The Promise and Perils of CNS Drug Delivery: A Video Debate

Neurodegenerative and infectious disorders related to host genetics, aging, and environment are rapidly increasing. Drugs, vaccines, or regenerative proteins offer “real” possibilities for positively affecting disease outcomes but are limited by access across the blood-brain barrier. New developments in nanomedicine and cell based drug delivery are becoming available. These discoveries can lead to improved neurological disease outcomes. Such obstacles include the toxicities inherent in the delivery systems de novo such as immuno- and neurological dysfunctions and perturbations of blood-brain barrier function. This debate by leading experts in the field highlights the promise and perils of CNS drug delivery. Click on Supplemental HTML to watch the streaming video

Viewing Ageing Eyes: Diverse Sites of Amyloid Beta Accumulation in the Ageing Mouse Retina and the Up-Regulation of Macrophages

Amyloid beta (Aβ) accumulates in the ageing central nervous system and is associated with a number of age-related diseases, including age-related macular degeneration (AMD) in the eye. AMD is characterised by accumulation of extracellular deposits called drusen in which Aβ is a key constituent. Aβ activates the complement cascade and its deposition is associated with activated macrophages. So far, little is known about the quantitative measurements of Aβ accumulation and definitions of its relative sites of ocular deposition in the normal ageing mouse. METHODOLOGY/PRINCIPAL FINDINGS: We have traced Aβ accumulation quantitatively in the ageing mouse retina using immunohistochemistry and Western blot analysis. We reveal that it is not only deposited at Bruch's membrane and along blood vessels, but unexpectedly, it also coats photoreceptor outer segments. While Aβ is present at all sites of deposition from 3 months of age, it increases markedly from 6 months onward. Progressive accumulation of deposits on outer segments was confirmed with scanning electron microscopy, revealing age-related changes in their morphology. Such progress of accumulation of Aβ on photoreceptor outer segments with age was also confirmed in human retinae using immunohistochemistry. We also chart the macrophage response to increases in Aβ showing up-regulation in their numbers using both confocal laser imaging of the eye in vivo followed by in vitro immunostaining. With age macrophages become bloated with cellular debris including Aβ, however, their increasing numbers fail to stop Aβ accumulation. CONCLUSIONS: Increasing Aβ deposition in blood vessels and Bruch's membrane will impact upon retinal perfusion and clearance of cellular waste products from the outer retina, a region of very high metabolic activity. This accumulation of Aβ may contribute to the 30% reduction of photoreceptors found throughout life and the shortening of those that remain. The coating of Aβ on outer segments may also have an impact upon visual function with ag

Fusobacterium necrophorum causando endocardite infecciosa e abscesso hepático e esplênico

A 25-year-old male without prior co-morbidities was admitted to hospital with Fusobacterium necrophorum bacteremia, where he was found to have liver and splenic abscesses. Further evaluation with echocardiography revealed a bicuspid aortic valve with severe insufficiency and a 1.68 x 0.86 cm vegetation. The patient required abscess drainage, intravenous antimicrobial therapy and aortic valve replacement. Complete resolution of the infection was achieved after valve replacement and a prolonged course of intravenous antimicrobial therapy. A brief analysis of the patient's clinical course and review of the literature is presented.Homem de 25 anos de idade, sem antecedentes mórbidos foi admitido ao hospital com bacteremia por Fusobacterium necrophorum e abscessos no fígado e no baço. Avaliação posterior com ecografia revelou válvula aórtica bicúspide com insuficiência severa e vegetação de 1,68 x 0,86 cm. Foi feita drenagem dos abscessos, terapia antimicrobiana intravenosa e substituição da válvula aórtica. Resolução completa da infecção foi conseguida após substituição valvular e curso prolongado de terapêutica intravenosa antimicrobiana. É apresentada breve análise do curso clínico do paciente e revisão da literatura

Applicability and Limitations of Simplified Elastic Shell Theories for Vibration Modelling of Double-Walled Carbon Nanotubes

