Drug transport in brain via the cerebrospinal fluid

The human brain has no lymphatic system, but produces over a half-liter each day of cerebrospinal fluid. The cerebrospinal fluid is secreted at the choroid plexus and occupies the cavities of the four ventricles, as well as the cranial and spinal sub-arachnoid space. The cerebrospinal fluid moves over the surfaces of the brain and spinal cord and is rapidly absorbed into the general circulation. The choroid plexus forms the blood-cerebrospinal fluid barrier, and this barrier is functionally distinct from the brain microvascular endothelium, which forms the blood-brain barrier. Virtually all non-cellular substances in blood distribute into cerebrospinal fluid, and drug entry into cerebrospinal fluid is not an index of drug transport across the blood-brain barrier. Drug injected into the cerebrospinal fluid rapidly moves into the blood via bulk flow, but penetrates into brain tissue poorly owing to the limitations of diffusion. Drug transport into cerebrospinal fluid vs. brain interstitial fluid requires knowledge of the relative expression of transporters at the choroid plexus versus the brain microvascular endothelium

Peritumoral tissue compression is predictive of exudate flux in a rat model of cerebral tumor: an MRI study in an embedded tumor

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115972/1/nbm3418.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115972/2/nbm3418_am.pd

Resonant nonlinear magneto-optical effects in atoms

In this article, we review the history, current status, physical mechanisms, experimental methods, and applications of nonlinear magneto-optical effects in atomic vapors. We begin by describing the pioneering work of Macaluso and Corbino over a century ago on linear magneto-optical effects (in which the properties of the medium do not depend on the light power) in the vicinity of atomic resonances, and contrast these effects with various nonlinear magneto-optical phenomena that have been studied both theoretically and experimentally since the late 1960s. In recent years, the field of nonlinear magneto-optics has experienced a revival of interest that has led to a number of developments, including the observation of ultra-narrow (1-Hz) magneto-optical resonances, applications in sensitive magnetometry, nonlinear magneto-optical tomography, and the possibility of a search for parity- and time-reversal-invariance violation in atoms.Comment: 51 pages, 23 figures, to appear in Rev. Mod. Phys. in Oct. 2002, Figure added, typos corrected, text edited for clarit

Overcoming the blood–brain barrier: the role of nanomaterials in treating neurological diseases

Therapies directed toward the central nervous system remain difficult to translate into improved clinical outcomes. This is largely due to the blood–brain barrier (BBB), arguably the most tightly regulated interface in the human body, which routinely excludes most therapeutics. Advances in the engineering of nanomaterials and their application in biomedicine (i.e., nanomedicine) are enabling new strategies that have the potential to help improve our understanding and treatment of neurological diseases. Herein, the various mechanisms by which therapeutics can be delivered to the brain are examined and key challenges facing translation of this research from benchtop to bedside are highlighted. Following a contextual overview of the BBB anatomy and physiology in both healthy and diseased states, relevant therapeutic strategies for bypassing and crossing the BBB are discussed. The focus here is especially on nanomaterial‐based drug delivery systems and the potential of these to overcome the biological challenges imposed by the BBB. Finally, disease‐targeting strategies and clearance mechanisms are explored. The objective is to provide the diverse range of researchers active in the field (e.g., material scientists, chemists, engineers, neuroscientists, and clinicians) with an easily accessible guide to the key opportunities and challenges currently facing the nanomaterial‐mediated treatment of neurological diseases

Osteopontin induces growth of metastatic tumors in a preclinical model of non-small lung cancer

