Carbohydrate-based micelle clusters which enhance hydrophobic drug bioavailability by up to 1 order of magnitude

Amphiphilic chitosan-based polymers (M-w < 20 kDa) self-assemble in aqueous media at low micromolar concentrations to give previously unknown micellar clusters of 100-300 nm in size. Micellar clusters comprise smaller 10-30 nm aggregates, and the nanopolarity/drug incorporation efficiency of their hydrophobic domains can be tailored by varying the degree of lipidic derivatization and molecular weight of the carbohydrate. The extent of drug incorporation by these novel micellar clusters is 1 order of magnitude higher than is seen with triblock copolymers, with molar polymer/drug ratios of 1:48 to 1:67. On intravenous injection, the pharmacodynamic activity of a carbohydrate propofol formulation is increased by 1 order of magnitude when compared to a commercial emulsion formulation, and on topical ocular application of a carbohydrate prednisolone formulation, initial drug aqueous humor levels are similar to those found with a 10-fold dose of prednisolone suspension.

Modelling methodology and forecast failure

We analyse by simulation the impact of model-selection strategies (sometimes called pre-testing) on forecast performance in both constant-and non-constant-parameter processes. Restricted, unrestricted and selected models are compared when either of the first two might generate the data. We find little evidence that strategies such as general-to-specific induce significant over-fitting, or thereby cause forecast-failure rejection rates to greatly exceed nominal sizes. Parameter non-constancies put a premium on correct specification, but in general, model-selection effects appear to be relatively small, and progressive research is able to detect the mis-specifications.

The global response to tropical heating in the Madden-Julian oscillation during the northern winter

A life cycle of the Madden–Julian oscillation (MJO) was constructed, based on 21 years of outgoing long-wave radiation data. Regression maps of NCEP–NCAR reanalysis data for the northern winter show statistically significant upper-tropospheric equatorial wave patterns linked to the tropical convection anomalies, and extratropical wave patterns over the North Pacific, North America, the Atlantic, the Southern Ocean and South America. To assess the cause of the circulation anomalies, a global primitive-equation model was initialized with the observed three-dimensional (3D) winter climatological mean flow and forced with a time-dependent heat source derived from the observed MJO anomalies. A model MJO cycle was constructed from the global response to the heating, and both the tropical and extratropical circulation anomalies generally matched the observations well. The equatorial wave patterns are established in a few days, while it takes approximately two weeks for the extratropical patterns to appear. The model response is robust and insensitive to realistic changes in damping and basic state. The model tropical anomalies are consistent with a forced equatorial Rossby–Kelvin wave response to the tropical MJO heating, although it is shifted westward by approximately 20° longitude relative to observations. This may be due to a lack of damping processes (cumulus friction) in the regions of convective heating. Once this shift is accounted for, the extratropical response is consistent with theories of Rossby wave forcing and dispersion on the climatological flow, and the pattern correlation between the observed and modelled extratropical flow is up to 0.85. The observed tropical and extratropical wave patterns account for a significant fraction of the intraseasonal circulation variance, and this reproducibility as a response to tropical MJO convection has implications for global medium-range weather prediction. Copyright © 2004 Royal Meteorological Society

Enhancement of the aerosol direct radiative effect by semi-volatile aerosol components: airborne measurements in North-Western Europe

A case study of atmospheric aerosol measurements exploring the impact of the vertical distribution of aerosol chemical composition upon the radiative budget in North-Western Europe is presented. Sub-micron aerosol chemical composition was measured by an Aerodyne Aerosol Mass Spectrometer (AMS) on both an airborne platform and a ground-based site at Cabauw in the Netherlands. The examined period in May 2008 was characterised by enhanced pollution loadings in North-Western Europe and was dominated by ammonium nitrate and Organic Matter (OM). Both ammonium nitrate and OM were observed to increase with altitude in the atmospheric boundary layer. This is primarily attributed to partitioning of semi-volatile gas phase species to the particle phase at reduced temperature and enhanced relative humidity. Increased ammonium nitrate concentrations in particular were found to strongly increase the ambient scattering potential of the aerosol burden, which was a consequence of the large amount of associated water as well as the enhanced mass. During particularly polluted conditions, increases in aerosol optical depth of 50–100% were estimated to occur due to the observed increase in secondary aerosol mass and associated water uptake. Furthermore, the single scattering albedo was also shown to increase with height in the boundary layer. These enhancements combined to increase the negative direct aerosol radiative forcing by close to a factor of two at the median percentile level. Such increases have major ramifications for regional climate predictions as semi-volatile components are often not included in aerosol models. The results presented here provide an ideal opportunity to test regional and global representations of both the aerosol vertical distribution and subsequent impacts in North-Western Europe. North-Western Europe can be viewed as an analogue for the possible future air quality over other polluted regions of the Northern Hemisphere, where substantial reductions in sulphur dioxide emissions have yet to occur. Anticipated reductions in sulphur dioxide in polluted regions will result in an increase in the availability of ammonia to form ammonium nitrate as opposed to ammonium sulphate. This will be most important where intensive agricultural practises occur. Our observations over North-Western Europe, a region where sulphur dioxide emissions have already been reduced, indicate that failure to include the semi-volatile behaviour of ammonium nitrate will result in significant errors in predicted aerosol direct radiative forcing. Such errors will be particularly significant on regional scales.

