Illustrating the effect of viscoelastic additives on cavitation and turbulence with X-ray imaging.

The effect of viscoelastic additives on the topology and dynamics of the two-phase flow arising within an axisymmetric orifice with a flow path constriction along its main axis has been investigated employing high-flux synchrotron radiation. X-ray Phase Contrast Imaging (XPCI) has been conducted to visualise the cavitating flow of different types of diesel fuel within the orifice. An additised blend containing Quaternary Ammonium Salt (QAS) additives with a concentration of 500 ppm has been comparatively examined against a pure (base) diesel compound. A high-flux, 12 keV X-ray beam has been utilised to obtain time resolved radiographs depicting the vapour extent within the orifice from two views (side and top) with reference to its main axis. Different test cases have been examined for both fuel types and for a range of flow conditions characterised by Reynolds number of 35500 and cavitation numbers (CN) lying in the range 3.0-7.7. It has been established that the behaviour of viscoelastic micelles in the regions of shear flow is not consistent depending on the cavitation regimes encountered. Namely, viscoelastic effects enhance vortical (string) cavitation, whereas hinder cloud cavitation. Furthermore, the use of additised fuel has been demonstrated to suppress the level of turbulence within the orifice.

Did postglacial sea-level changes initiate the evolutionary divergence of a Tasmanian endemic raptor from its mainland relative?

Populations on continental islands are often distinguishable from mainland conspecifics with respect to body size, appearance, behaviour or life history, and this is often congruent with genetic patterns. It is commonly assumed that such differences developed following the complete isolation of populations by sea-level rise following the Last Glacial Maximum (LGM). However, population divergence may predate the LGM, or marine dispersal and colonization of islands may have occurred more recently; in both cases, populations may have also diverged despite ongoing gene flow. Here, we test these alternative hypotheses for the divergence between wedge-tailed eagles from mainland Australia (Aquila audax audax) and the threatened Tasmanian subspecies (Aquila audax fleayi), based on variation at 20 microsatellite loci and mtDNA. Coalescent analyses indicate that population divergence appreciably postdates the severance of terrestrial habitat continuity and occurred without any subsequent gene flow. We infer a recent colonization of Tasmania by marine dispersal and cannot discount founder effects as the cause of differences in body size and life history. We call into question the general assumption of post-LGM marine transgression as the initiator of divergence of terrestrial lineages on continental islands and adjacent mainland, and highlight the range of alternative scenarios that should be considered.

Factors affecting decision making about fertility preservation after cancer diagnosis: a qualitative study.

OBJECTIVE: To increase our understanding of factors underlying the decision to store gametes after the diagnosis of cancer. DESIGN: Qualitative interview study. SETTING: Andrology, Haematology, and Oncology Departments of a Scottish teaching hospital, and patients' own homes. POPULATION: Sixteen men and 18 women aged 17-49 years recently diagnosed with cancer; 15 health professionals concerned in cancer care. METHODS: Audio-recorded semi-structured interviews were transcribed verbatim and analysed thematically. Topics included perceptions of diagnosis; prognosis; future reproductive choices; priorities; quality of information received; communication and decisions made about future reproductive choices; and the role of partners, family, friends and healthcare professionals. Professional interviews examined their role in decision making and that of protocols and guidelines, together with information emerging from patient interview analysis. MAIN OUTCOME MEASURE: Themes identified following analysis of interview transcripts. RESULTS: The primary barriers to pursuing fertility preservation were the way in which information was provided and the 'urgent need for treatment' conveyed by staff. Survival was always viewed as paramount, with future fertility secondary. Sperm banking was viewed as 'part and parcel' of oncology care, and the majority of men quickly stored sperm as 'insurance' against future infertility. Few women were afforded the opportunity to discuss their options, reflecting clinicians' reservations about the experimental nature of egg and ovarian tissue cryopreservation, and the need for partner involvement in embryo storage. CONCLUSIONS: Significant gaps in the information provided to young women diagnosed with cancer suggest the need for an early appointment with a fertility expert.

Uptake of folic acid supplements before and during pregnancy: focus group analysis of women's views and experiences.