The applicability and limitations of simplifiedmodels of thin elastic circular cylindrical shells for linear vibrations of double-walled carbon nanotubes (DWCNTs) are considered. The simplified models, which are based on the assumptions of membrane and moment approximate thin-shell theories, are compared with the extended Sanders–Koiter shell theory. Actual discrete DWCNTs are modelled by means of couples of concentric equivalent continuous thin, circular cylindrical shells. Van der Waals interaction forces between the layers are taken into account by adopting He’s model. Simply supported and free–free boundary conditions are applied. The Rayleigh–Ritz method is considered to obtain approximate natural frequencies and mode shapes. Different aspect and thickness ratios, and numbers of waves along longitudinal and circumferential directions, are analysed. In the cases of axisymmetric and beam-like modes, it is proven that membrane shell theory, differently from moment shell theory, provides results with excellent agreement with the extended Sanders–Koiter shell theory. On the other hand, in the case of shell-like modes, it is found that both membrane and moment shell theories provide results reporting acceptable agreement with the extended Sanders–Koiter shell theory only for very limited ranges of geometries and wavenumbers. Conversely, for shell-like modes it is found that a newly developed, simplified shell model, based on the combination of membrane and semi-moment theories, provides results in satisfactory agreement with the extended Sanders–Koiter shell theory in all ranges

Universal Scaling Laws for Shear Induced Dilation in Frictional Granular Media

Compressed frictional granular matter cannot flow without dilation. Upon forced shearing to generate flow, the amount of dilation may depend on the initial preparation and a host of material variables. On the basis of both experiments and numerical simulations we show that as a result of training by repeated compression-decompression cycles the amount of dilation induced by shearing the system depends only on the shear rate and on the (pre-shearing) packing fraction. Relating the rheological response to structural properties allows us to derive a scaling law for the amount of dilation after $n$ cycles of compression-decompression. The resulting scaling law has a universal exponent that for trained systems is independent of the inter-granules force laws, friction parameters and strain rate. The amplitude of the scaling law is analytically computable, and it depends only on the shear rate and the asymptotic packing fraction.Comment: 8 pages, 10 figures, Published Versio

Heat Conduction in One-Dimensional chain of Hard Discs with Substrate Potential

Heat conduction of one-dimensional chain of equivalent rigid particles in the field of external on-site potential is considered. Zero diameters of the particles correspond to exactly integrable case with divergent heat conduction coefficient. By means of simple analytical model it is demonstrated that for any nonzero particle size the integrability is violated and the heat conduction coefficient converges. The result of the analytical computation is verified by means of numerical simulation in a plausible diapason of parameters and good agreement is observedComment: 14 pages, 7 figure

17-AAG Induces Cytoplasmic α-Synuclein Aggregate Clearance by Induction of Autophagy

The accumulation and aggregation of α-synuclein in nerve cells and glia are characteristic features of a number of neurodegenerative diseases termed synucleinopathies. α-Synuclein is a highly soluble protein which in a nucleation dependent process is capable of self-aggregation. The causes underlying aggregate formation are not yet understood, impairment of the proteolytic degradation systems might be involved.Cl the aggregate clearing effects of 17-AAG were abolished and α-synuclein deposits were enlarged. Analysis of LC3-II immunoreactivity, which is an indicator of autophagosome formation, further revealed that 17-AAG led to the recruitment of LC3-II and to the formation of LC3 positive puncta. This effect was also observed in cultured oligodendrocytes derived from the brains of newborn rats. Inhibition of macroautophagy by 3-methyladenine prevented 17-AAG induced occurrence of LC3 positive puncta as well as the removal of α-synuclein aggregates in OLN-A53T cells.Our data demonstrate for the first time that 17-AAG not only causes the upregulation of heat shock proteins, but also is an effective inducer of the autophagic pathway by which α-synuclein can be removed. Hence geldanamycin derivatives may provide a means to modulate autophagy in neural cells, thereby ameliorating pathogenic aggregate formation and protecting the cells during disease and aging