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Background and study aims: Discomfort during colonoscopymay affect acceptability of the procedure. The study aim was to determine factors, including prior hysterectomy and gender, associated with higher levels of patient discomfort during colonoscopy to help with procedural planning such as choice of instrument and sedation. Methods: A retrospective cohort study of colonoscopies (n=1098) performed between February 2007 and March 2012at the Tees Bowel Cancer Screening Centre within the English Bowel Cancer Screening Programme (BCSP). Determinants of moderate/severe discomfort assessed using the Gloucester Scale were explored, using logistic regression with a range of participant and procedural variables. Results: Rates of moderate/severe discomfort varied significantly among men, women without hysterectomy, and women with hysterectomy (5.8 %, 10.4 %, and 17.8 %, respectively; P<0.001). In an unadjusted model, women with hysterectomy were significantly more likely to experience moderate/severe discomfort than those without (odds ratio [OR]1.87, 95% confidence interval [95 %CI] 1.05-3.32, P=0.005). The very strong influence of sedation on discomfort level precluded an adjusted model. In subgroup analysis of participants receiving sedation, adjusted comparison again showed increased odds for moderate/severe discomfort for women with hysterectomy, compared with women without (OR 1.70, 95%CI 1.03-2.80, P=0.036). Conclusions: Prior hysterectomy is associated with greater levels ofmoderate/severe discomfort in women undergoing colonoscopy. Minimizing participant discomfort is desirable in any screening or surveillance program. This should be considered in preprocedural counseling and in selecting equipment, sedation, and analgesia. Further studies should examine methods to minimize discomfort in those with prior hysterectomy. [ABSTRACT FROM AUTHOR]

We present here the molecular cloning and characterization of the mutator2 (mu2) gene of Drosophila melanogaster together with further genetic analyses of its mutant phenotype, mu2 functions in oogenesis during meiotic recombination, during repair of radiation damage in mature oocytes, and in proliferating somatic cells, where mu2 mutations cause an increase in somatic recombination. Our data show that mu2 represents a novel component in the processing of double strand breaks (DSBs) in female meiosis, mu2 does not code for a DNA repair enzyme because mu2 mutants are not hypersensitive to DSB-inducing agents. We have mapped and cloned the mu2gene and rescued the mu2phenotype by germ-line transformation with genomic DNA fragments containing the mu2 gene. Sequencing its cDNA demonstrates that mu2 encodes a novel 139-kD protein, which is highly basic in the carboxy half and carries three nuclear localization signals and a helix-loop-helix domain. Consistent with the sex-specific mutant phenotype, the gene is expressed in ovaries but not in testes. During oogenesis its RNA is rapidly transported from the nurse cells into the oocyte where it accumulates specifically at the anterior margin. Expression is also prominent in diploid proliferating cells of larval somatic tissues. Our genetic and molecular data are consistent with the model that mu2 encodes a structural component of the oocyte nucleus. The MU2 protein may be involved in controlling chromatin structure and thus may influence the processing of DNA DSBs.

Telomeres from Drosophila appear to be very different from those of other organisms – in size and the mechanism of their maintenance. In the absence of the enzyme telomerase, Drosophila telomeres are maintained by retrotransposition of three elements, HeT-A, TART, and TAHRE, but details of their transposition mechanisms are not known. Here we characterized some biochemical characteristics of the HeT-A Gag protein encoded by the HeT-A element to understand this mechanism. The HeT-A Gag protein when overexpressed in S2 cells was localized to the nucleus but was resistant to high salt, detergents and nuclease extraction treatments. Analysis of the HeT-A Gag protein by tandem mass spectrophotometry revealed that serines 216 and 221 are phosphorylated. Substituting these serines with alanine or aspartic acid by site-directed mutagenesis did not result in any changes in HeT-A Gag translocation across the nucleus, suggesting that phosphorylation of these sites is not associated with HeT-A Gag translocation, but time course experiments showed that these phosphorylation sites are important for Gag-protein stability. [ABSTRACT FROM AUTHOR]

