Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective

Although Huntington's disease (HD) is a neurodegenerative disease characterized by motor, cognitive and behavioural disturbances, there has been little empirical data examining what patients are most concerned about throughout the different stages of disease, which can span many years. Semi-structured face-to-face interviews were individually conducted with 31 people living with different stages of Huntington's, from pre-clinical gene carriers to advanced stage. We examined how often participants raised issues and concerns regarding the impact of Huntington's on everyday life. The Physical/functional theme hardly featured pre-clinically, but was strongly present from Stage 1, rose steadily and peaked at Stage 5. There were no significant changes between stages for the Emotional, Social, and Self themes that all featured across all stages, indicating that these issues were not raised more frequently over the course of the disease. Likewise, the more rarely mentioned Financial and Legal themes also remained similar across stages. However, the Cognitive theme only featured between Stages 1 and 4, and hardly at all pre-clinically and at Stage 5. These findings provide insight into patients' important and unique perspective and have implications for the management and development of interventions across the spectrum of HD stages.

A method to weight three categories of adaptive thermal comfort

The adaptive thermal comfort theory considers people as active rather than passive recipients in response to ambient physical thermal stimuli, in contrast with conventional, heat-balance-based, thermal comfort theory. Occupants actively interact with the environments they occupy by means of utilizing adaptations in terms of physiological, behavioural and psychological dimensions to achieve ‘real world’ thermal comfort. This paper introduces a method of quantifying the physiological, behavioural and psychological portions of the adaptation process by using the analytic hierarchy process (AHP) based on the case studies conducted in the UK and China. Apart from three categories of adaptations which are viewed as criteria, six possible alternatives are considered: physiological indices/health status, the indoor environment, the outdoor environment, personal physical factors, environmental control and thermal expectation. With the AHP technique, all the above-mentioned criteria, factors and corresponding elements are arranged in a hierarchy tree and quantified by using a series of pair-wise judgements. A sensitivity analysis is carried out to improve the quality of these results. The proposed quantitative weighting method provides researchers with opportunities to better understand the adaptive mechanisms and reveal the significance of each category for the achievement of adaptive thermal comfort.

Understanding the early stages of the innovation diffusion process: awareness, influence and communication networks

The themes of awareness and influence within the innovation diffusion process are addressed. The innovation diffusion process is typically represented as stages, yet awareness and influence are somewhat under-represented in the literature. Awareness and influence are situated within the contextual setting of individual actors but also within the broader institutional forces. Understanding how actors become aware of an innovation and then how their opinion is influenced is important for creating a more innovation-active UK construction sector. Social network analysis is proposed as one technique for mapping how awareness and influence occur and what they look like as a network. Empirical data are gathered using two modes of enquiry. This is done through a pilot study consisting of chartered professionals and then through a case study organization as it attempted to diffuse an innovation. The analysis demonstrates significant variations across actors’ awareness and influence networks. It is argued that social network analysis can complement other research methods in order to present a richer picture of how actors become aware of innovations and where they draw their influences regarding adopting innovations. In summarizing the findings, a framework for understanding awareness and influence associated with innovation within the UK construction sector is presented. Finally, with the UK construction sector continually being encouraged to be innovative, understanding and managing an actor’s awareness and influence network will be beneficial. The overarching conclusion thus describes the need not only to build research capacity in this area but also to push the boundaries related to the research methods employed.

Prediction and functional analysis of native disorder in proteins from the Three Kingdoms of Life

An automatic method for recognizing natively disordered regions from amino acid sequence is described and benchmarked against predictors that were assessed at the latest critical assessment of techniques for protein structure prediction (CASP) experiment. The method attains a Wilcoxon score of 90.0, which represents a statistically significant improvement on the methods evaluated on the same targets at CASP. The classifier, DISOPRED2, was used to estimate the frequency of native disorder in several representative genomes from the three kingdoms of life. Putative, long (>30 residue) disordered segments are found to occur in 2.0% of archaean, 4.2% of eubacterial and 33.0% of eukaryotic proteins. The function of proteins with long predicted regions of disorder was investigated using the gene ontology annotations supplied with the Saccharomyces genome database. The analysis of the yeast proteome suggests that proteins containing disorder are often located in the cell nucleus and are involved in the regulation of transcription and cell signalling. The results also indicate that native disorder is associated with the molecular functions of kinase activity and nucleic acid binding.

