Characteristics of compounds that cross the blood-brain barrier

Substances cross the blood-brain barrier (BBB) by a variety of mechanisms. These include transmembrane diffusion, saturable transporters, adsorptive endocytosis, and the extracellular pathways. Here, we focus on the chief characteristics of two mechanisms especially important in drug delivery: transmembrane diffusion and transporters. Transmembrane diffusion is non-saturable and depends, on first analysis, on the physicochemical characteristics of the substance. However, brain-to-blood efflux systems, enzymatic activity, plasma protein binding, and cerebral blood flow can greatly alter the amount of the substance crossing the BBB. Transport systems increase uptake of ligands by roughly 10-fold and are modified by physiological events and disease states. Most drugs in clinical use to date are small, lipid soluble molecules that cross the BBB by transmembrane diffusion. However, many drug delivery strategies in development target peptides, regulatory proteins, oligonucleotides, glycoproteins, and enzymes for which transporters have been described in recent years. We discuss two examples of drug delivery for newly discovered transporters: that for phosphorothioate oligonucleotides and for enzymes

A Physiological Role for Amyloid Beta Protein: Enhancement of Learning and Memory

Amyloid beta protein (A[beta]) is well recognized as having a significant role in the pathogenesis of Alzheimer's disease (AD). The reason for the presence of A[beta] and its physiological role in non-disease states is not clear. In these studies, low doses of A[beta] enhanced memory retention in two memory tasks and enhanced acetylcholine production in the hippocampus _in vivo_. We then tested whether endogenous A[beta] has a role in learning and memory in young, cognitively intact mice by blocking endogenous A[beta] in healthy 2-month-old CD-1 mice. Blocking A[beta] with antibody to A[beta] or DFFVG (which blocks A[beta] binding) or decreasing A[beta] expression with an antisense directed at the A[beta] precursor APP all resulted in impaired learning in T-maze foot-shock avoidance. Finally, A[beta]1-42 facilitated induction and maintenance of long term potentiation in hippocampal slices, whereas antibodies to A[beta] inhibited hippocampal LTP. These results indicate that in normal healthy young animals the presence of A[beta] is important for learning and memory

Vacuum infusion of natural fibre composites for structural applications

Numerous methods of manufacturing natural fibre composites have been reported in the literature, including compression moudling, often in conjunction with a hot press. Other forms of composite manufacture include 'Vacuum Assisted Resin Transfer Moulding' (VATRM) and the 'Seemann Composite Resin Infusion Moulding Process' (SCRIMP). These methods have been reported to produce natural fibre composies with reasonable mechanical properties [1-2]. In this paper, a vacuum infusion rig is described that has been developed to produce consistent quality composite plates for studies into optimising natural fibre composites. The process aims to harness the benefits of vacuum infusion and compression moulding, where vacuum infusion encourages the removal of trapped air in the system and hence avoid reduction, and additional compression moulding can help to achieve high volume fractions that are otherwise difficult in other processes

Mechanical testing of natural fibre reinforced polyester resin composites and Mode 1 fracture toughness testing of resin blocks

Recent European Parliament directive requires companies to achieve materials recycling greater than 80% in particular in the automotive sector [1]. The research on natural fibre based composite materials fits well into this ecological image. The advantages of natural fibres over synthetic materials include, low density, relative cheapness, availability and biodegradability. In this paper we explore the fabrication and mechanical testing of natural fibre composites and this is part of an on going study at Strathclyde University and describes the fabrication of composites using natural fibre and styrene polyester resin. The properties of the synthetic resin can be varied by changing the catalysts concentration and flexural (three point bending) and single-edged notched bending (SENB) properties are reported at different concentrations of the catalyst

The effect of alkalisation on the mechanical properties of natural fibres

A study on the effect of alkalisaton using 3% NaOH solution was carried out on Flax, Kenaf, Abaca and Sisal to observe the impact that the common pre-treatment process has on fibre mechanical properties. The result of the investigation indicated that over-treatment of natural fibres using NaOH could have a negative effect on the base fibre properties. It is concluded that a treatment time of less than 10 minutes is sufficient to remove hemicelluloses and to give the optimum effect

Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by luminal microvessel IL-6 and GM-CSF

Elevated levels of cytokines/chemokines contribute to increased neuroinvasion of human immunodeficiency virus type 1 (HIV-1). Previous work showed that lipopolysaccharide (LPS), which is present in the plasma of patients with HIV-1, enhanced transcellular transport of HIV-1 across the blood-brain barrier (BBB) through the activation of p38 mitogen-activated protein kinase (MAPK) signaling in brain microvascular endothelial cells (BMECs). Here, we found that LPS (100 μg/mL, 4 hr) selectively increased interleukin (IL)-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) release from BMECs. The enhancement of HIV-1 transport induced by luminal LPS was neutralized by treatment with luminal, but not with abluminal, antibodies to IL-6 and GM-CSF without affecting paracellular permeability as measured by transendothelial electrical resistance (TEER). Luminal, but not abluminal, IL-6 or GM-CSF also increased HIV-1 transport. U0126 (MAPK kinase (MEK)1/2 inhibitor) and SB203580 (p38 MAPK inhibitor) decreased the LPS-enhanced release of IL-6 and GM-CSF. These results show that p44/42 and p38 MAPK signaling pathways mediate the LPS-enhanced release of IL-6 and GM-CSF. These cytokines, in turn, act at the luminal surface of the BMEC to enhance the transcellular transport of HIV-1 independently of actions on paracellular permeability

Squares from products of integers

This is a preprint of an article published in the Gazette of the Australian Mathematical Society, 31 (2004) no.1, pp.40-42.Notice that 1_2_3_4+1 = 52 , 2_3_4_5+1 = 112 , 3_4_5_6+1 = 192 , . . . . Indeed, it is well known that the product of any four consecutive integers always differs by one from a perfect square. However, a little experimentation readily leads one to guess that there is no integer n, other than four, so that the product of any n consecutive integers always differs from a perfect square by some fixed integer c = c(n) depending only on n. The two issues that are present here can be readily dealt with. The apparently special status of the number four arises from the fact that any quadratic polynomial can be completed by a constant to become the square of a polynomial. Second, [5] provides an elegant proof that there is in fact no integer n larger than four with the property stated above. In [5] one finds a reminder that a polynomial taking too many square values must be the square of a polynomial (see [4, Chapter VIII.114 and .190], and [2]). One might therefore ask whether there are polynomials other than integer multiples of x(x + 1)(x + 2)(x + 3) and 4x(x + 1), with integer zeros and differing by a nonzero constant from the square of a polynomial. We will show that this is quite a good question in that it has a nontrivial answer, inter alia giving new insight into the results of [5]

Polymer Bound Elastase Inhibitors

Pharmaceutical compositions and methods of inhibiting the enzyme elastase and increasing the biological half-life and/or potency in terms of inhibitory activity of the enzyme elastase of peptide compounds is achieved by use of a polymer of the formula P--(L--R)q wherein P is a polymer containing at least one unit of the formula (An Bn) wherein An Bn is substantially nonbiodegradable, and has an average molecular weight of about 1,000 to 5,000 daltons, L is a covalent bond or a linker group and R is a peptide