Building synergies in development research: The application of the mosaic model to animal health research

Development research has responded to a number of charges over the past few decades. For example, when traditional research was accused of being 'top-down', the response was participatory research, linking the 'receptors' to the generators of research. As participatory processes were recognised as producing limited outcomes, the demand-led agenda was born. In response to the alleged failure of research to deliver its products, the 'joined-up' model, which links research with the private sector, has become popular. However, using examples from animal-health research, this article demonstrates that all the aforementioned approaches are seriously limited in their attempts to generate outputs to address the multi-faceted problems facing the poor. The article outlines a new approach to research: the Mosaic Model. By combining different knowledge forms, and focusing on existing gaps, the model aims to bridge basic and applied findings to enhance the efficiency and value of research, past, present, and future.

Non-hemagglutinating flaviviruses: molecular mechanisms for the emergence of new strains via adaptation to European ticks

Tick-borne encephalitis virus (TBEV) causes human epidemics across Eurasia. Clinical manifestations range from inapparent infections and fevers to fatal encephalitis but the factors that determine disease severity are currently undefined. TBEV is characteristically a hemagglutinating (HA) virus; the ability to agglutinate erythrocytes tentatively reflects virion receptor/fusion activity. However, for the past few years many atypical HA-deficient strains have been isolated from patients and also from the natural European host tick, Ixodes persulcatus. By analysing the sequences of HA-deficient strains we have identified 3 unique amino acid substitutions (D67G, E122G or D277A) in the envelope protein, each of which increases the net charge and hydrophobicity of the virion surface. Therefore, we genetically engineered virus mutants each containing one of these 3 substitutions; they all exhibited HA-deficiency. Unexpectedly, each genetically modified non-HA virus demonstrated increased TBEV reproduction in feeding Ixodes ricinus, not the recognised tick host for these strains. Moreover, virus transmission efficiency between infected and uninfected ticks co-feeding on mice was also intensified by each substitution. Retrospectively, the mutation D67G was identified in viruses isolated from patients with encephalitis. We propose that the emergence of atypical Siberian HA-deficient TBEV strains in Europe is linked to their molecular adaptation to local ticks. This process appears to be driven by the selection of single mutations that change the virion surface thus enhancing receptor/fusion function essential for TBEV entry into the unfamiliar tick species. As the consequence of this adaptive mutagenesis, some of these mutations also appear to enhance the ability of TBEV to cross the human blood-brain barrier, a likely explanation for fatal encephalitis. Future research will reveal if these emerging Siberian TBEV strains continue to disperse westwards across Europe by adaptation to the indigenous tick species and if they are associated with severe forms of TBE.

The neural response to emotional prosody, as revealed by functional magnetic resonance imaging

Prosody is an important feature of language, comprising intonation, loudness, and tempo. Emotional prosodic processing forms an integral part of our social interactions. The main aim of this study was to use bold contrast fMRI to clarify the normal functional neuroanatomy of emotional prosody, in passive and active contexts. Subjects performed six separate scanning studies, within which two different conditions were contrasted: (1) "pure" emotional prosody versus rest; (2) congruent emotional prosody versus 'neutral' sentences; (3) congruent emotional prosody versus rest; (4) incongruent emotional prosody versus rest; (5) congruent versus incongruent emotional prosody; and (6) an active experiment in which subjects were instructed to either attend to the emotion conveyed by semantic content or that conveyed by tone of voice. Data resulting from these contrasts were analysed using SPM99. Passive listening to emotional prosody consistently activated the lateral temporal lobe (superior and/or middle temporal gyri). This temporal lobe response was relatively right-lateralised with or without semantic information. Both the separate and direct comparisons of congruent and incongruent emotional prosody revealed that subjects used fewer brain regions to process incongruent emotional prosody than congruent. The neural response to attention to semantics, was left lateralised, and recruited an extensive network not activated by attention to emotional prosody. Attention to emotional prosody modulated the response to speech, and induced right-lateralised activity, including the middle temporal gyrus. In confirming the results of lesion and neuropsychological studies, the current study emphasises the importance of the right hemisphere in the processing of emotional prosody, specifically the lateral temporal lobes. (C) 2003 Elsevier Science Ltd. All rights reserved.

Small business legislation in Australia: does it provide a solution to part of the UK lease reform debate?

