An ongoing case-control study to evaluate the NHS Bowel Cancer Screening Programme

© 2014 Massat et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

On the Deformation of a Hyperelastic Tube Due to Steady Viscous Flow Within

In this chapter, we analyze the steady-state microscale fluid--structure interaction (FSI) between a generalized Newtonian fluid and a hyperelastic tube. Physiological flows, especially in hemodynamics, serve as primary examples of such FSI phenomena. The small scale of the physical system renders the flow field, under the power-law rheological model, amenable to a closed-form solution using the lubrication approximation. On the other hand, negligible shear stresses on the walls of a long vessel allow the structure to be treated as a pressure vessel. The constitutive equation for the microtube is prescribed via the strain energy functional for an incompressible, isotropic Mooney--Rivlin material. We employ both the thin- and thick-walled formulations of the pressure vessel theory, and derive the static relation between the pressure load and the deformation of the structure. We harness the latter to determine the flow rate--pressure drop relationship for non-Newtonian flow in thin- and thick-walled soft hyperelastic microtubes. Through illustrative examples, we discuss how a hyperelastic tube supports the same pressure load as a linearly elastic tube with smaller deformation, thus requiring a higher pressure drop across itself to maintain a fixed flow rate.Comment: 19 pages, 3 figures, Springer book class; v2: minor revisions, final form of invited contribution to the Springer volume entitled "Dynamical Processes in Generalized Continua and Structures" (in honour of Academician D.I. Indeitsev), eds. H. Altenbach, A. Belyaev, V. A. Eremeyev, A. Krivtsov and A. V. Porubo

Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility

How do Zimbabweans value health states?

Background Quality of life weights based on valuations of health states are often used in cost utility analysis and population health measures. This paper reports on an attempt to develop quality of life weights within the Zimbabwe context. Methods 2,384 residents in randomly selected small residential plots of land in a high-density suburb of Harare valued descriptors of 38 health states based on different combinations of the five domains of the EQ-5D (mobility, self-care, usual activities, pain or discomfort and anxiety or depression). The English version of the EQ-5D was used. The time trade-off method was used to determine the values, and 19,020 individual preferences for health states were analysed. A residual maximum likelihood linear mixed model was used to estimate a function for predicting the values of all possible combinations of levels on the five domains. The model was fit to a random subset of two-thirds of the observations, with the remaining observations reserved for analysis of predictive validity. The results were compared to a similar study undertaken in the United Kingdom. Results A credible model was developed to predict the values of states that were not valued directly. In the subset of observations reserved for validation, the mean absolute difference between predicted and observed values was 0.045. All domains of the EQ-5D were found to contribute significantly to the model, both at the moderate and severe levels. Severe pain was found to have the largest negative coefficient, followed by the inability to wash and dress oneself. Conclusion Despite a generally lower education level than their European counterparts, urban Zimbabweans appear to value health states in a consistent manner, and the determination of a global method of establishing quality of life weights may be feasible and valid. However, as the relative weightings of the different domains, although correlated, differed from the standard set of weights recommended by the EuroQol Group, the locally determined coefficients should be used within the Zimbabwean context

The fate of redundant cues: Further analysis of the redundancy effect

Pearce, Dopson, Haselgrove, and Esber (Journal of Experimental Psychology: Animal Behavior Processes, 38, 167–179, 2012) conducted a series of experiments with rats and pigeons in which the conditioned responding elicited by two types of redundant cue was compared. One of these redundant cues was a blocked cue X from A+ AX+ training, whereas the other was cue Y from a simple discrimination BY+ CY–. Greater conditioned responding was elicited by X than by Y; we refer to this difference as the redundancy effect. To test an explanation of this effect in terms of comparator theory (Denniston, Savastano, & Miller, 2001), a single group of rats in Experiment 1 received training of the form A+ AX+ BY+ CY–, followed by an A– Y+ discrimination. Responding to the individual cues was tested both before and after the latter discrimination. In addition to a replication of the redundancy effect during the earlier test, we observed stronger responding to B than to X, both during the earlier test and, in contradiction of the theory, after the A– Y+ discrimination. In Experiment 2, a blocking group received A+ AX+, a continuous group received AX+ BX–, and a partial group received AX± BX± training. Subsequent tests with X again demonstrated the redundancy effect, but also revealed a stronger response in the partial than in the continuous group. This pattern of results is difficult to explain with error-correction theories that assume that stimuli compete for associative strength during conditioning. We suggest, instead, that the influence of a redundant cue is determined by its relationship with the event with which it is paired, and by the attention it is paid

Levels of Alzheimer's disease blood biomarkers are altered after food intake—A pilot intervention study in healthy adults

INTRODUCTION: Blood biomarkers accurately identify Alzheimer's disease (AD) pathophysiology and axonal injury. We investigated the influence of food intake on AD-related biomarkers in cognitively healthy, obese adults at high metabolic risk. METHODS: One-hundred eleven participants underwent repeated blood sampling during 3 h after a standardized meal (postprandial group, PG). For comparison, blood was sampled from a fasting subgroup over 3 h (fasting group, FG). Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), amyloid-beta (Aβ) 42/40, phosphorylated tau (p-tau) 181 and 231, and total-tau were measured via single molecule array assays. RESULTS: Significant differences were found for NfL, GFAP, Aβ42/40, p-tau181, and p-tau231 between FG and PG. The greatest change to baseline occurred for GFAP and p-tau181 (120 min postprandially, p < 0.0001). CONCLUSION: Our data suggest that AD-related biomarkers are altered by food intake. Further studies are needed to verify whether blood biomarker sampling should be performed in the fasting state. Highlights: Acute food intake alters plasma biomarkers of Alzheimer's disease in obese, otherwise healthy adults. We also found dynamic fluctuations in plasma biomarkers concentration in the fasting state suggesting physiological diurnal variations. Further investigations are highly needed to verify if biomarker measurements should be performed in the fasting state and at a standardized time of day to improve the diagnostic accuracy