Telomeric regions in Drosophila are composed of three subdomains. A chromosome cap distinguishes the chromosome end from a DNA double-strand break; an array of retrotransposons, HeT-A, TART and TAHRE (HIT), maintains telomere length by targeted transposition to chromosome ends; and telomere- associated sequence (TAS), which consists of a mosaic of complex repeated sequences, has been identified as a source of gene silencing. Heterochromatin protein I (HPI) and HPl-ORC-associated protein (HOAP) are major l)t~~m components of the telomere cap in Drosophila and are required for telomere stability. Besides the chromosome cap, HPI is also localized along the HTT array and in TAS. Mutants for Su(var)205, the gene encoding HPI, have decreased the HPI level in the HIT array and increased transcription of individual HeTA elements. This suggests that HPl levels directly affect HeT-A activity along the HIT array, although they have little or no effect on transcription of a white reporter gene in the HIT Chromatin immunoprecipitation to identify other heterochromatic proteins indicates that TAS and the HTT array may he distinct from either heterochromatin or euchromatin. [ABSTRACT FROM AUTHOR]

The article presents a study that identifies the equivalent function of Drosophila telomeres and those from eukaryotes that use telomeres to extend their chromosome ends. It is noted the Drosophila telomeres maintain chromosome length and perform other activities that are less well understood. They can also form heterochromatin and silence neighboring genes, as do telomeres in yeast and humans.

Background: Based on equivocal clinical data, intravenous antioxidant therapy has been used for the treatment of severe acute pancreatitis. To date there is no randomised comparison of this therapy in severe acute pancreatitis. Methods: We conducted a randomised, double blind, placebo controlled trial of intravenous antioxidant (n-acetylcysteine, selenium, vitamin C) therapy in patients with predicted severe acute pancreatitis. Forty-three patients were enrolled from three hospitals in the Manchester (UK) area over the period June 2001 to November 2004. Randomisation stratified for APACHE-II score and hospital site, and delivered groups that were similar at baseline. Results: Relative serum levels of antioxidants rose while markers of oxidative stress fell in the active treatment group during the course of the trial. However, at 7 days, there was no statistically significant difference in the primary end point, organ dysfunction (antioxidant vs placebo: 32% vs 17%, p=0.33) or any secondary end point of organ dysfunction or patient outcome. Conclusions: This study provides no evidence to justify continued use of n-acetylcysteine, selenium, vitamin C based antioxidant therapy in severe acute pancreatitis. In the context of any future trial design, careful consideration must be given to the risks raised by the greater trend towards adverse outcome in patients in the treatment arm of this study. [ABSTRACT FROM AUTHOR]

Background and objective: An economic analysis of telemedicine support to improve glycemic control in patients with type 2 diabetes mellitus, illustrating the use of an analytic framework that efficiently combines telemedicine program findings with published estimates of treatment cost effectiveness. Method: The Pro-Active Call Centre Treatment Support (PACCTS) trial compared tailored, protocol-driven call-center support with usual care as methods to manage glycemic control in 591 patients with diabetes in Salford, UK. Economic analysis of the trial describes the cost of delivering telemedicine support and level of improved glycemic control achieved in patients. These findings are linked to current best evidence for the long-term cost effectiveness of treatment to help inform whether the provision of call-center support to improve glycemic control should become routine health policy. Results: Under trial conditions, the cost effectiveness of the PACCTS intervention was estimated to be £43 400/quality-adjusted life-year (QALY) [2003 costings]. Under routine-use call-center conditions (a full caseload of patients with moderate to poor glycemic control) cost effectiveness was estimated to be lower at £33 700/QALY. Set against a threshold of £30 000/QALY, Monte Carlo simulation suggests the probability of PACCTS being cost-effective in routine use is 29%. Discussion: Despite being received well by patients and healthcare professionals alike, telemedicine support solely to achieve improved glycemic control in patients with type 2 diabetes was found to be borderline cost effective. Major uncertainties that could change this result include the underlying cost effectiveness of improved glycemic control, which is currently imprecisely known. Research is ongoing in patients with type 2 diabetes to extend call-center support to improve blood pressure and lipid management, where if similar improvements are obtained, the call center should prove highly cost effective. The novel analytic approach illustrated provides a clear framework for thinking about the design and analysis of behavioral change policies for healthcare. [ABSTRACT FROM AUTHOR]

Developing from a previous review, this article revisits the generalisability theme to summarise recent advances in methodology and provide an update of challenges faced by producers and users of pharmacoeconomic data. Our original evaluative criteria encompassed technical issues, applicability and transferability.The technical elements of best practice are comparatively uncontroversial: choosing relevant alternatives; transparent reporting of methods and findings; accessing and applying the best-quality evidence; using best methods to synthesise data; and using deterministic sensitivity analysis to explore potential systematic bias whilst employing probabilistic sensitivity analysis to explore the influence of random error at the whole model level. The applicability of economic findings within their original policy context (e.g. national analyses based on generalisable within-country data) can be determined, provided that best practice guidelines for economic modelling are adhered to. The transferability of economic findings (from one policy setting to another, e.g. country, region, clinical setting or patient population) requires careful exploration of changes in resource implications, unit prices and outcomes, a process facilitated again by transparent reporting of methods, adjustment for baseline risk and potentially by recent statistical developments intended to deal with hierarchically structured data.Although there is considerable consensus in the published literature about these key issues, limitations remain for economic analysis as implemented because of its opaqueness of method, failure to reflect the opportunity cost of decisions and lack of societal mandate. If the primary purpose of health economic evaluation is to help society to obtain the best value from limited resources, then, at a time when most technologically advanced societies need to engage with the realities of limited healthcare funding, technocratic solutions alone appear insufficient. Making health economic findings accessible to patients, clinicians and society, in the form of relevant narratives, will help this essential debate and expose assumptions underpinning economic analysis to broader critical inspection. [ABSTRACT FROM AUTHOR]

Gene-based therapies for tissue regeneration involve delivering a specific gene to a target tissue with the goal of changing the phenotype or protein expression profile of the recipient cell; the ultimate goal being to form specific tissues required for regeneration. One of the principal advantages of this approach is that it provides for a sustained delivery of physiologic levels of the growth factor of interest. This manuscript will review the principals of gene-enhanced tissue engineering and the techniques of introducing DNA into cells. Part 2 will review recent advances in gene-based therapies for dental hard tissue regeneration, specifically as it pertains to dentin regeneration/pulp capping and periodontal regeneration. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the clinical effectiveness of lifestyle interventions for preventing osteoporotic fractures in people at high risk. Data sources were electronic bibliographic databases, reference lists of systematic reviews, meta-analyses and included trials, registers of trials and conference databases. There was no language restriction. Study selection comprised randomized controlled trials (RCTs), with appropriate comparator groups and at least 8 weeks of follow-up, reporting a fracture endpoint. Two reviewers independently abstracted data on the population, interventions evaluated, trial quality and outcomes of interest: fractures at any site, spinal, hip and wrist fractures. Six RCTs, enrolling over 1,656 participants, met the inclusion criteria. Overall, trials were of uncertain quality. We categorized trials by type of intervention: exercise ( n =3), multifactorial interventions (environmental modifications, exercise programs and review of medical conditions, medication and aids) ( n =2) and exposure to sunlight ( n =1), and used random effects meta-analyses to combine data within these categories. Exercise was associated with a non-significantly lower risk of spinal fractures (RR=0.52, 95% CI=0.17 to 1.60). Multifactorial interventions were associated with a lower risk of hip fracture, which was of borderline statistical significance (RR=0.37, 95% CI=0.13 to 1.03). Exposure to sunlight was associated with a non-significantly lower risk of hip fracture (RR=0.17, 95% CI=0.02 to 1.35). While withdrawals from treatment were poorly reported, there was no indication of adverse effects of treatment. Multifactorial interventions may reduce the risk of hip fractures when delivered by residential care staff and health visitors. More RCTs of higher quality, recording fractures at all sites susceptible to osteoporotic fractures, are necessary to evaluate exercise interventions, exposure to sunlight and the place of lifestyle alongside pharmacological interventions. [ABSTRACT FROM AUTHOR]

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Heterochromatin is a specialized chromatin structure in chromosomal regions associated with repeated DNA sequences and low concentrations of genes. Formation of heterochromatin is determined in large part by enzymes that modify histones and structural proteins that bind to these modified histones in a cooperative fashion. In Drosophila, mutations in genes that encode heterochromatic proteins are often dominant and increase expression of genes placed into heterochromatic positions. To find components of telomeric heterochromatin in Drosophila, we screened a collection of autosomal deficiencies for dominant suppressors of silencing of a transgene at the telomere of chromosome 2L. While many deficiency chromosomes are associated with dominant suppressors, in the cases tested on chromosome 2 the suppressor mapped to the 2L telomere, rather than the deficiency. We infer that background effects may hamper the search for genes that play a role in telomeric heterochromatin formation and that either very few genes participate in this pathway or mutations in these genes are not dominant suppressors of telomeric position effect. The data also suggest that the 2L telomere region plays a major role in telomeric silencing. [ABSTRACT FROM AUTHOR]

One model of telomeric position effect (TPE) in Drosophila melanogaster proposes that reporter genes in the vicinity of telomeres are repressed by subterminal telomere-associated sequences (TAS) and that variegation of these genes is the result of competition between the repressive effects of TAS and the stimulating effects of promoters in the terminal HeT-A transposon array. The data presented here snpport this model, but also suggest that TPE is more complex. Activity of a telomeric white reporter gene increases in response to deletion of some or all of the TAS on the homolog. Only transgenes next to fairly long HeT-A arrays respond to this trans-interaction. HeT-A arrays of 6-18 kb respond by increasing the number of dark spots on the eye, while longer arrays increase the background eye color or increase the number of spots sufficiently to cause them to merge. Thus, expression of a subtelomeric reporter gene is influenced by the telomere structure in cis and trans. We propose that the forces involved in telomere length regulation in Drosophila are the underlying forces that manifest themselves as TPE. In the wild-type telomere TAS may play an important role in controlling telomere elongation by repressing HeT-A promoter activity. Modulation of this repression by the homolog may thus regulate telomere elongation. [ABSTRACT FROM AUTHOR]

The telomeric regions in Drosophila cause transcriptional silencing of integrated transgenes. A complex satellite has recently been identified in the subterminal region of the left arm of chromosome 2 that is a good candidate for the source of the observed telomeric silencing, because genetically marked transposable elements that have inserted into this subtelomeric array show repression and variegation of the reporter gene. We asked whether this satellite can also cause transcriptional repression in ectopic chromosomal positions by placing it upstream of a mini- white reporter gene in P element constructs used for germ line transformation. The transgenes are shielded from external influences at the integration site using SU(HW) binding sites at either end. It was found that the satellite represses transcription of the reporter gene in an orientation dependent and an array length dependent manner. The satellite does not, however, induce variegation under the conditions used. The repressed transgenes do not respond to typical modifiers of centromeric position effect variegation, such as Su(var)205 5 , Su(var)2–1 1 , Su(var)3–1 1 , and Su(var)3–6 1 , or to the addition of a Y chromosome. However, as with the original variegating telomeric insertion, suppression in the transgenes is relieved by Su(z)2 5 , suggesting that suppression induced by the subtelomeric satellite retains aspects of telomeric silencing in ectopic positions. [ABSTRACT FROM AUTHOR]

Proposes that mu2, a mutator in Drosophila melanogaster, affect chromosomal structure during oogenesis, resulting in the modulation of deoxyribonucleic acid (DNA) repair. Information on chromosome length in the Drosophila melanogaster; Details on telomeres in Drosophila.

Telomeres are nucleoprotein structures at the ends of eukaryotic chromosomes that perform a number of vital functions. They allow a cell to distinguish between natural chromosome ends and chromosome breaks in order to delay the cell cycle and repair the broken end. Telomeres also compensate for the inability of DNA polymerase to replicate the chromosome completely. In most eukaryotes a special reverse transcriptase, telomerase, adds telomeric DNA repeats to the chromosome ends using an internal RNA template. However, evidence is accumulating for alternative elongation mechanisms in a variety of eukaryotes. In the yeast Saccharomyces cerevisiae, and possibly in humans, both of which normally use telomerase, a different mechanism can be used for chromosome length maintenance when telomerase is inactive or inactivated. Yeast apparently uses recombination for this purpose; the mechanism in humans is not known. Some insect and plant species, on the other hand, do not use telomerase as their primary mechanism for maintaining chromosome length. Drosophila makes use of specific retrotransposons for this purpose, while other dipterans use recombination. We summarize here the current knowledge of these alternative telomere elongation mechanisms. [ABSTRACT FROM AUTHOR]