BACKGROUND: To reduce risk of neural tube defects, current guidance recommends that all women who could become pregnant should take a daily 400 µg folic acid supplement before conception and until the 12th week of pregnancy. It is recognised that compliance with this guidance is sub-optimal, although little is known about the reasons why. The present study aims to explore the rationale behind women's decision-making on folic acid supplement use to inform health communications. METHODS: Women attending routine health visitor led baby clinics completed a questionnaire to establish their folic acid use in their most recent pregnancy. Participants were then invited to join focus group discussions to explore motivators and barriers to folic acid supplement use before and during pregnancy. RESULTS: Of 292 women approached, 211 (70%) provided information on supplement use. Of these, 67 (31%) reported having taken folic acid supplements as recommended; 118 (56%) only during pregnancy [22 (18%) only intermittently]; and 26 (12%) had not taken folic acid at all. Eight focus group discussions were held comprising 24 participants. Discussions indicated the rationale behind current recommendations was known. Participants often linked folic acid use with morning sickness, and invoked busy lives, competing priorities for concern, and poor memory in accounting for intermittent use. Building a 'lay evidence base' from their own experiences, many cited healthy pregnancy outcomes without supplement use and expressed scepticism about its preventive action. CONCLUSIONS: The findings of the present study highlight the importance of guidance on the importance of daily folic acid supplement use, the severity of neural tube defects and the provision of evidence on risk reduction.

The nonlinear Fano effect.

The Fano effect is ubiquitous in the spectroscopy of, for instance, atoms, bulk solids and semiconductor heterostructures. It arises when quantum interference takes place between two competing optical pathways, one connecting the energy ground state and an excited discrete state, the other connecting the ground state with a continuum of energy states. The nature of the interference changes rapidly as a function of energy, giving rise to characteristically asymmetric lineshapes. The Fano effect is particularly important in the interpretation of electronic transport and optical spectra in semiconductors. Whereas Fano's original theory applies to the linear regime at low power, at higher power a laser field strongly admixes the states and the physics becomes rich, leading, for example, to a remarkable interplay of coherent nonlinear transitions. Despite the general importance of Fano physics, this nonlinear regime has received very little attention experimentally, presumably because the classic autoionization processes, the original test-bed of Fano's ideas, occur in an inconvenient spectral region, the deep ultraviolet. Here we report experiments that access the nonlinear Fano regime by using semiconductor quantum dots, which allow both the continuum states to be engineered and the energies to be rescaled to the near infrared. We measure the absorption cross-section of a single quantum dot and discover clear Fano resonances that we can tune with the device design or even in situ with a voltage bias. In parallel, we develop a nonlinear theory applicable to solid-state systems with fast relaxation of carriers. In the nonlinear regime, the visibility of the Fano quantum interferences increases dramatically, affording a sensitive probe of continuum coupling. This could be a unique method to detect weak couplings of a two-level quantum system (qubits), which should ideally be decoupled from all other states.

Encapsulation in biodegradable microparticles enhances serum antibody response to parenterally-delivered beta-amyloid in mice.

Poly(lactide-co-glycolide) (PLG) microspheres were tested as a parenteral delivery system for human beta-amyloid (1-42) (Abeta), a potential immunotherapeutic undergoing assessment in Phase 1 studies for Alzheimer's disease (AD). Abeta was successfully encapsulated in PLG microspheres of average sizes of 3 or 15 microm diameter. Swiss Webster (SW) mice were injected by the sub-cutaneous (s.c.) or intra-peritoneal (i.p.) routes with 3-33 microg Abeta. Abeta-PLG microparticles (3 microm) induced dose-dependent antibody responses, which were maximal at 33 microg Abeta, while Abeta in phosphate-buffered saline (PBS) produced weak antibody responses at the same doses by both routes. Significantly increased antibody responses were seen for both small and large particle formulations given by the i.p. route in comparison to the s.c route. It was previously reported that passive immunisation with Abeta-specific antibodies cleared amyloid plaques in a mouse model of AD (Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med 2000;6:916-19), an indication that induction of serum antibody is a prerequisite for efficacy.

Automated skin lesion screening--a new approach.

Automated melanoma diagnosis is a popular focus of research, with numerous papers describing techniques and results. In our study, we identified two possible problems with the current method of automated diagnosis, where systems are intended to reproduce histopathology results. We propose a new method of identifying problematic skin lesions, namely attempting to reproduce algorithmically the perceptions of dermatologists as to whether the lesion should be excised. In the best case, our initial model reproduced the decision of dermatologists in over 80% of cases. These results suggest that reproducing the decision to excise may be a valuable adjunct to current methodology.