Constrained principal component analysis reveals functionally connected load-dependent networks involved in multiple stages of working memory

Constrained principal component analysis (CPCA) with a finite impulse response (FIR) basis set was used to reveal functionally connected networks and their temporal progression over a multistage verbal working memory trial in which memory load was varied. Four components were extracted, and all showed statistically significant sensitivity to the memory load manipulation. Additionally, two of the four components sustained this peak activity, both for approximately 3 s (Components 1 and 4). The functional networks that showed sustained activity were characterized by increased activations in the dorsal anterior cingulate cortex, right dorsolateral prefrontal cortex, and left supramarginal gyrus, and decreased activations in the primary auditory cortex and "default network" regions. The functional networks that did not show sustained activity were instead dominated by increased activation in occipital cortex, dorsal anterior cingulate cortex, sensori-motor cortical regions, and superior parietal cortex. The response shapes suggest that although all four components appear to be invoked at encoding, the two sustained-peak components are likely to be additionally involved in the delay period. Our investigation provides a unique view of the contributions made by a network of brain regions over the course of a multiple-stage working memory trial.

Assessment of the anti-genotoxic, anti-proliferative, and anti-metastatic potential of crude watercress extract in human colon cancer cells

Although it is known to be a rich source of the putative anti-cancer chemicals isothiocyanates, watercress has not been extensively studied for its cancer preventing properties. The aim of this study was to investigate the potential chemoprotective effects of crude watercress extract toward three important stages in the carcinogenic process, namely initiation, proliferation, and metastasis (invasion) using established in vitro models. HT29 cells were used to investigate the protective effects of the extract on DNA damage and the cell cycle. The extract was not genotoxic but inhibited DNA damage induced by two of the three genotoxins used, namely hydrogen peroxide and fecal water, indicating the potential to inhibit initiation. It also caused an accumulation of cells in the S phase of the cell cycle indicating (possible) cell cycle delay at this stage. The extract was shown to significantly inhibit invasion of HT115 cells through matrigel. Component analysis was also carried out in an attempt to determine the major phytochemicals present in both watercress leaves and the crude extract. In conclusion, the watercress extract proved to be significantly protective against the three stages of the carcinogenesis process investigated.

Tropical-extratropical interactions over Southern Africa: three cases of heavy summer season rainfall

The synoptic evolution of three tropical–extratropical (TE) interactions, each responsible for extreme rainfall events over southern Africa, is discussed in detail. Along with the consideration of previously studied events, common features of these heavy rainfall producing tropical temperate troughs (TTTs) over southern Africa are discussed. It is found that 2 days prior to an event, northeasterly moisture transports across Botswana, set up by the Angola low, are diverted farther south into the semiarid region of subtropical southern Africa. The TTTs reach full maturity as a TE cloud band, rooted in the central subcontinent, which is triggered by upper-level divergence along the leading edge of an upper-tropospheric westerly wave trough. Convection and rainfall within the cloud band is supported by poleward moisture transports with subtropical air rising as it leaves the continent and joins the midlatitude westerly flow. It is shown that these systems fit within a theoretical framework describing similar TE interactions found globally. Uplift forcing for the extreme rainfall of each event is investigated. Unsurprisingly, quasigeostrophic uplift is found to dominate in the midlatitudes with convective processes strongest in the subtropics. Rainfall in the semiarid interior of South Africa appears to be a result of quasigeostrophically triggered convection. Investigation of TTT formation in the context of planetary waves shows that early development is sometimes associated with previous anticyclonic wave breaking south of the subcontinent, with full maturity of TTTs occurring as a potential vorticity trough approaches the continent from the west. Sensitivity to upstream wave perturbations and effects on anticyclonic wave breaking in the South Indian Ocean are also observed.

