb}^{2}+\hat{h}_{Ab}^{2}}$, limits of \hat{h}_b < 0.59$and$h^{\ast}_{b} < 3.02$ are given at 95\% CL.Comment: 8 pages, 1 postscript figure, uses here.sty, epsfig.st

Limit on Bs0B^0_s oscillation using a jet charge method

A lower limit is set on the B_{s}^{0} meson oscillation parameter \Delta m_{s} using data collected from 1991 to 1994 by the ALEPH detector. Events with a high transverse momentum lepton and a reconstructed secondary vertex are used. The high transverse momentum leptons are produced mainly by b hadron decays, and the sign of the lepton indicates the particle/antiparticle final state in decays of neutral B mesons. The initial state is determined by a jet charge technique using both sides of the event. A maximum likelihood method is used to set a lower limit of \, \Delta m_{s}. The 95\% confidence level lower limit on \Delta m_s ranges between 5.2 and 6.5(\hbar/c^{2})~ps^{-1} when the fraction of b quarks from Z^0 decays that form B_{s}^{0} mesons is varied from 8\% to 16\%. Assuming that the B_{s}^{0} fraction is 12\%, the lower limit would be \Delta m_{s} 6.1(\hbar/c^{2})~ps^{-1} at 95\% confidence level. For x_s = \Delta m_s \, \tau_{B_s}, this limit also gives x_s 8.8 using the B_{s}^{0} lifetime of \tau_{B_s} = 1.55 \pm 0.11~ps and shifting the central value of \tau_{B_s} down by 1\sigma

Measurement of the Bs0^0_s lifetime and production rate with Ds−l+^-_s l^+ combinations in Z decays

The lifetime of the \bs meson is measured in approximately 3 million hadronic Z decays accumulated using the ALEPH detector at LEP from 1991 to 1994. Seven different \ds decay modes were reconstructed and combined with an opposite sign lepton as evidence of semileptonic \bs decays. Two hundred and eight \dsl candidates satisfy selection criteria designed to ensure precise proper time reconstruction and yield a measured \bs lifetime of \mbox{\result .} Using a larger, less constrained sample of events, the product branching ratio is measured to be \mbox{\pbrresult