Retention of the Alzheimer's amyloid precursor fragment C99 in the endoplasmic reticulum prevents formation of amyloid beta-peptide.

gamma-Secretase is a membrane-associated endoprotease that catalyzes the final step in the processing of Alzheimer's beta-amyloid precursor protein (APP), resulting in the release of amyloid beta-peptide (Abeta). The molecular identity of gamma-secretase remains in question, although recent studies have implicated the presenilins, which are membrane-spanning proteins localized predominantly in the endoplasmic reticulum (ER). Based on these observations, we have tested the hypothesis that gamma-secretase cleavage of the membrane-anchored C-terminal stump of APP (i.e. C99) occurs in the ER compartment. When recombinant C99 was expressed in 293 cells, it was localized mainly in the Golgi apparatus and gave rise to abundant amounts of Abeta. Co-expression of C99 with mutant forms of presenilin-1 (PS1) found in familial Alzheimer's disease resulted in a characteristic elevation of the Abeta(42)/Abeta(40) ratio, indicating that the N-terminal exodomain of APP is not required for mutant PS1 to influence the site of gamma-secretase cleavage. Biogenesis of both Abeta(40) and Abeta(42) was almost completely eliminated when C99 was prevented from leaving the ER by addition of a di-lysine retention motif (KKQN) or by co-expression with a dominant-negative mutant of the Rab1B GTPase. These findings indicate that the ER is not a major intracellular site for gamma-secretase cleavage of C99. Thus, by inference, PS1 localized in this compartment does not appear to be active as gamma-secretase. The results suggest that presenilins may acquire the characteristics of gamma-secretase after leaving the ER, possibly by assembling with other proteins in peripheral membranes.

Senior health professional's perceptions of variations in medical practice: a qualitative and quantitative study.

Following the introduction of the UK General Medical Council's regulations on the handling of poor medical performance, an interview and survey study was carried out among senior health professionals in the National Health Service (NHS). The aims of the study were to explore the respondents' perceptions of poor medical performance and to seek their experience of handling poorly performing doctors. Sixteen interviews were held face to face, followed by 28 telephone interviews. Subsequently, using similar questions to those in the interview schedule, a survey was carried out among senior health professionals across the NHS. Interview results identified a number of barriers to resolving poor performance, such as the unwillingness of some doctors to seek advice and the protective culture which prevented complaints being made against doctors. Survey respondents had high standards by which they judged poor performance, but they were more hesitant about considering poor consultation skills as being of the same significance as poor technical skills. However, problems with communication skills were the most frequently reported type of poor performance. The new arrangements for handling NHS doctors whose performance is perceived to be poor have much to do to overcome the barriers to effective action expressed by the respondents in this study.

Influence of Systematic Errors in Reference States on Image Quality and on Stability of Derived Information for dc Optical Imaging.

Optical measurements of tissue can be performed in discrete, time-averaged, and time-varying data collection modes. This information can be evaluated to yield estimates of either absolute optical coefficient values or some relative change in these values compared with a defined state. In the case of time-varying data, additional analysis can be applied to define various dynamic features. Here we have explored the accuracy with which such information can be recovered from dense scattering media using linear perturbation theory, as a function of the accuracy of the reference medium that serves as the initial guess. Within the framework of diffusion theory and a first-order solution, we have observed the following inequality regarding the sensitivity of computed measures to inaccuracy in the reference medium: Absolute measures ? relative measures > dynamic measures. In fact, the fidelity of derived dynamic measures was striking; we observed that accurate measures of dynamic behavior could be defined even if the quality of the image data from which these measures were derived was comparatively modest. In other studies we identified inaccuracy in the estimates of the reference detector values, and not to corresponding errors in the image operators, as the primary factor responsible for instability of absolute measures. The significance of these findings for practical imaging studies of tissue is discussed.

Normalized-constraint algorithm for minimizing inter-parameter crosstalk in DC optical tomography.

In this report, we present a method for reducing the inter-coefficient crosstalk problem in optical tomography. The method described is an extension of a previously reported normalized difference method that evaluates relative detector values, and employs a weight matrix scaling technique together with a constrained CGD method for image reconstruction. Results from numerical and experimental studies using DC measurement data demonstrate that the approach can effectively isolate absorption and scattering heterogeneities, even for complex combinations of perturbations in optical properties. The significance of these results in light of recent theoretical findings is discussed.

Three-dimensional optical tomography of hemodynamics in the human head.

We report on the first three-dimensional, volumetric, tomographic localization of vascular reactivity in the brain. To this end we developed a model-based iterative image reconstruction scheme that employs adjoint differentiation methods to minimize the difference between measured and predicted data. The necessary human-head geometry and optode locations were determined with a photogrammetric method. To illustrate the performance of the technique, the three-dimensional distribution of changes in the concentration of oxyhemoglobin, deoxyhemoglobin, and total hemoglobin during a Valsalva maneuver were visualized. The observed results are consistent with previously reported effects concerning optical responses to hemodynamic perturbations.

Optical tomographic imaging of dynamic features of dense-scattering media.