This paper addresses the commercial leases policy issue of how to deal with small business tenants. The UK has adopted a voluntary solution to commercial lease reform by using Codes of Practice which is in contrast to the legislative approach adopted by Australia to attempt to solve its perceived problems with small business retail tenancies. The major aim of the research was to examine the perceptions of the effectiveness of the legislation in Australia and discuss any implications for the UK policy debate but the results of the research also raise questions for the Australian regime. The research used a combination of literature and legislation review and a semi structured interview survey to investigate the policy aims and objectives of Australian Federal and State Governments, identify the nature and scope of the Australian legislation and examine perceptions of effectiveness of the legislation in informing small business tenants. The situation is complicated in Australia due to leases being a State rather than Federal responsibility therefore the main fieldwork was carried out in one case study State, Victoria. The paper concludes that some aspects of the Australian system can inform the UK policy debate including mandatory information provision at the commencement of negotiations and the use of lease registrars/commissioners. However, there are a number of issues that the Australian legislation does not appear to have successfully addressed including the difficulties of legislating across partial segments of the commercial property market and the collection of data for enforcement purposes.

Reduction of vestigial sideband effects due to multipath transmission in terrestrial broadcast television

In terrestrial television transmission multiple paths of various lengths can occur between the transmitter and the receiver. Such paths occur because of reflections from objects outside the direct transmission path. The multipath signals arriving at the receiver are all detected along with the intended signal causing time displaced replicas called 'ghosts' to appear on the television picture. With an increasing number of people living within built up areas, ghosting is becoming commonplace and therefore deghosting is becoming increasingly important. This thesis uses a deterministic time domain approach to deghosting, resulting in a simple solution to the problem of removing ghosts. A new video detector is presented which reduces the synchronous detector local oscillator phase error, caused by any practical size of ghost, to a lower level than has ever previously been achieved. From the new detector, dispersion of the video signal is minimised and a known closed-form time domain description of the individual ghost components within the detected video is subsequently obtained. Developed from mathematical descriptions of the detected video, a new specific deghoster filter structure is presented which is capable of removing both inphase (I) and also the phase quadrature (Q) induced ghost signals derived from the VSB operation. The new deghoster filter requires much less hardware than any previous deghoster which is capable of removing both I and Q ghost components. A new channel identification algorithm was also required and written which is based upon simple correlation techniques to find the delay and complex amplitude characteristics of individual ghosts. The result of the channel identification is then passed to the new I and Q deghoster filter for ghost cancellation. Generated from the research work performed for this thesis, five papers have been published. D

Impact of captions on deaf and hearing perception of multimedia video clips

We investigate the impact of captions on deaf and hearing perception of multimedia video clips. We measure perception using a parameter called Quality of Perception (QoP), which encompasses not only a user's satisfaction with multimedia clips, but also his/her ability to perceive, synthesise and analyse the informational content of such presentations. By studying perceptual diversity, it is our aim to identify trends that will help future implementation of adaptive multimedia technologies. Results show that although hearing level has a significant affect on information assimilation, the effect of captions is not significant on the objective level of information assimilated. Deaf participants predict that captions significantly improve their level of information assimilation, although no significant objective improvement was measured. The level of enjoyment is unaffected by a participant’s level of hearing or use of captions.

Subject-to-subject raising and the syntax of tense in L2 Spanish: a full access approach

This paper investigates the acquisition of syntax in L2 grammars. We tested adult L2 speakers of Spanish (English L1) on the feature specification of T(ense), which is different in English and Spanish in so-called subject-to-subject raising structures. We present experimental results with the verb parecer “to seem/to appear” in different tenses, with and without experiencers, and with Tense Phrase (TP), verb phrase (vP) and Adjectival Phrase (AP) complements. The results show that advanced L2 learners can perform just like native Spanish speakers regarding grammatical knowledge in this domain, although the subtle differences between both languages are not explicitly taught. We argue that these results support Full Access approaches to Universal Grammar (UG) in L2 acquisition, by providing evidence that uninterpretable syntactic features can be learned in adult L2, even when such features are not directly instantiated in the same grammatical domain in the L1 grammar.

Opportunistic assessment of hearing in elderly inpatients

Objective: To determine the prevalence of occult hearing loss in elderly inpatients, to evaluate feasibility of opportunistic hearing screening and to determine subsequent provision of hearing aids. Materials and methods: Subjects (>65 years) were recruited from five elderly care wards. Hearing loss was detected by a ward-based hearing screen comprising patient-reported assessment of hearing disability and a whisper test. Subjects failing the whisper test or reporting hearing difficulties were offered formal audiological assessment. Results: Screening was performed on 51 patients aged between 70 and 95 years. Of the patients, 21 (41%) reported hearing loss and 16 (31%) failed the whisper test. A total of 37 patients (73%) were referred for audiological assessment with 17 (33%) found to have aidable hearing loss and 11 were fitted with hearing aids (22%). Discussion: This study highlights the high prevalence of occult hearing loss in elderly inpatients. Easy two-step screening can accurately identify patients with undiagnosed deafness resulting in significant proportions receiving hearing aids.