Osteopontin (OPN), also known as SPP1 (secreted phosphoprotein), is an integrin binding glyco-phosphoprotein produced by a variety of tissues. In cancer patients expression of OPN has been associated with poor prognosis in several tumor types including breast, lung, and colorectal cancers. Despite wide expression in tumor cells and stroma, there is limited evidence supporting role of OPN in tumor progression and metastasis. Using phage display technology we identified a high affinity anti-OPN monoclonal antibody (hereafter AOM1). The binding site for AOM1 was identified as SVVYGLRSKS sequence which is immediately adjacent to the RGD motif and also spans the thrombin cleavage site of the human OPN. AOM1 efficiently inhibited OPNa binding to recombinant integrin αvβ3 with an IC50 of 65 nM. Due to its unique binding site, AOM1 is capable of inhibiting OPN cleavage by thrombin which has been shown to produce an OPN fragment that is biologically more active than the full length OPN. Screening of human cell lines identified tumor cells with increased expression of OPN receptors (αvβ3 and CD44v6) such as mesothelioma, hepatocellular carcinoma, breast, and non-small cell lung adenocarcinoma (NSCLC). CD44v6 and αvβ3 were also found to be highly enriched in the monocyte, but not lymphocyte, subset of human peripheral blood mononuclear cells (hPBMCs). In vitro, OPNa induced migration of both tumor and hPBMCs in a transwell migration assay. AOM1 significantly blocked cell migration further validating its specificity for the ligand. OPN was found to be enriched in mouse plasma in a number of pre-clinical tumor model of non-small cell lung cancers. To assess the role of OPN in tumor growth and metastasis and to evaluate a potential therapeutic indication for AOM1, we employed a KrasG12D-LSLp53fl/fl subcutaneously implanted in vivo model of NSCLC which possesses a high capacity to metastasize into the lung. Our data indicated that treatment of tumor bearing mice with AOM1 as a single agent or in combination with Carboplatin significantly inhibited growth of large metastatic tumors in the lung further supporting a role for OPN in tumor metastasis and progression

Ultrasound-Enhanced Drug Transport and Distribution in the Brain

Drug delivery in the brain is limited by slow drug diffusion in the brain tissue. This study tested the hypothesis that ultrasound can safely enhance the permeation of drugs in the brain. In vitro exposure to ultrasound at various frequencies (85 kHz, 174 kHz, and 1 MHz) enhanced the permeation of tritium-labeled molecules with molecular weight up to 70 kDa across porcine brain tissue. A maximum enhancement of 24-fold was observed at 85 kHz and 1,200 J/cm2. In vivo exposure to 1-MHz ultrasound further demonstrated the ability of ultrasound to facilitate molecule distribution in the brain of a non-human primate. Finally, ultrasound under conditions similar to those used in vivo was shown to cause no damage to plasmid DNA, siRNA, adeno-associated virus, and fetal rat cortical neurons over a range of conditions. Altogether, these studies demonstrate that ultrasound can increase drug permeation in the brain in vitro and in vivo under conditions that did not cause detectable damage

Alpha-aminoisobutyric acid uptake in primary cultures of astrocytes

Homotypically pure cultures of rat brain astrocytes were used to examine some aspects of non-neuronal A-system (alanine preferring) amino acid uptake. The Asystem specific probe, alpha-aminoisobutyric acid is transported rapidly, and a steady state distribution ratio of 9–25 is reached after 30 minute incubations. Kinetic estimates derived from uptake progress curves indicated a K m of 1.35 mM and a V max of 133 nmol/min/mg protein. Uptake is reduced in the absence of either Na + or K + . Elevations in extracellular K + , a putative metabolic modulator of neuroglia, did not affect uptake.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45428/1/11064_2004_Article_BF00965086.pd

Revisiting the five-facet structure of mindfulness

The current study aimed to replicate the development of the Five-Facet Mindfulness Questionnaire (FFMQ) in a sample of 399 undergraduate students. We factor analyzed the Mindful Attention and Awareness Questionnaire (MAAS), the Freiburg Mindfulness Scale, the Southampton Mindfulness Questionnaire (SMQ), the Cognitive Affective Mindfulness Scale Revised (CAMS-R), and the Kentucky Inventory of Mindfulness Skills (KIMS), but also extended the analysis by including a conceptually related measure, the Philadelphia Mindfulness Scale (PHLMS), and a conceptually unrelated measure, the Langer Mindfulness Scale (LMS). Overall, we found a partial replication of the five-factor structure, with the exception of non-reacting and non-judging which formed a single factor. The PHLMS items loaded as expected with theoretically related factors, whereas the LMS items emerged as separate factor. Finally, we found a new factor that was mostly defined by negatively worded items indicating possible item wording artifacts within the FFMQ. Our conceptual validation study indicates that some facets of the FFMQ can be recovered, but item wording factors may threaten the stability of these facets. Additionally, measures such as the LMS appear to measure not only theoretically, but also empirically different constructs