The association of health literacy with adherence in older 2 adults, and its role in interventions: a systematic meta-review

Background: Low health literacy is a common problem among older adults. It is often suggested to be associated with poor adherence. This suggested association implies a need for effective adherence interventions in low health literate people. However, previous reviews show mixed results on the association between low health literacy and poor adherence. A systematic meta-review of systematic reviews was conducted to study the association between health literacy and adherence in adults above the age of 50. Evidence for the effectiveness of adherence interventions among adults in this older age group with low health literacy was also explored. Methods: Eight electronic databases (MEDLINE, ERIC, EMBASE, PsycINFO, CINAHL, DARE, the Cochrane Library, and Web of Knowledge) were searched using a variety of keywords regarding health literacy and adherence. Additionally, references of identified articles were checked. Systematic reviews were included if they assessed the association between health literacy and adherence or evaluated the effectiveness of interventions to improve adherence in adults with low health literacy. The AMSTAR tool was used to assess the quality of the included reviews. The selection procedure, data-extraction, and quality assessment were performed by two independent reviewers. Seventeen reviews were selected for inclusion. Results: Reviews varied widely in quality. Both reviews of high and low quality found only weak or mixed associations between health literacy and adherence among older adults. Reviews report on seven studies that assess the effectiveness of adherence interventions among low health literate older adults. The results suggest that some adherence interventions are effective for this group. The interventions described in the reviews focused mainly on education and on lowering the health literacy demands of adherence instructions. No conclusions could be drawn about which type of intervention could be most beneficial for this population. Conclusions: Evidence on the association between health literacy and adherence in older adults is relatively weak. Adherence interventions are potentially effective for the vulnerable population of older adults with low levels of health literacy, but the evidence on this topic is limited. Further research is needed on the association between health literacy and general health behavior, and on the effectiveness of interventions

A Cross-Sectional Survey on Knowledge and Perceptions of Health Risks Associated with Arsenic and Mercury Contamination from Artisanal Gold mining in Tanzania.

An estimated 0.5 to 1.5 million informal miners, of whom 30-50% are women, rely on artisanal mining for their livelihood in Tanzania. Mercury, used in the processing gold ore, and arsenic, which is a constituent of some ores, are common occupational exposures that frequently result in widespread environmental contamination. Frequently, the mining activities are conducted haphazardly without regard for environmental, occupational, or community exposure. The primary objective of this study was to assess community risk knowledge and perception of potential mercury and arsenic toxicity and/or exposure from artisanal gold mining in Rwamagasa in northwestern Tanzania. A cross-sectional survey of respondents in five sub-villages in the Rwamagasa Village located in Geita District in northwestern Tanzania near Lake Victoria was conducted. This area has a history of artisanal gold mining and many of the population continue to work as miners. Using a clustered random selection approach for recruitment, a total of 160 individuals over 18 years of age completed a structured interview. The interviews revealed wide variations in knowledge and risk perceptions concerning mercury and arsenic exposure, with 40.6% (n=65) and 89.4% (n=143) not aware of the health effects of mercury and arsenic exposure respectively. Males were significantly more knowledgeable (n=59, 36.9%) than females (n=36, 22.5%) with regard to mercury (x²=3.99, p<0.05). An individual's occupation category was associated with level of knowledge (x²=22.82, p=<0.001). Individuals involved in mining (n=63, 73.2%) were more knowledgeable about the negative health effects of mercury than individuals in other occupations. Of the few individuals (n=17, 10.6%) who knew about arsenic toxicity, the majority (n=10, 58.8%) were miners. The knowledge of individuals living in Rwamagasa, Tanzania, an area with a history of artisanal gold mining, varied widely with regard to the health hazards of mercury and arsenic. In these communities there was limited awareness of the threats to health associated with exposure to mercury and arsenic. This lack of knowledge, combined with minimal environmental monitoring and controlled waste management practices, highlights the need for health education, surveillance, and policy changes

Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

Copyright @ 2013 Macmillan Publishers Limited. This is the author's accepted manuscript. The final published article is available from the link below.Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.Kay Kendall Leukemia Fund, NIH, Cancer Research UK, Italian Association for Cancer Research and the Foundation for Liver Research

Taking stock of gene therapy for cystic fibrosis

The identification of the cystic fibrosis (CF) gene opened the way for gene therapy. In the ten years since then, proof of principle in vitro and then in animal models in vivo has been followed by numerous clinical studies using both viral and non-viral vectors to transfer normal copies of the gene to the lungs and noses of CF patients. A wealth of data have emerged from these studies, reflecting enormous progress and also helping to focus and define key difficulties that remain unresolved. Gene therapy for CF remains the most promising possibility for curative rather than symptomatic therapy