Methods used in optical tomography have thus far proven to produce images of complex target media (e.g., tissue) having, at best, relatively modest spatial resolution. This presents a challenge in differentiating artifact from true features. Further complicating such efforts is the expectation that the optical properties of tissue for any individual are largely unknown and are likely to be quite variable due to the occurrence of natural vascular rhythms whose amplitudes are sensitive to a host of autonomic stimuli that are easily induced. We recognize, however, that rather than frustrating efforts to validate the accuracy of image features, the time-varying properties of the vasculature can be exploited to aid in such efforts, owing to the known structure-dependent frequency response of the vasculature and to the fact that hemoglobin is a principal contrast feature of the vasculature at near-infrared wavelengths. To accomplish this, it is necessary to generate a time series of image data. In this report we have tested the hypothesis that through analysis of time-series data, independent contrast features can be derived that serve to validate, at least qualitatively, the accuracy of imaging data, in effect establishing a self-referencing scheme. A significant finding is the observation that analysis of such data can produce high-contrast images that reveal features that are mainly obscured in individual image frames or in time-averaged image data. Given the central role of hemoglobin in tissue function, this finding suggests that a wealth of new features associated with vascular dynamics can be identified from the analysis of time-series image data.

The role of qualitative research in broadening the 'evidence base' for clinical practice.

This paper presents the case for seeking to broaden the 'evidence base' of medicine and health care by the inclusion of qualitative research findings. In order for qualitative research to make a significant contribution, advocates of this approach must demonstrate its ability to address questions of relevance to practice and proponents of EBM must rethink their ideas as to what may constitute a research question. A definition of qualitative research is provided, highlighting the somewhat different assumptions which underpin this model. The potential contribution of qualitative findings is assessed and the paper examines the ways in which such insights can be utilized. Finally it addresses the question as to how qualitative findings can be incorporated in the 'evidence base'.

Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.

One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with human amyloid beta-peptide reduces plaque burden and its associated pathologies. Several hypotheses have been proposed regarding the mechanism of this response. Here we report that peripheral administration of antibodies against amyloid beta-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid beta-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.

Acquiring qualitative skills for primary care research. Review and reflections on a three-stage workshop. Part 1: using interviews to generate data. Members of WoReN. Wolds Primary Care Research Network.

This paper reflects on one Primary Care Research Network's (WoReN's) experience of running a workshop on generating interview data, provided as the first of a three-part workshop concerned with acquiring qualitative interviewing skills. It discusses the aims and limitations of the short workshop format in meeting the needs of practitioners embarking on qualitative research, drawing upon and reviewing the relevant research methods literature, and makes suggestions with regard to designing and running research methods workshops within primary care.

Acquiring qualitative skills for primary care research. Review and reflections on a three-stage workshop. Part 2: analysing interview data. Members of WoReN. Primary Care Research Network.

This paper reflects on one Primary Care Research Network's (WoReN's) experience of running a workshop on analysing qualitative interview data, provided as the second of a three-part workshop concerned with acquiring qualitative interviewing skills. It discusses the aims and limitations of the short workshop format in meeting the needs of practitioners embarking on the process of analysing qualitative data, drawing upon and reviewing the relevant research methods literature. Particular attention is paid to the role of qualitative data analysis computer packages and the debate on 'grounded theory'. We conclude by making suggestions with regard to designing and running data analysis workshops within primary care.

Instrumentation and calibration protocol for imaging dynamic features in dense-scattering media by optical tomography.

Instrumentation is described that is suitable for acquiring multisource, multidetector, time-series optical data at high sampling rates (up to 150 Hz) from tissues having arbitrary geometries. The design rationale, calibration protocol, and measured performance features are given for both a currently used, CCD-camera-based instrument and a new silicon-photodiode-based system under construction. Also shown are representative images that we reconstructed from data acquired in laboratory studies using the described CCD-based instrument.

Purification and cloning of amyloid precursor protein beta-secretase from human brain.

Proteolytic processing of the amyloid precursor protein (APP) generates amyloid beta (Abeta) peptide, which is thought to be causal for the pathology and subsequent cognitive decline in Alzheimer's disease. Cleavage by beta-secretase at the amino terminus of the Abeta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated carboxy-terminal fragment. Cleavage of the C-terminal fragment by gamma-secretase(s) leads to the formation of Abeta. The pathogenic mutation K670M671-->N670L671 at the beta-secretase cleavage site in APP, which was discovered in a Swedish family with familial Alzheimer's disease, leads to increased beta-secretase cleavage of the mutant substrate. Here we describe a membrane-bound enzyme activity that cleaves full-length APP at the beta-secretase cleavage site, and find it to be the predominant beta-cleavage activity in human brain. We have purified this enzyme activity to homogeneity from human brain using a new substrate analogue inhibitor of the enzyme activity, and show that the purified enzyme has all the properties predicted for beta-secretase. Cloning and expression of the enzyme reveals that human brain beta-secretase is a new membrane-bound aspartic proteinase.