Cancer symptom awareness and barriers to symptomatic presentation in England – Are we clear on cancer?

Background: Low cancer awareness may contribute to delayed diagnosis and poor cancer survival. We aimed to quantify socio-demographic differences in cancer symptom awareness and barriers to symptomatic presentation in the English population. Methods: Using a uniquely large data set (n=49?270), we examined the association of cancer symptom awareness and barriers to presentation with age, gender, marital status and socio-economic position (SEP), using logistic regression models to control for confounders. Results: The youngest and oldest, the single and participants with the lowest SEP recognised the fewest cancer symptoms, and reported most barriers to presentation. Recognition of nine common cancer symptoms was significantly lower, and embarrassment, fear and difficulties in arranging transport to the doctor’s surgery were significantly more common in participants living in the most deprived areas than in the most affluent areas. Women were significantly more likely than men to both recognise common cancer symptoms and to report barriers. Women were much more likely compared with men to report that fear would put them off from going to the doctor. Conclusions: Large and robust socio-demographic differences in recognition of some cancer symptoms, and perception of some barriers to presentation, highlight the need for targeted campaigns to encourage early presentation and improve cancer outcomes

Elongase Reactions as Control Points in Long-Chain Polyunsaturated Fatty Acid Synthesis

Extent: 9p.Background: Δ6-Desaturase (Fads2) is widely regarded as rate-limiting in the conversion of dietary α-linolenic acid (18:3n-3; ALA) to the long-chain omega-3 polyunsaturated fatty acid docosahexaenoic acid (22:6n-3; DHA). However, increasing dietary ALA or the direct Fads2 product, stearidonic acid (18:4n-3; SDA), increases tissue levels of eicosapentaenoic acid (20:5n-3; EPA) and docosapentaenoic acid (22:5n-3; DPA), but not DHA. These observations suggest that one or more control points must exist beyond ALA metabolism by Fads2. One possible control point is a second reaction involving Fads2 itself, since this enzyme catalyses desaturation of 24:5n-3 to 24:6n-3, as well as ALA to SDA. However, metabolism of EPA and DPA both require elongation reactions. This study examined the activities of two elongase enzymes as well as the second reaction of Fads2 in order to concentrate on the metabolism of EPA to DHA. Methodology/Principal Findings: The substrate selectivities, competitive substrate interactions and dose response curves of the rat elongases, Elovl2 and Elovl5 were determined after expression of the enzymes in yeast. The competitive substrate interactions for rat Fads2 were also examined. Rat Elovl2 was active with C20 and C22 polyunsaturated fatty acids and this single enzyme catalysed the sequential elongation reactions of EPA→DPA→24:5n-3. The second reaction DPA→24:5n-3 appeared to be saturated at substrate concentrations not saturating for the first reaction EPA→DPA. ALA dose-dependently inhibited Fads2 conversion of 24:5n-3 to 24:6n-3. Conclusions: The competition between ALA and 24:5n-3 for Fads2 may explain the decrease in DHA levels observed after certain intakes of dietary ALA have been exceeded. In addition, the apparent saturation of the second Elovl2 reaction, DPA→24:5n-3, provides further explanations for the accumulation of DPA when ALA, SDA or EPA is provided in the diet. This study suggests that Elovl2 will be critical in understanding if DHA synthesis can be increased by dietary means.Melissa K. Gregory, Robert A. Gibson, Rebecca J. Cook-Johnson, Leslie G. Cleland and Michael J. Jame

Highly Unsaturated Fatty Acid Synthesis in Atlantic Salmon: Characterization of ELOVL5- and ELOVL2-like Elongases

Fish species vary in their capacity to biosynthesize the n-3 long-chain polyunsaturated fatty acids (LC-PUFA) eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids that are crucial to the health of higher vertebrates. The synthesis of LC-PUFA involves enzyme-mediated fatty acyl desaturation and elongation. Previously, a cDNA for an elongase, now termed elovl5a, had been cloned from Atlantic salmon. Here we report on the cloning of two new elongase cDNAs: a second elovl5b elongase, corresponding to a 294 aa protein, and an elovl2-like elongase, coding for a 287 aa protein, characterized for the first time in a non-mammalian vertebrate. Heterologous expression in yeast showed that the salmon Elovl5b elongated C18 and C20 PUFA, with low activity towards C22, while Elovl2 elongated C20 and C22 PUFA with lower activity towards C18 PUFA. All three transcripts showed predominant expression in the intestine and liver, followed by the brain. Elongase expression showed differential nutritional regulation. Levels of elovl5b and particularly of elovl2, but not of elovl5a, transcripts were significantly increased in liver of salmon fed vegetable oils (VO) compared to fish fed fish oil (FO). Intestinal expression showed a similar pattern. Phylogenetic comparisons indicate that, in contrast to salmon and zebrafish, Acanthopterygian fish species lack elovl2 which is consistent with their neglible ability to biosynthesise LC-PUFA and to adapt to VO dietary inclusion, compared to predominantly freshwater salmonids. Thus the presence of elovl2 in salmon explains the ability of this species to biosynthesise LC-HUFA and may provide a biotechnological tool to produce enhanced levels of LC-PUFA, particularly DHA, in transgenic organisms