High leverage interventions: three cases of defensive action and their lessons for OR/MS today.

This paper has two aims. First, to present cases in which scientists developed a defensive system for their homeland: Blackett and the air defense of Britain in WWII, Forrester and the SAGE system for North America in the Cold War, and Archimedes’ work defending Syracuse during the Second Punic War. In each case the historical context and the individual’s other achievements are outlined, and a description of the contribution’s relationship to OR/MS is given. The second aim is to consider some of the features the cases share and examine them in terms of contemporary OR/MS methodology. Particular reference is made to a recent analysis of the field’s strengths and weaknesses. This allows both a critical appraisal of the field and a set of potential responses for strengthening it. Although a mixed set of lessons arise, the overall conclusion is that the cases are examples to build on and that OR/MS retains the ability to do high stakes work.

Lack of flagella disadvantages Salmonella enterica serovar Enteritidis during the early stages of infection in the rat

The roles of flagella and five fimbriae (SEF14, SEF17, SEF21, pef, lpf) in the early stages (up to 3 days) of Salmonella enterica serovar Enteritidis (S. Enteritidis) infection have been investigated in the rat. Wild-type strains LA5 and S1400 (fim+/fla+) and insertionally inactivated mutants unable to express the five fimbriae (fim-/fla+), flagella (fim+/fla-) or fimbriae and flagella (fim-/fla-) were used. All wild-type and mutant strains were able to colonize the gut and spread to the mesenteric lymph nodes, liver and spleen. There appeared to be little or no difference between the fim-/fla+ and wild-type (fim+/fla+) strains. In contrast, the numbers of aflagellate (fim+/fla- or fim-/fla-) salmonella in the liver and spleen were transiently reduced. In addition, fim+/fla- or fim-/fla-strains were less able to persist in the upper gastrointestinal tract and the inflammatory responses they elicited in the gut were less severe. Thus, expression of SEF14, SEF17, SEF21, pef and lpf did not appear to be a prerequisite for induction of S. Enteritidis infection in the rat. Deletion of flagella did, however, disadvantage the bacterium. This may be due to the inability to produce or release the potent immunomodulating protein flagellin.

EOF analysis of three records of sea-ice concentration spanning the last 30 years

Several continuous observational datasets of Artic sea-ice concentration are currently available that cover the period since the advent of routine satellite observations. We report on a comparison of three sea-ice concentration datasets. These are the National Ice Center charts, and two passive microwave radiometer datasets derived using different approaches: the NASA team and Bootstrap algorithms. Empirical orthogonal function (EOF) analyses were employed to compare modes of variability and their consistency between the datasets. The analysis was motivated by the need for a reliable, realistic sea ice climatology for use in climate model simulations, for which both the variability and absolute values of extent and concentration are important. We found that, while there are significant discrepancies in absolute concentrations, the major modes of variability derived from all records were essentially the same.

From Hippocrates to commodities: three models of NHS governance

A series of inquiries and reports suggest considerable failings in the care provided to some patients in the NHS. Although the Bristol Inquiry report of 2001 led to the creation of many new regulatory bodies to supervise the NHS, they have never enjoyed consistent support from government and the Mid Staffordshire Inquiry in 2013 suggests they made little difference. Why do some parts of the NHS disregard patients’ interests and how we should we respond to the challenge? The following discusses the evolution of approaches to NHS governance through the Hippocratic, Managerial and Commercial models, and assesses their risks and benefits. Apart from the ethical imperative, the need for effective governance is driven both by the growth in information available to the public and the resources wasted by ineffective systems of care. Appropriate solutions depend on an understanding of the perverse incentives inherent in each model and the need for greater sensitivity to the voices of patients and the public.

Twenty-three cycles of changing open solar magnetic flux

This paper presents a comparison of various estimates of the open solar flux, deduced from measurements of the interplanetary magnetic field, from the aa geomagnetic index and from photospheric magnetic field observations. The first two of these estimates are made using the Ulysses discovery that the radial heliospheric field is approximately independent of heliographic latitude, the third makes use of the potential-field source surface method to map the total flux through the photosphere to the open flux at the top of the corona. The uncertainties associated with using the Ulysses result are 5%, but the effects of the assumptions of the potential field source surface method are harder to evaluate. Nevertheless, the three methods give similar results for the last three solar cycles when the data sets overlap. In 11-year running means, all three methods reveal that 1987 marked a significant peak in the long-term variation of the open solar flux. This peak is close to the solar minimum between sunspot cycles 21 and 22, and consequently the mean open flux (averaged from minimum to minimum) is similar for these two cycles. However, this similarity between cycles 21 and 22 in no way implies that the open flux is constant. The long-term variation shows that these cycles are fundamentally different in that the average open flux was rising during cycle 21 (from consistently lower values in cycle 20 and toward the peak in 1987) but was falling during cycle 22 (toward consistently lower values in cycle 23). The estimates from the geomagnetic aa index are unique as they extend from 1842 onwards (using the Helsinki extension). This variation gives strong anticorrelations, with very high statistical significance levels, with cosmic ray fluxes and with the abundances of the cosmogenic isotopes that they produce. Thus observations of photospheric magnetic fields, of cosmic ray fluxes, and of cosmogenic isotope abundances all support the long-term drifts in open solar flux reported by Lockwood et al. [1999a, 1999b].

Three decades of policy layering and politically sustainable reform in the European Union’s Agricultural Policy

The study of policy reform has tended to focus on single-stage reforms taking place over a relatively short period. Recent research has drawn attention to gradual policy changes unfolding over extended periods. One strategy of gradual change is layering, in which new policy dimensions are introduced by adding new policy instruments or by redesigning existing ones to address new concerns. The limited research on single-stage policy reforms highlights that these may not endure in the postenactment phase when circumstances change. We argue that gradual policy layering may create sustainability dynamics that can result in lasting reform trajectories. The European Union’s Common Agricultural Policy (CAP) has changed substantially over the last three decades in response to emerging policy concerns by adding new layers. This succession of reforms proved durable and resilient to reversal in the lead-up to the 2013 CAP reform when institutional and political circumstances changed.

Stimulation of "stress-regulated" mitogen-activated protein kinases (stress-activated protein kinases/c-Jun N-terminal kinases and p38-mitogen-activated protein kinases) in perfused rat hearts by oxidative and other stresses.

"Stress-regulated" mitogen-activated protein kinases (SR-MAPKs) comprise the stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) and the p38-MAPKs. In the perfused heart, ischemia/reperfusion activates SR-MAPKs. Although the agent(s) directly responsible is unclear, reactive oxygen species are generated during ischemia/reperfusion. We have assessed the ability of oxidative stress (as exemplified by H2O2) to activate SR-MAPKs in the perfused heart and compared it with the effect of ischemia/reperfusion. H2O2 activated both SAPKs/JNKs and p38-MAPK. Maximal activation by H2O2 in both cases was observed at 0.5 mM. Whereas activation of p38-MAPK by H2O2 was comparable to that of ischemia and ischemia/reperfusion, activation of the SAPKs/JNKs was less than that of ischemia/reperfusion. As with ischemia/reperfusion, there was minimal activation of the ERK MAPK subfamily by H2O2. MAPK-activated protein kinase 2 (MAPKAPK2), a downstream substrate of p38-MAPKs, was activated by H2O2 to a similar extent as with ischemia or ischemia/reperfusion. In all instances, activation of MAPKAPK2 in perfused hearts was inhibited by SB203580, an inhibitor of p38-MAPKs. Perfusion of hearts at high aortic pressure (20 kilopascals) also activated the SR-MAPKs and MAPKAPK2. Free radical trapping agents (dimethyl sulfoxide and N-t-butyl-alpha-phenyl nitrone) inhibited the activation of SR-MAPKs and MAPKAPK2 by ischemia/reperfusion. These data are consistent with a role for reactive oxygen species in the activation of SR-MAPKs during ischemia/reperfusion.