The levels of neopterin, biopterin and the neopterin/biopterin ratio in urine from control subjects and patients with Alzheimer’s disease and Down’s syndrome

The levels of neopterin, biopterin and the neopterin/biopterin ratio (N/B) were measured in urine samples taken from normal young and elderly control subjects, exceptionally healthy elderly control subjects classified according to the ‘Senieur’ protocol and patients with Down’s syndrome (DS) or Alzheimer’s disease (AD). The N/B ratio was approximately unity in control groups with the exception of the normal elderly controls. The levels of neopterin and biopterin declined with age in the exceptionally healthy ‘Senieur’ control group. The N/B ratio was elevated in young and old DS patients as a result of the significant increase in neopterin. Neopterin levels were significantly elevated in AD patients compared with the healthy elderly controls, but this did not result in a significant increase in the N/B ratio in these patients. The N/B ratio increased with age in AD patients as a result of a decline in biopterin. These results suggested that there is a cellular immune reponse in DS and AD patients which in DS, may precede the formation of beta-amyloid deposits in the brain. In addition, there may be a deficiency in tetrahydrobiopterin biosynthesis in AD which becomes more marked with age.

Elevated urinary neopterin suggests immune activation in Alzheimer’s disease and Down’s syndrome

Neopterin, an unconjugated pteridine, is secreted in large quantities by activated macrophages and can be used as a clinical marker of activated cellular immunity in a patient. Hence, neopterin levels were measured in urine samples taken from patients with Down’s syndrome (DS), non-hospitalized and hospitalized Alzheimer’s disease (AD) and age and sex matched controls. All subjects and patients were free from infectious and malignant disease. A significant effect of age on urinary neopterin levels was found in control subjects, levels being greater in younger and older subjects. No significant trends with age were found in AD and DS patients. The mean level of neopterin was significantly increased in DS and AD compared with age matched controls suggesting immune activation in these patients. In DS, elevated neopterin levels were present in individuals at least 17yrs old suggesting that immune activation could be associated with the initial deposition of beta/A4 in the brain.

Actin binding proteins:their ups and downs in metastatic life

In order to metastasize away from the primary tumor site and migrate into adjacent tissues, cancer cells will stimulate cellular motility through the regulation of their cytoskeletal structures. Through the coordinated polymerization of actin filaments, these cells will control the geometry of distinct structures, namely lamella, lamellipodia and filopodia, as well as the more recently characterized invadopodia. Because actin binding proteins play fundamental functions in regulating the dynamics of actin polymerization, they have been at the forefront of cancer research. This review focuses on a subset of actin binding proteins involved in the regulation of these cellular structures and protrusions, and presents some general principles summarizing how these proteins may remodel the structure of actin. The main body of this review aims to provide new insights into how the expression of these actin binding proteins is regulated during carcinogenesis and highlights new mechanisms that may be initiated by the metastatic cells to induce aberrant expression of such proteins. © 2013 Landes Bioscience.

Prodrugs of antiviral phosphonates

Phosphonoformate and phosphonoacetate are effective antiviral agents, however they are charged at physiological pH and as such penetration into cells and diffusion across the blood-brain bamer is limited. In an attempt to increase the lipophilicity and improve the transport properties of these molecules, prodrugs were synthesised and their stabilities and reconversion to the parent compound subsequently investigated by the techniques of 31P nuclear magnetic resonance spectroscopy and high performance liquid Chromatography. A series of 4-substituted dibenzyl (methoxycarbonyl)phosphonates were prepared and found to be hydrolytically unstable giving predominantly the diesters, benzyl (methoxycarbonyl)phosphonates. This instability arose from the electron-withdrawing effect of the carbonyl group promoting nucleophilic attack at phosphorus. It was possible to influence the mechanism and, to some extent, the rate of hydrolysis of the phosphonoformate triesters to the diesters by varying the electronic nature of the substituent in the 4-position of the aromatic ring. Strongly electron-withdrawing groups increased the sensitivity of phosphorus to nucleophilic attack, thus promoting P-O .bond cleavage and rapid hydrolysis. Conversely, weakly electron-withdrawing substituents encouraged C-O bond fission, presumably through resonance stabilisation of the benzyl carbonium ion. The loss of the protecting group on phosphorus was in competition with nucleophilic attack at the carbonyl group, resulting in P-C bond cleavage with dibenzyl phosphite formation. The high instability and P-C bond fission make triesters unsuitable prodrug forms of phosphonoformate. A range of chemically stable triesters of phosphonoacetate were synthesised and their bioactivation investigated. Di(benzoyloxymethyl) (methoxycarbonylmethyl)phosphonates degraded to the relevant benzoyloxymethyl (methoxycarbonylmethyl)phosphonate in the presence of esterase. The enzymatic activation was restricted to the removal of only one protecting group from phosphorus, most likely due to the close proximity of the benzoyloxy ester function to the anionic charge on the diester. However, in similar systems di(4-alkanoyloxybenzyl) (methoxycarbonylmethyl)phosphonates degraded in the presence of esterase with the loss of both protecting groups on phosphorus to give the monoester, (methoxycarbonylmethyl)phosphonate, via the intermediary of the unstable 4-hydroxy benzyl esters. The methoxycarbonyl function remained intact. The rate of enzymatic hydrolysis and subsequent removal of the protecting groups on phosphorus was dependent on the nature of the alkanoyl group and was most rapid for the 4-nbutanoyloxybenzyl and 4-iso-butanoyloxybenzyl esters of phosphonoacetate. This provides a strategy for the design of a prodrug with sufficient stability in plasma to reach the central nervous system in high concentration, wherein rapid metabolism to the active drug by brain-associated enzymes occurs.

Temporal lobe pathology in neurodegenerative disease:a comparative study of eight disorders with special reference to the hippocampus

The temporal lobe is a major site of pathology in a number of neurodegenerative diseases. In this chapter, the densities of the characteristic pathological lesions in various regions of the temporal lobe were compared in eight neurodegenerative disorders, viz., Alzheimer’s disease (AD), Down’s syndrome (DS), dementia with Lewy bodies (DLB), Pick’s disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), sporadic Creutzfeldt-Jakob disease (sCJD), and neuronal intermediate filament inclusion disease (NIFID). Temporal lobe pathology was observed in all of these disorders most notably in AD, DS, PiD, sCJD, and NIFID. The regions of the temporal lobe affected by the pathology, however, varied between disorders. In AD and DS, the greatest densities of ?-amyloid (A?) deposits were recorded in cortical regions adjacent to the hippocampus (HC), DS exhibiting greater densities of A? deposits than AD. Similarly, in sCJD, greatest densities of prion protein (PrPsc) deposits were recorded in cortical areas of the temporal lobe. In AD and PiD, significant densities of neurofibrillary tangles (NFT) and Pick bodies (PB) respectively were present in sector CA1 of the HC while in CBD, the greatest densities of tau-immunoreactive neuronal cytoplasmic inclusions (NCI) were present in the parahippocampal gyrus (PHG). Particularly high densities of PB were present in the DG in PiD, whereas NFT in AD and Lewy bodies (LB) in DLB were usually absent in this region. These data confirm that the temporal lobe is an important site of pathology in the disorders studied regardless of their molecular ‘signature’. However, disorders differ in the extent to which the pathology spreads to affect the HC which may account for some of the observed differences in clinical dementia.

Impact of Raman amplification on a 2 Tb/s coherent WDM system

The impact of hybrid erbium-doped fiber amplifier (EDFA)/Raman amplification on a spectrally efficient coherent-wavelength-division-multiplexed (CoWDM) optical communication system is experimentally studied and modeled. Simulations suggested that 23-dB Raman gain over an unrepeatered span of 124 km single-mode fiber would allow a decrease of the mean input power of ~6 dB for a fixed bit-error rate (BER). Experimentally we demonstrated 1.2-dB Q-factor improvement for a 2-Tb/s seven-band CoWDM with backward Raman amplification. The system delivered an optical signal-to-noise ratio of 35 dB at the output of the receiver preamplifier providing a worst-case BER of 2 × 10 -6 over 49 subcarriers at 42.8 Gbaud, leaving a system margin (in terms of Q -factor) of ~4 dB from the forward-error correction threshold.

All-optical OFDM and distributed Raman amplification : challenges to enable high capacities and extend reach

We review recent advances in all-optical OFDM technologies and discuss the performance of a field trial of a 2 Tbit/s Coherent WDM over 124 km with distributed Raman amplification. The results indicate that careful optimisation of the Raman pumps is essential. We also consider how all-optical OFDM systems perform favourably against energy consumption when compared with alternative coherent detection schemes. We argue that, in an energy constrained high-capacity transmission system, direct detected all-optical OFDM with `ideal' Raman amplification is an attractive candidate for metro area datacentre interconnects with ~100 km fibre spans, with an overall energy requirement at least three times lower than coherent detection techniques.

Unilateral versus coordinated effects:comparing the impact on consumer welfare of alternative merger outcomes

The nature of tacitly collusive behaviour often makes coordination unstable, and this may result in periods of breakdown, during which consumers benet from reduced prices. This is allowed for by adding demand uncertainty to the Compte et al. (2002) model of tacit collusion amongst asymmetric rms. Breakdowns occur when a rm cannot exclude the possibility of a deviation by a rival. It is then possible that an outcome with collusive behaviour, subject to long/frequent break downs, can improve consumer welfare compared to an alternative with sustained unilateral conduct. This is illustrated by re-examining the Nestle/Perrier merger analyzed by Compte et al., but now also taking into account the potential for welfare losses arising from unilateral behaviour.

Unilateral versus coordinated effects:comparing the impact on consumer welfare of alternative merger outcomes

The nature of tacitly collusive behaviour often makes coordination unstable, and this may result in periods of breakdown, during which consumers benefit from reduced prices. This is allowed for by adding demand uncertainty to the Compte et al. (2002) model of tacit collusion amongst asymmetric firms. Breakdowns occur when a firm cannot exclude the possibility of a deviation by a rival. It is then possible that an outcome with collusive behaviour, subject to long/frequent break downs, can improve consumer welfare compared to an alternative with sustained unilateral conduct. This is illustrated by re-examining the Nestle/Perrier merger analyzed by Compte et al., but now also taking into account the potential for welfare losses arising from unilateral behaviour.

Predicting the effect of mixing on oxygen transfer and nutrient removal in activated sludge basins

Activated sludge basins (ASBs) are a key-step in wastewater treatment processes that are used to eliminate biodegradable pollution from the water discharged to the natural environment. Bacteria found in the activated sludge consume and assimilate nutrients such as carbon, nitrogen and phosphorous under specific environmental conditions. However, applying the appropriate agitation and aeration regimes to supply the environmental conditions to promote the growth of the bacteria is not easy. The agitation and aeration regimes that are applied to activated sludge basins have a strong influence on the efficacy of wastewater treatment processes. The major aims of agitation by submersible mixers are to improve the contact between biomass and wastewater and the prevention of biomass settling. They induce a horizontal flow in the oxidation ditch, which can be quantified by the mean horizontal velocity. Mean values of 0.3-0.35 m s-1 are recommended as a design criteria to ensure best conditions for mixing and aeration (Da Silva, 1994). To give circulation velocities of this order of magnitude, the positioning and types of mixers are chosen from the plant constructors' experience and the suppliers' data for the impellers. Some case studies of existing plants have shown that measured velocities were not in the range that was specified in the plant design. This illustrates that there is still a need for design and diagnosis approach to improve process reliability by eliminating or reducing the number of short circuits, dead zones, zones of inefficient mixing and poor aeration. The objective of the aeration is to facilitate the quick degradation of pollutants by bacterial growth. To achieve these objectives a wastewater treatment plant must be adequately aerated; thus resulting in 60-80% of all energetic consummation being dedicated to the aeration alone (Juspin and Vasel, 2000). An earlier study (Gillot et al., 1997) has illustrated the influence that hydrodynamics have on the aeration performance as measure by the oxygen transfer coefficient. Therefore, optimising the agitation and aeration systems can enhance the oxygen transfer coefficient and consequently reduce the operating costs of the wastewater treatment plant. It is critically important to correctly estimate the mass transfer coefficient as any errors could result in the simulations of biological activity not being physically representative. Therefore, the transfer process was rigorously examined in several different types of process equipment to determine the impact that different hydrodynamic regimes and liquid-side film transfer coefficients have on the gas phase and the mass transfer of oxygen. To model the biological activity occurring in ASBs, several generic biochemical reaction models have been developed to characterise different biochemical reaction processes that are known as Activated Sludge Models, ASM (Henze et al., 2000). The ASM1 protocol was selected to characterise the impact of aeration on the bacteria consuming and assimilating ammonia and nitrate in the wastewater. However, one drawback of ASM protocols is that the hydrodynamics are assumed to be uniform by the use of perfectly mixed, plug flow reactors or as a number of perfectly mixed reactors in series. This makes it very difficult to identify the influence of mixing and aeration on oxygen mass transfer and biological activity. Therefore, to account for the impact of local gas-liquid mixing regime on the biochemical activity Computational Fluid Dynamics (CFD) was used by applying the individual ASM1 reaction equations as the source terms to a number of scalar equations. Thus, the application of ASM1 to CFD (FLUENT) enabled the investigation of the oxygen transfer efficiency and the carbon & nitrogen biological removal in pilot (7.5 cubic metres) and plant scale (6000 cubic metres) ASBs. Both studies have been used to validate the effect that the hydrodynamic regime has on oxygen mass transfer (the circulation velocity and mass transfer coefficient) and the effect that this had on the biological activity on pollutants such as ammonia and nitrate (Cartland Glover et al., 2005). The work presented here is one part to of an overall approach for improving the understanding of ASBs and the impact that they have in terms of the hydraulic and biological performance on the overall wastewater treatment process. References CARTLAND GLOVER G., PRINTEMPS C., ESSEMIANI K., MEINHOLD J., (2005) Modelling of wastewater treatment plants ? How far shall we go with sophisticated modelling tools? 3rd IWA Leading-Edge Conference & Exhibition on Water and Wastewater Treatment Technologies, 6-8 June 2005, Sapporo, Japan DA SILVA G. (1994). Eléments d'optimisation du transfert d'oxygène par fines bulles et agitateur séparé en chenal d'oxydation. PhD Thesis. CEMAGREF Antony ? France. GILLOT S., DERONZIER G., HEDUIT A. (1997). Oxygen transfer under process conditions in an oxidation ditch equipped with fine bubble diffusers and slow speed mixers. WEFTEC, Chicago, USA. HENZE M., GUJER W., MINO T., van LOOSDRECHT M., (2000). Activated Sludge Models ASM1, ASM2, ASM2D and ASM3, Scientific and Technical Report No. 9. IWA Publishing, London, UK. JUSPIN H., VASEL J.-L. (2000). Influence of hydrodynamics on oxygen transfer in the activated sludge process. IWA, Paris - France.

Variations in dentate gyrus pathology in neurodegenerative disease

The dentate gyrus (DG) is an important part of the hippocampal formation and is believed to be involved in a variety of brain functions including episodic and spatial memory and the exploration of novel environments. In several neurodegenerative disorders, significant pathology occurs in the DG which may be involved in the development of clinical dementia. Based on the abundance of pathological change, neurodegenerative disorders could be divided into three groups: (1) those in which high densities of neuronal cytoplasmic inclusions (NCI) were present in DG granule cells, e.g., Pick’s disease (PiD), frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions (FTLD-TDP), and neuronal intermediate filament inclusion disease (NIFID), (2) those in which aggregated protein deposits were distributed throughout the hippocampal formation including the molecular layer of the DG, e.g., Alzheimer’s disease (AD), Down’s syndrome (DS), and variant Creutzfeldt-Jakob disease (vCJD), and (3) those in which in there was significantly less pathology in the DG, e.g., Parkinson’s disease dementia (PD-Dem), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA), and sporadic CJD (sCJD). Hence, DG pathology varied significantly among disorders which could contribute to differences in clinical dementia. Pathological differences among disorders could reflect either differential vulnerability of the DG to specific molecular pathologies or variation in the degree of spread of pathological proteins into the hippocampal formation from adjacent regions.

Pathology of the dentate gyrus in neurodegenerative disease

The dentate gyrus (DG) is an important part of the hippocampal formation and is believed to be involved in a variety of brain functions including episodic and spatial memory and the exploration of novel environments. In several neurodegenerative disorders, significant pathology occurs in the DG which may be involved in the development of clinical dementia. Based on the abundance of pathological change, neurodegenerative disorders can be divided into three groups: (1) those in which high densities of neuronal cytoplasmic inclusions (NCI) are present in DG granule cells, e.g., Pick’s disease (PiD), frontotemporal lobar degeneration with TDP-43-immunoreactive inclusions (FTLD-TDP), and neuronal intermediate filament inclusion disease (NIFID), (2) those in which aggregated protein deposits are distributed throughout the hippocampal formation including the molecular layer of the DG, e.g., Alzheimer’s disease (AD), Down’s syndrome (DS), and variant Creutzfeldt-Jakob disease (vCJD), and (3) those in which in there is significantly less pathology in the DG, e.g., Parkinson’s disease dementia (PD-Dem), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA), and sporadic CJD (sCJD). Hence, DG pathology varies significantly among disorders which could contribute to differences in clinical dementia. Pathological differences among disorders could reflect either differential vulnerability of the DG to specific molecular pathologies or variation in the degree of spread of pathological proteins into the hippocampal formation from adjacent regions.

Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders

The hippocampus (HC) and adjacent gyri are implicated in dementia in several neurodegenerative disorders. To compare HC pathology among disorders, densities of ‘signature’ pathological lesions were measured at a standard location in eight brain regions of 12 disorders. Principal components analysis of the data suggested that the disorders could be divided into three groups: (1) Alzheimer’s disease (AD), Down’s syndrome (DS), sporadic Creutzfeldt–Jakob disease, and variant Creutzfeldt–Jakob disease in which either β-amyloid (Aβ) or prion protein deposits were distributed in all sectors of the HC and adjacent gyri, with high densities being recorded in the parahippocampal gyrus and subiculum; (2) Pick’s disease, sporadic frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions, and neuronal intermediate filament inclusion disease in which relatively high densities of neuronal cytoplasmic inclusions were present in the dentate gyrus (DG) granule cells; and (3) Parkinson’s disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy in which densities of signature lesions were relatively low. Variation in density of signature lesions in DG granule cells and CA1 were the most important sources of neuropathological variation among disorders. Hence, HC and adjacent gyri are differentially affected in dementia reflecting either variation in vulnerability of hippocampal neurons to specific molecular pathologies or in the spread of pathological proteins to the HC. Information regarding the distribution of pathology could ultimately help to explain variations in different cognitive domains, such as memory, observed in various disorders.

All-optical OFDM and distributed Raman amplification:challenges to enable high capacities and extend reach

We review recent advances in all-optical OFDM technologies and discuss the performance of a field trial of a 2 Tbit/s Coherent WDM over 124 km with distributed Raman amplification. The results indicate that careful optimisation of the Raman pumps is essential. We also consider how all-optical OFDM systems perform favourably against energy consumption when compared with alternative coherent detection schemes. We argue that, in an energy constrained high-capacity transmission system, direct detected all-optical OFDM with `ideal' Raman amplification is an attractive candidate for metro area datacentre interconnects with ~100 km fibre spans, with an overall energy requirement at least three times lower than coherent detection techniques.