On the effects of mechanical stress of biological membranes in modeling of swelling dynamics of biological systems

We highlight mechanical stretching and bending of membranes and the importance of membrane deformations in the analysis of swelling dynamics of biological systems, including cells and subcellular organelles. Membrane deformation upon swelling generates tensile stress and internal pressure, contributing to volume changes in biological systems. Therefore, in addition to physical (internal/external) and chemical factors, mechanical properties of the membranes should be considered in modeling analysis of cellular swelling. Here we describe an approach that considers mechanical properties of the membranes in the analysis of swelling dynamics of biological systems. This approach includes membrane bending and stretching deformations into the model, producing a more realistic description of swelling. We also discuss the effects of membrane stretching on swelling dynamics. We report that additional pressure generated by membrane bending is negligible, compared to pressures generated by membrane stretching, when both membrane surface area and volume are variable parameters. Note that bending deformations are reversible, while stretching deformation may be irreversible, leading to membrane disruption when they exceed a certain threshold level. Therefore, bending deformations need only be considered in reversible physiological swelling, whereas stretching deformations should also be considered in pathological irreversible swelling. Thus, the currently proposed approach may be used to develop a detailed biophysical model describing the transition from physiological to pathological swelling mode.National Aeronautics & Space Administration (NASA):80NSSC19M0049; PR Space Grant (NASA):NNX15AI11Hinfo:eu-repo/semantics/publishedVersio

Incidence rates and management of urinary tract infections among children in Dutch general practice: results from a nation-wide registration study

BACKGROUND: We aimed to investigate incidence rates of urinary tract infections in Dutch general practice and their association with gender, season and urbanisation level, and to analyse prescription and referral in case of urinary tract infections. METHOD: During one calendar year, 195 general practitioners in 104 practices in the Netherlands registered all their patient contacts. This study was performed by the Netherlands Institute for Health Services Research (NIVEL) in 2001. Of 82,053 children aged 0 to 18 years, the following variables were collected: number of episodes per patient, number of contacts per episode, month of the year in which the diagnosis of urinary tract infection was made, age, gender, urbanisation level, drug prescription and referral. RESULTS: The overall incidence rate was 19 episodes per 1000 person years. The incidence rate in girls was 8 times as high as in boys. The incidence rate in smaller cities and rural areas was 2 times as high as in the three largest cities. Throughout the year, incidence rates varied with a decrease in summertime for children at the age of 0 to 12 years. Of the prescriptions, 66% were in accordance with current guidelines, but only 18% of the children who had an indication were actually referred. CONCLUSION: This study shows that incidence rates of urinary tract infections are not only related to gender and season, but also to urbanisation. General practitioners in the Netherlands frequently do not follow the clinical guidelines for urinary tract infections, especially with respect to referral

Echoes of the Past: Recovering Blockchain Metrics From Merged Mining

So far, the topic of merged mining has mainly been considered in a security context, covering issues such as mining power centralization or crosschain attack scenarios. In this work we show that key information for determining blockchain metrics such as the fork rate can be recovered through data extracted from merge mined cryptocurrencies. Specifically, we reconstruct a long-ranging view of forks and stale blocks in Bitcoin from its merge mined child chains, and compare our results to previous findings that were derived from live measurements. Thereby, we show that live monitoring alone is not sufficient to capture a large majority of these events, as we are able to identify a non-negligible portion of stale blocks that were previously unaccounted for. Their authenticity is ensured by cryptographic evidence regarding both, their position in the respective blockchain, as well as the Proof-of-Work difficulty. Furthermore, by applying this new technique to Litecoin and its child cryptocur rencies, we are able to provide the first extensive view and lower bound on the stale block and fork rate in the Litecoin network. Finally, we outline that a recovery of other important metrics and blockchain characteristics through merged mining may also be possible

