Overcoming the blood-brain barrier to taxane delivery for brain tumors and neurodegenerative diseases and brain tumors

The original publication is available at www.springerlink.comThe blood-brain barrier (BBB) effectively prevents microtubule stabilizing drugs from readily entering the central nervous system (CNS). A major limiting factor for microtubule stabilizing drug permeation across the BBB is the active efflux back into the circulation by the over-expression of the multidrug resistant gene product (MDR1) or P-glycoprotein (P-gp). This study has focused on strategies to overcome P-gp-mediated efflux of taxol analogues, microtubule (MT) stabilizing agents that could be used to treat brain tumors and, potentially, neurodegenerative diseases such as Alzheimer’s disease. However, taxol is a strong P-gp substrate which limits its distribution across the BBB and therapeutic potential in the CNS. We have found that addition of a succinate group to the C-10 position of taxol results in an agent, Tx-67, with reduced interactions with P-gp and enhanced permeation across the BBB in both in vitro and in situ models. Our studies demonstrate the feasibility of making small chemical modifications to taxol to generate analogues with reduced affinity for the P-gp but retention of MT-stabilizing properties, i.e., a taxane that may reach and treat therapeutic targets in the CNS

Hearing Threshold of Korean Adolescents Associated with the Use of Personal Music Players

Purpose: Hearing loss can lead to a number of disabilities and can reduce quality of life. Noise-induced hearing losses have become more common among adolescents due to increased exposure to personal music players. We, therefore, investigated the use of personal music player among Korean adolescents and the relationship between hearing threshold and usage pattern of portable music players. Materials and Methods: A total of 490 adolescents were interviewed personally regarding their use of portable music players, including the time and type of player and the type of headphone used. Pure tone audiometry was performed in each subject. Results: Of the 490 subjects, 462 (94.3%) used personal music players and most of them have used the personal music player for 1-3 hours per day during 1-3 years. The most common type of portable music player was the MP3 player, and the most common type of headphone was the earphone (insert type). Significant elevations of hearing threshold were observed in males, in adolescents who had used portable music players for over 5 years, for those over 15 years in cumulative period and in those who had used earphones. Conclusion: Portable music players can have a deleterious effect on hearing threshold in adolescents. To preserve hearing, adolescents should avoid using portable music players for long periods of time and should avoid using earphones

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis

A comprehensive literature search was performed to collate evidence of mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations: ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (∼0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD. Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD. Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although improvements were noted in some studies with carnitine, co-enzyme Q10 and B-vitamins. Many studies suffered from limitations, including small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers and defining MD. Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD

VLF measurements and modeling of the D-region response to the 2017 total solar eclipse

Abstract In this paper, we report measurements in Colorado and Utah of the disturbed very-low-frequency (VLF) signals from the NML Navy transmitter in North Dakota during the 2017 solar eclipse. Using an occultation mask of solar fluxes together with detailed chemistry and VLF propagation simulations, we quantify the D-region response to the eclipse, in terms of electron density variation, as well as the expected signatures of VLF transmitter signals. The VLF measurements, including an anomalous amplitude enhancement recorded in UT, can be quantitatively explained using the Wait and Spies ionospheric profile with a sharpness parameter of β = 0.3 km⁻¹ above ~55 km and an increase in the D-region ionosphere height of Δh′ ≃ 8 km. This sharpness parameter is consistent with previously reported rocket measurements and first-principles calculations. The best-fit results suggest a reduction of D-region electron density by ~90% during the eclipse in the D-region, implying an occultation of Lyman-α by nearly 99%. This finding agrees with detailed calculations of time-dependent obscuration factors utilizing the He 30.4-nm images from Solar Dynamics Observatory as a proxy for the distribution of Lyman-α across the solar disk and limb. Moreover, the present results show that subionospheric VLF propagation is sensitive to the sharpness parameter of the electron density profile in the D-region. Previously reported first-principles simulations have shown that the sharpness parameter is mostly controlled by the background concentration of minor neutral species. Thus, the VLF technique can be likely used to remotely sense these neutral species at and below the effective reflection altitudes of VLF waves

Single-site chemical modification at C10 of the baccatin III core of paclitaxel and Taxol C reduces P-glycoprotein interactions in bovine brain microvessel endothelial cells

A single-site modification of paclitaxel analogs at the C10 position on the baccatin III core that reduces interaction with P-glycoprotein in bovine brain microvessel endothelial cells is described. Modification and derivatization of the C10 position were carried out using a substrate controlled hydride addition to a key C9 and C10 diketone intermediate. The analogs were tested for tubulin assembly and cytotoxicity, and were shown to retain potency similar to paclitaxel. P-glycoprotein interaction was examined using a rhodamine assay and it was found that simple hydrolysis or epimerization of the C10 acetate of paclitaxel and Taxol C can reduce interaction with the P-glycoprotein transporter that may allow for increased permeation of taxanes into the brain