For whom is a health-promoting intervention effective? Predictive factors for performing activities of daily living independently

BACKGROUND: Health-promoting interventions tailored to support older persons to remain in their homes, so-called "ageing in place" is important for supporting or improving their health. The health-promoting programme "Elderly Persons in the Risk Zone," (EPRZ) was set up for this purpose and has shown positive results for maintaining independence in activities of daily living for older persons 80 years and above at 1- and 2 year follow-ups. The aim of this study was to explore factors for maintaining independence in the EPRZ health-promoting programme.METHODS: Total of 459 participants in the original trial was included in the analysis; 345 in the programme arm and 114 in the control arm. Thirteen variables, including demographic, health, and programme-specific indicators, were chosen as predictors for independence of activities of daily living. Logistic regression was performed separately for participants in the health promotion programme and in the control arm.RESULTS: In the programme arm, being younger, living alone and self-rated lack of tiredness in performing mobility activities predicted a positive effect of independence in activities of daily living at 1-year follow-up (odds ratio [OR] 1.18, 1.73, 3.02) and 2-year, (OR 1.13, 2.01, 2.02). In the control arm, being less frail was the only predictor at 1-year follow up (OR 1.6 1.09, 2.4); no variables predicted the outcome at the 2-year follow-up.CONCLUSIONS: Older persons living alone - as a risk of ill health - should be especially recognized and offered an opportunity to participate in health-promoting programmes such as "Elderly Persons in the Risk Zone". Further, screening for subjective frailty could form an advantageous guiding principle to target the right population when deciding to whom health-promoting intervention should be offered.TRIAL REGISTRATION: The original clinical trial was registered at ClinicalTrials.gov. Identifier: NCT00877058 , April 6, 2009

Genomic Landscape of a Three-Generation Pedigree Segregating Affective Disorder

Bipolar disorder (BPD) is a common psychiatric illness with a complex mode of inheritance. Besides traditional linkage and association studies, which require large sample sizes, analysis of common and rare chromosomal copy number variants (CNVs) in extended families may provide novel insights into the genetic susceptibility of complex disorders. Using the Illumina HumanHap550 BeadChip with over 550,000 SNP markers, we genotyped 46 individuals in a three-generation Old Order Amish pedigree with 19 affected (16 BPD and three major depression) and 27 unaffected subjects. Using the PennCNV algorithm, we identified 50 CNV regions that ranged in size from 12 to 885 kb and encompassed at least 10 single nucleotide polymorphisms (SNPs). Of 19 well characterized CNV regions that were available for combined genotype-expression analysis 11 (58%) were associated with expression changes of genes within, partially within or near these CNV regions in fibroblasts or lymphoblastoid cell lines at a nominal P value <0.05. To further investigate the mode of inheritance of CNVs in the large pedigree, we analyzed a set of four CNVs, located at 6q27, 9q21.11, 12p13.31 and 15q11, all of which were enriched in subjects with affective disorders. We additionally show that these variants affect the expression of neuronal genes within or near the rearrangement. Our analysis suggests that family based studies of the combined effect of common and rare CNVs at many loci may represent a useful approach in the genetic analysis of disease susceptibility of mental disorders

Differential Effects of Antibiotic Therapy on the Structure and Function of Human Gut Microbiota

The human intestinal microbiota performs many essential functions for the host. Antimicrobial agents, such as antibiotics (AB), are also known to disturb microbial community equilibrium, thereby having an impact on human physiology. While an increasing number of studies investigate the effects of AB usage on changes in human gut microbiota biodiversity, its functional effects are still poorly understood. We performed a follow-up study to explore the effect of ABs with different modes of action on human gut microbiota composition and function. Four individuals were treated with different antibiotics and samples were taken before, during and after the AB course for all of them. Changes in the total and in the active (growing) microbiota as well as the functional changes were addressed by 16S rRNA gene and metagenomic 454-based pyrosequencing approaches. We have found that the class of antibiotic, particularly its antimicrobial effect and mode of action, played an important role in modulating the gut microbiota composition and function. Furthermore, analysis of the resistome suggested that oscillatory dynamics are not only due to antibiotic-target resistance, but also to fluctuations in the surviving bacterial community. Our results indicated that the effect of AB on the human gut microbiota relates to the interaction of several factors, principally the properties of the antimicrobial agent, and the structure, functions and resistance genes of the microbial community

Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD